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Part 1 Overall Abstract

The UCSF Clinical and Translational Science Institute (CTSI) has built a coordinated platform for clinical and translational research, successfully improved, integrated, and extended research services and infrastructure, and created comprehensive training programs. The program has expanded services and infrastructure by collaborating with regional partners, notably the 5 University of California CTSAs (UC BRAID), and measurably improved the health of vulnerable residents in the San Francisco Bay Area. Building on this foundational work, the CTSI now proposes to leverage these strengths by developing and linking emerging technologies to improve the quality, efficiency, and cost of conducting interdisciplinary, multisite clinical and translational research. This overarching goal will be achieved by coordinating informatics and technology with traditional research infrastructure, supported by highly effective training programs, and a traditionally strong focus on team science. These activities will also integrate expertise from and scale to CTSI’s regional partners, UC BRAID, the CTSA national network, and PCORnet. The UCSF CTSI Overall Specific Aims will focus on:

1. Informatics and Research Innovation;2. Community Engagement and Team Science;3. Translational Workforce Development and Pilot Translational and Clinical Studies;4. Expert Consultation and Regulatory Knowledge and Support;5. Integrating Special Populations and Participant and Clinical Interactions;6. Providing Liaison to NCATS’ Trial and Recruitment Innovation Centers;7. Product Development, and8. Precision Medicine.

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OVERVIEW Founded in 2006, the UCSF Clinical and Translational Science Institute (CTSI) built a coordinated platform for clinical and translational research at UCSF, successfully improved, integrated, and extended research services and infrastructure, and created a comprehensive training program. In the second funding period, we expanded services and infrastructure by collaborating with regional partners, notably the 5 University of California CTSAs (UC BRAID), and measurably improved the health of vulnerable residents in the San Francisco Bay Area. Building on our foundational work, we now propose to leverage UCSF’s strengths by developing and linking emerging technologies to improve the quality, efficiency, and cost of conducting interdisciplinary, multisite clinical and translational research at UCSF, in California, and across the nation. This overarching goal will be achieved by coordinating informatics and technology with traditional research infrastructure, supported by highly effective training programs, and our strong focus on team science. We will integrate expertise from and scale to our regional partners, UC BRAID, the CTSA national network, and PCORnet. OVERALL SPECIFIC AIMS 1. Informatics and Research Innovation. Our overarching aim is to enable high quality, efficient, cost-effective, and innovative research by improving access to and utilization of emerging technologies: electronic health records (EHR), mHealth sensors and apps, direct-to-participant research platforms, and omics/biomarker measurements. (Part B) 2. Community and Collaboration

a. Community Engagement. We will integrate community partners and policy-based research to improvehealth and health equity. We will also integrate EHR data from the Bay Area Accountable Care Network(BAACN) and safety net systems to merge practice-based and population health research. (Part C.1)

b. Team Science. We will promote and incentivize multidisciplinary team science through pilot funding,training, and resource support, and we will share our achievements with partners in the SF Bay Area,California, the CTSA network, and PCORnet. (Part C.2)

3. Translational Endeavorsa. Workforce Development. We will train and support a highly qualified, diverse workforce by expanding

our nationally recognized CTSI Training Program and provide training in the responsible conduct ofresearch, good clinical practice, clinical research coordination, research nursing, and regulatoryrequirements. (Part D.1)

b. Pilot Translational and Clinical Studies. We will provide pilot funding to support development ofinnovative research methods that advance our overall CTSI goals for the next funding period. (Part D.2)

4. Research Methodsa. Expert consultation. We will expand the CTSI consultation service, which includes biostatistics,

epidemiology, research design (BERD) and other specific expertise, with consultants to support emergingneeds in technology-enabled research, team science and research across the lifespan. (Part E.1)

b. Regulatory Knowledge and Support. We will continue to streamline regulatory processes, develop abiospecimen and clinical data eConsent system, and increase the use of central IRBs. (Part E.2)

5. Hub Resource Capacitya. Special Populations Initiative. We will promote translational research in children, the elderly, and those

socially and medically vulnerable, with an emphasis on diversity and disparities. (Part F.1)b. Participant and Clinical Interactions. We will streamline clinical research operations and ensure that

clinical research at UCSF is efficient, cost-effective, of the highest ethical and scientific quality, andsupported by integrated institutional and network processes and highly trained personnel. (Part F.2)

6. Network Capacity - Liaison to Trial and Recruitment Innovation Centers. (TICs and RICs) We willdevelop a Clinical Trial Unit (TIC liaison) to ensure a clear, flexible, and timely path to multisite clinical trialstart-up and implementation (Part G.1) and expand our Participant Recruitment Unit (RIC liaison) to facilitatemeeting timely enrollment goals. (Part G.2)

7. Optional Function 1 - Product Development. We will identify early stage projects with the potential todevelop therapeutics, diagnostics, devices, and digital health applications to improve health, and supportthe progression of these projects to commercial viability. (Part H.1)

8. Optional Function 2 - Precision Medicine. Partnering with the UCSF Precision Medicine initiative, we willengage diverse populations using streamlined, centralized consent procedures, establish a centralizedbiobanking platform, and link biospecimen and other rich data sources to drive precision medicine. (Part H2)

Part 1. Overall Vision and Strategy

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RESEARCH STRATEGY A. VISION & STRATEGIES FOUNDED ON ACHIEVEMENTS Over the last 2 years CTSI has brought together stakeholders and leaders from across UCSF and our collaborators, to develop our vision for clinical and translational reseach in the next 5 years (Figure, left). This

widely publicized process included the full spectrum of pre-clinical and translational researchers, new investigators and campus leaders, and external advisors. We engaged in a professionally facilitated strategic planning process and several full-day retreats. These efforts culminated in a shared commitment to expand current CTSI training, resources, infrastructure, and services. We set several new goals: to enable high-quality, efficient, cost-effective, and innovative research using emerging technologies (Part B), to intensify our focus on health research across the lifespan (Part F.1), to support and facilitate team science (Part C.2), to promote product development (Part H1), and to advance precision medicine (Part H2). In this section (Part 1), we describe our vision for each CTSI program, highlight achievements of the past 5 years, and briefly describe our strategies for achieving the vision. Part A presents CTSI’s organization,

leadership, governance, and program evaluation activities, and includes a description of our local, regional, and national collaborators. A full description of strategic plans to achieve our vision for required components follows in Parts B through G. Parts H1 and H2 describe plans for enhancement and maturing of 2 “Optional Functions,” which will focus on promoting product development to improve health, and partnering across California to advance the foundational knowledge needed to realize the promise of precision medicine. 1. Overall Aim 1: Vision & Strategies Founded on Achievements in Informatics and Research Innovation In the next decade, research will progressively rely on data from emerging digital technologies; studies will take place outside the geographic confines of academic medical centers, measurements will be made remotely, and database platforms will seamlessly integrate information from multiple sources. This revolution is underway, but multiple barriers limit our ability to fully realize the benefits of technology-enabled research. Investigators with little training in informatics are charged with identifying and vetting appropriate hardware and software, finding ways to link tools that were not built to work together, and overcoming challenges in data extraction, transformation, loading, storage, and harmonization – all while persuading traditional IRB committees, funding agencies, and regulatory groups that digital methods can ethically obtain informed consent, preserve participant privacy, and meet regulatory requirements. Our overall vision is to make it easy, rapid, and cost-effective for investigators at UCSF and beyond to use new methods to conduct high quality clinical and translational research. To achieve this vision, we have reorganized the CTSI Bioinformatics Program into a multidisciplinary Informatics and Research Innovation (IRI) Program. IRI will provide the strategic oversight and tools required for integrating healthcare and research (see Section B, below) and for achieving the promise of precision medicine (Part H2). The following is an overview of the achievements this vision is built upon, and the core features of our strategies for IRI. A full description of our achievements and plans appears in Part B.

Selected Achievements in Informatics and Research Innovation (past 4 years) Enabled investigators to use EHR data from UCSF and across UC BRAID

• Developed UCSF Clinical & Research Data Warehouse with secure access to EHR data that allows investigators to: determine numbers of patients potentially eligible for research; (during the last year, used by 252 investigators); contact and invite patients with specific characteristics to enroll in research (used to contact 22,729 patients in the last year); extract data on specific patients for research

• Academic Research Systems fulfilled 108 data extraction requests for EHR data, supported 4631 REDCap users, and 2739 MyResearch (secure data portal) users

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• Partnered with UC BRAID to develop UC Research Exchange (ReX) which provides secure access to EHR data from ~13M patients across the 5 UC Medical Centers (each with a CTSA Award)

Participated in national networks for multisite trials

• NCATS Accrual to Clinical Trials (ACT): “Wave 1” member and met all milestones • PCORnet: UCSF hosts a pScanner Clinical Data Research Network node and 2 Patient-Powered Research

Networks; will help lead ADAPTABLE, PCORnet’s first RCT Enabled real time recruitment

• Participated in development of and now hosts PatientLocate, software that uses real-time data feeds to identify patients in UCSF hospitals/clinics who appear to be eligible for research

IRI has developed an approach that includes broad stakeholder engagement, coordination of multiple UCSF IT units, continuous assessment of needs and existing resources, and strategic investment in technology. Our process includes support for demonstration projects that push the boundaries of technology-enabled research, identifies gaps in our infrastructure, and helps us develop and support generalizable solutions. All CTSI programs and UCSF’s IT arms will align activities and expertise to help achieve this overall vision. • Extend our ability to obtain and derive research measurements from EHR data. We will provide access to a de-identified version of our Clinical and Research Data Warehouse, extract, transform, and load data into common data models used by developing networks, support a reusable code library, and provide educational and consultative resources for investigators interested in using EHR data for research. • Coordinate and develop infrastructure to use “non-traditional” data sources within clinical trials. We will develop mechanisms for integrating data from EHR systems, sensors, and smartphones (mHealth), and imaging/omics-type biomarkers into research study management platforms that support clinical trials. • Enable development of EHR-based interventions and data collection. • Support development of scalable direct-to-participant trial platforms and novel consent systems. Engaging participants in research directly (via Internet or mobile technologies) has major advantages for efficient conduct of research. We will develop a low-cost infrastructure to support these studies, improve the design of consents, and create mechanisms to support long-term engagement from all segments of the population. • Coordinate efforts with colleagues across the CTSA Consortium, UC BRAID, PCORnet, and BD2K in development of methods, shared informatics infrastructure, and multisite research. Novel informatics resources, methods, and research networks are developing nationwide, and we aim to contribute to and coordinate with these efforts. 2. Overall Aim 2: Vision & Strategies Founded on Achievements in Community and Collaboration 2.A. Community Engagement (CE) The vision of the CTSI Community Engagement Program is to use our innovative Systems Based Participatory Research model, which integrates community-based, practice-based and policy research methods, to advance the health of the SF Bay Area and enrich community-engaged research across the CTSA network. CE brings together researchers with health system, community, and policy stakeholders to develop sustainable initiatives to improve health and health equity. Following is an overview of achievements, and the core strategies for CE activities. A full description of achievements and plans appears in Part C.1.

Selected Achievements in Community Engagement (past 4 years) San Francisco

Developed SF Health Improvement Partnership (SFHIP), a collaborative of CE with community partners, adopted by SF Mayor Lee as the platform for SF’s city-wide health improvement plan

• Provided evidence base for citywide initiative to reduce consumption of sugary beverages; SF high school student consumption of ≥12oz sugary beverage per day has decreased from 15.5% (2009) to 9.7% (2013)

• Focused local attention on health harms of alcohol consumption, including routine blood alcohol content screening for trauma cases at SF General Hospital Trauma Center; screening rate has increased from 45% to 85% of trauma cases

Regional Developed SF Bay Collaborative Research Network (SFBayCRN), with >100 community clinics and >1000 clinicians from 9 Bay Area counties

• Since 2013, CE consultation and linkage contributed to 11 new SFBayCRN grant awards to UCSF investigators and collaborators totaling $5.3 million.

• SFBayCRN research led to fluoride varnish application at 8 clinical serving 100,000 low-income children resulting in a 95% fluoride varnish application rate at all well-child checkup visits (2012-2014)

National SFHIP and SFBayCRN best practices have been widely disseminated and adopted

• SFBayCRN study demonstrated that providing colon cancer screening kits at flu shot clinics increased screening from 42.5% to 55.8%; intervention adopted by American Cancer Society, CDC, and Kaiser Permanente

• SFHIP sugary beverage methods are being adopted by Dignity Health (with hospitals in 20 states), Health Alliance Network, and internationally

• SFBayCRN, and faculty from the UCSF School of Pharmacy and Safeway conducted a 3-month RCT in 20 stores to evaluate approaches to integrate brief smoking cessation interventions into routine care. More than 15,000 patients were asked about tobacco use, >1,100 received smoking cessation counseling. Based on these results, the smoking cessation program was launched in more

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than 1,100 Safeway pharmacies nationwide in 2015

We will accelerate our work to strengthen academic and community capacity to conduct stakeholder-engaged research through several new strategies: • Offer a core portfolio of consultative, training, linkage and other technical assistance. CE will forge new partnerships to improve health outcomes for stakeholder-identified health priorities. We will accomplish this by building on our core activities to provide structured consultations for UCSF investigators and the community and didactic courses and trainings in stakeholder-engaged research methods, and by facilitating linkages between UCSF investigators and community-based partners with a focus on research in diverse community settings. • Advance innovative community-engaged translational methods and practices to local, regional, and national stakeholders. We will intensify a knowledge exchange plan to highlight the role of our innovative model of stakeholder-engaged translational research to address health disparities. As examples: 1) we will share the interactive online geomapping tool that we developed in collaboration with the SF Department of Public Health and community stakeholders to visualize the relationship of alcohol retail outlets and alcohol-related health outcomes in low-income neighborhoods with UC BRAID and national CTSA network partners; and 2) we will disseminate evidence-based sugary beverage policy using digital and social media and provide technical assistance for adoption of healthy beverage policies by large health systems and community organizations. • Apply our CE model of Systems-Based Participatory Research to fully engage regional community-based health organizations as partners in translational science using EHR data. CE will complement the strategies of CTSI’s new Informatics and Research Innovation program (Part B) by applying our model to engage regional health organizations as partners in community-based research using the EHR. Accelerating EHR-based research in these settings requires overcoming both the technical IT challenges and the cultural, organizational, and political sensitivities regarding sharing data from diverse non-academic clinical organizations. With technical assistance from IRI and UCSF Academic Research Systems, SFBayCRN will collaborate with community partners to develop standard operating procedures to support EHR-based translational research across the network and with the newly formed Bay Area Accountable Care Network (BAACN), a regional federation of community hospitals and large medical groups. These initiatives will provide access to EHR data for about 1 million ethnically and economically diverse patients from community-based settings across the region. 2.B. Collaboration and Team Science (TS) UCSF has a strong culture of collaboration and team science, which, as early as the 1980s, allowed our integrated teams of basic scientists, clinical investigators, clinicians, and community activists to make major strides in understanding the AIDS epidemic, leading to the development of effective treatments and integrated clinical care. This legacy continues as our scientists, clinicians, patients, and communities collaborate to advance translational science. Our vision is to promote team science in all CTSI activities, with pilot funding, coaching and consultation, education and training, and cultural changes to ensure that investigators working effectively in teams are recognized for their accomplishments. The following is an overview of selected achievements, and core features of our strategies in TS. A complete description appears in Part C.2; our multiple local, regional, and national collaborations are described in Part A Sec. B.1.

Selected Achievements in Team Science (past 4 years) Initiated Team Science Pilot Awards

• CTSI funded 6 team science pilots, other UCSF entities supported an additional 7 awards

Participated in team science projects across California

• UCSF leads the California Precision Medicine Initiative, a $3MM project funded by the State aimed at creating teams of academic and industry partners to build the infrastructure and resources necessary to advance precision medicine.

Facilitated team development • Created UCSF Profiles, a top-rated research networking tool that has had almost 1.2MM visits in 2014, over 1MM of these from potential “teammates” outside UCSF

• Held “speed networking” events to acquaint investigators from different communities • Provided team leadership workshops and consultation for TS Pilot Award investigators

Recognition for team scientists

• Worked with UCSF Dept. of Medicine to change promotions guidelines to recognize team science

• Annual Academic Senate Faculty Research Lecture awarded to a team

We will advance team science at UCSF and among our partners using the following strategies:

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• Facilitate and support formation and development of multidisciplinary research teams. In collaboration with the CTSI Pilot Translational and Clinical Studies program (Part D.2), we will continue to provide pilot funding for collaborative research teams, extend the duration of funding to 2 years to allow teams to mature, and focus on teams with members outside UCSF.

• Ensure that the contributions of members of multidisciplinary research teams are recognized for academic advancement. We will build on our success in revising promotions guidelines in the Department of Medicine and work with other departments, and at the campus level to ensure that promotions guidelines at UCSF recognize team scientists for merit and advancement.

• Train junior investigators to develop and work effectively in multidisciplinary teams. We will develop an online course on team science that will be open to all, but required of K and T Scholars, as well as case-studies. The KL2 and TL1 programs will provide training in team science at regular works-in-progress meetings and seminars, and we will develop a “Team Science” consultation capacity in the CTSI Consultation Service.

3. Overall Aim 3: Vision & Strategies Founded on Achievements in Translational Endeavors 3.A. Translational Workforce Development (TWD) Through a process of life-long learning and mentoring, we aim for our diverse workforce of trainees, faculty, and staff to be uniquely qualified to design, conduct, analyze, and disseminate high quality clinical and translational research across the lifespan and in special populations. Our training focuses on traditional research methods as well as rapidly emerging technology-enabled approaches using electronic data sources, remote sensors, Web-based platforms, and computationally intensive analyses. We aim to disseminate UCSF’s exceptional education and training programs to other CTSA hubs and research organizations. Achieving this vision will depend on integrating didactic and degree-granting programs, level-specific training programs for trainees and faculty, online, and Web-based offerings. Following is an overview of selected achievements, and core features of our strategies in TWD. A complete description appears in Part D.1.

Selected Achievements in Workforce Development (past 4 years) UCSF PhD Programs CTSI K and T trainees have access to 18 PhD programs, including the interdisciplinary Biomedical

Sciences, Biological Sciences, TETRAD, Neurosciences, and Epidemiology and Translation PhD programs at UCSF

Training in Clinical Research (TICR)

TICR offers 44 courses, a summer Research Methods Workshop, 1-year Advanced Training in Clinical Research Certificate, 2-year Master’s, and a combined MD/Master’s. Over the last 4 years, 274 students have completed the Advanced Training or Master’s Degree

Master’s in Translational Medicine (MTM)

The MTM (with UC Berkeley College of Engineering) has prepared nearly 100 bioengineers and clinicians for careers in product development, including drugs, devices, therapeutics, and diagnostics

CTSI Training Program (CTST)

CTST includes the Prehealth Undergraduate Program (PuP), TL1 for UCSF professional students (Dentistry, Medicine, Nursing, Pharmacy), Residency Research Training Program (RRTP), and KL2 for junior faculty. Over the last 5 years, we have trained 105 PuPs, 80 professional students, 357 clinical residents, and 79 KL2 Scholars

Online Learning Developed online Designing Clinical Research, delivered to >200 students outside UCSF and Responsible Conduct of Research, which fulfills the NIH requirements for didactic training in research ethics, scientific misconduct, authorship and conflict of interest

We will accelerate our work in translational workforce development via the following strategies: • Expand existing didactic and degree-granting programs by adding courses on research informatics and

research in special populations, including health disparities. • Enhance our existing level-specific training programs (KL2 and TL1, RRTP, PuP), programs with training and

research experience supporting medical informatics, precision health, multisite trials, and research in special populations, as well as skills in mentoring, leadership, and conduct of team science.

• Enhance our investigator and staff training by ensuring that investigators and staff are trained in Responsible Conduct of Research and Good Clinical Practice, and establish a research training program for Clinical Research Coordinators and Clinical Research Nurses.

• Expand online offerings with Scientific Writing; Introduction to Clinical Trials; Translating Evidence into Practice; Product Development; 15-minute “just-in-time” Web modules on IRB issues.

• Prioritize development of a diverse scientific workforce through our selection processes for all trainees and faculty; reinforce with staff education and training programs.

• Support a culture of mentorship with a Web-based Mentor Training Program; form a “Mentoring Advisory Group” across all 10 UC campuses and collaborate with the National Research Mentoring Network.

3.B. Pilot Translational and Clinical and Studies (PTC) CTSI’s Pilot Translational and Clinical Studies program (PTC) has had a transformational impact by creating the organization and infrastructure that now supports UCSF’s unified Resource Allocation Program (RAP). Our

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uniform and unbiased application and review process awards almost all intramural funding at UCSF, and the RAP system for centralized administration and review has become a model for other CTSAs. PTC has 5 grant categories: Junior Faculty; Underrepresented Minority (URM) Faculty; Family Caregiving Leave; Digital Health; and Team Science. For all of these, we will now prioritize research focused on special populations and projects that include multidisciplinary teams.

Core features of our strategies in PTC are described below, and a complete description appears in Part D.2. We will accelerate our work in PTC by providing pilot funding to: • Advance new translational research methods, tools, and infrastructure, especially those using research

informatics and technology (in collaboration with the Informatics and Research Innovation program [Part B]), with awards for demonstration projects and pilots with a high likelihood of demonstrating efficiency and cost-effectiveness and that are likely to develop approaches generalizable to other studies.

• Promote multisite collaboration and team science (in collaboration with Team Science [Part C.2]) by encouraging collaborations both inside and outside of UCSF; provide team consults; extend funding; and learn from the experience of funded teams.

• Support research that advances precision medicine by supporting demonstration projects to test the feasibility of disease-focused projects in precision medicine.

• Support underrepresented minority clinical and translational researchers conducting cutting-edge clinical and translational science.

4. Overall Aim 4: Vision & Strategies Founded on Achievements in Research Methods 4.A. Expert Consultation Our vision is to create a single portal where investigators can access all necessary expertise to plan, conduct, analyze, and disseminate clinical and translational research. We have built a consultation service (CS) that

includes traditional expertise in biostatistics, ethics, and research design (BERD), but also provides expertise in a broad range of other disciplines. Investigators access the CS through the CTSI Web site, where their requests are triaged to the appropriate consultant, and customer satisfaction and return on investment is tracked.

Building on these achievements, our strategies for expert consultation are briefly described below and in detail in Part E.1. To accelerate our work in Consultation Services we will: • Enhance the expertise provided by the Consultation Service by adding new consultants or training current

consultants to provide expertise related to technology-enabled research, team science, and research across the lifespan.

• Extend the reach of our consultation services to our partner institutions locally and through the 5 University of California CTSA Consortium (UC BRAID).

• Support development of novel methods with small methodology grants to foster innovative and multidisciplinary team science approaches to solving clinical and translational research problems.

4.B. Regulatory Knowledge and Support (RKS) The vision of RKS is to promote high quality, ethical, and streamlined regulatory services to investigators at UCSF, across UC BRAID, and throughout the CTSA network. RKS has provided education, advice, and support regarding regulatory issues, developed IRB reliance across UC BRAID and the NCATS Accrual to Clinical Trials (ACT) consortium, and developed agreements to use central and commercial IRBs.

Selected Achievements in Regulatory Knowledge and Support (past 4 years) Reduced time from submission to IRB approval 32%, to an average of 57 days for full IRB review

• Instituted IRB “pre-review” • Created “Minimum IRB Submission Standards” • Simplified IRB application, revised fields, order and format

CTSI Pilot Grant Awards (overview: 2007-2015) Applications N=1518

Awards N =320; all 4 schools and 38 departments; Jr. Faculty (239) URM (41); Family caregiving (14); Digital Health (20); Team Science (6)

Awarded $$ $9,743,533

Publications 222

Subsequent Awards N=154 totaling $150 million

Selected Achievements in Expert Consultation (past 4 years) • Built a 70+ person consultation service that provides access to

expertise in biostatistics, ethics, and research design, as well as, data management, community-engaged research, implementation sciences, regulatory support, participant recruitment, mentoring, digital health, and science writing

• Provided over 13,206 hours of consultation in support of 2271 unique projects at UCSF and our partner institutions

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Reduced time to approval for ancillary reviews • Used Lean/Six Sigma approaches to process improvement • Developed Radiology Dosimetry Calculator

Trained researchers and staff • 2,209 individuals completed “Responsible Conduct of Research” course • Provided 1,283 hours of expert advice on regulatory issues

Implemented IRB reliance across UC BRAID and NCATS Accrual to Clinical Trials networks

• UCSF relied on another UC hub for IRB approval for 85 studies, and other UC campuses relied on UCSF for 165 studies

In the next funding period, we will continue these efforts, develop uniform electronic consent processes for use of biospecimens and clinical data, monitor and facilitate clinical trial recruitment, establish a UC-wide Food and Drug Administration (FDA) Regulatory Unit, and provide just-in-time training to improve the quality of IRB applications. Our strategies for regulatory support are briefly described below and in detail in Part E.2. • Develop and implement the UCSF Biospecimen and Clinical Data eConsent system - a patient-centered

portal for obtaining and documenting consent to use biospecimens and clinical data for research. We plan to enable the UCSF EHR (Epic) patient portal, MyChart, to allow patients to securely and conveniently express their preferences for use of biospecimens and clinical data obtained in the course of clinical care.

• Monitor and facilitate success for studies that are not meeting recruitment goals. Using data from required IRB recruitment reports, we will identify clinical trials with low enrollment, help investigators develop a remediation recruitment plan, and consider trial closure if enrollment does not improve.

• Establish a UC-wide Food and Drug Administration (FDA) Regulatory Unit. Each of the UC BRAID hubs provides advice on core FDA requirements, but does not have adequate expertise on certain specific issues. In collaboration with UC BRAID and the UCSF-Stanford Center of Excellence in Regulatory Science and Innovation (CERSI), we propose to create a UC-wide consultation service to provide expertise on FDA-regulated drug and device studies.

• Develop and implement embedded real-time IRB application support materials to improve investigator and staff understanding of the components of the IRB application and reduce time to approval.

5. Overall Aim 5: Vision & Strategies Founded on Achievements in Hub Resource Capacity 5.A. Special Populations Initiative (SPI) Research conducted among children, the elderly, and those socially and medically vulnerable, requires sensitivity to multiple clinical and social factors. These special populations have a higher likelihood of social and environmental exposures leading to increased disease burden, morbidity, mortality and costs, and greater cumulative risk exposures over the lifetime, and they are significantly underrepresented in research. The distinctive strengths that have evolved from these research domains will inform the design and conduct of cross-cutting research within each CTSI program and initiative. Following is an overview of selected achievements this vision is built upon and core features of our strategies to integrate research over the lifespan into our programs. A complete description of our achievements and plans appears in Part F.1.

Selected Achievements in Clinical and Translational Research across the Lifespan (past 4 years) Pediatrics UC BRAID Child Health (UCSF Representative Roberta Keller)

• Fetal Consortium - developed “best practices” for fetal gastroschisis, monochorionic twins, congenital heart disease • Autism Consortium - organized UC-Wide Autism Spectrum Disorders summit to develop plans for multisite research Children’s Hospital Oakland Research Institute (CHORI Bertram Lubin) • Seminal work on vaccine development, breakthroughs in sickle cell and thalassemia treatment and cures, bone

marrow transplants; source of most pediatric samples in the Human Genome Project UCSF Benioff Children’s Hospital Oakland Federally Qualified Health Center (Bertram Lubin) • CTSI satellite that has participated in 5 NIH clinical trials in the last 5 years.

Geriatrics UCSF Division of Geriatrics and NIA Pepper Center (PIs Ken Covinsky/Louise Walter) • Research on role of medical and social vulnerability in disability among elders • Career development and pilot studies on care for older patients in medical and surgical subspecialties • Beeson-funded research on functional and frailty measures to improve selection of older patients for liver transplant NIA Center for Aging in Diverse Populations (PIs Eliseo Perez-Stable /Anna Napoles-Springer) • Supported >50 junior faculty with research funding and mentoring

Vulnerable Populations

Center for Vulnerable Populations SF General Hospital (PIs Kirsten Bibbins-Domingo/Dean Schillinger) • Seminal work on health literacy and food insecurity • NIMHD P60 Chronic Illness Risk in Minority Youth; NIH U54 BUILD grant to develop research at SF State University

We will accelerate our work through several new strategies: • Create a UCSF-wide Special Populations Initiative (SPI) to promote cross-fertilization and teamwork among

researchers and provide resources to access our unique expertise in critical measurement domains common to these populations (Part E.1).

• Enrich and expand our research networks to practices and settings where SPs disproportionately receive

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care including UCSF Benioff Children’s Hospital Oakland, San Francisco General Hospital, and the AHRQ-funded PHoENIX (the Public Hospital Evidence Network and Innovations Exchange).

• Strengthen UCSF research capacity by developing tools and communication expertise for research in special populations across the lifespan to catalyze translational research involving California’s low-income and vulnerable populations.

5.B. Participant and Clinical Interactions (CTSI’s Clinical Research Service) The CTSI Clinical Research Service (CRS) provides infrastructure, administrative expertise, and research personnel to conduct high-quality clinical research that involves human subjects participation. Services include specialized adult and pediatric nursing support, both inpatient and outpatient accommodations; phlebotomy; customized specimen processing, tracking and inventory, including peripheral blood mononuclear cells, blood, urine, cerebrospinal and other body fluids; body composition and exercise physiology consultation and services; and pediatric neurodevelopmental testing. Our approach is to provide access to these commonly needed services, benefitting from economies of scale. We will work continually to ensure the highest level of ethical clinical research while improving efficiencies and eliminating barriers to enhance the quality of human subjects research. Following is an overview of selected achievements and the core features of our strategies for CRS. A full description appears in Part F.2.

Selected Achievements in Participant and Clinical Interactions (Clinical Research Services) (past 4 years) Extensive program review to prioritize CRS services

• Conducted online user and non-user surveys • Internal review: CRS Taskforce; External Advisory review (CTSAs, industry)

Streamlined efficiencies across UCSF campuses

• Consolidated from 8 to 4 CRS sites (SFGH, SFVA, UCSF-Parnassus, Mission Bay) • Negotiated access to inpatient beds as needed • Coordinated infusion center to maximize access and reduce redundancies on Parnassus campus

Expanded, consolidated, and retired cores

• Increased sites and capacity of SPL, supporting >200 clinical research protocols annually • Merged Body Composition, Exercise Physiology and Energy Metabolism into one Core with a full-

cost recharge. This Core offers expert consultation and access to state-of-the-art Hologic Horizon™/A DXA

• Neurodevelopmental Testing Core reorganized to provide study design consultation and psychological and behavioral assessments for pediatric studies with a full-cost recharge

• Planned closure of the bionutrition core due to under-utilization and high costs

Our strategies to optimize the quality and efficiency of CRS services include: • Streamline CRS operations to enhance clinical trial implementation to:

- Develop efficient electronic systems for research planning and budgeting, scheduling, and billing - Improve scheduling for clinical studies - Integrate Clinical Trial Management System (CTMS)/OnCore with IRB submission and study management - Establish an incentive voucher program for early-stage investigators conducting clinical research - Coordinate scientific review and ensure quality

• Provide highly trained research staff to support clinical research efforts: - Establish a Clinical Research Coordinator Core - Develop a clinical research training program for CRS staff

6. Overall Aim 6: Vision & Strategies Founded on Achievements in Network Capacity: Trial and Recruitment Innovation Centers (TICs and RICs) Multisite trials have the potential to contribute greatly to translational breakthroughs but are challenging to implement. They are often encumbered by lack of harmonization of financial, ethical, legal, and regulatory approval. We have actively engaged key institutional stakeholders to improve multisite clinical trial start-up at UCSF with an emphasis on increasing parallel, rather than sequential, approval processes. To serve as an outstanding hub partner in the CTSA Trial Innovation Centers (TICs), we have led cross-institutional efforts to implement IRB reliance and pre-negotiated master contracts. In concert with our work in trial innovation, CTSI has built a successful Participant Recruitment Unit (PRU) that will act as liaison to NCATS’ Recruitment Innovation Centers (RICs). Our commitment to this role is evidenced by our participation in the ACT Network, PCORI networks, and several other national initiatives. Following is an overview of selected achievements, and core features of our strategies to serve the TICs and RICs initiatives. A complete description of our achievements and plans appears in Part G.

Selected Achievements in Trial Innovation Centers (UCSF Clinical Trials) (past 4 years) Reduce redundant requirements for IRB review

• Studies that require UCSF scientific review are clearly defined – revised policy reduces administrative barriers for IRB submission for peer-reviewed studies (163/216 trials submitted to UCSF IRB over a 6-month period in 2015)

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Selected Achievements in Trial Innovation Centers (Multisite Clinical Trials) Collaboration across the NCATS Accrual to Clinical Trials Network

• Developed and tested national federated network of 21 CTSA hubs for cohort exploration • Demonstrated access to detailed data on potential study participants • Established governance and regulatory frameworks, implemented a common technology

platform, and created and disseminated a data harmonization schema • Signed network and data use agreements that allow identification of potential study participants

for any condition and identify potential healthy control subjects

We will accelerate our work in trial innovation and propose to: • Function as a highly efficient clinical trial site in NCATS’ nationwide efforts to create large-scale clinical

research collaboratives. • Work in coordination with regional and national CTSA hubs to develop shared technology and tools that

enable networks to improve multisite trial start-up and execution. Selected Achievements in Recruitment Innovation Centers: Participant Recruitment Unit (PRU) (past 4 years) Used EHR at UCSF and across UC BRAID (UC Research Exchange: ReX) to identify and contact potentially eligible participants.

• Investigators without IRB approval can use the Research Data Browser (RDB), a software tool developed at UCSF with pull-down data menus, to quickly determine the number of eligible patients (de-identified data) at UCSF and across UC BRAID; In 2015, 252 uses of the RDB at UCSF

• Investigators with IRB approval work with PRU to define eligibility based on EHR variables; Academic Research Systems (the “honest broker”) extracts a list of potentially eligible patients and provides contact information to PRU; PRU contacts these patients and invites to contact the study team. In 2015, PRU supported recruitment for 108 studies

Drawing on innovations in our Patient Recruitment Unit, we have refined and enhanced our recruitment services at UCSF, and will scale these for use at NCATS’ planned RICs. We will: • Enhance CTSI’s Patient Recruitment Unit to ensure successful recruitment for multisite trials and for all

human research studies at UCSF. • Contribute our expertise, experience, and tools to help NCATS develop efficient and effective networks of

recruitment centers. Our shareable EHR-based tools for recruitment and emerging recruitment networks will help inform the NCATS RICs and network-wide recruitment. Approaches developed at UCSF are being adopted across UC BRAID (e.g., UC ReX Research Data Browser, de-identified versions of EHR-derived data, “do not contact” approaches); UC BRAID is a perfect regional network in which to beta test, refine, and disseminate recruitment approaches that can inform national recruitment networks.

7. Overall Aim 7: Vision & Strategies Founded on Achievements in Product Development (UCSF’s Catalyst Program) Entrepreneurship and commercialization are critical to facilitating the translation of discoveries made in academic research environments to products that improve health. The CTSI Catalyst Program is an internal accelerator that addresses key gaps in product development at UCSF and across the UC BRAID network. Organized to support 4 tracks (therapeutics, diagnostics, devices, and digital health), Catalyst identifies, advises, and supports promising projects with high likelihood of producing commercial products. Our innovative approach draws on an extensive network of industry experts with intellectual property, venture capital and financing, regulatory, and other relevant insights into product development. Catalyst combines customized feedback and advice from these volunteer advisors with competitive funding to translate promising early technologies into health products with meaningful clinical benefit. Complete plans appear in Part H1.

Selected Achievements in Product Development (PD) (past 4 years) Catalyst Pilot Awards (Total funding to date $3MM)

• Over 200 expert volunteer consultants (industry, biotech, venture capital, intellectual property) • Projects supported by tracks: therapeutics (69), diagnostics (39), devices (24), digital health (36) • $3MM awarded by competitive review process (primarily institutional support): $43MM follow-on

funding • 14 total start-up companies;126 disclosures/patents; 3000+ consultation hours

Strategic Innovation Partnerships

• Targeted ”matchmaking” events have brought together industry partners and UCSF researchers • Successful launch of novel long-term collaborations with: − Quest Diagnostics ($140K to Catalyst + $1.95MM project funding) − MedImmune ($170K to Catalyst + $3.8MM project funding in negotiation) − Sigma-Aldrich ($50K + $50K in-kind) and Surpass (pre-clinical CRO, $20K per year in-kind) funding

for Catalyst awardees − Genentech $200K gift to Catalyst

• Initiatives with Pfizer Center for Therapeutic Innovation, GSK (Pre-DPAC), Onyx, AbbVie and others

We will accelerate our work in Product Development through the following activities:

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• Address gaps in resources to enable product development at UCSF by expanding Catalyst services to better support high-risk early therapeutics development, expand its project management resources, develop an Entrepreneur-in-Residence Program, expand access to Contract Research Organization (CRO) services, expand the Strategic Innovation Partnership Program, and enhance funding sources.

• Build and scale product development education and training by expanding the Catalyst Internship program and developing a case-based curriculum in product development.

• Extend product development activities in collaboration with other CTSA hubs by facilitating access to the Catalyst advisor network by our UC BRAID partners, expanding the UC BRAID Drugs, Devices, Diagnostics Development (D4) to focus on early therapeutics, and enhancing multi-campus industry partnerships with a unified contract negotiation process.

8. Overall Aim 8: Vision & Strategies Founded on Achievements in Precision Medicine Precision medicine (PM) aggregates, integrates, and analyzes information about biological events and processes, drawing on diverse data to produce a knowledge network with the potential to provide accurate health advice, predictions, diagnoses, and treatments tailored to the individual. UCSF has established a tri-pillar PM Platform Committee to coordinate and operationalize PM efforts across the campus, including development of a state-of-the-art tissue biospecimen phenomics laboratory for optimal tissue processing, biomarker detection, and analysis. CTSI leads the Clinical Discovery pillar (the other pillars are Basic Discovery and Social and Behavioral Discovery). As such, CTSI will direct and provide key elements of support for PM activities at UCSF and in collaboration with our regional and national collaborations. These critical supports include optimizing the consent process for biospecimen collection and the creation of disease-specific data registries to serve the clinical and translational research community. Our overarching goal is to enable data-driven, mechanism-based health and healthcare for each individual. Following is an overview of the achievements this vision is built on, and the core features of our strategies to build precision medicine at UCSF and in collaboration with our regional partners, UC BRAID and CTSA Hubs. A complete description of our achievements and plans appears in Part H2.

Selected Achievements to Advance Precision Medicine (past 4 years) Led establishment of ENGAGE-UC: UC BRAID research undertaking to determine optimal engagement of public and patients re: importance of biospecimens to PM

• Identified components of consenting process that require further clarity in outpatient settings

• Determined approaches to best engage general public, biobankers, researchers, institutional regulatory officials, and UC leaders to ultimately enhance acquisition and use of human biospecimens (EngageUC1)

• Developed a transparent, equable, and efficient infrastructure to share biospecimens and data across UC BRAID

Hosted State of California Initiative to Advance Precision Medicine

• Coordinated RFA and review of applications for statewide effort to identify 2 demonstration projects

• Hosted 2 day-long workshops to engage stakeholders and focus objectives of initiative

• Will administer the 2 funded trans-UC collaborative projects Facilitated development of specifications for a Web-based laboratory information management system (LIMS) to enable biospecimen annotation from multiple databases and tracking across multiple biobanks and helped to select vendor

• Selected LIMS-based software platform (LabVantage) to develop a coordinated approach to biospecimen collection and management

Our plans to accelerate PM efforts include: • Support high-quality biospecimen consenting, acquisition, and biobanking from diverse patient populations.

We will develop a centralized biobanking consent form, create a Research Specialist Core to coordinate biospecimen collection in clinics and operating rooms throughout UCSF, build an infrastructure for optimized biospecimen collection, processing, and storage, and develop scalable, compliant, biospecimen storage facilities to accommodate the needs of legacy and new biobanks.

• Facilitate PM research by creating a Biospecimen Resources Program, a richly annotated centralized, searchable, Web-based biospecimen database. We will implement a configurable, Web-based LIMS software platform to optimize specimen collection and management.

• Enable the practice of PM by creating portals to integrate selected population and research data with the electronic health record (EHR). We will develop the tools and policies necessary to

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create portals to integrate population and research data into the EHR for point-of-care guidance. B. INTEGRATION OF HEALTHCARE AND RESEARCH A key aspect of our defining vision for this next 5-year period will be integrating healthcare and research. This will hinge, in part, on enabling clinical trials embedded in the healthcare system, such that the system continuously improves. Such integration is a major paradigm shift that was first articulated by the Institute of Medicine in 2012 (“Learning Health System”2), supported by national leaders and substantial investment (e.g., PCORnet3) and further developed in subsequent commentaries,4 including publications by members of our CTSI team.5,6 The barriers to realizing this vision are substantial and will require a true multidisciplinary effort with contributions from all of our CTSI programs. These efforts will include: Informatics infrastructure development. A key goal and Innovation Priority of our newly reconfigured Informatics and Research Innovation Program (IRI: Part B) is to enable clinical trials embedded within healthcare delivery systems. IRI Aims 1-3 are designed to make tangible progress toward this goal by developing systems and infrastructure to derive research-grade measurements from data points captured during the delivery of healthcare (IRI Aim 1), to import these measurements into a research study management system, and use them to support clinical trial operations (e.g., screening, consent, randomization, intervention delivery, adherence and follow-up tracking; IRI Aim 2), and to develop the science of delivering interventions that influence healthcare delivery through the EHR system (IRI Aim 3). IRI supports demonstration projects designed to develop relevant methods and identify and overcome the practical barriers to achieving the vision. Current projects that embody the integration of research and clinical care include a randomized trial of an EHR-based decision support system to improve management of chronic kidney disease and a blood pressure control “laboratory” (see Part B: Table 2). Methodological support and training. CTSI Consultation Service hosts a large group of consultants with expertise in study design and biostatistics, including specialized methods designed for causal analysis of observational data, data management, and EHR data extraction. Our consultation panel will include clinicians with expertise in clinical workflows and EHR toolkits who can help researchers design effective EHR-based interventions to influence care. These experts will also need to develop and support the implementation of new methodologies, e.g., for randomized, embedded, multifactorial, adaptive platform (REMAP) trials4 as well as the analysis of observational follow-up data generated during healthcare delivery and subject to informative non-random visit intervals (a methods project led by one of our consultants and funded by PCORI7). Our training programs will support these methods with new courses on Data Science (Part D.1). Regulatory science. Patients presenting to a medical center for treatment naturally expect that the care they receive is the best that exists and may not immediately understand that reducing clinical uncertainty requires population-based research to build the evidence that supports clinical care; they may be resistant to the idea of being included in research during care delivery. Concurrently, the Office of Human Research Protections (OHRP) supports strict regulations that carefully respect and protect the rights of human research subjects. Emerging science and ethical discourse support methods that enable respectful, ethical, and efficient science embedded within healthcare systems.6,8-10 The CTSI Regulatory Knowledge and Support Program (Part E.2, led by UCSF’s IRB Director) will continue to work closely with IRI to advance these methods and regulatory pathways for clinical trials embedded in clinical care. Administration, clinician, and community engagement. Critical to success of the Learning Health System will be engagement at all levels. We have secured support for our mission not only from our Chancellor and Deans (see Letters of support), but also from key operational leaders including the Chief Medical Information Officer (who manages our EHR system) and our Chief Innovations Officer (who manages quality improvement and innovation in care delivery), both of whom are members of the IRI team. We have recruited local clinical champions and clinical workflow experts who will consult on integrated research projects across a broad range of clinical departments and units (Part B, IRI Aim 3). These clinicians will help us implement interventions using the EHR but will also garner critical local support among clinicians for our research integration efforts. The CTSI Community Engagement Program, in concert with our IRB, will help us extend our reach beyond academic health centers and involve more representative community-based hospitals, clinicians, and health organizations as partners to promote learning health systems and ensure that safety net organizations caring for vulnerable populations are included. Network partnerships for multisite research and collaboration on methods. While many types of high impact research projects can be conducted within a single institution, multisite studies provide critical opportunities for larger and more diverse samples and wider dissemination of results, as well as for sharing critical methodology and infrastructure advances. Leveraging our partnerships – local (our clinical affiliates), regional (the UC BRAID network), and national (CTSA network) partners – we will help each other develop and test new

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platforms and develop “Learning Health System Networks” where interventions and systems proven effective in one system can subsequently be tested and disseminated in networked institutions. Accelerating EHR-based research in these settings requires not only overcoming the technical IT challenges described in Part B, but also surmounting cultural, organizational, and political sensitivities surrounding sharing of EHR data from diverse non-academic clinical organizations (Part C.1). Through these and other efforts, we hope to empower a broad base of clinical and translational researchers to conduct studies integrated within our care delivery system that promote discovery, advance precision medicine, and improve the health of our patients. C. OVERALL AIM 4: WORKFORCE DIVERSITY Our vision is that UCSF trainees, staff, faculty, and study participants will represent the rich diversity of the San Francisco Bay Area. CTSI will collaborate with the UCSF Office of Diversity and Outreach, led by Vice Chancellor Renee Navarro, PharmD MD (see Letter of Support), a member of the Advisory Committee to the NIH Director Working Group on Diversity, to achieve this vision.

Selected Achievements in Workforce Diversity (past 4 years) Students and Trainees Pre-health Undergraduate Program (PuP)

CTSI created PuP, a summer training program that pairs URM and disadvantaged undergraduates (from 52 universities) with UCSF students in the TL1 program to learn research methods and inspire selection of a career in clinical research; applications for 20 PuP slots were >150 in 2015; >50% of enrolled students are URM or disadvantaged; 76% have been admitted to professional schools

Visiting Elective Scholarship Program (VESP)

VESP offers stipends, mentoring, and an introductory course in clinical research methods to URM senior medical students who aim to come to UCSF for residency; the program brought 8 URM clerks to UCSF for clinical rotations; 3 have come to UCSF for residency

NIH Diversity Supplements

To raise awareness of NIH diversity supplements, we periodically emailed NIH-funded PIs at UCSF to describe supplements and how to apply: from 2012-2015 supplements increased from 8 to 20 awards

Faculty Unconscious Bias

Developed and implemented unconscious bias training for UCSF Dept. and Division Chairs, Selection Committees, and others; total of >1,100 persons trained

Professional Development Awards

Funds faculty to attend the American Association of Medical Colleges Minority and Early or Mid-Career Women Faculty Leadership Training Programs; 14 URMs and 24 women have attended

URM Faculty Research Awards

Through an annual pilot-funding award aimed at young investigators who are URM or disadvantaged, CTSI funded 41 URM Faculty Research Awards

New Child Award Funded 14 faculty via an annual award for returning to work after childbearing or adoption for relief from non-research responsibilities for up to 3 months

Pilot funding awards Rate of pilot funding in 2014-15 was 44% among women, 42% among men, 46% among URM, and 43% among non-URM faculty

To better understand the specific challenges to improving workforce diversity at UCSF, CTSI partnered with the UCSF Office of Diversity and Outreach to obtain data on URM and women trainees and faculty and to define key problems and opportunities. UCSF is home to a representative proportion of American Indian, Black, and Hispanic students, but this drops as students progress in their careers: URMs comprise 14% of

trainees, but only 6% of faculty. Given this, and the difficulty of recruiting faculty to the expensive SF Bay Area, a major aim will be to nurture and retain our own superb trainees and eliminate barriers for career advancement. Women are well-represented among UCSF trainees and faculty, but not among UCSF leadership. For example, only 10 of 43 departments and organized research units at UCSF are headed by women. Thus, our strategy for advancement of women is to promote leadership training, ensure that search committees for high-level positions are trained on unconscious bias, and identify qualified women (and URM) candidates. Based on these data and achievements, our strategies for sustaining and improving diversity across the UCSF workforce are described below and in the TL1 and KL2 proposals. We will continue to collaborate with the Vice Chancellor for Diversity to

support diversity efforts for clinical and translational researchers; new aims in the next funding period include: • To improve the culture of diversity at UCSF. With robust advocacy from CTSI leaders, UCSF Chancellor

Sam Hawgood has set a major strategic goal to inculcate the UCSF “Culture of Inclusion and Diversity (COI)” across all UCSF missions – clinical care, education, and research. With full participation from CTSI Director. Grandis (a member of the Executive Advisory Board for the initiative), UCSF will launch an initiative focused on 6 areas (Figure, below), each with high impact and clear goals. A Project Charter with detailed information

Gender and Diversity at UCSF, June 2015 Trainees* Faculty Female 3,241 (57%) 1,116 (45%) Male 2,463 (43%) 1,381 (55%) American Indian 33 (1%) 8 (0%) Black 216 (4%) 45 (2%) Hispanic 475 (9%) 90 (4%) Hawaii/Pacific Is. 17 (0%) 0 (0%) Total URM 741 (14%) 143 (6%) Asian 1,766 (33%) 582 (23%) Other 496 (9%) 72 (3%) White 2356 (44%) 1,700 (68%) TOTAL 5,359

(100%) 2,497

(100%) * professional & graduate, post-docs, residents &

fellows.

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on the scope, objectives, and strategies for the initiative has been drafted, and work will begin in early 2016. UCSF will enrich our already diverse culture by concentrating on each of the 6 focus areas with the same innovation and rigor with which we approach education, clinical care, and research. Finally, CTSI will extend our reach by developing an online version of our Unconscious Bias training, making it widely available at UCSF and to our CTSA partners.

• To improve the diversity of our students and trainees, we will support efforts to diversify the workforce at all levels of training. We will expand our successful undergraduate PuP program, provide training opportunities to more URM students, and include longitudinal research experiences in collaboration with an NIH R25 (PI: Lubin) that supports research experiences at Children’s Hospital Oakland Research Institute (CHORI) and the U54 SF BUILD (Building Infrastructure that Leads to Diversity: UCSF PI Bibbins-Domingo), a partnership with San Francisco State University. The BUILD program was developed to encourage ongoing career development of URM students

in science and biomedical research. The successful CTSI-initiated Visiting Elective Scholarship Program, which supports senior URM medical students to complete clerkships at UCSF, will be taken over by the School of Medicine, with plans to expand the program to all Departments of the School and to increase the number of URM clerks. To further increase the number of NIH Diversity Supplements, we will develop a system to periodically contact URM students and trainees, solicit interest in focused areas of clinical research, and help them to use UCSF Profiles to find potential mentors and PIs who can submit Diversity Supplements. The TL1 and KL2 employ active approaches to identify, enroll, and support diverse trainees, working tirelessly to ensure that URM trainees successfully transition to the next level of training (full details in the TL1 and KL2 proposals).

• Improve diversity of our faculty. We will continue to support the URM Faculty Research Awards, the New Child/Family Caregiving Award, and the AAMC Professional Development Awards for URM and women faculty. With strong advocacy from CTSI, the UCSF Chairs’ Diversity Initiative will be established to provide $9.7MM per year for 1 URM retention package; 4 new URM faculty start-up packages; and 4 packages to help URM trainees transition to faculty.

• Supporting NIH and national efforts to promote diversity. The NIH has made a significant investment in diversifying the workforce through U54 BUILD grants and the National Mentoring Research Network (NRMN). As noted above, UCSF is a recipient of a BUILD (in partnership with SF State University: UCSF PI Bibbins-Domingo) and participates in the regional and national BUILD and the National Research Mentoring Network (NRMN Pilot Award Co-PIs Feldman and Khalili.). We will also participate in the national organization, Building the Next Generation of Academic Physicians, which is focused on nurturing the pipeline of underrepresented trainees to faculty and will host a national conference in 2016/17.Our goal is to ensure the sustainability of these efforts and broaden the number of UCSF faculty engaged in national diversity activities by integrating with other training and mentoring activities at UCSF.

Pictured are undergraduates at the 2015 UC Diversity Pipeline Initiative Leadership Conference, now in its fifth year, which addresses issues facing minority women who are interested in pursuing an academic career. The Conference is sponsored by the UC Office of the President, the UCSF Multicultural Resource Center, the California HealthCare Foundation, and the 5 UC Clinical and Translational Science Institutes.

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References for Part 1. Overall Vision and Strategy

1. Garrett, S.B., et al., EngageUC: Developing an Efficient and Ethical Approach to Biobanking Research at the University of California. Clinical and translational science, 2015.

2. Roundtable on Value and Science-Driven Health Care, et al., Large Simple Trials and Knowledge Generation in a Learning Health System. 2013.

3. Selby, J.V., et al., Network news: powering clinical research. Science translational medicine, 2013: p. 3006298.

4. Angus, D.C., Fusing Randomized Trials With Big Data: The Key to Self-learning Health Care Systems? JAMA, 2015. 314(8): p. 767-768.

5. Grumbach, K., C.R. Lucey, and S.C. Johnston, Transforming from centers of learning to learning health systems: the challenge for academic health centers. JAMA, 2014. 311(11): p. 1109-1110.

6. Pletcher, M.J., B. Lo, and D. Grady, Informed consent in randomized quality improvement trials: a critical barrier for learning health systems. JAMA internal medicine, 2014. 174(5): p. 668-670.

7. pcornet. Methods for Analysis and interpretation of Data Subject to Informative Visit Times. [cited 2015 Sep 8]; Available from: http://www.pcori.org/research-results/2013/methods-analysis-and-interpretation-data-subject-informative-visit-times.

8. Faden, R., et al., Ethics and informed consent for comparative effectiveness research with prospective electronic clinical data. Medical care, 2013. 51: p. S53-S57.

9. McKinney, R., et al., Use of altered informed consent in pragmatic clinical research. Clinical Trials (In press).

10. Finkelstein, J., et al., Oversight on the borderline: quality improvement and pragmatic research. Clinical Trials (In press).

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FACILITIES AND OTHER RESOURCES UNIVERSITY OF CALIFORNIA, SAN FRANCISCO (UCSF) GENERAL The University of California, San Francisco (UCSF), one of the ten campuses of the University of California, is devoted solely to graduate education and research in the health sciences. UCSF is composed of the Schools of Medicine, Dentistry, Pharmacy, and Nursing, and the Graduate Division. In both size and number of students, UC San Francisco is the smallest of the UC campuses. Nevertheless, its relative size belies its distinction as one of the leading biomedical research and health science education centers in the world. In addition, UCSF is a major health care delivery center in northern California with a high volume of regional, national, and international patient referrals. Over the last century, the original nucleus of academic schools and divisions has grown to include a School of Nursing (1939); the Langley Porter Psychiatric Institute (1942), which contains the city's first psychiatric hospital; and a Graduate Division (1961). The Graduate Division functions as the administrative and quality control unit for more than 2,940 students enrolled in PhD and Master’s programs and 1,030 academic postdoctoral fellows, representing 94 countries. UCSF also is home to 11 research institutes, 1,500 laboratories, more than 5,000 ongoing research projects, and a library with a state-of-the-art computing and communications infrastructure. UCSF’s four professional schools (Dentistry, Medicine, Nursing, and Pharmacy) are ranked in the top tier nationally and internationally (measured by academic quality, publication citations of faculty, and amount of extramural support for research and education) as centers for education and research in the various disciplines. UCSF’s graduate academic PhD programs are also ranked in the top tiers of programs in the biomedical bio-psychosocial disciplines. There are 35 academic departments, 17 multidisciplinary research centers, and many NIH-funded multidisciplinary research grants including 19 Research Program Projects (P01), 12 Center Core Grants (P30), 12 Specialized Center Grants (P50), and 64 Project (U01)/Program (U19)/Center (U54) Cooperative Agreements. The Graduate Division offers 19 degree programs to students pursuing masters and doctoral degrees in disciplines ranging from bioengineering to chemical biology, from biopharmaceutical sciences and pharmacogenomics to nursing, and from global health to sociology. Graduate programs are organized around several interdisciplinary research areas that often contain members from several departments. UCSF also offers a CTSI-supported Advanced Training in Clinical Research Certificate program and a Master’s Degree in Clinical Research as part of the Training in Clinical Research Program described below. UCSF has taken national leadership in the establishment of quality standards for the selection, appointment, compensation, and education of postdoctoral scholars. UCSF is committed to recruiting and retaining a diverse population. Of the 20,400 UCSF staff, 56% are minorities and 68% are women. Of the 2,500 faculty, 29% are minorities and 45% are women. Of the 3,000 students and trainees, 49% are minorities and 57% are women. UCSF is one of the leading biomedical research and graduate education centers in the world, and it ranks in the top group of institutions of higher learning in total federal funding for research and training. UCSF has an annual budget of over $3.3 billion to support its various research, teaching, and patient care activities. A large portion of the extramural funds received is allocated for biomedical research. Research funding primarily is obtained on a competitive basis from the federal government. Additional research funding is received annually from the State of California, the University of California Office of the President, private research foundations, state and local government agencies, private philanthropy, and industry. UCSF was awarded $546.5M in NIH funding in 2014, which was first among public institutions and second among all institutions nationwide. In 2014, the UCSF School of Dentistry received $15.5M (ranked first), the School of Nursing received $10.1M (ranked first), the School of Pharmacy received $31.8M (ranked first), and the School of Medicine received $480.6M (ranked first). Among its faculty are five Nobel laureates, 39 National Academy of Sciences members, 57 American Academy of Arts and Sciences members, 79 National Academy of Medicine (formerly the Institute of Medicine) members, and 16 Howard Hughes Medical Institute investigators. Over the past decade, UCSF’s capacity for clinical and translational research in the context of world-class graduate education has been redoubled by the construction of academic facilities at the new UCSF Mission Bay Campus, which is continuing with the 265,000 sq. ft. Global Health & Clinical Sciences Building, which houses the CTSI, and the 878,000 sq. ft. children’s, women’s specialty, and cancer hospital complex. Currently, UCSF has over 1.5 million assignable square feet (ASF) of research space: ~62,000 ASF in the School of Dentistry, ~1.3 million ASF in the School of Medicine, ~32,000 ASF in the School of Nursing, and ~126,000 ASF in the School of Pharmacy. This total space supports approximately 2,400 Principal

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Investigators with active sponsored awards. Research and clinical activities take place on the six main San Francisco campuses of UCSF: Parnassus, Mount Zion, Laurel Heights, San Francisco General Hospital, San Francisco Veterans Administration Medical Center, and Mission Bay. A frequent UCSF shuttle bus service (running every 20 minutes) allows for efficient staff, reagent, and mail travel between all main campus facilities. FACILITIES AND SPACE FOR Training in Clinical Research, TL1, and KL2 PROGRAMS: MISSION BAY CAMPUS The core components of the Training in Clinical Research (TICR: see below), TL1 and KL2 Programs take place at Mission Hall, the newest building on the UCSF Mission Bay Campus completed in September 2014. Mission Hall provides a flexible arrangement for staff and faculty and removes traditional hierarchies. Every individual has an assigned workstation and unscheduled access to all additional spaces used in day-to-day work. This might involve moving to enclosed space for concentrated and focused work or moving to more informal shared spaces which enhance interaction and collaboration. • Approximately 1500 people in 1453 assigned open workstations (includes space for future growth) • 52 hotel work stations (drop-in) • 376 focus rooms for 1-2 people (non-scheduled); 1 focus room for 4 workstations • 76 huddle rooms for 3-4 people (non-scheduled); 1 huddle room for 20 workstations • Variety of small, medium and large conference rooms • Variety of storage rooms per floor (200 ASF, 250 ASF, 80 ASF) • Secure personal storage at each work station (9 Linear Feet)

The following major departments or units of UCSF are housed in Mission Hall on Floors 2-7 including: Epidemiology & Biostatistics, Global Health Sciences, Pacific Aids Education & Training Center (PAETC), Prevention Science, Helen Diller Family Comprehensive Cancer Center Finance, Clinical and Translational Institute (CTSI), Research Management Services Women's Health Clinical Research Center (WHCRC) Mission Hall also houses a learning center on the first floor, including 11 classrooms with seating for 15-100 persons. The classrooms include state of the art technology: video/audio conferencing; lecture capture (recording); SMART podiums with built in computer and multiple displays; touch panel controls to name a few features. All TICR courses are delivered in Mission Hall, making this facility the central hub for TL1 Fellows and K Scholars matriculated in the Master’s Degree or ATCR programs or taking individual courses. UCSF PROFESSIONAL SCHOOLS UCSF School of Medicine Established in 1864, the SOM is the oldest continuously operating medical school in the western states. Ranked as one of the top five medical schools in the country, it operates facilities at seven campuses in San Francisco and Fresno. It was ranked number one in NIH funding, receiving over $439M in total awards and over $14.5M in training awards in FY2013. With 28 departments, nine organized research units and seven interdisciplinary centers, medical school faculty and staff reach beyond the neighborhood to bring cutting-edge scientific research and complex clinical care to the nation and the world. UCSF School of Pharmacy Founded in 1872, the in the UCSF School of Pharmacy (SOP) was the first college of pharmacy established in the west and the tenth in the US. It continues to be ranked as the best Doctor of Pharmacy degree program in the nation by US News and World Report and has been the largest school of pharmacy recipient of NIH research funding every year since 1979 (with $292M in FY2013). It was the first to train pharmacists as clinical health care providers who specialize in a patient's comprehensive drug therapy and management. The School of Pharmacy administers the California Poison Control System and responds to approximately 600,000 poisoning inquiries each year, saving $30 million annually in medical treatment costs. UCSF School of Dentistry The UCSF School of Dentistry (SOD) ranks first among all dental schools in research funding from National Institutes of Health. The school has held this ranking for the past 13 years. School of Dentistry has created multiple centers for creativity and research: an NIH-funded Comprehensive Oral Health Research Center of Discovery (one of only three centers hosted by US dental schools and the only such in California); the Center for the Health Professions; the UC San Francisco AIDS Specimen Bank; the Oral AIDS Center; the NIH-funded

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Oral Cancer Research Program; the Center on Oral Health Disparities; and SICCA, an international registry network dedicated to the study of Sjögren's Syndrome. UCSF School of Nursing The UCSF School of Nursing (SON), founded in 1939 as the first autonomous School of Nursing in any state university, was the first university west of the Mississippi to offer a doctoral degree in nursing. The school ranks first in NIH funding, with $8.6 million in 2013. It is designated as a World Health Organization Collaborating Center in Nursing and is one of five John Hartford Centers for Geriatric Nursing Excellence. UCSF Schools of Nursing and Dentistry have joined forces in Elev8 Healthy Students & Families, a new model for inter-disciplinary education of advanced practice nursing and dental students in community-based health care, delivering primary health and dental care to vulnerable children in middle schools. Community partners include Safe Passages, Alameda County Health Care Services Agency, the Oakland Unified School District, community federally-qualified health clinics and the UCSF Institute for Health Policy Studies. Space for the SON is distributed as follows: research space, including research labs, offices, and service areas is 20,484 ASF; academic office space is 12,991 ASF; and the total School of Nursing space is 65,007 ASF, which includes classrooms, administrative, learning labs, and other such non-research or academic office space. The administrative structure of the School includes Associate Deans for Student Affairs, Academic Affairs, Research, International Programs, and Administration who report to the Dean. In addition, each of the five units identified above also report to the Dean. A Center for Symptom Management promotes cross departmental and multidisciplinary research focusing on interventions to prevent and alleviate symptoms; a Center for Research and Innovation in Patient Care focuses on patient safety, nurse staffing effectiveness, and strategic performance improvement through collaboration with partners. The UCSF School of Nursing has an Office of Research that is to facilitate the nursing research enterprise by offering programs and resources to support faculty and staff in the development, submission, conduct and publication of research. UCSF GRADUATE DIVISION The Graduate Division of UCSF offers top-ranked Graduate Programs in the biological, biomedical, pharmaceutical, nursing, and social and behavioral sciences. UCSF graduate students conduct research in basic, clinical, social, and behavioral sciences. Their work ultimately will help to ensure the health of human beings, shape health care systems, and influence public education about the prevention of disease. Our degree-granting programs are organized around several inter-disciplinary research areas, which often contain members from several departments. Currently, there are 25 degree programs, the majority of which are ranked in the top ten, nationally, according to a survey released by the National Research Council (NRC) in September 2010. The survey, the first of its kind since 1995, did not assign a single rank to any program, but intentionally placed the programs within a range in their fields, such as first to third. Based on the NRC analysis, ten of the 12 UCSF programs fell within a range that included the top six programs in their fields, with three of those including the No. 1 rank. The top-ranked UCSF programs were Nursing, Biochemistry and Molecular Biology, and Bioengineering. The range for three other programs included second place: Neuroscience, Biophysics, and Biomedical Sciences. The range for Cell Biology started at No. 3. The other five programs in which UCSF was scored—Medical Anthropology, Chemistry and Chemical Biology, Sociology, Genetics, and Oral and Craniofacial Sciences—also ranked among the nation’s best. UCSF CLINICAL FACILITIES Patients for clinical studies are recruited from Moffitt, Long, and Benioff Children’s Hospitals, the San Francisco General Hospital, the San Francisco Veterans Affairs Medical Center, Langley Porter Psychiatric Institute, UCSF outpatient clinics, and from community health clinics. A new, 289-bed, 878,000 gross sq. ft. children’s, women’s specialty, and cancer hospital complex at Mission Bay opened in 2015, and a new 448,000 sq. ft. SFGH building, which will have 284 inpatient beds will open in 2016. The Medical Center at Mission Bay will be the third major site providing patient care and will focus on children’s health, women’s health, and cancer medicine.

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UCSF Medical Center (Moffitt-Long Hospitals) UCSF Medical Center is one of the most distinguished healthcare institutions in the world, renowned for its integration of medical research and clinical care for the benefit of patients. The 600-bed hospital admits approximately 23,000 patients annually and has an extensive outpatient program, with more than 600,000 visits a year in 90 specialty clinics. The physicians, nurses, and other health professionals are leaders in their fields, providing a wide range of services from routine exams to highly specialized diagnosis and treatment. UCSF Benioff Children’s Hospital SF UCSF Benioff Children’s Hospital SF is one of the top children's hospitals in the nation, according to a ranking by US News & World Report. Expertise covers virtually all pediatric conditions, including cancer, heart disease, neurological disorders, organ transplants and orthopedics as well as the care of critically ill newborns. The 180-bed UCSF Benioff Children's Hospital is a "hospital within a hospital" with more than 150 specialists in almost 50 specialties. We have programs designed specifically for young patients, such as a 50-bed Neonatal Intensive Care Nursery, recreational therapy for recovering kids and 60 specialty care clinics throughout Northern California. Our doctors were the first in the world to successfully perform surgery on a baby still in the womb. They also developed life-saving treatments for premature infants whose lungs aren't fully developed. Hospital services customized for young patients include: • Child Life to help children and their families adjust to hospitalization and make their stay as positive as

possible • Compass Care, comprehensive palliative care for children with chronic life-threatening conditions, as well

as those who need end-of-life care • Social workers, who are trained in the needs of children and their families In the area of neurology and neurosurgery, Benioff Children’s Hospital is one of the leading hospitals in the nation. We have the largest brain tumor treatment program in the nation and the only comprehensive epilepsy center in Northern California. Benioff Children’s Hospital also has one of one of the nation's largest centers for kidney and liver transplants. Its AIDS program is the most comprehensive in the nation, and its surgical eye care program is the largest in Northern California. In the area of orthopedics, it is internationally recognized for treating the spine, including deformities, degenerative disc disease, tumors and fractures. UCSF Benioff Children’s Hospital Oakland UCSF Benioff Children’s Hospital Oakland, now merged with UCSF Benioff Children’s Hospital San Francisco, provides care for more than 10,000 inpatients and 250,000 outpatients annually from across the Bay Area and is the largest pediatric hospital in Northern California. Benioff Children’s Hospital Oakland is dedicated to advancing care for children. The Oakland site is notable for serving as an ACS Certified Level 1 Pediatric Trauma Center and a nearly 100-year history of caring for children in Northern California and beyond UCSF Mount Zion Medical Center Mount Zion Hospital was established in 1887 as a voluntary, non-profit hospital to render "medical and surgical aid and service to the needy and distressed sick of the community... without regard to race or creed." Today, Mount Zion is operated by UCSF. It is located in the heart of San Francisco, about two and a half miles from the UCSF Medical Center at Parnassus and connected by frequent shuttle bus services. The growing network of outpatient care includes comprehensive diagnostic services, dermatology, general medicine, and sports medicine as well an Outpatient Surgery Center and Urgent Care. Much of Mount Zion is devoted to specialized centers and clinics. The Center is dedicated to researching, diagnosing, and treating many forms of the disease. A state-of-the-art, five-story Clinical Cancer Building is part of this complex. The Center offers a variety of support services to patients and their families. For example, the Cancer Resource Center contains books, pamphlets, and other reading material and provides computers with Internet access for gathering health information. Other specialized centers include the national Center of Excellence in Women's Health, Osher Center for Integrative Medicine, Sleep Disorders Center, Multiple Sclerosis Center, and the Pain Management Center. The Center on Aging helps older adults maintain health and independence and includes an Alzheimer's Day Center, which provides nursing and social work services and structured activities. San Francisco General Hospital (SFGH) SFGH is a large public general hospital owned and operated by the Department of Public Health of the City and County of San Francisco. It is licensed for 550 hospital beds and offers acute inpatient care in the areas of general medicine, AIDS care, surgery, critical care, women and children services, and psychiatry. The hospital

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treats approximately 100,000 inpatients and 80,000 outpatients annually, more than one-third of whom are uninsured. Outpatient services are provided through over 100 primary care, specialty care, and subspecialty care clinics. These clinics are organized under the general services of Medicine, Surgical Specialties, Obstetrics/Gynecology, Pediatrics, and Family Practice. Emergency services are available 24 hours a day. SFGH is the designated trauma center for the West Bay counties. UCSF physicians and residents provide one-third of the teaching for students and house staff. SFGH is also home to more than 20 UCSF research centers, affiliated institutes, and major laboratories, including a CTSI CRC site, the Division of Experimental Medicine, the Rice Liver Laboratories, and the Rosalind Russell Arthritis Center. More than 160 UCSF principal investigators are based at SFGH.

Veterans Affairs Medical Center (VAMC) The VAMC in San Francisco is part of the nationwide Federal health-care system for veterans operated by the US Department of Veterans Affairs. Established in 1934, it is the major health care center for veterans from the City of San Francisco to the Oregon border. SF-VAMC has its major affiliation with the Medical, Dental, Pharmacy, and Nursing Schools at UCSF. SF-VAMC is recognized for its quality of patient care, its strong educational programs, and its leadership in medical and scientific research. SF-VAMC is a 344-bed acute general medical and surgical center. State-of-the-art primary, secondary, and tertiary care in all major diagnostic and treatment specialization is provided. In addition, the VAMC serves as a major diagnostic referral center for veterans throughout the Western Region and is a tertiary referral center for acute care patients. A 120-bed nursing home provides skilled nursing and hospice care. SF-VAMC provides extensive outpatient services through clinics in most subspecialty areas. An estimated 190,000 outpatient visits are made each year to the various clinics. SF-VAMC is renowned for its state-of-the-art acute medical, neurological, surgical, and psychiatric care. It is at the leading edge of medical technology in such subspecialty areas as: cardiac and vascular surgery, interventional radiology, neurology and neurosurgery, ophthalmology, otolaryngology, oral surgery, urology, endocrinology and metabolism, dermatology, hematology and oncology, dialysis, orthopedics, cardiac catheterization and angioplasty, alcohol and drug abuse, and mental hygiene. SF-VAMC plays a leading role in the treatment and research of AIDS and has been designated as one of the six nationwide AIDS Clinical Centers. Langley-Porter Psychiatric Hospital and Clinics (LPPH&C) The LPPH&C is located at 401 Parnassus Avenue, and is part of the Parnassus campus of UCSF. LPPH&C consists of an adult inpatient unit (22 licensed beds), an adult Partial Hospitalization Program (daily census ranges from 12-17) and adult/child outpatient services (approximately 20,200 visits per year). Primary diagnoses for patients in all services include major depression, anxiety and psychosis. LPPH&C serves all ethnic and socio-economic groups who reside in San Francisco and the greater Bay Area, as well as those referred from areas throughout the Western United States. Departmental administrative and computer support offices are available at this site, and it is the hub for a shuttle service that links the main campus and other sites, including SFGH and SF-VAMC.

UCSF CLINICAL AND TRANSLATIONAL RESEARCH RESOURCES UCSF Clinical Trials Our patients have the opportunity to participate in clinical trials, which are studies to test the safety and effectiveness of new, experimental medications and treatments. Clinical trials make new drugs, therapies and surgical procedures available to patients before they're widely available to the general public. In addition to the national search tool found at ClinicalTrials.gov, Similarly, UCSF has a trial search tool (http://www.ucsfhealth.org/clinical_trials/index.html) to enable patients to identify clinical trial opportunities specifically at UCSF. CTSI Clinical Research Service (CRS) The CTSI Clinical Research Service (CTSI-CRS) program offers infrastructure and services at multiple locations. These units are available to UCSF investigators and provide specialized research services, including skilled nursing for a wide variety of multidisciplinary clinical research protocols conducted in both inpatient and outpatient settings. The CRS provides services to more than 289 clinical investigators, representing the UCSF Schools of Medicine, Nursing and Pharmacy. The CRS provides Nursing, Sample Processing, Body Composition, Neuropsychological Development, and Neonatal Clinical Research cores. CRS Inpatient Units

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• The adult unit at Moffitt Hospital is comprised of 2 inpatient beds. Protocols include the Islet Cell Transplant program, Fronto-temporal Dementia studies, CJD protocols, Drugs of Abuse NIDA studies, and the large Brain Tumor Consortium Clinical Trials.

• The 5270 sq. ft. adult unit at San Francisco General Hospital includes 8 inpatient beds. The world-renowned unit develops treatment and prevention innovations for diseases that particularly afflict vulnerable urban populations.

CRS Outpatient Units • The UCSF Clinical Research Center at Parnassus features 2500 sq. ft. of newly opened outpatient

space is specially staffed and equipped for phase l, ll and lll trials. The center includes a large waiting room, infusion space and multiple exam and procedure rooms.

• The Pediatric Clinical Research Center, located at UCSF Benioff Children’s Hospital, is a 3080 sq. ft. facility. Acute care mobile research nurse staff also complete research procedures and data collection within inpatient Pediatric units

• The outpatient unit at San Francisco Veterans Affairs Medical Center (VAMC) includes an outpatient suite and consultation rooms with 202 sq. ft. of exclusive use facilities and 445 sq. ft. of shared use facilities.

• The 2700 sq. ft. CHORI Children’s Hospital Adult and Pediatric outpatient centers located at the Children’s Hospital and Research Center Oakland (CHRCO) serves both children and adults in Oakland's diverse population of 400,000. Research groups include adult neurology, pediatric endocrinology, pediatric hematology, family medicine, complementary medicine, and the Cholesterol Research Center.

Other CRS Cores • The Sample Processing Core supports more than 200 clinical research protocols annually. Dedicated

laboratories are located at Parnassus, SFGH, Mission Bay, and Mount Zion Hospitals, comprising 1600 sq. ft. in total. Each facility is staffed with dedicated research laboratory technicians. Services available include routine sample processing, shipping of hazardous materials, PBMC isolation and viable cryopreservation of cells, and short-term sample storage.

• The Body Composition, Exercise Physiology and Energy Metabolism Core provides diverse services to support multiple principal investigators at the Parnassus campus. Exercise testing services include treadmill testing, cycle ergometry, 6-minute walk tests, gait-speed, and shuttle walk. Other services offered include muscle function testing, respiratory gas analysis, high resolution 3D optical whole body scanning, bioimpedance measures, and DXA scanning.

• The Neuropsychological Development Core carries out extensive neuropsychological evaluations of children with various medical conditions who participate in medical studies under the auspices of the CRS. The association between neuropsychological outcomes and imaging studies, as well as clinical phenotype, is an important component of the pediatric clinical research portfolio. Besides the direct neuropsychological assessment of children, this work has increasingly included participation in study design for upcoming projects and consultation about choice of goal-appropriate measures, test use, scoring, data collection in ongoing studies, as well as the publication of findings. When appropriate, services will be provided to investigators at other CRS units with neuro-developmental assessments.

• The Neonatal Clinical Research Center facilitates the research process through support of multidisciplinary investigators in the conduct of innovative clinical research in the UCSF Neonatal Intensive Care Unit (NICU), Pediatric Intensive Care Unit (PICU), and Pediatric Cardiac Intensive Care Units (PCIC). A Clinical Research Coordinator offers the following services: eligibility screening, coordination of procedure scheduling and follow-up with the families of participants.

UCSF CLINICAL RESEARCH EDUCATION AND CAREER DEVELOPMENT RESOUCES Training in Clinical Research (TICR) The TICR Program at UCSF was established in 1999 to provide high quality and comprehensive research training to investigators who are focused on human subjects and populations, defined as those participating in patient-oriented, translational, epidemiologic, behavioral, outcomes or health services research. TL1 Fellows and K Scholars interact with the TICR Program through one of 44 different graduate-level individual courses or by participating in one or more of four educational programs. These programs include: • Clinical Research Workshop (over 200 students 8-weeks each summer)

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• One-year Advanced Training in Clinical Research Certificate (ATCR) Program (25-30 students each year)

• Two-year Master’s Degree in Clinical Research program (25-30 students each year) The Master's Degree Program in Clinical Research is a two-year course of study intended for scholars who wish to master clinical research methods and pursue clinical research careers. The TICR Program is directed by Dr. Jeffrey Martin, Professor of Epidemiology and Biostatistics. It is administratively housed in the UCSF Department of Epidemiology and Biostatistics and supported by the UCSF Clinical and Translational Science Institute. The program is guided by policies from the UCSF Graduate Division, informed by an internal advisory committee, and accredited by the Western Association of Schools and Colleges. TL1 Training Program: see TL1 Application KL2 Career Development Program: see KL2 Application PhD in Epidemiology & Translational Science The PhD program in Epidemiology and Translational Science is a new degree track in the Department of Epidemiology and Biostatistics (DEB) at the UCSF School of Medicine, offered in collaboration with UCSF's renowned Clinical and Translational Sciences Institute. Doctoral students receive high caliber training in core skills of epidemiologic and biostatistical methods along with opportunities for practical experience to enhance classroom training. UCSF/UCB Joint Graduate Group in Bioengineering The close proximity of UCSF and UCB has fostered numerous collaborations among faculty members on the two campuses with regard to developing quantitative approaches to addressing fundamental problems in biological and clinical sciences. In the early 1980s, scientists who were heavily involved in these interactions on the two campuses proposed the formation of the UCSF/UCB Joint Graduate Group in Bioengineering (JGGB). This fully integrated educational program was approved in 1983 and is authorized to offer Ph.D. degrees that are conferred jointly by the Graduate Divisions of both campuses. Over the past twenty-three years, the JGGB has become one of the pre-eminent educational programs in the country and is well known for the diversity and excellence of the training it provides. Its objective is to teach doctoral students to bring the methods of modern engineering to bear on problems in biology and medicine, and to learn how to teach others to do the same. This combination of expertise is very much in demand in academia and in industry, and provides a wide range of employment opportunities to graduates of the JGGB. Of particular interest to students is the multi-disciplinary environment that is provided by the two campuses, which means that the breadth and depth of the training offered to students is of an order larger than a single department could provide. Faculty in the JGGB come from more than twenty departments in the professional schools at UCSF, six departments from the College of Engineering at UCB and several non-engineering departments. Hence, there is a wide array of research opportunities and state-of-the art facilities available to the students. Master of Translational Medicine (MTM) This multidisciplinary program focuses on technology and teaches the critical-thinking skills needed to navigate the challenges inherent in translating research from the laboratory bench to patient bedside. The course work, which is designed to complement this diversity, gives students the opportunity to address real-world problems, such as the critical need for expediting new therapies to treat devastating diseases, and it is anticipated that some of this work will lead to innovations with commercial potential. The master’s program spans an intensive 12-month curriculum with coursework that includes fundamentals of bioengineering, physiology, disease processes, core medical principles, clinical research methods, clinical trials design, and key concepts in business and management. The program culminates in a capstone design-project experience in which students work in interdisciplinary teams co-advised by an engineering faculty member and an MD, PharmD, or clinician. Projects cover various phases of the translational process, and often have the potential to continue beyond the scope of the master’s program. Biological and Medical Informatics Program (BMI) The development of the current BMI Program began in 1997 and led to the creation of tracks in basic biology and medical sciences. The focus for faculty in BTS will be the Biological Informatics (BI) component, which has its own training grant and recruitment process. There are 23 faculty members in this track from six departments whose mission is to train students from quantitative backgrounds in computer science, mathematics and statistics, whose interests are aimed at performing research at the interface of biology, computation and informatics. There are currently 29 students in the program, with expected incoming classes of 6-10 students per year. To enhance the range of training opportunities that are available to their students, the BI group has

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formed an alliance with faculty focused on Biophysics and Systems Biology to develop a core curriculum for training students in quantitative biology. The recent HHMI/NIBIB Interfaces Grant Program that was designed to sponsor graduate training programs in interdisciplinary research has funded curriculum development. This includes boot camps in biology, mathematics and computation, as well as team challenges that teach students to rely upon interdisciplinary collaboration to solve complex biological questions. Electives in algorithm design, objective oriented programming, statistical methods in bioinformatics and scientific software development ensure that the students get exposure to quantitative analysis methodology. A new Bioinformatics track in Quantitative Genetics/Genomics is under development in collaboration with the Institute for Human Genetics, and is expected to attract students with interests in statistical and population genetics and related areas. Biomedical Sciences Graduate Program (BMS) The UCSF BMS Program is an interdisciplinary graduate research program that seeks to equip students with the training and research tools to study the function of tissue and organ systems in development, physiology, and disease. The Program is based on training students for higher levels of biological systems integration by the incorporation of two features that were not part of traditional department-based graduate instruction in fields such as physiology, experimental pathology, and anatomy. First, students in the program must acquire a level of competence in molecular biology, biochemistry, and cell biology comparable to that expected of students in traditional biochemistry and molecular biology programs. Second, the study of key developmental, physiological, and pathological features of human biology is also incorporated into the curriculum. This new approach to training will result in a new generation of inter-disciplinary biomedical scientists who are able to forge collaborations that break down traditional research boundaries. Masters Of Science In Biomedical Imaging (MBI) This MS program in Biomedical Imaging enrolled its first entering class in the fall of 2011. The program is intended for advanced pre-doctoral students, postdoctoral fellows, medical residents, and faculty members who wish to utilize imaging sciences to broaden their investigative projects. Coursework includes instruction in core theory drawn from imaging physics, engineering, and mathematics, linked to physiology and disease processes. Hands-on laboratory courses are an important part of the curriculum with experiments relevant for characterizing pathologies, monitoring response to therapy, and assessing underlying disease processes. Specialized topics such as quantitative imaging, research design, image analysis, and technology assessment will be available through electives. Neuroscience Graduate Program UCSF offers an interdisciplinary program for graduate training in neuroscience. The purpose of this program is to train doctoral students for independent research and teaching in neuroscience. The UCSF Neuroscience program seeks to train students who will be expert in one particular approach to neuroscientific research and in its related basic science disciplines, but who will have a strong background in other areas of neuroscience as well. Pharmaceutical Sciences & Pharmacogenomics (PSPG) The graduate program leading to a PhD in PSPG is multidisciplinary. It has a dual focus on Pharmaceutical Sciences, which includes the scope of disciplines from chemistry to biology and from pharmacology to bioinformatics that are involved in the discovery and development of medications, and Pharmacogenomics, which covers the application of genetics and genomics to drug action and disposition. The 51 faculty members in the program come from both the School of Pharmacy and the School of Medicine. There are currently 51 graduate students in the program; of those who have selected research advisors, 24 are mentored in SOP laboratories and 19 are mentored in SOM laboratories. The program is based at Mission Bay but there are a significant number of faculty and students at Parnassus and at other UCSF locations. The PSPG program is partially funded by a NIH training grant. The graduates are highly sought after and upon completion of their thesis, 39% of the graduates go into academic positions or postdoctoral fellowships, 44% go into industry; the remainder goes into other health related occupations. Bioinformatics Sciences Graduate studies in Bioinformatics (BI) equip PhD students with the skills and knowledge in applied mathematics, informatics, statistics, computer science, physics, chemistry, and biology needed to study biological composition, structure, function, and evolution at the molecular, cellular, and systems levels. The goal of the BI pathway is to train the next generation of bioinformatics researchers for academia and industry by focusing on three research areas: bioinformatics and computational biology, genetics and genomics, and systems biology. Within the curriculum, core courses provide training in bioinformatics, algorithms, and

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statistics with optional courses in macromolecular structures, cellular biophysics, and computation of biological molecules. The BI pathway also offers two optional designated emphases in Computational Biology and Bioinformatics (CBBI) and Complex Biological Systems (CBS). Center for the Health Professions at UCSF Since 1992, the Center for the Health Professions at the University of California, San Francisco has offered solutions-driven approaches to the toughest health care challenges through three areas of focus:

• Leadership Programs to empower change agents at every level and within all sectors of the health care system

• Research to understand today's workforce issues and design actionable strategies to solve them. • Consulting Services to creatively and collaboratively address individual and organizational needs

The Center offers customized services in the areas of Leadership Development, Research, Assessment and Coaching and in 2014, the Center for the Health Professions designed and led a Leadership Program tailored to clinical and translational research trainees (See Appendix 5). This pilot program was successful and we plan to make improvements based on Scholar feedback and offer this in the next funding period. Office of Career and Professional Development (OCPD) The UCSF Office of Career and Professional Development (OCPD) and the UCSF Graduate Student Internships for Career Exploration (GSICE) program provide seminars, workshops, individual services and resources addressing a wide variety of training topics recognized as critical for the career advancement of graduate-level students and postdoctoral trainees in the biomedical, biological, social and health sciences. Breadth and Depth of Career and Professional Development Offerings: With a staff of more than 6.0 combined FTE specifically serving the career development needs of graduate student and postdocs in the biomedical sciences, UCSF is able to offer both depth and breadth in the area of career development training and support. The following topics are addressed: • Grant and fellowship writing skills • Oral presentation skills • Manuscript-writing skills • Mentoring skills and how to be mentored effectively • Career awareness for academic and non-academic career paths • Conflict management and negotiation skills • Classroom and small group teaching skills and practice • Ethics and the responsible conduct of research • Management and scientific leadership skills • Job search workshops for both academic and non-academic career options • Individual job search coaching for both academic and non-academic career options • Individual career counseling and guidance for trainees exploring non-academic career options • Support for UCSF’s unique internship program for graduate students, “GSICE” • Individual Development Plan training, using the “myIDP” web-based career planning tool, authored by OCPD

staff For each of the training topics listed, the OCPD provides didactic instruction, online self-help resources, and/or individual counseling or guidance. Program Formats: Some of the training topics listed above are offered through organized annual series, including: • “Job Hunting in Biotech” Series • “PFF-Preparing Future Faculty” Series (academic job search skills, academic career awareness) and the • “PSR-Professional Skills for Researchers” series (grant writing, manuscript writing, oral presentation,

mentoring, negotiation, communication skills). Depending on the audience and area being addressed, other training topics are offered as single seminars. Annually, the OCPD delivers 130-150 seminars and workshops. Utilization: At UCSF, participation in career development activities has become part of the campus training culture. Career development offerings are highly utilized and many seminars and workshops are over-subscribed. A 2008 survey of UCSF postdoctoral scholars (N=476; 48% response rate), showed that nearly

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80% of postdocs who had been at UCSF at least 3 years reported that they had voluntarily attended one or more OCPD seminars. Motivating INformed Decisions (MIND) Program MIND is an experimental career exploration program that provides training and resources to UCSF students and postdocs, as well as a resource for career exploration that can be utilized by trainees nationwide (MINDbank), and challenges the current perceptions of PhD training. The program will bring together UCSF students and postdocs, UCSF faculty, and professional partners who are applying their PhD in diverse fields outside tenure-track research, so that UCSF can meet the growing need to place exceptional trainees into positions where they will make exceptional impacts on society, both within and outside basic research. The program’s first cohort was recruited in 2014 and the grant program runs through until mid-2018. MIND participation is voluntary, and is open only to PhD students after they pass their qualifying exams, as well as postdocs during or after their 2nd year at UCSF. Graduate Student Internships for Career Exploration Program Founded in 2009, the Graduate Student Internships for Career Exploration (GSICE) Program at UC San Francisco (UCSF) addresses current gaps in graduate training by preparing doctoral students in the basic and biomedical sciences for careers outside of academia. There are four main components to the GSICE program • structured career path education • professional skills training • mentorship • hands-on experience (the actual internship) The program is designed to incorporate all of these components into a cohesive training experience that will prepare students to pursue the diversity of available science careers post-graduation. In support of this work, the Gordon and Betty Moore Foundation (GBMF) awarded GSICE with a $0.7 M dollar three-year non-renewable grant in February 2013. The goal of this grant is for GSICE to demonstrate a proof-of-concept, scalable model that will ensure future PhD scientists can pursue the multiple careers that will contribute to strengthening the workforce across all sectors of science. Here at UCSF, the GSICE program is now entering its seventh year. Since its inception, GSICE has trained over 150 students. About half of them matriculate to actual internships, so far hosted by more than 20 different internship sites. The program continues to be a thriving collaboration between the School of Medicine, the Office of Career and Professional Development, and the Graduate Division. The GSICE Executive Committee will be: • Keith Yamamoto, Vice Chancellor for Research; Executive Vice Dean, School of Medicine; Professor,

Cellular & Molecular Pharmacology • Terri O’Brien, Associate Dean for Research Strategy, School of Medicine; Assistant Vice Chancellor for

Research; Assistant Professor, Cellular & Molecular Pharmacology • Bill Lindstaedt, Director, Office of Career and Professional Development RELEVANT UCSF ADMINISTRATIVE RESOURCES Office for Innovation, Technology & Alliances (ITA) The UCSF ITA brings research and industry together to advance health science through innovation and entrepreneurship. Its services and programs are designed to 1) optimize the creation and management of innovative alliances with commercial, non-profit, and government funding and regulatory organizations; 2) aid in the transfer of UCSF technologies to commercial organizations for development and public benefit; and 3) help the creation of new companies focused on the commercialization of UCSF intellectual property. The ITA works in close coordination with the CTSI to support the commercialization of academic inventions. The individual programs within ITA include the Entrepreneurship Center, which provides courses and networking opportunities; Strategic Alliances, whose business development team catalyzes creation of innovative partnerships and drives the alliance development with team members from contracting and licensing, the scientists and the partner, and whose alliance management team provides continuing support of the partnership; the Industry Contracts Division, which is responsible for negotiating and signing all industry research contracts between UCSF and Industry Sponsors; and the Office of Technology Management, which has the mission of transferring and commercializing UCSF's life science and medical technologies for public use and benefit, while generating income to support campus research and education.

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• The Office of Technology Management (OTM) is an active partner in the technology development process and works to develop individualized out-licensing strategies from the moment a project enters the Hub, and coordinates partnering strategies with the Strategic Alliances team. This support, together with project management and tracking of each project, maximizes the likelihood of achieving stated development milestones and translation into highly valuable out-licensing opportunities. Once a technology has reached a commercially attractive stage in development, the OTM team works with the research team to market the invention to appropriate candidate partners. The OTM considers industry needs and market trends when developing licensing strategies, including whether exclusivity is needed to attract the investment required for commercialization, and if so, whether field-limited exclusivity might be appropriate. During license negotiations, whether with UCSF start-ups or with existing companies, the OTM works with industry partners to find mutually beneficial terms under which the technology can be most efficiently and effectively commercialized. For start- ups, this includes taking into consideration some of the start-up specific challenges that need to be addressed, such as funding status. To ensure that a promising technology is diligently developed and isn’t used solely for defensive purposes, the OTM includes diligence milestones in all of its exclusive licenses, while allowing for some flexibility for our licensees to address the uncertainties that come with taking life science inventions to market.

• The Entrepreneurship Center is a UCSF resource that supports entrepreneurial interests in life sciences and healthcare. The Center has built a cluster of resources to educate campus entrepreneurs about the elements required to commercialize an invention that are not technology-based. It accomplishes this through a suite of courses and workshops, networking events, speakers on topics of interest to entrepreneurs, a cadre of mentors and advisors and other resources. Program offerings are open to the entrepreneurial ecosystem in the Bay Area to encourage diversity, as well as to the UC Berkeley and Stanford communities. The Center is housed in the ITA for close coordination with the OTM.

• Bay Area NSF Innovation Corps (I-Corps™) is a collaboration between the University of California Berkeley, University of California San Francisco and Stanford University funded by the National Science Foundation. The goal of I-Corps is to increase the impact of NSF-funded research by setting up innovation ecosystems within universities that will train the next generation of entrepreneurs, encourage partnerships between academia and industry, and commercialize science and technology.

UCSF Research Development Office (RDO) The RDO’s mission is to promote, support, strengthen, and grow the research enterprise at UCSF. The RDO works through individual faculty members, teams of researchers, and various institutional administrators to nurture the institutional research enterprise: fostering innovative approaches and novel partnerships; and developing and implementing strategies that increase institutional competitiveness and attract research funding. • Resource Allocation Program (RAP): The RAP manages the dissemination, submission, review, and award

for these opportunities, while enabling the funding agencies to maintain full oversight of their funding mechanisms and awardees. The Resource Allocation Program (RAP) was created by CTSI and is now a campus-wide program that acts as a one-stop shop for intramural funding mechanisms. This program makes the application process for intramural research funding more efficient, increases accessibility to funding for a broad range of applicants, and minimizes the redundancy of the application and review process among different funding agencies. Currently, it coordinates a consortium of 18 funding sources and up to 30 different grant mechanisms.

• Limited Submission Program (LSP): The LSP manages the dissemination, solicitation and selection of proposals for limited submission funding opportunities. Limited submission opportunities (LSOs) are extramural funding opportunities that either limit the number of applications UCSF may put forward to a given sponsor or require another kind of internal coordination (e.g., to eliminate unnecessary duplication of instrument requests). LSP is responsible for notifying the campus of these opportunities, coordinating the internal review and selection process, and notifying all applicants of outcomes.

• Large Grant Development Program (LGDP): Project grants are, by necessity, complex in nature and may present obstacles during the proposal development stage that investigators are not used to encountering. The RDO assists investigators navigate through the rough waters of developing and preparing these proposals. The PhD-trained staff of the LGDP are with investigators every step of the way, from the initial scientific brainstorm sessions to the later stages of writing and editing. Specifically, the RDO offers: project management of the proposal development and preparation process, including timeline development and tracking, liaison with the funding agency or Research Management Services; access to a library of template language for grant proposals; technical writing and editing; strategy input

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• Team Science for Research innovation Program (TSRIP): RDO TSRIP fosters and facilitates scientific collaborations between internal and external research teams. TSRIP utilizes several different formats for team formation, including facilitated networking symposiums and workshops, ”speed-networking” events, “collaboratory meet-ups”. In addition, the TSRIP offers teaming consults to increase collaborative effectiveness, addressing topics such team diversity, conflict management, communication methods, and leadership.

UCSF Library The UCSF Library and Center for Knowledge Management is one of the preeminent health sciences libraries in the world, containing an extensive and exceptionally rich collection of monographic and periodical literature in the health sciences, with substantial holdings in the biological and physical sciences, the social sciences, psychiatry, and psychology. The collection contains over 844,214 volumes, 57,440 electronic full-text serials and 13,068 electronic health sciences serials. The library incorporates state of the art library computer systems, such as MyAccess that replaces the card catalog with a streamlined computer search system. The library also houses The Center for Instructional Technology, which offers a wide range of documentation and training on using the Collaborative Learning Environment (CLE). The CLE provides a versatile framework designed to meet the current and future needs for learner-centered environments, collaborative learning, and other collaborative activities at UCSF. Library materials not available on the San Francisco campus may be requested through other University of California campuses. Special collections contain both secondary and primary source material from the earliest medical history to contemporary projects in AIDS, tobacco control, biotechnology, and managed care. Historical materials are concentrated in the history of the health sciences, California medicine, anesthesia, Osleriana, medical artifacts, and East Asian medicine. All faculty and students have access to print and electronic resources regardless of UCSF departmental or programmatic affiliation. • Digital Library: GALEN is the Digital Library at UCSF. PubMed@UCSF is publicly available, but access to full

text articles is limited to computers on the UCSF network or to approved offsite computers. It provides access to the MEDLINE database as well as other NLM databases, and is strong in clinical and basic sciences, nursing, dentistry, and health care planning and administration from 1966 to the present. References published between 1958 and 1965 can be viewed through OLDMEDLINE. The MELVYL Catalog is used to locate books at all UC libraries, and California Periodicals to find journals/titles at other University of California, California State University, and California libraries. Many other important databases are available, including Current Contents, BIOSIS, and PsycINFO.

• Center for Knowledge Management: The Center for Knowledge Management is an innovative division of the library. Its multidisciplinary staff develops knowledge bases and on-line tools for the health sciences, pursues applied research projects related to UCSF informatics problems, serves as a laboratory for graduate students who are interested in using new technologies to solve important health sciences information problems, and supports the library's sophisticated computing and communications infrastructure.

• Interactive Learning Centers: The Interactive Learning Centers maintain student-computing facilities in the library and in the Medical Sciences Building, with PC and Macintosh computers, printers, software, documentation, consulting support, and connections to the Internet. Electronic classrooms are available at both locations for reservation by UCSF faculty members. The Multimedia Development Lab (MDL) provides hardware, software, and consulting support for development of curriculum-integrated, educational materials. Video digitizing, flat art scanning and slide scanning are among the capabilities available in the MDL. Education and Consulting Services offers curriculum-integrated instruction and scheduled seminars that assist students and faculty in the use of information management tools such as databases, the Internet, and personal file management software. Librarians consult with faculty and students topics of high interest.

INFORMATICS & COMPUTATIONAL RESOURCES Enterprise Information Management and Analytics (EIA) EIA’s charge is to advance UCSF’s ability to care, heal, teach and discover by providing ubiquitous access to relevant and high quality information and analytics. It performs this function by collaborating and partnering with clinical, research, education and business customers to organize, integrate and govern UCSF’s information assets. From these data assets it develops targeted data sets and analyses. EIA was charged with developing an enterprise and analytics technology platform and set of processes that could be used to coordinate efforts, whether they are performed by EIA or other UCSF teams who are performing similar functions in clinical care, finance, education or research. The platform incorporates a number of innovative

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technologies that work in concert to manage and govern UCSF’s data and information architecture. These are: (1) the InfoSphere Information Governance Catalogue; (2) a data management environment that consolidates operational data stores, data warehouse and data marts; and (3) research, education, and business driven dashboards.

Cogito Data Warehouse EIA has implemented the Clinical and Research Data Warehouse (CRDW) using Epic’s Cogito Data Warehouse, a star-schema data warehouse that is populated from Epic’s Clarity reporting data repository. The initial implementation of CRDW was completed in May 2014, making UCSF was one of the first 5 Epic customers to successfully implement the Cogito Data Warehouse. In addition, the EIA has influenced the 4 other UC Medical Centers (Davis, Irving, LA, San Diego; each with a CTSA Award) to join forces and collaborate to form a Big Cogito, a UC wide data warehouse, to consolidate data among UC medical campuses. This would make it among the largest clinical data warehouse in the US and has attracted the attention of the vendor, Epic to collaborate with us directly. While this project is in progress, implications would allow all the UC Campuses to share data, discover best practices, identify opportunities to work together, create populations with tremendous statistical power to support research and quality improvement. UC Los Angeles has selected and implemented the Cogito Data Warehouse, and UC Davia and UC San Digeo are currently pursuing Cogito Data Warehouse as their clinical data warehouse. As part of implementation, EIM thoroughly profiled and assessed quality and completeness of the data in the CRDW and worked with Epic to resolve issues. The team also updated the CRDW’s metadata repository to provide UCSF-specific business and technical definitions for data in the CRDW along with data lineage back to Epic’s Clarity and Chronicles data database. These data have been loaded into the InfoSphere Data Governance Catalogue.

Analytic Dashboards and Data Governance EIA’s technology platform and processes facilitated the ease in development of analytic dashboards for information delivery. An iterative dashboard development process was created that spans the request intake and prioritization, requirements elicitation, data management and governance, development, testing and implementation. EIA trained other departments’ staff on the QlikView dashboarding tool and the iterative dashboard development process so that all dashboards, whether developed by EIA or other departments, follow the same development process and have the same dashboard architecture design patterns. To date, 12 dashboards have been developed of which 7 were created by EIA and 5 were created by other departments. These dashboards contain over 750 metrics.

Academic Research Systems (ARS) ARS is the arm of EIA that serves the needs of the UCSF research community by facilitating access to the CRDW of clinical and life sciences data and by providing a centralized, secure, professionally managed infrastructure for the storage and management of research data. ARS provides the following services. • Research Data Browser To support UCSF’s research mission, EIA/ARS developed the Research Data Browser (RDB), a self-service front end that allows researchers to characterize patient populations of interest. The RBD uses the information in the CRDW to enable researchers to analyze the entire UCSF patient populations by over 50 data dimensions, such as age, gender, diagnosis and procedure. The RDB permits researchers to have easy access and analysis of de-identified patient data without IRB approval. Researchers are able to quickly and efficiently identify and understand populations and sub-populations. The tool enables nimble, well-informed responses to grant opportunities making UCSF better able to compete. Once an IRB approval is obtained, the Program has the ability to automatically re-identify the patient cohort selected.

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• MyResearch. When research data and analyses require added security, UCSF's Secure MyResearch environment is available for use. This HIPAA compliant desktop environment is hosted on servers housed at the UCSF Data Center on Minnesota Street. The MyResearch environment is hosted on six Dell PowerEdge R710s and Five EqualLogic PS6100E SAN, which are located inside the locked rack. There are two layers of physical redundant Cisco firewalls that protect the servers and SAN. The MyResearch environment utilizes VM Ware View Virtual Desktop, which must be logged into using UCSF Active Directory credentials. The servers are locked inside a rack locked with a combination lock which is located in a data center secured by two sets of locked doors. Data sets can be stored in the Principal Investigator's group network folder in the remote MyResearch environment where only the research team members are able to view the data sets and this access is audited. This folder is physically located in a data store on the SAN in the locked rack. Network traffic between MyResearch and the UCSF campus network traverses a SSL VPN tunnel in encrypted format. Analysis tools are hosted in the environment contiguous to data storage

• Clinical Data Research Consultations (including the Honest Broker service) • Research Electronic Data Capture (REDCap) • University of California Research eXchange consulting and facilitation of use UCSF Information Technology Services (ITS) The ITS provides a campus-wide high-speed network infrastructure, which allows investigators to access a wide variety of computing technologies. Because the UCSF campus is geographically diverse, ITS uses a high speed SONNET Ring backbone infrastructure to allow virtually instantaneous access to campus computing resources from any campus location, including a number of clinical facilities affiliated with UCSF. The computing capabilities of the campus are constantly growing and expanding. Computing resources are conveniently located throughout the campus. All investigators and research staff have a high-speed desktop personal computer connected to the UCSF ITS backbone and the Internet. The Information Services Unit (ISU) technical support staff offer a full range of computing and network-based services, including a private, secure wired network, along with a wireless network that contains secure internal and visitor zones, a server room with fire suppression that meets all security and safety requirements, and a disaster-recovery failover site for critical functions co-located in a separate building one mile away. ISU provides standardization of hardware/software and centralization of services for the user. Utilizing a server-based support model, users store files in a central location and can access them from any remote computer that has Internet access. This model offers some additional benefits, such as heightened security, a longer useful life for end user hardware, streamlined labor for ISU support staff, and the availability of many applications running from a central server. An overview of the services provided by ISU support staff is listed below: • Email: maintenance of email servers and administration of email accounts • Nightly workstation and server backups, offsite tape storage, failover site for mission critical servers • Maintenance of remote access servers, Terminal Server accounts, and network storage space • Centralized management of software licensing agreements • Maintenance of network printers and print servers • Full hardware/software support for workstations and laptops • Support of private wired and wireless networks • Server/infrastructure support for housed database systems and websites • Operation of recharge for cost distribution • Support for fiber uplink to internet • Infrastructure support for HIPAA compliance All research data reside in Microsoft SQL 2005 Server databases and are backed up daily. There is an on-site, self-managed electronic mail/group collaboration system (Microsoft Exchange) that is used extensively for memos, document transfer, and outside communications with project collaborators via email on the Internet, as well as three private web servers, an automated forms-processing system and a computerized voice-mail system. All servers are physically housed within a restricted-access server room within a restricted-access computer support suite. All systems (i.e. network and servers) are monitored 24 hours a day, seven days a week. The LAN features a 100 MB uplink to the Internet. All servers and workstations run Sophos Antivirus software that is automatically updated from the vendor site via the Internet. Hosted based and hardware

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firewalls with Intrusion Detections Systems within the datacenter further protect the system from intrusion. Software supported: • Operating systems: Windows XP • Word processing: Microsoft Word • Internet browsers: Internet Explorer and Mozilla • Email: Microsoft Outlook and Webmail • Accounting: Excel • Survey Design: Adobe Framemaker, Microsoft Word • Statistical: SAS, Stata, SPSS • Web Design and Graphics: Macromedia Dreamweaver, Adobe Photoshop CS3, Microsoft Publisher • Data Management: CSPro, EpiInfo, Mindware, Microsoft Excel, Microsoft Access • Dietary Collection and Analysis: Nutrition Data System for Research (NDSR) • Security/secure shell: Internet Connection Firewall, Sophos Antivirus, Hosted based and hardware firewalls

with Intrusion Detections Systems • Miscellaneous: Adobe Acrobat 7.0, Endnote, Microsoft PowerPoint Computer Resources Laboratory—Interactive Learning Center (ILC) Located in the UCSF Library, the ILC provides computer services (70 desktop computers, slide-makers, scanners, and color and laser printers) and UCSF intranet and internet access for UCSF students and faculty in all four schools. In addition, it maintains a small facility that allows 24-hour student access to laptop network ports and five computer workstations. In addition, the ILC holds classes throughout the year on such topics as statistical software (SPSS, SAS), reference software (EndNote), Galen, Melvyl/MedLine, Internet, and Netscape Communicator, which are available to all grant staff. High Performance Computing At the University of California, San Francisco (UCSF), we currently maintain a high performance computing (HPC) cluster to support the research of a range of quantitative/computational investigators. This cluster is associated with the California Institute for Quantitative Biosciences (QB3) and is located in Byers Hall at the Mission Bay campus. This cluster has been in operation since 2005, and is periodically upgraded with additional nodes; the last major upgrade was 2 years ago when 1152 cores were added to the system. The cluster operates on a co-op basis, whereby individual investigators provide funds for the addition of new hardware, maintenance, and system administration; the access to the cluster is then proportional to the amount of funds invested. The cluster currently has 4,678 cores of a variety of types (most are dual-processor 4- or 6-core Xeon64 machines, each with at least 2 GB RAM per core and a 120 GB hard disk), primarily backed by 36 TB of fast network array storage. The cluster supports approximately 30 research groups, primarily in the areas of structural biology, systems biology and biomedical imaging. At the same time, UCSF has a large group of genetics researchers who are now benefiting from recent developments in human genomics, in particular the ability to produce vast amounts of human DNA sequence data at continuously lower prices. This has created a serious challenge for these researchers because the computing demand greatly exceeds the capabilities of the QB3 cluster, especially in terms of rapid and long term storage. To support this need, the UCSF Institute for Human Genetics invested internal funds in a new HPC cluster installed at the UCSF Data Facility located at Minnesota Street, near the Mission Bay campus. In addition, the university established a high-speed (10Gbit) link between the Genomics Core Facility at the Parnassus Campus, which maintains several Illumina HiSeq 2500 and other DNA sequencers, and the IHG computing cluster at Minnesota Street to facilitate rapid data transfer and analysis. This pipeline was created to support a variety of high throughput next generation sequencing projects. This system currently has 52/864 nodes/CPUs and 52TB of fast storage and 300TB of archival storage to support the genomic applications. Moreover, as part of a general platform supporting the advancement of Precision Medicine, UCSF has recently established an Institute for Computational Health Sciences (ICHS; see below), whose mission is to create a world class environment for health science researchers, including the further development of high performance computing infrastructure and recruitment of additional computational faculty. VIDEOCONFERENCES AND CLASSROOM COMPUTING UCSF is committed to providing students with technology that will enhance their education and learning. The division of Student Academic Affairs (SAA) continues to update the classrooms and large lecture halls with state of the art videoconference resources, computers, large color monitors, Internet connection through the

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campus backbone and fiber optic network, and high technology equipment to be able to tap the educational promise of electronic communication via the Internet. Grand rounds, seminars, and satellite downlinks can be received at the Parnassus site and broadcast via microwave transmission or intranet links to any of the campus classrooms at the Parnassus site as well as Mission Bay, Mount Zion, and SFGH campus sites. Additionally, faculty members are able to connect their laptops to the backbone and download information from the Internet, the UCSF intranet, and/or to display instructional material via video projectors in the classrooms and lecture halls. UCSF CORE RESEARCH FACILITIES There are 79 core research facilities (CRFs) across UCSF and its affiliates that offer a wide variety of services such as genomics, proteomics, flow cytometry, microscopy, drug development, imaging, drug studies (with CLIA and GCLP compliant facilities), preclinical and clinical therapeutics, and comprehensive specimen banking and repositories. In addition, there are a number of cores that offer even more specialized services such as drug-resistant genotyping of HIV, in-situ biomechanical testing of orthopedic implants, and generation of tumor-bearing animals for preclinical oncology trials. Users have easy access to the CRFs via web-based research cores search tool managed by the Research Resource Program (RRP), including an updated database with summaries of services, equipment, and contact information. The UCSF Cores Search website (currently supporting 867 resources, 246 categories, and 83 providers) is designed to help researchers easily find shared research resources at UCSF. This site was developed by UCSF's Research Resource Program (RRP) and Clinical and Translational Science Institute (CTSI) and is powered by the open source Plumage interface to eagle-i. Plumage was developed by CTSI at UCSF, and builds on the eagle-i research resource ontology developed by the eagle-i Consortium, also supported by NIH. MyCORES RRP also offers MyCORES, a web-based management system that facilitates the purchase of products and services from the University's core facilities and shared resources. This software is a system developed Vanderbilt University called Core Ordering and Reporting Enterprise SystemTM (CORES™). RELEVANT CROSSCUTTING RESEARCH INSTITUTES AND CENTERS These multidisciplinary units are organized around specific themes and have faculty members from multiple departments. They provide substantial resources to the biomedical research community and receive funding from the NIH, NSF, state, private foundations and industrial partnerships, as well as acting as a focus for philanthropy. California Institute for Quantitative Biosciences (QB3) The QB3 Institute was created by Governor Gray Davis as one of the four California Institutes of Science and Innovation. Spanning UCSF, UC Berkeley and UC Santa Cruz, it promotes basic research in quantitative biosciences and works to ensure that new discoveries are commercialized as quickly as possible. QB3 has grown to include over 220 research groups with 40 members of the National Academies and two Nobel laureates. It has helped to launch 65 companies and has formed three major industry partnerships. The QB3 incubator network began in 2006 and has grown dramatically to include three campus sites and two private partners, with 51 companies currently renting space. Companies in the network have created more than 280 jobs and raised over $230 million in venture financing. The QB3 building at the Mission Bay campus has 96,000 sq. ft. of space on five floors designed to house multi-department and multi-disciplinary laboratories, lecture halls, and shared scientific resources. It also includes the Surbeck Lab for Advanced Imaging, of which Dr. Nelson is the Director. Other critical technology resources are the QB3 Cluster (described below), the Nikon Imaging Center, the Biomedical Micro-and Nanotechnology Fabrication Laboratory, and the Center for Advanced Technology. Institute For Computational Health Sciences The UCSF Institute for Computational Health Sciences (ICHS) was created by the Chancellor in 2012 to develop and enhance UCSF’s computational efforts and strategies in basic, translational, clinical and population-based biomedical research. It will be a campus hub for computer scientists and for researchers who employ computation as a primary tool in their biomedical research and will serve as a cornerstone of the university’s efforts to harness the power of “big data,” to lead to faster and more effective cures for patients worldwide. ICHS is a critical component of a global UCSF initiative in Precision Medicine, which seeks to aggregate and integrate vast, disparate datasets to advance understanding of biological processes, determine

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mechanisms of disease, and inform diagnosis and treatment of patients. UCSF recruited a world-renowned expert in medical technology, Atul Butte, MD, PhD, to lead the ICHS. A noted expert in pediatrics and medical informatics, most recently from Stanford University, Butte brings the rare combination of deep knowledge in medicine and biomedical research, and technological fluency to lead in the new realm of computational health. Butte's research laboratory builds and applies tools that convert more than 400 trillion points of molecular, clinical, and epidemiological data – measured by researchers and clinicians over the past decade and now colloquially known as “big data” – into diagnostics, therapeutics, and new insights into disease. In addition to his own computational biomedical research, as the Director of the ICHS, he will coalesce the computational faculty already dispersed among our four top-ranked professional schools (Dentistry, Medicine, Nursing, and Pharmacy) and Graduate Division, superb research programs and outstanding Medical Center, establish a central convening center around biomedical research, computational science and bioinformatics, hire additional faculty, and build programs for research and education that will include substantive training in bioinformatics and computational science. Dr. Butte co-directs the Informatics and Research Innovation part of the CTSI. Institute for Human Genetics (IHG) The Institute for Human Genetics (IHG) is the central hub for human genetics research, education, and practice at UCSF. Initiated in 2006, the Institute has grown considerably over the past 7 years through active recruitment, whereby 29 new faculty members have joined the IHG. The major aim of the IHG is to create an exciting, productive, and collaborative environment for research, training, and clinical application in human genetics. The IHG also provides institutional support and resources, such as the Genomics Core Facilities, which have a large variety of state of the art technology platforms and support services for cost effective, flexible solutions for genomics projects of any size, ranging from full-service, large-scale projects to equipment only support. The UCSF Genomics Core is made up of several satellites located across the UCSF campuses. The current membership includes 72 active researchers, educators, and practitioners. Most of these individuals use the latest in genomics technology in their research, and quite a few are highly computational in their research. With the advent of high throughput sequencing based methods, such as next generation approaches to whole genome and whole exome sequencing, along with RNA-seq and ChIP-Seq applications, and continuously dropping prices, the demand for access to these technologies by our faculty has dramatically increased over the past several years. As a consequence, the IHG and the EVCP’s office have made several important investments to advance genomics research. Specifically, the IHG has acquired and upgraded two Illumina HiSeq 2500 systems. Helen Diller Family Comprehensive Cancer Center (HDFCCC) The original facility at Mt. Zion is an NCI-designated matrix center, conducting a wide range of inter-disciplinary research in the areas of laboratory, clinical, and population sciences. The HDFCCC integrates activities of more than 250 members working at four major campus and hospital locations (Parnassus, Mt. Zion, SF General Hospital, VA Hospital). The HDFCCC has placed a major emphasis on the integration of programs that include new therapeutic approaches, new ways of detecting cancers and classifying them by molecular markers, population studies that identify risk factors for the disease, and strong basic efforts to increase the understanding of cancer at the molecular level. The HDFCCC also provides support for several core facilities that are used extensively by faculty at UCSF and are available for use by trainees (http://cancer.ucsf.edu/cores/index.php). These include a state-of-the-art Mass Spectroscopy Core, an Array and Genome Analysis Core, a Cell Analysis Core for quantitative PCR and flow cytometry, a Transgenic Mutagenesis core for engineering mutations into the mouse germline, Mouse and Molecular Pathology Cores for analysis of mouse and human tissues and a Pre-Clinical Core for carrying out preclinical oncology trials. Gladstone Institutes The J. David Gladstone Institutes of Neurological Disease (GIND) brings together nine independent laboratories in a highly interactive environment that is squarely focused on unraveling disease mechanisms underlying major neurological disorders and on discovering novel therapeutic strategies for these conditions. Since its inauguration in 1998, the GIND has been directed by Dr. Lennart Mucke, who also is an Associate Director of the ADRC. Supported by outstanding core facilities, most investigators in this institute study processes that result in neurodegeneration and cognitive impairments, with particular emphasis on the pathogenesis of AD, FTD, and dementia with Lewy bodies (DLB). In this research program, potential etiologic factors and pathways are dissected at the molecular, cellular, network, and behavioral level in transgenic mouse models and neural cultures. The relevance of results obtained in experimental models is assessed by

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comparative analyses of human postmortem tissues and clinical specimens. Animal models are also used to examine the efficacy and safety of novel treatment strategies at the preclinical level. The ADRC has enabled several GIND investigators to validate and follow up on their experimental discoveries in human subjects and clinical investigations. Based in good part on the pioneering efforts of Nobel laureate Shinya Yamanaka, who holds joint appointments at GIND, UCSF and Kyoto University, GIND has become a leading force in the application of stem cell technology in neuroscience and other areas of biomedical research, an exciting development that is reflected in Dr. Huang’s new ADRC project. In projects supported fully or partially by the ADRC, they identified novel compounds as well as already FDA-approved drugs that we are looking forward to testing in clinical trials for AD or FTD in the near future. The GIND has an endowment that provides funds for pilot projects, major equipment, facility upgrades, and a proportion of administrative/operational services. The GIND has been ranked, seven times in a row, one of the top 10 best places to work in academia and among the top 10 best institutions for postdoctoral training in North America by The Scientist magazine, which reflects the exceptional quality of its research environment and training program. UCSF/Kaiser Center for Transdisciplinary ELSI Research in Translational Genomics (CT2G) CT2G is UCSF’s NHGRI-funded "Center of Excellence” in ELSI Research (CEER). UCSF CTSI Co-investigator, Dr. Barbara Koenig, is the co-director of the center. CT2G is committed to building a network of social scientists, basic scientists, clinicians, bioethicists, and legal scholars to foster interdisciplinary research on the ethical, legal, social, and policy implications of emerging genomic technologies. Based on the core themes of translation and transdisciplinarity, the center is a collaborative effort among UCSF, Kaiser Permanente, and UC Hastings College of Law. The Center provides core infrastructure for a range of funded empirical bioethics research projects, focused on topics such as non-invasive prenatal genetic testing, using genetic markers to guide prevention and early detection efforts to reduce the burden of breast cancer, newborn screening policy and practice, and issues raised by the use of next generation sequencing technologies, such as the management of incidental genetic findings. Since its inception in 2013, CT2G has developed active research working groups focused on ELSI issues, including, 1) the changing research/care boundary which challenges established practices in human research protection, 2) the use of race categories in structuring research and providing clinical care, and 3) best practices in community engagement and governance, including a focus on community engagements based on deliberative democracy theories. CT2G’s relationship with Kaiser Permanente encourages interaction among experts in the fields of genomics, health policy, and epidemiology, and allows for consideration of the perspective of an integrated health care system’s approaches to translating genomics into the clinic. The collaboration also offers links to Kaiser Permanete’s biorepository known as the “Research Program on Genes, Environment, and Health,” which is home to over 200,000 patient biospecimens linked to electronic medical record data. The CT2G explores issues of governance that arise from research biorepositories and clinical collections of biospecimens. The primary purpose of CT2G is to create intellectual community and support collaborative research. CT2G includes seminars and symposia focused on specific topics in the translation of genomic findings into clinical practice and educational programs for clinical fellows and post doctoral trainees. CT2G provides the intellectual home for “responsible conduct of research” activities at UCSF, with CTSI’s education program providing infrastructure support. In addition to CT2G’s funding as an NHGRI P20 center, infrastructure support for cross-UCSF bioethics activities comes from the office of the UCSF executive vice chancellor and provost. UCSF CLINICAL LABORATORIES The Clinical Laboratories are directed by faculty of the UCSF Department of Laboratory Medicine and are affiliated with the San Francisco General Hospital Clinical Laboratories, the San Francisco Veterans Administration Medical Center Laboratories and the Blood Centers Research Institute (BSRI). The various laboratories, along with the Departmental research faculty, are constantly involved in the evaluation of new testing technologies as well as the development of industry partnerships to bring new testing methods into clinical use. Examples include: the Center for Accelerated Innovation (CAI) work to develop next-generation sequencing (NGS) in the diagnosis of pneumonia, the TickChip assay for Lyme disease diagnosis, and software analysis for the evaluation of NGS data in pathogen detection; BSRI is actively engaged with industry partners to implement new pathogen reduction methods in blood component and to develop novel cellular therapeutics; Dr. Alan Wu (SFGH) is involved in evaluating Point-of-Care devices for Troponin and CD4/CD8 counts as well as high resolution mass spectrometry for forensic toxicology. Therefore the Dept. of Laboratory

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Medicine faculty, the UCSF Clinical laboratories and the affiliated laboratories that we direct provide a robust environment for test evaluation, translational development and industry partnerships. Blood Systems Research Institute (BSRI) The Blood Systems Research Institute (BSRI) is a UCSF CTSI-affiliated research institute embedded within Blood Centers of the Pacific and Blood System, Inc., the blood banking/transfusion medicine organization that serves UCSF and much of the western and Southern US. In addition to sophisticated research facilities, BSRI’s unique placement and organizational structure facilitate extensive collaborations between academia and industry. While the bulk of BSRI funding is from traditional government sources (NIH, DoD), funded product development projects include partnerships with Novartis Diagnostics (recently acquired by Grifols) and TerumoBCT. These translational projects aim to improve blood bank diagnostics and develop and implement new pathogen reduction methods for traditional blood components and novel cellular therapies. One of the unique skill sets that BSRI brings is in regulatory interactions with the FDA, and this expertise is shared with UCSF collaborators in advancing novel therapies through the FDA testing and approval process.

UCSF LABORATORY ANIMAL RESOURCE CENTER All animal research is monitored by the UCSF Laboratory Animal Resource Center (LARC), which occupies extensive facilities, and is staffed by full time veterinarians. UCSF animal imaging facilities have access to physiological monitors, equipment for intubation and respiratory support, anesthesia, and surgical equipment. Digital autoradiography (Molecular Dynamics Phosphor Imager), a dedicated scintillation camera for animal research, radioisotope well-counters, and cryogenic autoradiography are available. The China Basin Facility animal research suite is designed to accommodate small animal research. It includes a procedure room, adjacent preparation and recovery space, holding areas with self-contained cage storage, non-recirculating air, and 24/7 ventilation and heating.

The LARC maintains animal facilities at all UCSF sub-campuses. The use of a common administrative structure and guidelines enables research animals to be freely transferred between all facilities. The LARC's mission is to (1) provide quality care for all animals used at UCSF, (2) assist the faculty in their mission of quality research with respect to the use of laboratory animals, (3) act as a resource center for the faculty on all issues relating to laboratory animals, and (4) assist the University to meet its goal of humane treatment of laboratory animals. The LARC achieves these goals through a staff of trained husbandry technicians responsible for the everyday care, health monitoring, and sanitation of the UCSF animal facilities; rodent veterinary nurses responsible for monitoring rodent health, and attending to any rodent health conditions that are in need of attention; and veterinarians who provide clinical services and support for the UCSF research animals. Veterinarians are also responsible to ensure the humane use and care of all animals.

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Part A Administration Abstract The key objectives of CTSI’s Administration, Governance, and Program Evaluation (Part A) are to oversee and coordinate clinical and translational research activities at the 5 hospitals comprising the University of California, San Francisco (UCSF), the Graduate Division, the 7 major interdisciplinary centers, and 8 organized research units. Part A also describes CTSI services and shared governance, strategic planning and resource allocation with its regional partners, including the San Francisco VA Medical Center, San Francisco Health Network (San Francisco General Hospital (SFGH), Laguna Honda Rehabilitation Hospital, and San Francisco Department of Public Health Community Clinics), SF Health Improvement Partnership (SFHIP), SF Bay Collaborative Research Network, Kaiser Permanente Division of Research of Northern California (Kaiser), and UC Berkeley. The administrative structure is collaborative, transparent, and responsive. As co-founders of the UC Biomedical Research Acceleration, Innovation and Development (UC BRAID) initiative, UCSF continues to play a leading role in its activities at the 5 UC medical centers (Davis, Irvine, Los Angeles, San Diego and San Francisco), each of which is home to a CTSA award. CTSI was also an initial member of the National Center for Acceleration of Translational Science (NCATS) Advancing Clinical Trials (ACT) consortium. CTSI proposes: Administrative Aim 1. To provide organization, governance, and leadership that support CTSI programs and the collaborations between its regional and national partners. CTSI will maintain an effective, flexible structure that is transparent and responsive to input from stakeholders, takes advantage of external opportunities, meets internal needs, and provides efficient, high-quality services and training; Administrative Aim 2. To enhance collaboration and communication among UCSF faculty and trainees, as well as CTSI’s partners in the San Francisco Bay Area, UC-wide, and across the CTSA consortium. In particular, CTSI will use its university-wide networking platform, UCSF Profiles, to enhance collaboration, and the idea forum, Open Proposals, to ensure transparency and community input; and Administrative Aim 3. To support program development and perform efficient tracking and evaluation by providing timely and effective planning and feedback, with a focus on continuous quality improvement. CTSI will continue to use balanced scorecards and twice-yearly formal reviews, in addition to frequent consultations with programs and institutional leadership. These process improvement techniques and innovative evaluation methods will continue to inform capacity planning, resource allocation, accountability, and efficacy as CTSI aligns programs with NCATS’ system-wide evaluation metrics.

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SPECIFIC AIMS The University of California, San Francisco (UCSF) consists of 5 hospitals (Moffitt-Long; Mt. Zion; Betty Irene Moore Women’s Hospital; Benioff Children’s Hospital San Francisco; Benioff Children’s Hospital Oakland), 4 professional schools (Dentistry; Medicine; Nursing; Pharmacy), the Graduate Division, 7 major interdisciplinary centers, and 8 organized research units. Regional partners of the Clinical and Translational Science Institute (CTSI) at UCSF include the San Francisco VA Medical Center, San Francisco Health Network (San Francisco General Hospital (SFGH), Laguna Honda Rehabilitation Hospital, and San Francisco Department of Public Health Community Clinics), SF Health Improvement Partnership (SFHIP), SF Bay Collaborative Research Network, Kaiser Permanente Division of Research of Northern California (Kaiser), and UC Berkeley. These stakeholders share in CTSI services and participate in governance, strategic planning and resource allocation, resulting in an administrative structure that is collaborative, transparent, and responsive. Former CTSI PI (S. Claiborne Johnston, MD) was founding Chair of the Executive Committee of the UC Biomedical Research Acceleration, Innovation and Development (UC BRAID) initiative, and UCSF continues to play a leading role in its activities at the 5 UC medical centers (Davis, Irvine, Los Angeles, San Diego and San Francisco), each of which is home to a CTSA award. CTSI was also an initial member of the National Center for Acceleration of Translational Science (NCATS) Advancing Clinical Trials (ACT) consortium. CTSI was established in 2006 with the goal of transforming clinical and translational research at UCSF and our partner institutions. Our overall mission has been to accelerate the pace of translational research to improve health. Since its inception, CTSI has evolved to provide the increasingly complex infrastructure, services, and training required to develop and implement cutting edge research in collaboration with academic centers, community and industry partners. CTSI coordinates with multiple UCSF campus offices and programs to reduce redundancies and optimize efficiencies. Integration of CTSI’s mission was recently enhanced by the 2015 appointment of Daniel Lowenstein, MD, former Associate Director of CTSI, as UCSF Executive Vice Chancellor and Provost. We work continuously to transform and improve our efficacy and productivity. Annually, each CTSI program develops goals, initiatives, and metrics using balanced scorecard software, a measurement-based strategic management system with dashboards and budgets tied to each initiative. The Program Evaluation Team tracks progress against these scorecards, and 2 formal reviews are conducted each year to assess progress and set/re-set directions. Lean Six Sigma approaches are used to evaluate and improve research processes. CTSI’s communications team coordinates across CTSI programs and the campus to ensure accurate and timely flow of information throughout the organization, to our partners, and to the public. To ensure that CTSI continues to optimally facilitate clinical and translational research at UCSF and in collaboration with our regional and national partners, we propose the following Administrative Aims: Administrative Aim 1. To provide organization, governance, and leadership that support CTSI programs and the collaborations between our regional and national partners. We will maintain an effective, flexible enterprise that is transparent and responsive to input from stakeholders, takes advantage of external opportunities, meets internal needs, and provides efficient, high-quality services, infrastructure, and training. Administrative Aim 2. To enhance collaboration and communication among UCSF faculty and trainees, as well as our partners in the San Francisco Bay Area, UC-wide, and across the CTSA consortium. In particular, we will use our university-wide networking platform, UCSF Profiles, to enhance collaboration, and our idea forum, Open Proposals, to ensure transparency and community input. Administrative Aim 3. To support program development and perform efficient tracking and evaluation by providing timely and effective planning and feedback, with a focus on continuous quality improvement. We will continue to use balanced scorecards and twice-yearly formal reviews, in addition to frequent consultations with programs and institutional leadership. Our process improvement techniques and innovative evaluation methods will continue to inform capacity planning, resource allocation, accountability, and efficacy as we align programs with NCATS’ system-wide evaluation metrics. Administrative Aim 4. To ensure that clinical research conducted at UCSF is high quality, ethical, feasible and efficient.

Part A. Administration, Governance, and Program Evaluation

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RESEARCH STRATEGY A. Administrative Aim 1: Organization, Governance and Leadership A.1. UCSF CTSI Organization and Governance A.1.a. CTSI Organization CTSI includes broad representation from across UCSF’s schools and major centers that integrates seamlessly with UCSF leadership, and optimizes the efficacy of external partnerships in support of translational science. CTSI reports to Executive Vice Chancellor and Provost (EVCP), Daniel Lowenstein, MD, who reports directly to Chancellor Samuel Hawgood, MBBS. CTSI Director is Associate Vice Chancellor for Clinical and Translational Research, Jennifer Grandis, MD; Co-Director is Deborah Grady, MD, Associate Dean for Clinical and Translational Research, (Figure: Organizational Chart). CTSI is overseen by an Internal Advisory Board (IAB) and an External Advisory Board (EAB). The IAB includes the EVCP, Deans of the 4 professional schools and the Graduate Division, Chief Medical Officer of the UCSF Medical Center, Chairs of the Departments of Pediatrics and Geriatrics, and CEO of the Comprehensive Cancer Center. The EAB is comprised of both standing and ad hoc members. Standing members include leaders of other CTSAs, directors of community health foundations, industry leaders, community representatives, and venture capitalists. Directors of CTSI programs and senior staff, representing a broad array of disciplines and expertise, comprise CTSI’s Senior Leadership Group (SLG), which reports to the Director and Co-Director. The Operations Committee, consisting of the Director, Co-Director, Chief Information Officer, Chief Administrative Officer, and the leaders of the 3 largest programs meets weekly to address CTSI-related issues as they arise. In the next funding period, CTSI will consist of 8 integrated programs that include 2 optional functions and 2 cross-cutting initiatives. The optional functions are Product Development, an initiative of the Catalyst program, and Precision Medicine. Our cross-cutting initiatives are the Special Populations Initiative and Multidisciplinary Team Science (Table: Core and Optional CTSI Functions).

Core and Optional CTSI Functions‡ Informatics and Research Innovation (IRI) Director: Mark Pletcher, MD MAS Co-Director: Atul Butte, MD PhD Co-Director: Ida Sim, MD PhD

IRI will be charged with building efficient, innovative research infrastructure and services focused on electronic and digital approaches to research, and will be home to our Precision Medicine optional function (Parts B, H.2)

Community Engagement (CE) Co-Director: Kevin Grumbach, MD Co-Director: Laura Schmidt, PhD

CE leads CTSI’s community-based research and health improvement initiatives, our policy initiatives, and will be home to our cross-cutting Special Populations initiative (Parts F.1, C.2)

Workforce Development: CTSI Training (CTST) Director: Kirsten Bibbins-Domingo, MD PhD Associate Directors: o Joel Palefsky, MD (TL1 Director) o Douglas Bauer, MD (KL2 Director) o Jeffrey Martin, MD MPH (TICR Director)

CTST includes Training in Clinical Research (TICR - 44 courses, Summer Workshop, 1-year Certificate, 2-year Master’s) and 4 level-specific training programs: Pre-health Undergraduate; TL1 for pre-doctoral, professional, and post-doctoral trainees; Residency Research Training Program, KL2 Faculty Mentored Career Development program (Overall Aim 4; Part D.1; and TL1 and KL2 proposals). Home to our Multidisciplinary Team Science Initiative (Part D.1)

Consultation Service (CS) Director: Alka Kanaya, MD MAS

CS provides access to expert advice in biostatistics, ethics and research design (BERD), as well as expertise in Data Access and Management, Participant Recruitment, and Mentoring (Part E.1)

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Regulatory Knowledge and Support (RKS) Director: Christopher Ryan, PhD

RKS focuses on streamlining, educating, and developing innovative processes for IRB approvals (including reliance and central IRBs), conflict of interest, and FDA regulation (Part E.2).

Participant and Clinical Interactions: Clinical Research Service (CRS) Director: Henry (Chip) Chambers, MD

CRS will oversee clinical research operations, research nursing/coordination, and specimen management. CRS will also be home to initiatives related to Trial Innovation Centers (Parts F.2 and G.1).

Pilot Translational and Clinical Studies Program (PTC) Director: Kristine Yaffe, MD

PTC supports innovative pilot studies designed to promote clinical and translational research methods (Part D.2).

Catalyst Program for Product Development Director: June Lee, MD

Catalyst identifies promising ideas with potential to be developed into products that improve health, provides training for early translational researchers, and will be home to our Product Development optional function (Part H1).

Precision Medicine (PM) Director: Scott VandenBerg, MD PhD

In partnership with the UCSF Precision Medicine initiative and our regional partners, the CTSI Precision Medicine program will engage diverse populations using uniform consent procedures, establish a robust centralized biobanking platform, and link biospecimen and other rich data sources to high quality phenotypic data to support PM research (Part H2).

‡ CTSI will no longer support the Global Health program, which successfully transitioned to UCSF Global Health Sciences. A.1.b. CTSI Governance Our governance structure is designed to foster active collaboration among leaders both internal and external to CTSI and UCSF. CTSI Director Jennifer Grandis holds delegated authority over all clinical research at UCSF. The External Advisory Board is charged with providing specific advice and recommendations to guide the development of programs and initiatives. Each year, CTSI leadership selects a priority area for assessment by external advisors and convenes the EAB, with standing members supplemented by ad hoc members with particular expertise. For example, the 2014 EAB meeting focused on re-organization of both inpatient and outpatient clinical research services, including approaches to improve quality and efficiency, identifying services that should be supported or discontinued, and processes to equitably distribute support for space, research nursing and staff, and special services. Ad hoc members (from other CTSAs, pharma, and clinical research organizations) with expertise in clinical research services assisted our deliberations. The Internal Advisory Board is a forum for collaboration

among senior leaders from the 4 UCSF professional schools, the Graduate Division, campus, and medical center. The IAB guides overall direction and priorities for CTSI and ensures integration and synergy with other campus and School initiatives. All proposed new CTSI initiatives and partnerships are discussed at IAB meetings, as well as overall approaches to managing revenue and spending. The Senior Leadership Group (SLG), composed of CTSI program directors and senior staff, meets quarterly to provide an informal forum for programmatic updates, sharing of ideas, and social interaction. The SLG

advises CTSI leadership on specific strategies to achieve new goals, communicates regarding program-specific and collaborative initiatives, and focuses on encouraging synergy and eliminating overlap.

CTSI Standing External Advisory Board Warren S. Browner, MD MPH CEO, California Pacific Medical Center,

Adjunct Professor of Epidemiology, UCSF Garret Fitzgerald, MD Director, Institute for Translational Medicine

and Therapeutics, U. Penn. Victoria Hale, PhD Founder and Former CEO, One World

Health; current CEO, Medicines360 Sandra R. Hernández, MD President and CEO, California HealthCare

Foundation David W. Martin, Jr., MD Chairman and Chief Executive Officer of

AvidBiotics

CTSI Internal Advisory Board Jennifer Grandis, MD CTSI Director, Associate Vice Chancellor for

Clinical and Translational Research Deborah Grady, MD MPH CTSI Co-Director and Assoc. Dean for

Clinical and Translational Research Daniel Lowenstein, MD Executive Vice Chancellor and Provost Talmadge King, MD Dean, School of Medicine B. Joseph Guglielmo, PharmD Dean, School of Pharmacy John Featherstone, MSc PhD Dean, School of Dentistry David Vlahov, RN PhD Dean, School of Nursing Elizabeth Watkins, PhD Dean, Graduate Division Joshua Adler, MD Chief Medical Officer, UCSF Medical Center Alan Ashworth, PhD CEO, UCSF Comprehensive Cancer Center Donna Ferriero, MD Chair, Department of Pediatrics; Physician-

in-Chief, Benioff Children’s Hospital SF Louise Walter, MD Chief, Geriatrics Division, Dept. of Medicine Henry (Chip) Chambers, MD Director, CTSI Clinical Research Service Kirsten Bibbins-Domingo, MD PhD Director, CTSI Training Programs June Lee, MD Director, CTSI Catalyst Program Jon Rueter, MBA CTSI Chief Administrative Officer

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CTSI Operations Committee (OC), chaired by Dr. Grady, is composed of the CTSI Director and Co-Director, Chief Administrative Officer (CAO), Chief Informatics Officer (CIO), and the directors of the 3 largest CTSI programs (Clinical Research Service, CTSI Training, and Catalyst [Product Development]). The OC meets weekly for 2 hours to oversee and direct day-to-day activities and to provide program oversight, evaluation, and support; it escalates issues and decisions to the SLG or IAB, as needed. CTSI’s other Program Directors meet with the OC on a regular basis, and each program undergoes a formal evaluation twice annually to establish metrics, track progress, and plan for the coming year (Section D.1, below). Program budgets are tracked by programmatic initiatives and are evaluated continuously by CTSI administrative team led by our CAO. In addition, each CTSI program holds regular (typically monthly) team meetings to review progress and revise plans. These meetings are attended by members of the OC and the Program Evaluation Team to ensure 2-way communication, synergy with CTSI and other program initiatives, and to minimize redundancies. A.2. Integrated Organization and Governance of the Clinical and Translational Science Training (CTST) Program, including the TL1 and KL2 Programs CTST (Part D.1) includes didactic education (TICR: 44 courses; Research Methods Workshop, 1-year Certificate program and 2-year Master’s) and multiple level-specific training programs (Pre-health Undergraduate Program; Residency Research Training Program; TL1 pre-doctoral, professional, and post-doctoral training program; KL2 mentored career development). Despite their separate funding mechanisms, the TL1 (see TL1 proposal) and KL2 (see KL2 proposal) will continue to function as integral programs in the CTST. CTST Director, Kirsten Bibbins-Domingo, MD PhD, reports to CTSI Co-Director Deborah Grady, MD MPH. Dr. Bibbins-Domingo is a member of the IAB and SLG. The Directors of the education and each of the training programs report to Dr. Bibbins-Domingo: the TL1 is led by Joel Palefsky, MD, the KL2 by Douglas Bauer, MD, and TICR is directed by Jeffrey Martin, MD MPH. All are members of the SLG. CTST is governed by a Steering Committee chaired by Dr. Bibbins-Domingo that includes the senior faculty training program leaders. The Steering Committee meets monthly to assure that the program leaders are aware of and contribute to all CTSI and CTST activities, and to encourage collaboration and cross-program activities. This close integration of our educational and training programs has increased efficiency, improved administrative systems, reduced redundancy, facilitated communication, and promoted collaboration among the programs and trainees. For example, a Steering Committee discussion about mentoring led to the launch of the Big Sib/Little Sib program, in which KL2 scholars are paired with TL1 trainees. A.3. Institutional Perspectives, Culture, and Support CTSI is housed on the new UCSF Mission Bay Campus in Mission Hall, the Global Health and Clinical Sciences Building, which opened in September 2014 (see images below). In her dual roles as Director of CTSI and Associate Vice Chancellor for Clinical and Translational Research at UCSF, Dr. Grandis is poised to identify and manage competing institutional perspectives, address disparities in institutional cultures and resources, and spearhead efforts to share institutional expertise and resources. She meets weekly with EVCP Lowenstein, and monthly with the Deans of the Schools of Medicine, Pharmacy, Dentistry, and Nursing to coordinate clinical and translational research efforts and resources. In addition, she communicates regularly with the Vice Dean at SFGH (Sue Carlisle, MD PhD, and the Associate Chief of Staff for Research at the SFVA, Carl Grunfeld, MD PhD). Investigators based at SFGH and the VA are leaders and active participants in CTSI programs, and members of the SLG.

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Based on NCATS guidelines, NIH funding for CTSI will decrease progressively over the next 5 years. We will take a multi-faceted approach to meeting this challenge by securing increasing institutional support, increasing philanthropy (see Chancellor Hawgood LOS), increasing efficiencies, and increasing cost recovery for our services (see Table of UCSF Institutional Support). CTSI leaders manage priorities in accordance with NCATS’ goals and policies, and approach change management by working closely with stakeholders to ensure that decisions are consensus-based with clear rationales. All CTSI leaders make themselves readily accessible individually to stakeholders, and are well positioned to escalate specific problems to the Operations Committee or Advisory Boards, as needed. Programmatic changes are implemented thoughtfully. For example, we recently streamlined the delivery of clinical research services provided to investigators and implemented new budgeting and cost recovery processes (Part F.2). Throughout this process, we engaged the IAB, developed a special task force comprised of representative investigators, conducted a series of town hall meetings to communicate specifics about upcoming changes, and responded to individual and group feedback by proposing compromises and adapting plans. A.4 Leadership A.4.a. CTSI Leaders CTSI leadership includes senior clinical and translational researchers, administrators, and staff with a wide range of training, expertise, and experience.

Daniel Lowenstein, MD: UCSF Executive Vice Chancellor and Provost (EVCP). CTSI reports to Dr. Lowenstein, the Robert B. and Ellinor Aird Professor of Neurology. Dr. Lowenstein leads UCSF’s research enterprise, and works closely with UCSF Chancellor Samuel Hawgood, MMBS. Dr. Lowenstein has served as Vice Chair of the Department of Neurology, Director of the Epilepsy Center, Director of the Physician-Scientist Education Training Programs, and was Dean for Medical Education at Harvard Medical School. Dr. Lowenstein was one of the founding leaders and Associate Director of the UCSF CTSI. He is known internationally for his contributions in the field of epilepsy, and advocacy for the needs of patients and family members living with epilepsy. Jennifer Grandis, MD: UCSF Associate Vice Chancellor and CTSI Director. Dr. Grandis is Professor of Otolaryngology and PI/Director of CTSI, appointed 2014; She holds designated authority from the EVCP for key aspects of clinical research: data security, good clinical practice, HIPAA compliance, research personnel training, clinical trial contracting and billing; and works closely with the Associate Vice Chancellor of Ethics and Compliance to optimize human subject research practices including developing IRB policies, IRB reliance agreements, certificates of confidentiality, conflict of interest, and other regulatory requirements. Dr. Grandis chairs CTSI’s Internal and External Advisory Boards, and Senior Leadership Group. She is an international expert on precision medicine approaches for treatment of head and neck cancer; elected member of American Society for Clinical Investigation, Association of American Physicians, and National Academy of Medicine (formerly the Institute of Medicine). Deborah Grady, MD MPH: UCSF Associate Dean for Clinical and Translational Research in the Schools of Medicine and Nursing, CTSI Co-Director and LRIC Director. Dr. Grady is Professor of Medicine and one of the founding Co-Directors of the UCSF CTSI. Dr. Grady directed the CTST Programs for multiple years, and led the institute through a period of transition by serving as PI and Interim Director of the UCSF CTSI in 2014. She is an internationally renowned clinical researcher and clinical trialist with a focus on women’s health. Dr. Grady is Deputy Editor of JAMA Internal Medicine, and an editor of “Designing Clinical Research”, a widely used textbook on clinical research methods. She received the UCSF Chancellor’s Award for the Advancement of Women, and was the recipient of the UCSF Lifetime Achievement in Mentoring Award. She is an elected member of the National Academy of Medicine (formerly the Institute of Medicine). Kirsten Bibbins-Domingo, MD PhD MAS: Director of CTSI Training Programs. Dr. Bibbins-Domingo is the Lee Goldman, MD, Endowed Chair in Medicine. She is the incoming Chair or the US Preventive Services Task Force, and Director of the UCSF Center for Vulnerable Populations at SF General Hospital. Dr. Bibbins-Domingo is a cardiovascular epidemiologist with expertise in the development of cardiovascular disease, chronic kidney disease, and diabetes risk in young adults. Her work focuses on racial, ethnic and income differences in manifestations of chronic disease, the intersection of biological, behavioral, and environmental factors that influence risk, and effective clinical, public health, and policy interventions aimed at prevention. Joel Palefsky, MD: Director of TL1 Program. Dr. Palefsky is Professor of Medicine and Lab Medicine; Chair of the HPV Working Group of the Aids Malignancy Consortium (AMC) and is the head of the AMC HPV Virology Core Lab. He has led the Doris Duke Charitable Foundation program at UCSF since its inception in 2001. He was the head of the Roadmap T32 student research program in 2005 before it transitioned to the TL1 program, and has led UCSF’s CTSA’s TL1 program since its inception in 2006. Dr. Palefsky plays an active role in promoting student research programs at UCSF, advising and recruiting students, supervising their research and providing active career guidance and has won numerous student teaching awards. Douglas Bauer, MD: Director of CTSI KL2 Program. Dr. Bauer is a Professor of Medicine, Epidemiology and Biostatistics and was a member of the Planning Committee of the NIH Consensus Conference on Osteoporosis, and the Advisory Committee on Biochemical Markers of Bone Turnover of the National Osteoporosis Foundation. He continues to serve on the NOF Scientific Advisory Committee and is an ad hoc member of the NIH Skeletal Biology, Disease and Development Study Section. Dr. Bauer serves as Chair for several NIH funded multisite trials. He is an Associate Editor for the Primer on Metabolic Bone Diseases and Disorders of Mineral Metabolism, 8th Edition and serves on the Editorial Board of the Journal of Clinical Endocrinology and Metabolism and Biomarker Insights. As an executive member of the San Francisco Coordinating Center, he directs the Endpoints and Medication Coding Groups.

UCSF Institutional Support Chancellor $6,850,000 Exec Vice Chancellor/Provost $750,000 School of Medicine $15,000,000 School of Nursing $250,000 School of Pharmacy $450,000 School of Dentistry $225,000 Medical Center $9,000,000 SUBTOTAL CASH $32,525,000 Other Institutional Support $29,055,545 TOTAL $61,580,545

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All of our CTSI directors are established leaders in their fields; each is exceptionally qualified for, and strongly committed to her/his CTSI role. For detailed information, please see their biosketches and the referenced program Parts: Atul Butte, MD PhD, Director: Institute for Computational Health Sciences and Co-Director: Informatics and Research Innovation Program (Part B), Henry (Chip) Chambers, MD, Director: Clinical Research Service (CRS) (Parts F.2 and G.1), Peter Chin-Hong, MD, Director: Pre-Health Undergraduate Training Program (TL1), Kenneth Covinsky, MD MS, Associate Director, Special Populations Initiative (Part F.1), Laura Esserman, MD MBA, Director: Trial Innovation Centers (Part G.1), Kevin Grumbach, MD, Co-Director: Community Engagement Program (Part C.1), Alison Huang, MD MAS, Director: Residency Research Training Program (Part D.1), Alka Kanaya, MD, Director: Consultation Services (including Biostatistics, Ethics and Research Design Consultation Service [BERD]) (Part E.1), Roberta Keller, MD, Associate Director of Pediatric Research Services, Clinical Research Service (Part F.1), June Lee, MD, Director: Catalyst Program and Product Development Optional Function (Part H.1), Bertram Lubin, MD, Associate Director: Special Populations Initiative (Pediatrics) (Part F.1), Annie Luetkemeyer, MD, Associate Director for Adult Services, Clinical Research Service (Part F.1), Jeffrey Martin, MD MPH, Director: Training in Clinical Research (Part D.1), Joseph (Mike) McCune, MD PhD, Leader: Team Science Working Group (Part C.2), J. Renee Navarro, PharmD MD, Liaison: Diversity (Part 1), Mark Pletcher, MD, Director: Informatics and Research Innovation Program (Part B), Jon Rueter, MBA, CTSI Chief Administrative Officer (Part A), Christopher Ryan, PhD, Director: Regulatory Knowledge and Support Program (Part E.2), Dean Schillinger, MD, Director: Special Populations Initiative (Part F.1), Laura Schmidt, PhD, Co-Director: Community Engagement Program (Part C.1), Dean Sheppard, MD, Co-Director: TL1 Program (TL1), Ida Sim, PhD MD, Co-Director: Informatics and Research Innovation Program (Part B), Scott VandenBerg, MD PhD, Director: Precision Medicine (Part H.2), Laura van ‘t Veer, PhD, Clinical Research Service (Part F.1), Co-director Louise Walter, MD, Co-Director Special Populations Initiative (Geriatrics), Co-Director: KL2 Scholars Program (Part F.1 and KL2), and Kristine Yaffe, MD, Director: Pilot Translational and Clinical Studies Program (Part D.2), A.4.b. Succession Plan CTSI continuously develops leaders among program directors, faculty, and staff, and cultivates expertise through training, mentoring, annual performance reviews, and career planning. Membership on the Internal Advisory Board is based on position (EVCP, Deans, etc.), providing a clear succession plan as these key leadership positions change and are filled. The IAB includes both breadth and depth of leadership expertise, affording both stability during periods of transition, and flexibility to recruit and designate leaders according to specific needs. To fill executive positions, UCSF is committed to performing extensive national searches to identify the most qualified candidates. For example, Dr. Johnston, the previous CTSI PI Director, left his position on relatively short notice in early 2014 to become the inaugural Dean of the Dell School of Medicine at the University of Texas, Austin. Co-Director Grady seamlessly stepped into the Director role on an interim basis while UCSF conducted a national search that culminated in the recruitment of Dr. Grandis. In annual planning exercises, CTSI program directors are encouraged to identify and include potential successors. We develop staff-level leaders through campus-wide and national development programs and by providing careful attention to performance evaluation and career planning. B. Administrative Aim 2: Collaboration and Communication CTSI collaborates broadly with clinical affiliates, partners in the San Francisco Bay Area, across California, and the nation. Below, we describe the roles, organization, governance, and leadership of our collaborations. B.1. Collaboration B.1.a. Clinical Affiliates. In addition to participating in all CTSI programs, the clinical affiliates described below receive on-site support to carry out clinical research. Faculty leaders from each of these affiliates are represented on the Senior Leadership Group, and several CTSI programs are led by faculty from these institutions. These stakeholders participate in CTSI governance, strategic planning, and resource allocation, assuring high-quality multi-institutional research that includes broad input. San Francisco Health Network provides direct health services to the city and county of San Francisco’s most socially and medically vulnerable residents. The network includes San Francisco General Hospital (SFGH) and Trauma Center, Laguna Honda Hospital and Rehabilitation Center, and 45 public health community clinics. San Francisco General Hospital and Trauma Center is the Level 1 Trauma Center for the over 1.5 million people

Clinical Affiliate Leader for CTSI Activities San Francisco Health Network A. Sue Carlisle, PhD MD, Vice Dean San Francisco VA Medical Center Carl Grunfeld, MD PhD, Associate

Chief of Staff for Research Benioff Children’s Hospital of Oakland Bertram Lubin, MD, President/CEO

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living and working in San Francisco and northern San Mateo County. As part of a city-wide integrated health care system, it serves approximately 100,000 patients each year providing primary, specialty, inpatient and outpatient care for vulnerable populations, including children and adults. A major UCSF teaching hospital, SFGH is recognized as a top academic medical center in its own right, with research awards totaling $160 million annually. It is internationally known for research in the areas of infectious diseases, including HIV/AIDS and tuberculosis, harmful effects of tobacco, trauma, and health disparities. CTSI currently supports 61 active protocols for 35 investigators at this site. An example of the high quality research CTSI-supported is the original discovery that HIV infection disrupts the gut microbiome and mucosal immunity leading to a state of chronic inflammation and disease progression despite viral suppression.1 This observation has stimulated further research exploring the potential of modulating the microbial communities as a therapeutic strategy not only in HIV but in other chronic inflammatory conditions as well. San Francisco Veterans Affairs Medical Center provides comprehensive health care to 65,000 veterans in the region. The SFVA is home to major disease-focused research programs, as well as health services research and rehabilitation medicine. The SFVA receives more funding for research from the Department of Veterans Affairs than any other VA medical center in the US. Investigators have access to extensive EHR-based clinical data at the SFVA, as well as EHR data from VA medical centers across the nation. It is currently building the “Million Veteran Program” which will provide electronic access to genomic and phenotypic data on one million VA patients. CTSI currently supports 23 active protocols for 16 investigators at this site. Benioff Children’s Hospital of Oakland, now merged with UCSF Benioff Children’s Hospital San Francisco, provides care for more than 10,000 inpatients and 250,000 outpatients annually from across the Bay Area and is the largest pediatric hospital in Northern California. Benioff Children’s Hospital Oakland is dedicated to advancing care for children. The Oakland site is notable for serving as an ACS Certified Level 1 Pediatric Trauma Center and a nearly 100-year history of caring for children in Northern California and beyond.

B.1.b. Regional Collaborators Leaders of each of our regional collaborators are members of the SLG, and also meet regularly with CTSI’s Director and Co-Director to develop aims and strategies for collaborative activities, communicate progress, identify obstacles, and plan solutions. This structure allows us to innovate, test new processes, and rapidly build on success. Kaiser Permanente Division of Research (DOR) of Northern California. Kaiser is one of the nation’s largest not-for-profit health plans. The Kaiser DOR is a key clinical research partner for UCSF, with access to clinical records and recruitment among 3.6 million patients in Northern California. The DOR is home to 55 investigators and >500 employees involved in >400 research studies. There are currently 32 ongoing collaborative clinical studies involving Kaiser and UCSF collaborators. Kaiser is home to the Research Program on Genes, Environment and Health (RPGEH), one of the largest research projects in the United States to examine the genetic and environmental factors that influence common diseases. Led by Neil Risch, PhD, at UCSF and Cathy Schaefer, PhD, at Kaiser, RPGEH contains rich demographic and clinical data on over 200,000 consented adult members, with geocoding, genome-wide genotyping, and telomere length. The goal of the research program is to discover which genes and environmental factors – the air we breathe, the water we drink, as well as lifestyles and habits – are linked to specific diseases such as heart disease, cancer, diabetes, high blood pressure, Alzheimer's disease, and asthma, among many others.3 CTSI will continue to foster research collaborations between UCSF and Kaiser investigators, and will also support a new UCSF-Kaiser Fellowship program to facilitate use of the RPGEH resource as part of the TL1 program (see TL1 proposal). Children’s Hospital of Oakland Research Institute (CHORI) is an internationally renowned biomedical research institute affiliated with Benioff Children’s Hospital Oakland. CHORI is one of the top 10 NIH-funded pediatric research institutes in the US with >350 investigators working on >150 clinical trials. Over the past 50 years, CHORI has developed cures for debilitating blood diseases and cancers, developed new vaccines for infectious diseases, and discovered new treatments for previously fatal or debilitating conditions. CHORI investigators led a 10-year multi-institutional study on children with mucopolysaccharidosis VI, a clinically

Vignette: VA Big Data Study Resolves Association between Tenofovir and Kidney Disease. The antiretroviral drug tenofovir was known to cause small changes in creatinine, but whether longer term exposure was linked to increased kidney disease was controversial. Using the VA database, Scherzer et al. followed outcomes in 10,841 HIV-infected patients; they found tenofovir was associated with a 34% increased risk of proteinuria, 11% increased risk of rapid decline of kidney function and a 33% increased risk of CKD. This paper is widely viewed as resolving the controversy.2

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heterogeneous and progressive disorder, demonstrating that enzyme replacement therapy was associated with significantly increased survival.4 San Francisco Bay Collaborative Research Network. The SFBayCRN is a network of over 100 community health centers employing nearly 1000 physicians in the 9 Bay Area counties. Most of these clinics are federally qualified heath centers and primarily serve uninsured and vulnerable populations. The SFBayCRN provides community input on research design and conduct, community-based study recruitment, especially of vulnerable populations, and is leading a CTSI effort to federate EHR data from the SFBayCRN for quality improvement, patient recruitment and clinical and translational research. Bay Area Accountable Care Network (BAACN) is a newly-created partnership between 12 hospitals and medical groups across 6 Bay Area counties, including the UCSF Medical Center and John Muir Health (the major provider of health care in Contra Costa County with 2 major hospitals, a trauma center, psychiatric hospital, and over 900 physicians) for the purpose of building a regional health network committed to providing the safest, highest quality, patient-centered care at an affordable price. BAACN will build an enterprise data warehouse across institutions that is expected to include over 1 one million patients. We anticipate that a significant number of focused clinical trials will follow from this partnership. UC Berkeley (UCB) and Lawrence Berkeley National Laboratory. CTSI’s partnership with UCB focuses on the UCB College of Engineering and the School of Public Health. The College of Engineering brings together UCB’s strength as one of the top 3 engineering schools in the US, and UCSF’s faculty expertise in biomedical sciences, medicine and clinical and translational research. We collaborate with UCB on specific initiatives within our Community Engagement and CTST programs, and jointly support the Master’s in Translational Medicine. Through our Research to Researcher (R2R) initiative, CTSI is implementing Profiles, UCSF’s research networking platform, for the Lawrence Berkeley National Laboratory (LBNL) on our hosted model. Currently, investigators at the SF VA Medical Center and SF Health System have full and equal access to CTSI services, infrastructure, and training. We will extend this collaboration to develop data access and utilization services that will streamline access to local and national VA clinical data (which also includes access to the 5% Medicare sample) and to data from the SF Health System of safety-net hospitals and clinics. Similarly, we will extend our current collaboration with Kaiser Permanente Division of Research of Northern California (DOR) to include a combined precision research fellowship program and a service to provide access to the Kaiser RPGEH database. In collaboration with CHORI, we will also facilitate access to pediatric clinical data by streamlining access to EHRs from the Benioff Children’s Hospital San Francisco and the Benioff Children’s Hospital of Oakland. We will also extend our clinical data sharing across the SFBayCRN and BAACN (Part B). Finally, we are collaborating with the College of Engineering at UC Berkeley to support joint funding for pilot projects focused on healthcare device development, improvement in processes for cross-campus support of investigators and staff, and streamlined data use agreements and contracting. B.1.c. Collaborators across California: UC BRAID UC Biomedical Research, Acceleration, Innovation and Development (UC BRAID) is a consortium of the 5 UC Medical Centers at San Francisco, Davis, Irvine, San Diego, and Los Angeles, each of which is home to a CTSA hub. The overall aim of UC BRAID is to streamline and catalyze research to improve health across California and around the world. Since its inception in 2010, BRAID has developed a strong governance and versatile infrastructure to support clinical and translational research, including IRB reliance processes, and streamlined contracting with a focus on child health and drug, diagnostic, and device development. The UC BRAID Research Exchange (ReX) has implemented a state-of-the-art informatics system that allows access to 13.9 million patient records across California, setting the stage for multicenter clinical trial, clinical cohort studies, and precision medicine efforts. UCSF played a leadership role in the development of UC BRAID, with former CTSI PI and Director Clay Johnston serving as the first Chair of its Executive Committee. The CTSA organizations have formed a closely linked and well-functioning partnership built on inclusion, sharing, and trust among campus leaders, faculty, administrators, and UC Office of the President. UC BRAID has enabled IRB reliance, master contracting, and the launch of UC TrialQuest (Web-based search tool of clinical trials across the 5 UCs). UC BRAID facilitated the successful implementation of California Accelerated Innovation (CAI), an NHLBI-funded project to

UC BRAID Site CTSA PI UC Davis Lars Berglund, MD PhD, PI and Senior Associate

Dean for Research UC Irvine Dan M. Cooper, MD, PI and Chair of Pediatrics UC Los Angeles Steven Dubinett, MD, PI and Associate Vice

Chancellor of Research UC San Diego Gary Firestein, MD, PI and Associate Vice

Chancellor of Translational Medicine UC San Francisco Jennifer Grandis, MD, PI and Associate Vice

Chancellor for Clinical and Translational Research

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accelerate early discoveries for development of diagnostics, devices, and therapeutics. Of the first 8 CAI projects, 4 are led by investigators at UCSF. UC BRAID organizes cross-campus multi-disciplinary studies, including PCORI clinical data research networks, rare disease centers, and a CIRM coordinating center. UC BRAID governance strives to strike a balance between equitable decision-making based on consensus, while minimizing obstructive bureaucracy. UC BRAID is led by an Executive Committee comprised of the PIs from the 5 UC CTSAs. The Executive Committee meets by phone at least weekly, and convenes an annual face-to-face, full-day retreat. The Chair of the Executive Committee rotates bi-annually and decisions are made by consensus. UC BRAID supports 5 working groups, including IRB Reliance, Contracting, UC ReX, Children’s Health, and Drug, Device, and Diagnostic Development. Working Group Leaders meet regularly with the Executive Committee. Review of UC BRAID activities occurs quarterly, supported by the CTSA evaluation programs, with feedback to project leads and work groups as needed. Overseen by UC BRAID, ReX is managed through a Steering Committee with a collective management governance model comprised of informatics representatives from the 5 UC campuses. The ReX Steering Committee Chair serves as liaison to the UC BRAID Executive Committee. Each UC site has staff dedicated to common data governance, harmonization, and quality; technical infrastructure; and user support. B.1.d. Collaborators across the Nation Accrual to Clinical Trials Network (ACT). Over the past 9 months we have participated in developing and testing a functional national federated network consisting of 21 geographically diverse CTSA hubs utilizing a common informatics platform (i2b2/SHRINE) for cohort exploration. We demonstrated that we can provide access to sufficiently detailed data on potentially eligible study participants across the 21 academic health centers who met specific study entry criteria. This network established governance and regulatory frameworks, implemented a common technology platform, and created and disseminated a data harmonization schema. The 21 participating institutions have all signed network and data use agreements that allow researchers to search for potential study participants for any known disease or condition, as well as identify potentially healthy control subjects across the 21 CTSA hubs. UCSF has met all ACT milestones and timelines. CTSA National Network. UCSF is participating in all 3 supplemental projects initiated by NCATS this year (Accrual to Clinical Trials, Good Clinical Practice, and IRB reliance), and is represented at the national CTSA PI meetings and on monthly calls, and on each of the 5 NCATS domain task forces: 1) Collaboration and Engagement (Kevin Grumbach), 2) Lifespan (Bert Lubin), 3) Methods and Processes (Mark Pletcher), 4) Workforce Development (Kirsten Bibbins-Domingo), and 5) Informatics (Doug Berman). Our UCSF domain task force representatives participate in the regular calls and communicate with Drs. Grandis and Grady about task force agendas and plans. Dr. Grandis attended the in-person PI meeting in February 2015 and either she or Dr. Grady will represent UCSF at each annual face-to-face meeting. Dr. Grandis also participates in the monthly CTSA PI calls and interacts regularly with the steering committee member assigned to UCSF (Dr. Khosla from the Mayo Clinic). CTSI has collaborated with other CTSAs and institutions to share and support the Profiles research-networking platform at their sites (currently: LBNL, UCSD, University of Southern California; and we are in discussions with San Francisco State University and the World Health Organization). CTSI has also taken advantage of developments by other CTSA Hubs, most notably by advancing the Harvard-developed research networking software (Profiles), tailoring and advancing the Medical University of South Carolina-developed software for research scheduling (SPARC), using REDCap, ResearchMatch, and many other CTSA tools. PCORnet, PCORI’s National Patient-Centered Clinical Research Network. PCORnet is comprised of 11 Clinical Data Research Networks (CDRNs), 18 Patient-Powered Research Networks (PPRNs), and a Coordinating Center that supports a common data model and distributed research network infrastructure. UCSF is home to a CDRN site (pScanner) and 3 PPRNs (Health eHeart Alliance, PRIDEnet and CENA) that specialize in online patient engagement, delivery of data from wearable sensors and smartphones for research, and novel trial coordination; the Health eHeart Alliance, based at UCSF, will help lead PCORnet’s first major clinical research project – a 20,000-person randomized trial of aspirin dosing.5 In addition to these major collaborations, described in detail in Parts B-H, CTSI collaborates with >170 local, regional, and national partners on projects ranging from improving children’s oral health outcomes to the evaluation of HIV/AIDS care strategies and treatment, from developing innovative diagnostics and devices to leading precision medicine efforts, from accelerating improved and safe access to electronic health care records to advancing IRB governance and participant recruitment.

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B.2. Communication The Communications team, led by Melissa Telli, reports directly to CTSI Director Grandis, and works closely with the UCSF campus media group and the communication teams of our affiliates and collaborators. CTSI’s communications team works proactively to distribute up-to-date information about changes and new activities through targeted email, Twitter feeds, and regular newsletter distribution. The team tracks and coordinates the dissemination of information about research findings to communities of interest across CTSI programs, enhances opportunities for collaborative clinical and translational investigation through strategic and targeted communication, information services, and technology-enhanced collaboration tools. It creates the cohesive and engaging face of CTSI to the UCSF community, the national health science research community, and the public. With a focus on audiences that include researchers, the broader UCSF community, industry and community partners, and the national CTSA consortium, the team works with program representatives to identify priorities, encourage cross-program communication and promotion, and to amplify news of scientific advances. Featured tools and applications leveraged by the Communications team include UCSF Profiles, a sophisticated research networking platform that is now widely used at UCSF and several external institutions; Open Proposals, a Web-based platform that enables transparent and collaborative proposal development; Open Research Networking Gadgets, a library of open source gadgets designed to enhance research networking cross-institutionally; and Cores Search, a tool to help researchers locate shared equipment and services.

We use Open Proposals to communicate broadly about CTSI initiatives, to solicit ideas from the UCSF community and our partners, to seek feedback and interaction from the community, and to invite community members to join teams. The open source platform has been adopted enterprise-wide to: 1) improve efficiencies through early elimination of redundant or uncompetitive proposals, 2) improve proposal quality, 3) enhance team composition, and 4) enable introduction of interdisciplinary ideas. Open Proposals now reaches beyond our institution, and is in use at UC Merced and Harvard Medical School. It has also been implemented for a PCORI PPRN project, gathering parents’ input into research on a rare pediatric disease, and most recently was selected for use by the Parker Institute for Cancer Immunotherapy, a consortium of research institutions including UCSF, Sloan Kettering, MD Anderson, and the University of Pennsylvania.

C. Administrative Aim 3: Program Planning, Evaluation, and Tracking CTSI’s program planning, evaluation, and tracking is conducted in the context of overall performance management, combining direct oversight by the Operations Committee with the use of balanced scorecards and initiatives, or project portfolios, for each CTSI program. This strategic planning and management approach is well-established, designed to be practical with control points for manageability, and will continue to act as the foundation for promoting program effectiveness, impact, and the efficient use of resources. For greater effectiveness and efficiency, evaluation is integrated into programs from early stages of development and is part of the “backbone” for managing them throughout their lifespans. This approach accomplishes alignment for USCF CTSI leadership with the emerging evaluation criteria of the national program, and at the level of individual programs with their specific aims and unique models of service delivery. The Program Evaluation Team (PET) is committed to working with the CTSA Network and NCATS leadership to develop and adopt “common metrics,” and has already laid the groundwork for the metrics suggested for several essential modules: Research Methods, Participant and Clinical Interactions, Network Capacity, and Optional Functions. Because PET has established the infrastructure for balanced scorecards, it will continue to focus on early integration of newly proposed and evolved programs. Our evaluation process is organized around 3 activities: 1. Facilitate performance management and reporting for CTSI programs and cross-CTSA collaborations.

Vignette: UCSF Profiles – facilitating collaborations, providing research analytics & reducing administrative inefficiencies, with software and practical approaches to engagement. With over 1 million visits per year, UCSF Profiles, a publicly available online research networking system, is a major “doorway” to the research enterprise and includes online, public-facing access to over 7000 profiles and 125,000 publications and other scholarly activities. UCSF’s Medical Centers, Schools, Departments, labs, investigators and administrators rely on this system for everything from research analytics to syndicated data, with “gadgets” to search for mentorship and collaboration, and for visualizations of co-author networks within and beyond UCSF. As the first non-Harvard installation of Profiles, UCSF has contributed significantly by transforming Profiles into a software platform, creating and populating the first free app library to extend functionality, and greatly enhancing search engine optimization and user interfaces.

Vignette: Crowdsourcing to Optimize “Caring Wisely” Targets. UCSF implemented a “Caring Wisely” program to engage clinicians, staff, and Medical Center leaders to improve healthcare value. Through Open Proposals, the community crowdsourced areas of waste reduction, formed multidisciplinary teams, and implemented programs to improve health and conserve resources.

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We have established a management program of twice-yearly formal program reviews supported by an infrastructure of Web-based balanced scorecards and frequent consultations with programs. The balanced scorecard is a strategic planning and management system that is used extensively in business and industry, government, and nonprofit organizations worldwide to align business activities to the vision and strategy of the organization, improve internal and external communications, and monitor organization performance against strategic goals. Each CTSI program develops goals, initiatives, and metrics annually, with budgets tied to each initiative. Program aims, metrics, initiatives, and budgets are all stored in a Web-based balanced scorecard system called “Process Based Leadership.” PET and CTSI Finance continuously track progress against these scorecards, and support the Operations Committee in formal mid-year and end-of-year reviews that focus on the performance of programs against targets and objectives; strategic, operational, and tactical guidance; and allocation of resources in budgets. The end-of-year review is directly aligned, by schedule and both programmatic and financial outputs, with CTSA grant reporting, and is structured to generate the required information. Below is a partial view of the Catalyst Program’s scorecard. Goals, initiatives, and metrics are also reviewed with the UCSF Executive Vice Chancellor and Provost and the IAB. We regularly seek the advice of the EAB, which is convened to assess specific opportunities and challenges. CTSI’s Co-Director and CAO meet monthly with senior staff to support greater cross-program integration and collaboration. Monthly meeting topics feature in-depth looks at programmatic activities, and provide discussions on supervision, management and efficiency techniques to improve CTSI program management. 2. Plan strategies, consult on, and facilitate implementation of process improvements. PET has taken a 2-level approach to this aim: metrics and evaluation from the viewpoint of CTSI management and NCATS, and measures at the program level to ensure accountability for use, quality, and cost of proposed activities, as well as effectiveness and outcomes, all catalogued in the Process Based Leadership system. In addition, PET will continue to offer process improvement services and advice locally, acting as a resource to UCSF, and to the national CTSA network. PET has employed Lean Six Sigma techniques to reduce IRB time-to-approval, accelerate the post-award process, and identify and track research-related patients for treatment and billing. We have also generated a broad analysis of the clinical research landscape at UCSF that informed the deployment of central campus resources and the re-alignment of CTSI’s Clinical Research Services. Additionally, we provide a center for advising other research endeavors at UCSF (Delaney AIDS Research Enterprise to Find a Cure, UCSF Center for AIDS Research) and other CTSAs (University of Texas Medical Branch Institute for Translational Science and Scripps Translational Sciences Institute). 3. Develop innovative evaluation methods to complement NCATS’ system-wide evaluation program. To prepare CTSI programs for the implementation of the NCATS common metrics, we are surveying available UCSF systems for the required data and are consulting with relevant programs to add these metrics to their existing data collection. We expect to easily incorporate the new common metrics into our balanced scorecard system. In addition to accommodating common data metrics, PET will continue to innovate with attention to: • Business modeling, including service pricing, revenue options, and ascertaining the readiness of mature programs for transfer or siting outside CTSI • Process- and network-oriented metrics and predictors of success derived from Collective Impact and Community-Based Participatory Research for community engagement activities • Emphases on team science composition impacts on attitudes, team process, and quality outcomes • New models for research management with reliable data for management decision-making

D. Administrative Aim 4: Ensure High Quality, Ethical, Feasible, and Efficient Research Ensuring highest quality clinical and translational research requires the concerted effort of many UCSF and CTSI programs and initiatives (see relevant Parts, cited below):

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• Safe and ethical human subjects research is addressed by CTSI Training Programs (Part D.1, KL2 and TL1 proposals), the UCSF IRB, and the CTSI Regulatory Knowledge and Support Program (Part E.2).

• Appropriateness of scientific design, measurements, feasibility, and analysis plans are addressed by the IRB, the CTSI Consultation Service (BERD: Part E.1), and reviewed by the Clinical Research Service Scientific Review Committee (Part F.2).

• High quality and efficient recruitment plans are supported by the Participant Recruitment Unit (Part G.2). The Regulatory Knowledge and Support Program will monitor trial recruitment, address low enrollment, and close trials that fail to recruit (Part E.2).

• High quality dissemination of study results is supported by Scientific Writing consultants in the Consultation Service (Part E.1) and the CTSI Communications Group; complete posting on CT.gov is supported by the CTSI Regulatory Knowledge and Support program (Part E.2).

• Study drug management is ensured in coordination with the office of the Executive Director of Clinical Services in the School of Pharmacy, Dr. Daniel Wandres.

• Post-IRB approval, overall study quality, appropriate investigator and staff training, and adherence to all regulations (UCSF, NIH, and FDA ) and to the scientific protocol are monitored by the Quality Improvement Unit (QIU) of the UCSF Human Research Protections Program. QIU staff audit all high-risk studies and clinical trials (those with IND or IDE, investigator-initiated, department-sponsored, industry sponsored, greater than minimal risk, or involve a vulnerable population), a random selection of other studies, and all studies with serious adverse events or participant complaints. QIU performs FDA-style audits with written reports and may provide specific education and training, require remediation, suspend enrollment pending remediation, or close trials with on-going deficiencies.

E. Milestones and Metrics We will adhere to NCATS common metrics as these are developed and finalized.

Aim / Milestone Metric for Assessment and Frequency Increase use of CTSI services across UCSF • % of investigators accessing CTSI resources/services Develop solutions to support clinical and translational research mission and address gaps

• # of papers from CTSI projects submitted/published • % of CTSI users who report satisfaction with programs/services • Service solutions (services and technology) delivered on time and in full • Savings achieved from Lean Six Sigma efficiency improvement activities

Develop processes to assess maturity / transfer of CTSI initiatives

• # of programmatic initiatives transferred/adopted outside of UCSF

Develop and sustain partnerships with regional & national CTSA Hubs

• % of non CTSA funding sources

Improve clinical research and regulatory processes at UCSF

• Reduce time from IRB submission to approval • Reduce time from IRB approval to first patient visit • Increase IRB reliance and use of central IRB for multicenter trial • Consider UCSF as a central IRB • Ensure safe and ethical human subjects research • Monitor trial accrual and implement processes to assist and/or close studies that

fail to meet accrual targets Improve contracting at UCSF and network • Reduce time from contract receipt to execution

• Increase # of master contracts Support clinical and translational research careers and multi-disciplinary teams

• Increase # of UCSF faculty engaged in C&T research • Increase # of publications with co-authors from >1 specialty

Effectively execute CTSI operations • % annual targets achieved by each CTSI program • Ensure quality and efficiency of clinical and translational research

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References for Part A. Administrative Core

1. Vujkovic-Cvijin, I., et al., Dysbiosis of the gut microbiota is associated with HIV disease progression and

tryptophan catabolism. Science translational medicine, 2013. 5(193): p. 193ra91-193ra91. 2. Scherzer, R., et al., Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS

(London, England), 2012. 26(7): p. 867. 3. Kvale, M.N., et al., Genotyping informatics and quality control for 100,000 Subjects in the Genetic

Epidemiology Research on Adult Health and Aging (GERA) Cohort. Genetics, 2015. 200(4): p. 1051-1060.

4. Beck, M., et al., Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis. Molecular Genetics and Metabolism Reports, 2015. 3: p. 21-27.

5. pcornet. Which Aspirin Dose is Best to Protect Patients with Heart Disease? The First PCORnet Study. [cited 2015 Sep 8]; Available from: http://www.pcori.org/sites/default/files/PCORI-Aspirin-Trial-Fact-Sheet.pdf.

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Part B Informatics and Research Innovation

Emerging technology is generating major new opportunities for innovation in clinical and translational research. With near universal use of electronic health record (EHR) systems and increasing societal penetration of Internet technologies, investigators have many new ways to interface with potential research subjects around the globe and in nearly every subset of American society, including previously underserved and understudied populations. Emerging wearable sensor technologies, e.g., sensors built into smartphones, are making it possible to collect real-time physiologic and behavioral data as well as enabling novel interventions that might improve health. Plummeting costs of genome sequencing and other high-throughput biomarker testing have made “Precision Medicine” possible. Growing regional and national research networks are facilitating large-scale collaborative research and making major investments in harmonizing data and technology. The multi-disciplinary Informatics and Research Innovation (IRI) Program will capitalize on these opportunities with the goal of enabling the following Aims: IRI Aim 1. Extend the ability to obtain and derive research measurements from EHR data. IRI will provide access to a Safe Harbor version of UCSF’s Clinical and Research Data Warehouse (CRDW), support extract-transform-load of CRDW data into i2b2, OMOP, PCORnet CDM, and other common data models, enhance tooling and support for defining and reusing computable phenotypes, support an external-facing API, and provide educational and consultative resources for investigators interested in using EHR data for research; IRI Aim 2. Coordinate and develop infrastructure to use “non-traditional” data sources within clinical trials. IRI will lead the development of an integrated cross-institutional strategy for using non-traditional mHealth, EHR, genomics, and biomarker data in clinical and research systems, and invest in specific infrastructure enhancements designed to enable use of non-traditional data for real-time study management needs; IRI Aim 3. Enable development of EHR-based interventions and data collection. IRI will support flow of research measurements, mHealth data, and decision support information into the EHR, and recruit clinician experts in clinical workflow and EHR implementation to serve as research/intervention consultants; IRI Aim 4. Support development of scalable direct-to-participant trial platforms and novel consent systems. IRI will develop or adapt an existing scalable low-cost modular infrastructure to support these studies, while supporting innovation in consent design and long-term engagement from all segments of the population; and IRI Aim 5. Coordinate efforts with colleagues across the CTSA Consortium, UC BRAID, PCORnet, and BD2K in development of methods, shared informatics infrastructure, and multisite research.

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SPECIFIC AIMS Emerging technology is generating major new opportunities for innovation in clinical and translational research. Federal legislation has brought near universal use of electronic health record (EHR) systems that provide a rich source of health-related data on the majority of Americans. Increasing societal penetration of Internet technologies, including mobile access through smartphones, provides new ways to interface with potential research subjects around the globe and in nearly every subset of American society, including previously under-served and understudied populations. Emerging wearable sensor technologies (e.g., sensors built into smartphones), are making it possible to collect real-time physiologic and behavioral data as well as enabling novel interventions that might improve health. Plummeting costs of genome sequencing and other high-throughput biomarker testing have made “Precision Medicine” possible. Growing regional and national research networks are facilitating large-scale collaborative research and making major investments in harmonizing data and technology. The Learning Health System (Part 1.B) and Precision Medicine (Part H2) capitalize on these emerging opportunities, but will require additional informatics infrastructure. We have reorganized our existing CTSI Biomedical Informatics Program into a multidisciplinary Informatics and Research Innovation (IRI) Program with the goal of enabling the following Innovation Priorities: • Multisite network research • Clinical trials embedded within healthcare delivery systems • Optimal use of mHealth technology for measurement and intervention • Direct-to-participant trials • Biospecimen collection and biobanking to support pre-clinical innovation and precision medicine • Engagement of community members in research Going forward, UCSF’s investment in informatics infrastructure will be carefully guided by a multidisciplinary Steering Committee composed of senior leaders of campus-wide clinical and research units that will both advise IRI and help ensure a coordinated implementation plan that deploys CTSI and other UCSF resources most effectively (Part B.1, below). IRI’s efforts will receive critical support from new CTSI Director and Associate Vice Chancellor for Research Jennifer Grandis, MD (to whom all infrastructure and services related to clinical research at UCSF have been delegated, and who will sit on the Health System Leadership Executive Committee), from the new UCSF Institute for Computational Health Sciences (directed by Atul Butte, MD, PhD), and from other CTSI programs that will support IRI’s technology investments. This includes new educational programs and workforce development, consultative services, regulatory innovation, and community/stakeholder engagement to promote and support broad and creative use of IRI infrastructure (Part 1, Overall Vision). With the goal of enabling high-quality, efficient, cost-effective and innovative clinical and translational research, we propose the following Aims for IRI: IRI Aim 1. Extend our ability to obtain and derive research measurements from EHR data. We will provide access to a Safe Harbor version of our Clinical and Research Data Warehouse (CRDW), support extract-transform-load of CRDW data into i2b2, OMOP, PCORnet CDM, and other common data models, enhance tooling and support for defining and reusing computable phenotypes, support an external-facing API, and provide educational and consultative resources for investigators interested in using EHR data for research. IRI Aim 2. Coordinate and develop infrastructure to use “non-traditional” data sources within clinical trials. We will lead the development of an integrated cross-institutional strategy for using non-traditional mHealth, EHR, genomics, and biomarker data in clinical and research systems, and invest in specific infrastructure enhancements designed to enable use of non-traditional data for real-time study management needs. IRI Aim 3. Enable development of EHR-based interventions and data collection. We will support flow of research measurements, mHealth data, and decision support information into the EHR, and recruit clinician experts in clinical workflow and EHR implementation to serve as research/intervention consultants. IRI Aim 4. Support development of scalable direct-to-participant trial platforms and novel consent systems. We will develop or adapt a scalable low-cost modular infrastructure to support these studies, while supporting innovation in consent design and long-term engagement from all segments of the population. IRI Aim 5. Coordinate efforts with colleagues across the CTSA Consortium, PCORnet, BD2K, and UC BRAID, in development of methods, shared informatics infrastructure, and multisite research. We will be proactive at adopting and sharing data, data model standards, tools, and methods throughout the CTSAs and beyond.

Part B. Informatics and Research Innovation

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RESEARCH STRATEGY B.1. Overview and Achievements Over the past 10 years, CTSI has worked in close collaboration with UCSF IT leadership and institutional informatics and technology departments to support a broad range of informatics tools, services, and resources that meet key infrastructure needs and are heavily used by investigators (Table 1).

Table 1. Selected UCSF Achievements (and Metrics) in Informatics and Technology that Support Research Innovation Enabled investigators to use UCSF EHR data

• Developed a Clinical & Research Data Warehouse that allows investigators to count eligible patients (without IRB approval), identify those patients and invite them to enroll in studies, and extract specific data elements. Services were accessed by 252 investigators in last year

Developed and deployed a secure portal, tools and technology for recruitment, data collection, analysis and collaboration

• Developed MyResearch, a secure Web-based data hosting service where research teams can store and analyze sensitive data using SAS, STATA, R and many other applications; 2,700+ users

• Hosted REDCap, with regular webinars, training, expert consultation supported 4,631 users across CTSI • Deployed real-time HL7-based recruitment tool currently supports 8 studies; recruited 5,100 patients • Developed and deployed UCSF Profiles and Open Proposals, which support research networking (>1M

visits/year) and collaborative research proposal development (>700 proposals)1 • Supported >30 multicenter RCTs and prospective cohort studies through SF Coordinating Center services

Co-developed cross-UC data resources

• Partnered with UC BRAID to develop UC Research Exchange (ReX), which provides secure access to EHR data from 14 million patients across the 5 University of California Medical Centers

• Developed a self-serve UC ReX Data Explorer query tool that has supported at least 14 grants (6 multi-campus/network), a total of $28MM was received to support single, multisite, and nationwide studies

Participated in national networks for multi-site trials

• NCATS Accrual to Clinical Trials (ACT): “Wave 1” member, met all milestones • PCORnet: UCSF hosts a pScanner Clinical Data Research Network node and 2 Patient-Powered

Research Networks; will help lead ADAPTABLE, PCORnet’s first RCT Two years ago, to develop our next 5-year plan, CTSI leadership undertook an extensive, widely-publicized process of stakeholder engagement and needs assessment that included the full spectrum of pre-clinical and translational researchers, new investigators and campus leaders, researchers from our UCSF campus and CTSI partners, and external advisors. This culminated with a retreat that included campus informatics partners.

Table 2. IRI Steering Committee Members Mark Pletcher – IRI Director and Steering Committee Chair Ida Sim – IRI Co-Director Atul Butte – IRI Co-Director Leslie Yuan – CTSI Chief Information Officer Michael Blum – UCSF Chief Medical Information Officer, Director of Center for Digital Health Innovation Ralph Gonzales – Assoc. Dean for Clinical Innovation; Chief Innovation Officer for UCSF Health; Dir. of Clinical Innovations Center David Dobbs – Director of UCSF Enterprise Information and Analytics Team Edwin Martin – Director of UCSF Dept. of Medicine Information Services Unit Michael Potter – Director of SF Bay Collaborative Research Network and liaison to the Bay Area Accountable Care Network Steve Cummings – Professor Emeritus, Director, SF Coordinating Center Jennifer Creasman – CTSI Director, Consultation Service Data Management and Participant Recruitment Units Chris Ryan – Director, UCSF IRB & CTSI Regulatory Knowledge and Support Jennifer Grandis – CTSI Director, Associate Vice Chancellor for Research

This process gave rise to our overarching vision (enabling high-quality, efficient, low-cost, innovative research using emerging technology), reorganization into our new IRI Program with a multidisciplinary leadership team and Steering Committee (Table 2), and several IRI Demonstration Projects, supported by CTSI funding and IRI leadership, that have helped define infrastructure gaps and drive innovation (Table 3).

Table 3. Ongoing IRI-supported demonstration projects in the areas of our Innovation Priorities The Chronic Kidney Disease (CKD) Decision Support Study. This RCT, embedded within UCSF’s healthcare delivery system, will test the effectiveness of EHR-delivered decision support for CKD. The project generated a complex computable phenotype (persistent eGFR<60) and outcome measures defined exclusively with EHR data, received IRB approval for an innovative opt-out consent procedure, and helped us define critical infrastructure needs for an efficient Learning Health System (Aims 1-3). Brain-M (Bringing Relief to Adolescents Naturally with Melatonin). This direct-to-participant RCT was designed to test the effectiveness of melatonin at reducing migraine frequency in adolescents, measured via smartphone app diary. Building the Web platform and supporting online recruitment for this project have helped define a need for a repurposeable modular platform to support efficient trials at scale (Aim 4) and integrate novel outcome measurement technology (Aim 2). The Blood Pressure (BP) Control Laboratory. Designed as a framework for supporting an ongoing series of efficient RCTs to improve BP control embedded in healthcare delivery, this “Laboratory” will start by testing an Epic “in-basket message” intervention delivering smartphone-enabled home BP measurements and novel decision support for BP medication adjustment. The project has helped define needs for bidirectional data flow between EHR, study management systems, and mHealth devices (Aims 2 and 3). PRIDE. Developed and launched an Apple ResearchKit app that engages sexual and gender minorities in research, study has recruited >13,000 participants to the network; gathered >3,000 crowd-sourced and crowd-prioritized research ideas from network participants. The novel technology and design have spurred planned innovations in participant consent and engagement to support direct-to-participant research (Aim 4). Recently funded as PRIDEnet, a PCORnet patient-powered research network.

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The overriding goal of IRI will be to establish an effective campus leadership mechanism that brings together campus administration, medical center clinical and IT personnel, and campus academic informatics leaders to make the IRI vision a reality. IRI will contribute the research innovation vision and use cases, and ensure appropriate sharing of tools and methods with CTSA and other research consortia. Our Steering Committee, which includes IRI operational leadership and directors of key informatics resources across campus, will oversee the development of an actionable technical roadmap and will augment CTSI investments with in-kind support and coordinated co-investment from their own programs (see Letters of Support). Roadmap development will be shaped by annual solicitations of IRI Demonstration Projects that will both showcase newly available infrastructure and drive the development of new functionality. These projects will be supported by our Open Proposals community/crowd-sourcing platform for proposal development and will be shepherded closely by IRI leadership and project managers to meet both project-specific as well as IRI-wide objectives.B.2. Approach IRI Aim 1. Extend our ability to obtain and derive research measurements from EHR data. • Overview. UCSF’s Enterprise Information and Analytics (EIA) team, led by IRI Steering Committee member

David Dobbs, maintains this critical infrastructure in close collaboration with IRI and with network data partners.

• Achievements and current status. EIA currently maintains data tables, derived from our Epic-based EHR system, that are used for healthcare operations and research. These tables include nightly ETLs (Extract, Transform and Load) from our Clarity Data Store, as well as 200+ tables from Cogito that EIA defined to include the highest value Clarity data for UCSF research purposes. They are integrated with registry, survey, and financial data in the UCSF Clinical and Research Data Warehouse (CRDW), which then feeds various resources used by clinicians, operations teams, and researchers (Figure 1). Researchers can browse de-identified summary views of these data through the Research Data Browser (RDB) without IRB approval or, with IRB approval and under stringent access control and monitoring, they can access and analyze the data through the MyResearch secure portal that provides SAS, SPSS, STATA, R, MATLAB, ATLASti, REDCap, M-plus, and other tools within the secure environment.

• Identified barriers. Despite our current instantiation of the CRDW and RDB, UCSF researchers still face significant barriers to effectively using EHR data for the recruitment, design or data collection phases of their research. The RDB displays data cross-tabbed by general purpose variables (e.g., gender, age, diagnosis), but offers researchers minimal capability to define more custom variables. To perform more robust querying, researchers need to access the Clarity database directly, which requires IRB approval and researchers must either be Clarity-certified or they must use EIA’s non-clinically-oriented data analysts. It is unreasonable to expect researchers to be Clarity-certified, and too expensive to fully staff EIA with clinical data analysts. Finally, even if researchers can identify Epic variables, there is, as yet, no infrastructure for providing automated periodic data feeds to research systems, which are required for trials, registries, and other longitudinal studies.

• Planned enhancements. We will address these shortcomings by increasing the richness of data available without IRB approval; by building automated and staff-supported processes for defining, instantiating, and supporting reusable computable phenotypes; and by increasing training and consultation services in this critical aspect of research infrastructure. National NIH- and PCORI-supported research networks are developing common data models (e.g., i2b2 SHRINE, OMOP and the PCORnet CDM) that offer starting points for shared phenotypes, and automated ETLs of CRDW data into these models will also facilitate UCSF’s participation in these research networks. IRI and EIA are jointly planning the following enhancements:

Figure 1. Clinical data flow, transformation and usage for research

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a) Create CMS-sanctioned Safe Harbor2 (de-identified) versions of CRDW tables and a streamlined, IRB-sanctioned pathway for accessing those tables without a fully developed research protocol (see Letter of Support from UCSF’s IRB Director).

b) Host production-grade ETLs for Network-defined common variables and data models, and provide access to these data tables within the CRDW. This work is currently under way for NCATS ACT (i2b2 SHRINE), UCReX (UC Research Exchange, an integrated clinical data warehouse maintained by the UC BRAID network of the 5 CTSA-funded UC Medical Centers that supports SHRINE), and PCORnet (UCSF hosts a pScanner Clinical Data Research Network node that supports the PCORnet CDM and OMOP).

c) Develop API-based mechanisms for exporting EHR data to external systems. IRI is working with EIA, CTSI Regulatory Knowledge and Support, and the UCSF IRB to develop and implement technical and policy specifications for a highly secure API for exporting EHR data for real-time study management and to drive interventions and outcome assessments in healthcare system-embedded clinical trials.

d) Create a reusable code library and metadata repository for computable phenotypes. The EIA team is implementing IBM’s InfoSphere Platform as a trusted, one-stop information hub for registering and storing metadata and code for queries and computable phenotypes.

e) Develop educational and consultative resources to support investigators. In close collaboration with CTSI Consultation Services, the CTST Training Programs and the EIA team, IRI will help CTSI develop new consultation expertise (Part E.1), and curriculum (Part D.1), including a 1-day focused workshop for skilled researchers who would like to start analyzing EHR-derived data.

• Key Collaborators. UCSF EIA. (See Dobbs Letter of Support) IRI Aim 2. Coordinate and develop infrastructure to use “non-traditional” data sources within clinical trials. • Overview and barriers. Modern clinical research will increasingly require collection and integration of EHR,

mHealth, genomic, biomarker, imaging, and other “non-traditional” data. Challenges to optimal use of these new data sources include data security and privacy, data standards and exchange, real-time integration into the care and research workflow, and analysis of structured and unstructured data. Because mHealth, genomic, and biomarker data are predominantly collected and controlled by disparate entities, integration with each other and the EHR is particularly challenging. As revealed by our stakeholder sessions and several campus-wide surveys, there is high demand from UCSF faculty for centralized approaches to these challenges.

• Achievements and current status. UCSF is at the forefront nationally of integrating mHealth data into research and care. Open mHealth,3 co-founded by Ida Sim, IRI Director of Informatics and mHealth, provides open APIs and community-driven open schemas for mHealth data, which are critical for bringing research-grade data into care. Open mHealth is part of the NIH Big Data to Knowledge (BD2K) consortium and is working with BD2K and both commercial (e.g., RunKeeper, Google) and non-profit entities (e.g., Global Alliance for Genomics and Health) to develop APIs spanning mHealth, genomics, and EHR data that will be acceptable and useful to both industry and academia. The Health eHeart Study,4 launched in 2013 and led by Mark Pletcher, IRI Director, is a leading research platform for patient-engaged distributed online studies. It will be using the Open mHealth approach, and will serve as the underlying platform for the newly NIH-funded U2C (“Mobilizing Health”5) mHealth research resource. Dr. Pletcher is helping lead ADAPTABLE,6 the first PCORnet multisite clinical trial of aspirin dosing, which will afford an opportunity to learn from and influence the national approach to expanding the scope of data routinely usable in clinical research of all types. The UCSF Center for Digital Health Innovation (CDHI, led by Michael Blum and Ed Martin, IRI Steering Comm. members) validates commercial apps and sensors and further expands UCSF’s reach and influence. UCSF is also pushing the boundaries on integrating real-time genomic and biomarker analysis into clinical care. With this deep expertise and experience, UCSF is well placed to lead CTSA and the broader research community on optimizing use of non-traditional data for Precision Medicine (Part H2) and Learning Health Systems (Part 1.C). Progress has been more limited on integrating UCSF’s EHR and other data with clinical research data and management systems. The OnCore clinical trials management system supports an HL7 data feed, but cannot ingest research-grade variables extracted from Clarity or other external data sources. UCSF participates in the i2b2 SHRINE UC ReX and PopMedNet PCORnet distributed query networks, but those networks have not yet defined strategies for incorporating non-traditional data.

• Planned enhancements. IRI will work closely with relevant stakeholders across campus to establish a clear leadership structure for ensuring a coherent UCSF-wide strategy that can be responsive and adaptive to the opportunities of “big non-traditional data” for research. Concurrent with defining this broader strategy, we will enhance the ability of Epic and our various supported study management systems to exchange existing

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EHR, mHealth, and genomic and biomarker data from our core labs to support real-time study management as well as adaptive, just-in-time randomization, and embedded interventions in clinical care. These activities will be driven by selected Demonstration Projects (see Part B.1) to ensure iterative development that is relevant and sensitive to the needs of frontline researchers. For example: a) Provide an mHealth data collection module that includes informed consent, OAuth2-based

authentication, and data normalization protocols supported by Open mHealth. The Health eHeart Study, leveraging newly-awarded U2C (“Mobilizing Health”5) funding, Open mHealth standards and tools, and planned MD2K analytic platforms, will develop an easily-modified module for collection of mHealth data from sensors and smartphones that can be integrated into research study management systems.

b) Develop an EHR data collection module that supports an EHR data feed into study management systems, utilizing the API described in IRI Aim 1c, that can be integrated into research study management systems to support longitudinal research data collection and outcome ascertainment.

c) Coordinate with pre-clinical labs and biospecimen banking facilities to transfer critical data elements to study management and frontline care systems. Pre-clinical labs generating genomic and other biomarker data will use API-based systems to deliver time-sensitive process data (e.g., failed specimen collection) and results (e.g., to guide stratified randomization or precision medicine interventions).

• Key Collaborators. EIA (for clinical data); Open mHealth and the Health eHeart Study (for mHealth data); Pre-clinical labs and biospecimen banking facilities for pre-clinical studies and Precision Medicine (Part H2). (See Dobbs, Sim, Olgin, Rubin, and Butte Letters of Support)

IRI Aim 3. Enable development of EHR-based interventions and data collection. • Overview. EHR systems provide many tools for influencing care and collecting clinical data, including alerts,

order templates, “in-basket messages” to caregivers, and direct-to-patient messaging and survey systems, but it remains unclear how best to use these tools without adversely impacting efficiency of healthcare delivery.

• Achievements, current status, and barriers. CTSI and the UCSF Medical Center (represented by Chief Medical Information Officer (CMIO), Michael Blum and Chief Innovation Officer, Ralph Gonzales: see Steering Committee, Table 2) collaborate closely on healthcare delivery research that uses and impacts Medical Center IT. We jointly support, for example, highly trained Epic programmers who work closely with clinician researchers and quality improvement teams to implement care and efficiency improvement solutions. Examples include Epic-based intervention mechanisms for 2 of our demonstration projects (CKD Decision Support and BP Control Laboratory, Table 3), integrated decision support systems for CT scan ordering, improving price transparency for operating room costs, and integrating sensor measurements of blood sugar into the EHR. These teams have defined technological, cultural and consultative barriers to their work; these are also barriers to innovative research for a Learning Health System that IRI will help overcome.

• Planned enhancements. In close collaboration with the CMIO and Clinical Innovations Teams, we plan to: a) Create the technical and governance processes for introducing collection of research-grade variables

using the EHR. In collaboration with the EHR operations team (which reports to Dr. Blum) and the Medical Center’s process improvement teams, IRI will help provide researchers the ability to collect variables from within the clinical workflow required for registry data collection, research network participation, etc.

b) Develop mechanisms to import externally-generated measurements and decision support information into the EHR. We have started using Epic’s Interconnect API for importing measurements (e.g., blood sugar) and decision support systems (e.g., BP Control Laboratory project), and a third party API Manager that handles security and authentication requirements for external systems integrating with our EHR.

c) Support local clinical “champions” to provide multidisciplinary research consultation. Clinical champions with deep expertise in the use of Epic to support clinical workflows are embedded in all care delivery departments at UCSF and work closely with the CMIO and Process Improvement teams. CTSI’s Consultation Service has started recruiting these clinical champions to consult on designing interventions for research and will seek out others so that researchers interested in improving quality of care through integrating research into healthcare delivery will have expert resources for designing interventions that work for clinicians.

• Key collaborators. UCSF’s Chief Medical Information Officer and Chief Innovation Officer, Center for Digital Health Innovation, and Clinical Innovations Center. (See Blum and Gonzales Letters of Support)

IRI Aim 4. Support development of scalable direct-to-participant trial platforms and novel consent systems.

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• Overview. Direct-to-participant research platforms can reduce the cost of multisite research dramatically by eliminating study visits and can provide new ways of engaging underrepresented communities in research.

• Achievements, current status, and barriers. Notable examples of Internet-based research are few but UCSF is in the vanguard. The Health eHeart Study and Health eHeart Alliance (a Patient-Powered Research Network [PPRN] funded by PCORI) have recruited nearly 30,000 participants over the Internet and will host RCTs on its platform. Mytrus, a commercial company founded by IRI Steering Committee member Steve Cummings, has pioneered novel Web-based consent systems and will support PCORnet’s ADAPTABLE trial.6 The UCSF Coordinating Center currently hosts a direct-to-participant platform for the Brain-M Study7 (Table 3), which is randomizing participants and delivering active and placebo pills by mail. The PRIDE Study and PRIDEnet (a new UCSF-based PCORI-funded PPRN; Table 3) has launched a ResearchKit app that has engaged sexual and gender minorities nationwide in crowdsourcing research questions at a grand scale – PRIDE enrolled over 13,000 participants in 1 week (Table 3). Trialist, a mobile platform for n-of-1 studies, is being tested as a means to optimize treatment of chronic pain.8 We believe many direct-to-participant studies can be executed relatively simple, with an on-boarding sequence (information, screening, consent, randomization) and then timed online outcome measures. Success, however, requires artful design to inform participants fully and be user-friendly, implement effective engagement and retention strategies, and deliver individualized survey prompts based on prior responses and user preferences.

• Planned enhancements. To enable burgeoning innovation in this area and support participatory study design and recruitment of underserved populations, we will: a) Develop a modular “plug-and-play” system to support direct-to-participant research. Along with our

UCSF-based solutions, a number of commercial (e.g., Apple’s ResearchKit, Google’s PACO) and academic systems (e.g., Sage Bridge) already exist for delivering scriptable direct-to-participant surveys. After due diligence, we will build or partner with existing systems to provide UCSF researchers with an affordable platform and options for defining, delivering, and managing participant surveys and engagement for a variety of Web and mobile platforms. This platform will use Open mHealth and other open standards to promote interoperability, and will integrate with the larger IRI infrastructure.

b) Develop infrastructure to engage participant communities in research and novel consent development. (See also Part E.2) PPRNs in PCORnet such as the Health eHeart Alliance, PRIDEnet and the Community Engaged Network for All (CENA) are collaborating on design and implementation of community engagement mechanisms such as UCSF’s Open Proposals platform (Part A) and CENA’s eConsent system, the Platform for Engaging Everyone Responsibly (PEER; see Part E.2). We aim to share these technical solutions and strategies through PCORnet and the CTSA consortium.

c) Coordinate efforts with the Participant Recruitment Unit (RIC Liaison) and Special Populations Initiative to support participant recruitment for direct-to-participant studies via paid advertising, social media, and other means with a focus on engagement of underrepresented populations (Parts F.2 and G.2).

IRI Aim 5. Coordinate efforts with colleagues across the CTSA Consortium, PCORnet, BD2K, and UC BRAID in development of methods, shared informatics infrastructure, and multisite research. We anticipate and will help lead a new world of distributed participatory research, incorporating multi-modal “big data” that can easily be embedded in frontline care. In this connected world, UCSF must plan to be a node within a larger research cyberinfrastructure.9,10 Our team is highly engaged with all major national biomedical research consortia: the CTSA Consortium (Pletcher and Berman from EIA sit on Domain Task Forces), PCORnet (through 1 CDRN and 2 PPRNs), BD2K (Sim is Consortium Lead of the Mobile Data to Knowledge Center BD2K center), and the UC BRAID network. Our consortium activities will include:

a) Data standards adoption. The EIA team will oversee adherence to EHR data standards and evaluation of new standards such as FHIR. Dr. Sim will head the data standards strategy for mHealth data, and will be the key liaison to evolving BD2K standards around metadata, data discovery (from the BioCADDIE project11), and NIH Commons specifications. We plan to use Global Alliance APIs12 for genomic data.

b) Adopting/adapting tools from other CTSA hubs, dissemination of locally built tools, and other network activities. We will continue to proactively build and adapt CTSA-wide tools (e.g., Profiles) for internal use and support external adoption/adaptation of tools we build (see Resource Sharing Plan, Part A). Through UC ReX (represented by CTSI CIO Yuan and EIA’s Dobbs), we will collaborate with i2b2 SHRINE standards and tools, and through our 2 PPRNs and 1 CDRN, we will adopt and adapt both OMOP and PCORnet CDM data models and tools. We will also adapt tools from the U2C-funded Health eHeart Study for mHealth research, and from the Mobile Data to Knowledge Center for sensor-data analytics.

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Security and Protection of Research Data and Patient Privacy. Keeping our data secure and private is a top priority for UCSF and an area of intense focus over the past 2 years. UCSF’s Chief Information Officer (see Bengfort Letter of Support) reports directly to the Chancellor for all IT Security matters, oversees IT security for our campus with input from key governance committees including the IT Governance Committee (on which CTSI is heavily represented) and the Privacy and Security Committee. UCSF IT maintains clear security policies,13 which include universal encryption of laptops and desktops, hard drives, password standards, network firewalls, regular updates to most recent security patches, and use of anti-virus software. IT enforces these policies through a highly centralized IT Field Services Unit, use of an Endpoint Management client (installation of which is required on all laptops, desktop computers, and servers connected to the UCSF network), and formal access control provisions to ensure appropriate access approvals and attestations are in place. All UCSF faculty and staff involved with research undergo required training that includes a major focus on data security and privacy. The EIA team (which reports to Bengfort) maintains MyResearch, the heavily-used state-of-the-art secure research portal that provides critical analytic tools within a secure environment that carefully restricts and audits access to data (see IRI Aims 1 and 2). David Dobbs, Executive Director of EIA and IRI Steering Committee member, will help us coordinate with IT and plan security audits of all IRI efforts to facilitate access to data. B.3. Leadership Director Mark Pletcher is PI of the Health eHeart Study and a multisite trialist; Co-Director Ida Sim is co-founder of Open mHealth, Consortium lead for MD2K; and Co-Director Atul Butte is Director of UCSF Institute for Computational Health Sciences. Pletcher, with CTSI CIO Leslie Yuan, will lead operations, coordinate technical development, and support Demonstration Projects through weekly operations meetings and will chair the IRI Steering Committee (Table 2), which will meet monthly to oversee IRI operations and coordinate efforts with the key informatics resources they lead across campus. Sim will oversee data standards implementation and coordinate consortium activities. Butte will lead efforts to develop informatics infrastructure to support early translational research and precision medicine interventions. B.4. Evaluation and Tracking The metrics below will be reviewed regularly by the IRI Steering Committee (via automated reports as possible), and used in operational decision-making and prioritization of resource use.

Aim / Milestone Metric for Assessment Aim 1. Support efforts to derive research measurements from clinical EHR data Safe Harbor Tables available for research exploration # of investigators/projects utilizing this resource Support for i2b2 SHRINE & PCORnet common data models # of requests serviced; # distributed research data queries (via

PopMedNet) responded to API-based mechanism for exporting EHR data # of studies utilizing this mechanism; # of data elements transferred IBM InfoSphere-based code library launched # of registered code entries and # of searches conducted Consultants and courses to support usage # of consultants; # requested consults; # of students registered Aim 2. Coordinate and develop infrastructure for using “non-traditional” data sources within clinical trials mHealth data collection module # of UCSF studies incorporating mHealth measurements EHR data collection module # of UCSF studies incorporating EHR outcome measurements Core Lab interface with research study management system # of Core Lab systems integrated Randomization embedded in care delivery systems # of randomization events supported during care delivery Aim 3. Enable development of interventions and data collection via Epic-based EHR system Introduce collection of research-grade variables via EHR # of measurement types collected via EHR Import measurements and decision support into EHR # of measurements/decision support tools importable into EHR Develop local clinical champions who consult on research # of clinical champion consultants; # of consultations; # of hours Aim 4. Support development of scalable direct-to-participant trial platforms and novel consent systems Develop modular direct-to-participant system # of studies supported; cost/study; time to launch Develop mechanisms to engage communities # of studies incorporating engagement features Develop a “consent laboratory” # of studies using the laboratory methods and IRB protocol Coordinate with Participant Recruitment Service/RIC Liaison # of direct-to-ppt studies supported by Participant Recruitment Unit Aim 5. Coordinate efforts with colleagues across the CTSA Consortium, UC BRAID, and PCORnet Data standards adoption # of research projects incorporating IRI-supported standards Collaborate in networks # of methods/resources co-developed or adapted for UCSF; # of

methods/resources released to networks from UCSF; # of multisite network studies engaging UCSF researchers

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References for Part B. Informatics and Research Innovation

1. Kahlon, M., et al., The use and significance of a research networking system. Journal of medical Internet research, 2014. 16(2).

2. U.S. Department of Health & Human Services. Guidance Regarding Methods for De-identification of Protected Health Information in Accordance with the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule. [cited 2015 Sep 14]; Available from: http://www.hhs.gov/ocr/privacy/hipaa/understanding/coveredentities/De-identification/guidance.html.

3. Open mHealth. Health Data that Makes Sense. 2015 [cited 2015 Aug 27]; Available from: http://www.openmhealth.org/.

4. Health eHeart. Join the study to end heart disease. [cited 2015 Aug 27]; Available from: https://www.health-eheartstudy.org

5. Department of Health and Human Services. Mobilizing Research: A Research Resource to Enhance mHealth Research (U2C). [cited 2015 Aug 27]; Available from: http://grants.nih.gov/grants/guide/rfa-files/RFA-OD-15-129.html.

6. PCORnet. ADAPTABLE Aspirin Study. [cited 2015 Aug 27]; Available from: http://www.pcornet.org/aspirin/.

7. BRAiN-M. Migraine Study. [cited 2015 Aug 27]; Available from: https://brain-m.epi-ucsf.org/. 8. Barr, C., et al., The PREEMPT study-evaluating smartphone-assisted n-of-1 trials in patients with

chronic pain: study protocol for a randomized controlled trial. Trials, 2015. 16(1): p. 67. 9. Farcas, C., N. Balac, and L. Ohno-Machado. Biomedical CyberInfrastructure challenges. in

Proceedings of the Conference on Extreme Science and Engineering Discovery Environment: Gateway to Discovery. 2013. ACM.

10. National Institutes of Health. The Commons - Overview. [cited 2015 Sep 15]; Available from: https://datascience.nih.gov/commons.

11. bioCADDIE. [cited 2015 Sep 14]; Available from: https://biocaddie.org/. 12. GA4GH. GA4GH Data Working Group. [cited 2015 Sep 14]; Available from: http://ga4gh.org/. 13. UCSF Information Technology. All IT Standards and Policies. [cited 2015 Sep 14]; Available from:

http://it.ucsf.edu/security/policies.

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Part C. Community and Collaboration The CTSI Community Engagement (CE) Program brings together faculty, staff, and trainees with expertise in community-based participatory research, practice-based research networks, and evidence-based policymaking. CE’s activities are woven deeply into the fabric of the San Francisco Bay Area, as it partners in a true team science approach with civic agencies, community-based organizations, health plans, providers, and policymakers to conduct stakeholder-engaged translational research aimed at improving the health of vulnerable populations. The CE Program will work with its partners with the goal of enabling the following CE Aims: CE Aim 1. Offer a core portfolio of consultative, training, linkage, and other technical assistance to strengthen academic and community capacity to conduct stakeholder-engaged research; CE Aim 2. Advance innovative community-engaged translational methods and practices to local, regional, and national stakeholders; and CE Aim 3. Apply CE’s model of Systems-Based Participatory Research to fully engage regional community-based health organizations as partners in translational science using EHR data. The CTSI Multidisciplinary Team Science (TS) Program is focused on helping investigators identify collaborators within and outside of UCSF, catalyze the robust multidisciplinary teams that are required to successfully conduct complex translational science, and ensure that team scientists receive appropriate academic recognition. The TS Program will accomplish this goal by addressing the following TS Aims: TS Aim 1. Facilitate and support formation and development of multidisciplinary research teams, particularly teams that include CTSI’s clinical affiliates and regional partners (Kaiser Permanente, Benioff Children’s Hospital Oakland, Children’s Hospital Oakland Research Institute, and UC Berkeley), statewide collaborators (UC BRAID), and with national CTSA and PCORI partners; TS Aim 2. Advocate to ensure that contributions of members of multidisciplinary research teams are recognized for academic advancement; and TS Aim 3. Train junior investigators to develop and work in effective multidisciplinary teams.

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SPECIFIC AIMS The CTSI Community Engagement Program (Section C.1) brings together faculty, staff, and trainees with expertise in community-based participatory research, practice-based research networks, and evidence-based policymaking. Our activities are woven deeply into the fabric of the San Francisco Bay Area, as we partner in a true team science approach with civic agencies, community-based organizations, health plans, providers, and policymakers to conduct stakeholder-engaged translational research aimed at improving the health of vulnerable populations. CTSI Multidisciplinary Team Science initiatives (Section C.2) are aimed at helping investigators identify collaborators within and outside of UCSF, catalyze the robust multidisciplinary teams that are required to successfully conduct complex translational science, and ensure that team scientists receive appropriate academic recognition. COMMUNITY ENGAGEMENT (CE) CE has developed and demonstrated the effectiveness of an innovative approach to community-engaged research that fuses principles of Community-Based Participatory Research and Practice-Based Research Networks and stresses partnering with organized systems to increase translational science efficiency and impact. Using these Systems-Based Participatory Research methods, we have built the San Francisco Health Improvement Partnership (SFHIP), which has recently been adopted as the platform for the San Francisco citywide Community Health Improvement Plan. An emphasis on the science of health policy has helped us develop acceptable and sustainable interventions, such as the Alcohol Environment Index for monitoring alcohol as a public health risk factor, now supported by the SF Department of Public Health and the UCSF Healthy Beverage Initiative, which has made UCSF the first academic medical center in the US to ban the sale of sugary beverages. We will continue and expand this work with the following Aims: CE Aims CE Aim 1. Offer a core portfolio of consultative, training, linkage, and other technical assistance to strengthen academic and community capacity to conduct stakeholder-engaged research. CE Aim 2. Advance innovative community-engaged translational methods and practices to local, regional, and national stakeholders. CE Aim 3. Apply our CE model of Systems-Based Participatory Research to fully engage regional community-based health organizations as partners in translational science using EHR data. MULTIDISCIPLINARY TEAM SCIENCE (TS) Today’s complex clinical and translational research demands fluid input from teams composed of investigators from multiple disciplines, domains of expertise, and methodologic capabilities. Team science has the potential to greatly accelerate both scientific discovery and the implementation of scientific advances, yet there continue to be important barriers to effectively developing teams and gaining appropriate recognition for team members. The CTSI Team Science Working Group, in collaboration with the Pilot Translational and Clinical Studies program (Part D.2), created “Team Science” pilot awards, worked with the CTSI technology team to implement UCSF Profiles as a premier research networking tool, partnered with the K Scholars program to provide team science workshops, and worked with leaders of the Department of Medicine to revise guidelines for advancement that specifically recognize contributions to team science. We will build on these accomplishments with the following Aims: TS Aims TS Aim 1. Facilitate and support formation and development of multidisciplinary research teams, particularly teams that include our clinical affiliates and regional partners (Kaiser Permanente, Benioff Children’s Hospital Oakland, Children’s Hospital Oakland Research Institute, and UC Berkeley), statewide collaborators (UC BRAID), and with national CTSA and PCORI partners. TS Aim 2. Advocate to ensure that contributions of members of multidisciplinary research teams are recognized for academic advancement. TS Aim 3. Train junior investigators to develop and work in effective multidisciplinary teams.

Part C. Community and Collaboration

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RESEARCH STRATEGY C.1. COMMUNITY ENGAGEMENT (CE) C.1.a. Overview and Innovation CE is dedicated to a fundamental principle articulated by NCATS: improvements in health are accelerated when non-academic stakeholders are deeply involved as partners in the research enterprise. CE has crafted and demonstrated the effectiveness of an innovative approach to stakeholder-engaged translational research. Although grounded in the disciplines of Community-Based Participatory Research (CBPR) and Practice-Based Research Networks (PBRN), our unique approach fuses those approaches into a methodology we have defined as Systems-Based Participatory Research1 (SBPR). SBPR stresses partnering not just with individual patients, clinicians, and community members, but also with organized systems to increase translational science efficiency and impact. As described below, our local efforts in San Francisco have built strong countywide partnerships with the public health department, school district, hospitals, Board of Supervisors, and other stakeholder groups to study and implement sustainable community-based interventions. Similarly, our PBRN, the SF Bay Collaborative Research Network (SFBayCRN), has partnered with large medical groups and consortia of community health centers to study primary care innovations and develop processes for sharing electronic health record (EHR) data for translational research. An additional unique aspect of our SBPR methodology is an emphasis on the science of health policy, which provides insights into the structural, regulatory, organizational, payment, and financial factors that often determine the success of efforts to translate stakeholder-engaged research into sustainable practice. Engagement with policymakers also creates opportunities to sustain interventions with new funding streams and public policies. C.1.b. CE Achievements In 2010, CE catalyzed establishment of the SF Health Improvement Partnership (SFHIP), a multi-stakeholder collaborative dedicated to improving health and eliminating health disparities. SFHIP was selected by San Francisco Mayor Ed Lee as the platform for San Francisco’s citywide Community Health Improvement Plan. CE serves on the SFHIP Steering Committee with the SF Department of Public Health and SF Hospital Council, along with 12 organizations including representatives of ethnic-based community health equity coalitions and the SF Unified School District. Driven by stakeholder concerns, SFHIP’s efforts to improve health have centered on childhood obesity, hepatitis B screening and treatment in Asian Americans, childhood dental caries, and alcohol-related violence in low-income neighborhoods. CE brings translational science capabilities to these efforts, including content and methodology expertise, data analysis, evaluation skills, and facilitation of mutually respectful partnerships among researchers and diverse stakeholders. Another major CE initiative, the SFBayCRN, includes a network of over 1000 clinicians working at more than 100 clinical sites in the 9 Bay Area counties, and has provided research design consultation and practice recruitment services for multiple federally funded studies over the last decade. SFBayCRN has also contributed to the growing literature on strategies to increase research participation in PBRNs.2,3 Recently, SFBayCRN, with a subgroup of members, has been testing the feasibility of using EHR data for regional collaborative quality improvement initiatives to identify potentially eligible study participants and to conduct practice-based translational research.

CE Achievements SFHIP Overall • 2012 AAMC Spencer Foreman Award for Outstanding Community Service

• 2012 Special Commendation from the SF Board of Supervisors SFHIP Physical Activity and Nutrition

• Provided scientific evidence to support sugary beverage policies introduced in SF Bay Area counties • With UCSF Wellness, developed and implemented the UCSF Healthy Beverage Initiative, making UCSF the

first academic medical center in the US to ban the sales of sugary beverages SFHIP Alcohol Policy

• With SF General Hospital, measured blood alcohol on all trauma patients, demonstrating a strong association between alcohol-related trauma and geographic density of retail alcohol outlets

• With SF DPH and community groups developed an Alcohol Environment Index for monitoring alcohol as a public health risk factor and created an online interactive mapping tool to visualize relationship between density of alcohol retail outlets and alcohol-related health outcomes

SFHIP Children’s Oral Health

• Translated scientific evidence on prevention and treatment of childhood caries into the first Children’s Oral Health Strategic Plan for San Francisco, which was endorsed by the SF Health Commission and included using fluoride varnish applied by SF School District nurses

SF Bay CRN • Provided research design and recruitment services to federally funded projects engaging >50 clinical sites • Partnered with major health systems in SF to develop the Hepatitis B Quality Improvement Collaborative • Launched the Hypertension Data Collaborative (HDC) to demonstrate the feasibility of using EHR data for

regional QI initiatives and practice-based research in community health centers serving vulnerable populations

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CE Consultation • Since 2010, provided 183 consultations for proposals, publications, evaluations, data sources, and linkages CE Training • Trained 248 students in formal courses and 580 students in best practices in community-engaged research

• Provided service learning activities to 48 students (medical, nursing, public health, public administration) • Trained 8 community members in qualitative research methods and 12 in community research board roles • Trained more than 200 community members on translational science content material

C.1.c. Approach to CE CE Aim 1. Offer a core portfolio of consultative, training, linkage, and other technical assistance. CE will build on our existing core activities that engage UCSF researchers with our community-based SFHIP and SFBayCRN partners, as well as forging new partnerships to improve health outcomes for stakeholder-identified health priorities. The portfolio of options are: 1) structured consultations for UCSF investigators and community stakeholders on methods and strategies for specific translational research projects; 2) trainings in stakeholder-engaged research methods targeting both academic and community settings - including formal courses in the CTSI Training Program Implementation Science pathway, workshops for community-based organizations on implementation and evaluative science, and mentoring and supervising KL2 and TL1 Scholars for service learning projects integrated into CE activities; and 3) actively facilitating linkages between UCSF investigators and community-based partners with a focus on research in diverse community settings. CE Aim 2. Advance innovative community-engaged translational methods and practices to local, regional, and national stakeholders. SFHIP and SFBayCRN are laboratories for developing and field-testing CE’s unique model of stakeholder-engaged translational science. We will intensify a knowledge exchange plan targeting local, regional, and national stakeholders to highlight the role of our SBPR model of stakeholder-engaged translational research in addressing health disparities. The process will entail engaging our academic and community partners to more systematically evaluate and reflect on key accomplishments and lessons learned. From our many projects, we will together identify our model’s most promising strategies and methods, and prioritize academic and community venues to achieve optimal knowledge transfer, including via the CTSA Domain Task Force (represented by Dr. Grumbach). Examples of planned dissemination activities are sharing best practices to limit sugary beverages with Dignity Health, the nation’s fifth largest health system, and spreading our novel geomapping database tool for alcohol outlets in SF (Figure, right) through the Community Commons, a national online interactive mapping utility. We will also collaborate with our community partners to organize a biannual “Participatory Research Symposium” at UCSF to highlight exemplary stakeholder-engaged research involving UCSF and community partners. CE Aim 3. Apply our CE model of Systems-Based Participatory Research to fully engage regional community-based health organizations as partners in translational science using EHR data. Part B (Informatics and Research Innovation [IRI]) describes CTSI’s emerging capabilities and proposed initiatives to accelerate application of EHR data for translational research. CE plans to complement these initiatives to engage regional health organizations, reaching beyond academic health centers to partner with community-based health systems. Accelerating EHR-based research in these settings requires not only overcoming the technical IT challenges described in Part B, but also surmounting the cultural, organizational, and political difficulties and sensitivities regarding sharing data from diverse non-academic clinical organizations. The great promise of doing so is to enable more efficient translational research in much more representative practice settings and populations. The key to gaining access to these data is to engage health system stakeholders as research partners motivated to function collaboratively as Learning Health Systems4 whereby research advances both local system improvement and broader scientific aims. Our SBPR approach positions us to engage organizations as a whole, including the organization’s governing body and IT leadership, which control EHR systems and data access. With technical assistance from IRI and UCSF Academic Research Systems (ARS), SFBayCRN will work with regional community partners to develop standard operating procedures to promote EHR-based translational science. SFBayCRN has already established the Hypertension Data Collaborative (HDC), a partnership among UCSF and Bay Area safety net health center consortia representing over 55 clinical sites in 6 counties. With assistance from CE and ARS, the HDC is developing a shared EHR clinical data repository to facilitate

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hypertension research and quality improvement activities. A new opportunity has arisen to gain access to EHR data from several large health care organizations in the same counties. In 2015, the UCSF Health System helped organize a federation of more than a dozen SF Bay Area community hospitals and medical groups to create the Bay Area Accountable Care Network (BAACN). CE Co-Director Dr. Grumbach, in his role as Vice President for Population Health for UCSF Health, serves on BAACN’s Board. Harmonization of EHR data is essential for BACCN’s clinical operations, providing an unprecedented opportunity for digitally empowered translational research across BAACN organizations. Together, the BAACN and HDC safety net initiatives can potentially provide access to EHR data for about 1 million ethnically and economically diverse patients from community-based settings in the region. In addition to providing data for clinical research, the large, representative population will permit us to assess community-level trends in health behaviors and risks. Our goal for the coming years will be to systematically build the infrastructure for conducting EHR-based research among these community-based organizations. To do this we will: 1) strengthen our multi-stakeholder relationships by explicitly defining shared translational science objectives involving use of EHR data (as has occurred for the HDC project); 2) address regulatory and governance issues (e.g., institutionalizing “opt out” patient consent procedures; deciding who can access shared data under what terms), and 3) develop and refine data management processes (e.g., beginning with standard procedures for uploading de-identified data into a common analytic database—the approach being used for the initial HDC project-- and moving towards more robust common data models and ETLs that permit cross-institutional analyses of EHR data). C.1.d. CE Leadership Kevin Grumbach, MD, CE Co-Director, is Professor and Chair, Department of Family and Community Medicine; Vice President for Population Health, UCSF Health. With Dr. Schmidt, he will oversee all operations of CE, serve on the SFHIP Steering Committee, and facilitate research collaborations with BAACN. Laura Schmidt, PhD MSW MPH, CE Co-Director, is Professor of Health Policy Studies. With Dr. Grumbach, she will oversee all operations of CE, serve as the primary faculty resource for consultation, training, and technical assistance on policy, and provide substantive support in obesity and alcohol research. Michael Potter, MD, Associate Director for Practice-Based Research, is Professor of Family and Community Medicine. As Director of the SFBayCRN, he will oversee SFBayCRN operations, including the new regional EHR-based data projects. C.1.e. CE Evaluation and Tracking

Aim / Milestone Metric for Assessment and Frequency Aim 1: Offer core portfolio of consultative, training, linkage, and other technical assistance Consultations Annual # of consultations

Annual # case studies of consultations for special populations Trainings Annual # of trainings

Annual # of trainings focused on/for special populations Linkages Annual # of linkages made between UCSF and community

Annual # case studies of linkages for special populations Aim 2: Advance innovative community-engaged translational methods and practices to local, regional, and national stakeholders CE knowledge transfer and exchange plan Plan and timeline in place for CE knowledge transfer and exchange Community-engaged publications/presentations Annual # of CE local publications/presentations

Annual # of CE regional publications/presentations Annual # of CE national publications/presentations

Aim 3: Engage and support regional health system stakeholders to integrate EHR data Convene BAACN and safety net clinic consortia collaborative Annual # of meetings of governance and research planning groups

Written agreements on EHR data sharing Annual # of EHR analytic data bases created for research Bi-annual social network analysis Annual sustainability and network effectiveness index

C.2. COLLABORATION AND MULTIDISCIPLINARY TEAM SCIENCE (TS) C.2.a. Overview and Innovation UCSF is an institution built on multidisciplinary teamwork. From our cross-cutting PhD programs in Biomedical Sciences, to our multidisciplinary “Organized Research Units,” to our collaborations with Bay Area biotech companies, we have been at the forefront of this discipline for decades (see Vignette). CTSI created the

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TS Working Group to advocate and promote TS activities across Campus.

C.2.b. TS Achievements Funding team science. The CTSI TS Working Group collaborated with the CTSI Pilot Translational and Clinical Studies (PTC) program to initiate Team Science Awards that support multidisciplinary teams to develop multisite clinical trials. PTC has funded 6 team pilot projects; other intramural funding sources supported an additional 7 projects. As an example, we funded a project entitled: “Managing Uncertainty in Translational Research: Developing a Transdisciplinary Approach to the Ethics of Patient Choice in Breast Cancer Screening” that included members from the Schools of Nursing and Medicine, with specializations in bioethics, breast oncology, genomics, medical anthropology, and radiology. Facilitating Multidisciplinary Team Development. UCSF Profiles, a nationally recognized research networking tool, provides faculty with a Web page to feature their work (with listings of publications, grants, and co-authors), indexed to searchable keywords, which allows them to be easily found by, and to find, potential collaborators within and outside of UCSF. Profiles had 1.2MM visits last year, over 1MM of these from potential “teammates” outside UCSF. CTSI, in partnership with the UCSF Research Development Office (RDO), is developing an innovative online tool “UCSF Collaborators Wanted,” which allows investigators to list ideas, projects, and resources when searching for collaborators. Investigators who “find” each other are provided with in-person support, including team leadership training and help developing funding opportunities. Training young investigators in team science. Young investigators at UCSF have a wealth of role models and mentors who strongly promote team science, including UCSF Executive Vice Chancellor and Provost, Dan Lowenstein (See Vignette).

With background didactics from Northwestern University’s SciTS initiative and other shared CTSA team science materials, workshops on team science have been integrated into the curriculum of both the KL2 and TL1 training programs. In addition, works-in-progress sessions have served as incubators for new teams to develop among junior investigators: 45% of K Scholars recently surveyed (N = 42) reported publications or grants with other K scholars. Collaborative teams have been sustained over time, including a recent publication from a team with both current and former K scholars from pulmonary, general medicine, genetic epidemiology, and nephrology.5 Updating promotions guidelines to support team science. Traditional academic culture values individual contributions to science, operationalized by serving as the Principal Investigator on grants and contracts and as first or last author on publications. This meme is a major barrier to recognition for investigators involved in team science who play a key role, but may not be the PI or first author. The TS Working Group initiated discussions with the Department of Medicine, by far the largest department at UCSF, to identify ways to recognize the unique contributions of members of multidisciplinary teams. Led by Dr. Mike McCune (TS Working Group leader and founding Director of CTSI), the Department of Medicine explicitly incorporated recognition of team science in its revised promotions guidelines by providing a specific mechanism for evaluating the importance of contributions by team scientists and “middle authors,” including attestation letters from the department chair, team leaders, PIs and senior authors. These changes allow faculty a mechanism to highlight their important contributions to team science in the promotions process and provide a clear model for improving the promotions process in other departments and across the institution and other CTSA hubs. Promoting a culture of team science by recognizing outstanding teams. CTSI’s efforts to promote team science have tangibly changed the environment at UCSF and have increased recognition of teams. For example, the 2013 UCSF Academic Senate Annual Faculty Research Lecture was awarded not to a single scientist (as is traditional), but to a research team. The lecture highlighted the many contributions that led to the team’s

Vignette: Team science advances understanding and treatment of HIV. UCSF faculty have led a multidisciplinary response to the AIDS epidemic since 1980. Jay Levy’s team co-discovered HIV-1. Paul Volberding’s team developed the nation’s first multidisciplinary clinical care units, integrating oncologists, pulmonologists, and ID specialists, and led the first clinical trials of antiretroviral therapy. These early efforts integrated basic scientists, clinical investigators, clinicians, and community activists. The legacy continues as our multidisciplinary HIV research programs tackle the highest research priorities of the modern HIV epidemic - HIV cure, multi-morbidity and aging, prevention, and the cascade of care.

Vignette: Dr. Dan Lowenstein leads The Epilepsy Phenome Genome (EPGP) Project, an international, multisite, NIH-funded study aimed at identifying the gene mutations causing various forms of epilepsy. At the core of EPGP’s success has been its reliance on a large team of scientists and clinicians, representing a broad range of disciplines, who work together collaboratively and recognize that this form of close scientific collaboration can accelerate the pace of science and its translation into benefits for patients.

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groundbreaking work on strategies to cure HIV, rather than the specific accomplishments of the team leaders. The fliers advertising the lecture included a group photo along with headshots of the lead researchers (see image, right). We will advocate for the Academic Senate to add an annual campus-wide “Team Science Research Award” to our existing Faculty Research Lecture. C.2.c. Approach to Multidisciplinary Team Science Going forward, we will integrate the emerging science of team science6,7 into our team identification and development/coaching programs, as well as leverage local resources and expertise, including management and team organization expertise in the UCSF Center for the Health Professions and the RDO. Offerings cover a progressive series of team-building activities that include structured mechanisms to support team formation, fostering of nascent collaborations, maintenance of good team health, and coaching of mature teams through challenges associated with large group dynamics, such as evolving team vulnerabilities and managing conflict. The team science activities have the ultimate goal of fostering innovation and enabling deep knowledge integration within the team. TS Aim 1. Facilitate and support formation and development of multidisciplinary research teams. • TS Pilot Award Program. In collaboration with the CTSI Pilot Translational and Clinical Studies program (Part

D.2), TS will continue to provide pilot funding for collaborative research teams. The goal of the TS Pilot Award is to stimulate new collaborations of scientists from diverse fields, including basic, clinical, behavioral and social research, that address research questions requiring an innovative, multidisciplinary approach. We strongly encourage teams that are diverse based on gender, ethnicity, race and other characteristics. This award will provide funding to develop complex transdisciplinary research projects, including arranging meetings of investigators, performing preliminary studies, evaluating success, and preparing collaborative grant applications. In the coming years, we plan to improve and expand our TS Pilot Award program by: − Extending funding. The initial round of single-year awards supported projects with high potential, but

recipients reported that 1 year was not adequate to mature successful teams. In response, we plan to allow teams to apply for a second year of funding, contingent on meeting specified deliverables.

− Discovering what works. To learn from the experience of funded teams, our funding agreement will require preparation of a semi-annual written report on challenges and opportunities for team development and operation, and meetings with the TS Working Group to discuss issues and how we might address them.

− Advertising broadly. To encourage teams with broad expertise, the TS Pilot Award program will be advertised at UC Berkeley, Kaiser Permanente, Benioff Children’s Hospital Oakland and across the UC BRAID network.

• Team consults. In addition to funding, we will provide expert consultation for funded teams by the RDO staff, who will meet regularly with teams to provide advice on team leadership, diversity, organization, communication, mutual fair recognition, and conflict management.

• Team Science Workshops. We will convene disease-focused workshops that include researchers from multiple disciplines and include short presentations followed by small group sessions to brainstorm potential collaborative projects. The initial workshop will feature the newly formed CTSI Special Populations Initiative (Part F.1) with a focus on vulnerable populations and include faculty and trainees from Pediatrics, Benioff Children’s Hospitals of SF and Oakland, Children’s Hospital Oakland Research Institute, the Division of Geriatrics and its affiliated Pepper Research Center, and the Center for Vulnerable Populations.

• Speed Networking. We will collaborate with the RDO to facilitate a series of interactive events that will bring targeted investigators, community members, and commercial partners together, provide a structured environment where each researcher makes a brief “elevator pitch,” and allow potential partners to state interest in further communication. We will provide small seed funding for up to 3 multidisciplinary projects per event to encourage interdisciplinary approaches to outstanding healthcare issues.

TS Aim 2. Ensure that the contributions of members of multidisciplinary research teams are recognized for academic advancement. • Promotions guidelines revisions to recognize team science. CTSI will build on its success in developing the

Department of Medicine promotions guidelines by helping other department chairs in the Schools of Medicine, Pharmacy, Nursing, and Dentistry to similarly revise promotions guidelines. CTSI’s Team Science

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Working Group will meet with individual department chairs (starting with Pediatrics, Neurology, Obstetrics and Gynecology, and Surgery), provide the Department of Medicine promotions guidelines as a template, and assist departments to implement these changes. We will also advocate with the Vice Provost for Academic Affairs to revise the UCSF-wide CV to provide a standardized format for describing team science activities. Dr. Peter Hunt, a member of the TS Working Group, has joined the Vice-Provost for Academic Affairs’ Committee on updating UCSF’s electronic CV format to help promote this initiative.

• Effective descriptions of team science activities. We will create, and draw attention to a library of effective descriptions of the value of team science contributions, via our Web site and other avenues. These will provide language and examples for letters of support from Chairs and letters of attestation from team leaders and first authors, as well as provide language for investigators to use on their own CV.

TS Aim 3. Train junior investigators to develop and work effectively in multidisciplinary teams. • Courses. In collaboration with team science experts in the Center for the Health Professions, RDO and the

CTSI Online Education program, we will develop and share an online, interactive course that focuses on the fundamentals of team science (leadership, diversity, organization, communication, mutual fair recognition, conflict management, etc.), incorporating resources from Northwestern University’s SciTS initiative and other shared CTSA materials, as well as instructive “case studies” of both successful and unsuccessful teams. Beginning in Spring 2016, this course will be required in all of our level-specific training programs, including the KL2 and TL1 trainees; we will also tailor the course for research coordinators and staff.

• Training. Both the TL1 and KL2 will continue their required multidisciplinary works-in-progress and seminar sessions that foster an appreciation for the value of multiple disciplines, and have been shown to nurture novel collaborations. The KL2 will expand focus on conduct and leadership of multisite trials and observational studies, and develop career development activities examining the unique opportunities and challenges faced by junior investigators on multidisciplinary teams. The KL2 will develop a new “teamlet” structure of scholars with complementary interests to actively promote new collaborations. (KL2 proposal). The TL1 plans to organize professional and post-doctoral scholars around theme-based research teams and organize didactic sessions that require team-based approaches to problem-solving (TL1 proposal).

• Expert consultation. The CTSI Consultation Service in partnership with the RDO, will offer expert consultation to teams of researchers seeking to form successful collaborations. Consultation will include assessment of team strengths and weaknesses and advice on leadership, diversity, organization, communication, mutual fair recognition, and conflict management. A toolkit of policies regarding the responsibilities of participating institutions and investigators, and guidelines on dissemination of findings and authorship will be provided.

C.2.d. TS Leadership TS Working Group Leader: Joseph “Mike” McCune, MD PhD, Professor and Chief of the Division of Experimental Medicine, first Director of CTSI, has extensive experience in team science focused on HIV pathogenesis, has been recognized by the Academic Senate for his team’s work on HIV cure, and prepared the initial draft of the revised Department of Medicine promotions guidelines promoting team science. TS Working Group Member Peter W. Hunt, MD, Associate Professor of Medicine (Infectious Diseases), is engaged in team science, has unique insights into the barriers to promotion for junior investigators, and serves on the UCSF Vice Provost of Academic Affairs committee on the format of UCSF CVs. TS Working Group Member Kirsten Bibbins-Domingo, MD PhD MAS, Professor of Medicine and Epidemiology and Biostatistics, is Director of the CTSI Training Program, Director of the UCSF Center for Vulnerable Populations at SFGH, and PI or joint PI of several U54 or P60 NIH collaborative research grants. Gretchen Kiser, PhD, Director of the UCSF Research Development Office, has been teaching and training teams for over 12 years, and is an expert consultant on Team Science. C.2.e. TS Evaluation and Tracking Aim / Milestone Metric for Assessment and Frequency TS Aim 1: Facilitate development of multidisciplinary research teams

# of Team Science grants awarded: annual # of teams that submit an extramural multidisciplinary grant after pilot period: annual # of publications arising from awarded teams: annual

TS Aim 2: recognized team science achievements

# of departments that change promotion guidelines to recognize unique contributions to multidisciplinary research: annual

TS Aim 3: Train junior investigators

# of teams formed by CTST trainees and # of resultant grants/publications: annual # of teams accessing consultations in team management and # of resulting grants/publications/presentations: annual

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References for Part C. Community and Collaboration

1. Schmittdiel, J.A., K. Grumbach, and J.V. Selby, System-based participatory research in health care: an

approach for sustainable translational research and quality improvement. The Annals of Family Medicine, 2010. 8(3): p. 256-259.

2. Spears, W., et al., Use of Community Engagement Strategies to Increase Research Participation in Practice-based Research Networks (PBRNs). The Journal of the American Board of Family Medicine, 2014. 27(6): p. 763-771.

3. Getrich, C.M., et al., Cultivating a cycle of trust with diverse communities in practice-based research: a report from PRIME Net. The Annals of Family Medicine, 2013. 11(6): p. 550-558.

4. Grumbach, K., C.R. Lucey, and S.C. Johnston, Transforming from centers of learning to learning health systems: the challenge for academic health centers. JAMA, 2014. 311(11): p. 1109-1110.

5. Kangelaris, K.N., et al., Increased Expression Of Neutrophil-Related Genes In Patients With Early Sepsis-Induced ARDS. American Journal of Physiology-Lung Cellular and Molecular Physiology, 2015: p. ajplung. 00380.2014.

6. Stokols, D., et al., The science of team science: overview of the field and introduction to the supplement. American journal of preventive medicine, 2008. 35(2): p. S77-S89.

7. Vogel, A.L., et al., The team science toolkit: Enhancing research collaboration through online knowledge sharing. American journal of preventive medicine, 2013. 45(6): p. 787-789.

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Part D Translational Endeavors: Translational Workforce Development and Pilot Translational and Clinical Studies The CTSI Translational Endeavors Programs aims to educate, train, and mentor a highly qualified, diverse translational workforce by sustaining and expanding its nationally recognized CTSI Training Program (CTST), providing training and certification for research staff, and broadening its reach through focused online offerings. This highly trained workforce will be supported by providing pilot funding to advance the development of innovative clinical and translational methods that advance CTSI’s overall goals for the next funding period. In Translational Workforce Development (TWD), CTSI will address the following Aims: TWD Aim 1. Continue and expand didactic and degree-granting programs. The Training in Clinical Research (TICR) Program will address specific needs for the conduct of high quality research in the areas of research informatics, precision medicine, multi-level risk prediction, and research in special populations; TWD Aim 2. Continue, expand, and enhance existing level-specific training programs. The CTSI Training Program (CTST) will include a greater emphasis on research informatics, precision medicine, multisite trials, research in special populations, as well as skills in leadership and the conduct of team science; TWD Aim 3. Continue and expand investigator and staff training in Responsible Conduct of Research and Good Clinical Practice, and develop research competency-based training for research staff; TWD Aim 4. Continue and expand online offerings to provide training to a broader group of investigators at UCSF, to other CTSAs, and to other institutions nationally; TWD Aim 5. Prioritize development of a diverse scientific workforce through the selection processes for all training programs, culturally competent mentoring, and specific diversity initiatives; and TWD Aim 6. Create and support a culture of mentorship, particularly for young clinical and translational researchers. In Pilot Translational and Clinical (PTC) Studies CTSI will address the following Aims: PTC Aim 1. Advance translational research methods, tools and infrastructure, especially those using research informatics and technology; PTC Aim 2. Promote multisite collaboration and team science; PTC Aim 3. Support research that advances precision medicine; PTC Aim 4. Advance research in special populations (children, the elderly, and disadvantaged groups), especially studies focused on vulnerable populations across the lifespan; and PTC Aim 5. Support underrepresented minority clinical and translational researchers conducting cutting-edge clinical and translational science.

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SPECIFIC AIMS We aim to educate, train, and mentor a highly qualified, diverse translational workforce by sustaining and expanding our nationally recognized CTSI Training Program (CTST), providing regular training and certification for research staff, and broadening our reach through focused online offerings. We will support this highly trained workforce by providing pilot funding to advance the development of innovative clinical and translational methods that advance our overall CTSI goals for the next funding period. TRANSLATIONAL WORKFORCE DEVELOPMENT (TWD) Through a process of life-long learning, trainees, faculty, and staff at UCSF will be positioned to design, conduct, analyze, and disseminate high quality clinical and translational research. We also aim to disseminate UCSF’s unique education and training programs to other CTSA hubs and research organizations. Achieving this vision will depend on integrating didactic and degree-granting programs, level-specific training and mentoring for trainees and faculty, and targeted training for research staff. Web-based learning opportunities will enhance accessibility of our training programs to the broadest possible national audiences. TWD Aims TWD Aim 1. Continue and expand our didactic and degree-granting programs. The Training in Clinical Research (TICR) Program will address specific needs for the conduct of high quality research in the areas of research informatics and research in special populations, including health disparities. TWD Aim 2. Continue and enhance our existing level-specific training programs. The CTSI Training Program (CTST) will include a greater emphasis on research informatics, multisite trials, research in special populations, as well as skills in leadership and the conduct of team science. TWD Aim 3. Continue and enhance investigator and staff training in responsible conduct of research and Good Clinical Practice, and develop research competency-based training for research staff. TWD Aim 4. Continue and expand our online offerings to provide training to a broader group of investigators at UCSF, to other CTSAs, and to other institutions nationally. TWD Aim 5. Prioritize development of a diverse scientific workforce through the selection processes for all training programs, culturally competent mentoring, and specific diversity initiatives. TWD Aim 6. Create and support a culture of mentorship, particularly for young clinical and translational researchers. PILOT TRANSLATIONAL AND CLINICAL STUDIES (PTC) PTC has been a powerful stimulus for research at UCSF by administering both NIH and UCSF institutional opportunity funds to support translational research and novel methods development by young faculty, underrepresented faculty, and those who aim to develop multidisciplinary teams. In the next funding period, we plan to use pilot funding to support CTSI overall aims to advance new technology-enabled research methods, team science, precision medicine, and research in special populations. PTC Aims PTC Aim 1. Advance translational research methods, tools and infrastructure, especially those using research informatics and technology. PTC Aim 2. Promote multisite collaboration and team science. PTC Aim 3. Support research that advances precision medicine. PTC Aim 4. Advance research in special populations (children, the elderly, and disadvantaged groups), especially studies focused on vulnerable populations across the lifespan. PTC Aim 5. Support underrepresented minority clinical and translational researchers conducting cutting-edge clinical and translational science. Through concerted TWD efforts, combined with meaningful research support from the PTC program, we expect our next generation of creative clinical and translational scientists/clinicians to be representative of our region’s rich diversity, expertly trained in cutting-edge methods, and poised to thoughtfully accelerate the evolutionary progress of 21st century science.

Part D. Translational Endeavors: Translational Workforce Development and Pilot Translational and Clinical Studies

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RESEARCH STRATEGY D.1. TRANSLATIONAL WORKFORCE DEVELOPMENT (TWD) D.1.a. Overview and Innovation Traditional competencies and mentoring in research design, biostatistics, and responsible conduct of research now must include facility with rapidly emerging, technology-enabled approaches to research. Investigators increasingly utilize electronic data sources, remote sensors, Web-based platforms, “big data,” and computationally intensive analyses, as well as skills in reaching populations currently understudied with our traditional approaches. In the next funding period, we will expand our nationally recognized degree-granting programs and level-specific training programs to anticipate specific needs for the conduct of high quality research and multisite studies. We will also provide broad regional and national access to our training programs with online offerings, and prioritize development of a highly diverse workforce. D.1.b. TWD Achievements To provide first-rate education and training for clinical researchers at all levels of experience, we created the CTSI Training (CTST) program. CTST has developed and integrated a comprehensive set of programs that serve a broad range of learners and provide flexibility for students to focus on research across the translational spectrum. Training in Clinical Research (TICR) is the core didactic program that serves all trainees, and we offer a PhD in Epidemiology and Translational Science. TICR includes 44 courses, a 4-course Research Methods Workshop, 1-year Advanced Training in Clinical Research (ATCR) Certificate, 2-year Master’s, and 5-year combined MD/Master’s. Students can focus their education across the translational spectrum, including early translational methods, clinical trials, and implementation science. Over the last 5 years, 274 students have completed ATCR or the Master’s. CTSI collaborated to develop the Master’s in Translational Medicine: a 1-year joint UCSF-UC Berkeley training program for engineers and clinicians integrating the scientific, technological, and business expertise required to drive health technology discoveries into clinical use. Our nationally acclaimed Comprehensive Mentoring Program has trained 102 mid-career mentors; 16 graduates have obtained NIH K24 Midcareer Awards and >100 faculty have completed the “Mentor Profile” on their UCSF Profiles page. In addition to courses and degree programs, CTST integrates level-specific training programs for undergraduates, professional students, residents, fellows, and faculty (Figure, right). Each CTST training component draws on TICR course offerings, provides level-specific mentoring and research experience, and is led by senior researchers who are nationally recognized for contributions to research methods and mentoring. D.1.c. Approach to TWD TWD Aim 1. Continue and expand our didactic and degree-granting programs. We will: • Continue the Master’s Programs in Translational Medicine and in Clinical Research, and ATCR Certificate. • Develop a series of courses on research informatics and precision medicine: “Medical Informatics,” led by Ida Sim, MD PhD, provides instruction in core concepts of informatics and

how computers are used to manage information and to support clinical research “Big Data Science,” led by Chuck McCulloch, PhD, (fall 2016) will address methods for obtaining data from

large datasets and data sensors, data storage, management, processing, and visualization “Machine Learning,” “Multi-level Risk Prediction,” and “Simulation Modeling” are planned for 2017-18 “UCSF Clinical and Research Data Warehouse (CRDW),” led by David Dobbs, Executive Director of

Networked Data Warehousing, will provide an introduction to healthcare syntactic and semantic data standards to facilitate understanding the structure and meaning of clinical data. Students will be trained in hands-on exercises to pull datasets from UCSF’s CRDW to address specific research questions

• Expand didactic offerings to support research in special populations across the lifespan, including short courses for a broad audience, and development of a track in the Master’s on health disparities

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• Collaborate with Community Engagement and the Special Populations Initiative (SPI) to ensure that course content supports research needs in these areas (see Parts C.1 and F.1)

TWD Aim 2. Continue and enhance our existing level-specific training programs: • K Scholars Program: We will continue our successful KL2 Mentored Career Development Program for ~10

junior faculty with support for protected time and research funding, as well as weekly seminars and works-in-progress, research mentoring, career development, and support from epidemiologists, biostatisticians, scientific editors, and other experts (see KL2 proposal). The K Scholars Program is made available (through institutional funding) to a broader group of 20-30 junior faculty with individual career development awards and diversity supplements, reinforcing the goal of broadening the reach of CTSI activities and ensuring the development of a robust, well-prepared cadre of junior faculty team scientists. The Program will enhance its focus on methodological and career development support to build careers in research informatics, multisite trials, research in special populations, and to enhance competencies in team science and leadership.

• TL1: The TL1 includes ~20 professional students annually from all 4 UCSF Schools (Dentistry, Medicine, Nursing, Pharmacy) supported by both NIH and institutional funding. We will refocus the TL1 on training in precision medicine, and expand our successful predoctoral program to include postdoctoral fellows (see TL1 proposal). We will attract professional students interested in precision medicine who will be admitted to an expanded 5-year program resulting in a Master’s in Clinical Research. The TL1 will provide stipend, tuition, works-in-progress, seminars, and mentoring over the year between the 3rd and 4th year of professional school. We will provide UCSF postdoctoral fellows - clinical fellows who desire a career in precision medicine and basic science PhD postdoctoral fellows who seek to pursue translational work - with 1-2 years of support to enhance training in clinical research methods and precision medicine research. Two fellows per year will be primarily located at Kaiser Division of Research and will use the UCSF/Kaiser “Research Program in Genes, the Environment and Health” database, which includes clinical, genomic, and geocoding data on over 200,000 persons. For these trainees, the TL1 Program will provide stipend, tuition, tailored didactic training, works-in-progress, seminars, and mentoring.

• Residency Research Training Program (RRTP): We will continue and enhance our program for ~110 clinical residents annually that includes a research methods course, development of a research protocol, mentored research projects, and competitive access to research funding (supported by institutional funds). The RRTP curriculum will be expanded to include the “Big Data Science” course described above, increased didactic emphasis on precision medicine, fund small research awards for projects that use electronic datasets to answer key clinical questions, and give priority to projects that involve residents from multiple clinical backgrounds.

• Pre-health Undergraduate Program: PuP hosts ~20 undergraduate students from across the country interested in clinical research (half from URM or disadvantaged backgrounds) teamed with TL1 trainees in a summer immersion program supported through institutional funds. PuP will be expanded and integrated with the newly funded U54 SF BUILD project (PI: Bibbins-Domingo-CTST Director) and R25 UCSF-CHORI (Children’s Hospital Oakland Research Institute) (PI: Lubin-CTSI SPI Co-Director) to provide more robust longitudinal research experience.

TWD Aim 3. To continue and enhance our investigator and staff training, we will ensure that investigators and staff are trained in Responsible Conduct of Research and Good Clinical Practice. We will create a research training program for Clinical Research Nurses, establish a Clinical Research Coordinator Core to provide on-going training, networking, and opportunities for professional development, and make basic clinical research education available to senior research staff via online courses, including “Designing Clinical Research” and “Responsible Conduct of Research.” Each of these efforts is described in detail in Part F. 2. TWD Aim 4. To continue and expand our online offerings, we will engage learners with full-time jobs by providing online and Web-based offerings that pair didactic education with robust faculty-led and peer-to-peer learning. The current asynchronous online courses created by the CTSI Online Education Program (which can also be used in the “flipped classroom” model) focused on research methods and responsible conduct of research will be extended to include: • Science writing – “Writing Clinical Research Reports”: an 8-module course providing readings, video

lectures, editing demonstrations, and exercises focused on each element of a manuscript • Clinical trials – “Introduction to Clinical Trials”: a 14-module course providing readings, video lectures,

exercises, and faculty-led development of a clinical trial protocol

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• Implementation sciences – “Translating Evidence into Practice”: a 7-module course providing readings, video lectures, exercises, and faculty-led development of an implementation project

• Product development – “Product Development and Commercialization”: a 20-module course including readings, Harvard Business School-like cases, and expert discussions to illustrate steps in development and commercialization of therapeutics, devices, diagnostics, and digital health (see Part H1)

TWD Aim 5. To prioritize development of a diverse scientific workforce, we will ensure that the selection processes for all of our education and training programs recognize and value diversity and that selection committee members are trained in unconscious bias. Detailed plans to maintain diverse training programs are described in the KL2 and TL1 proposals, and plans to promote faculty diversity are in Part 1, Sec. 1.5. TWD Aim 6. To create and support a culture of mentorship, the CTSI Comprehensive Mentoring Program1-

3 (directed by Mitchell Feldman, MD MPhil) created the Mentor Development Program (training for mid-career research faculty on effective mentoring), the Mentoring Unit of CTSI’s Consultation Service (which provides expert advice on difficult mentoring issues), the UCSF Profiles mentoring gadget, where faculty list accomplishments and availability for mentoring, the electronic mentor evaluation tool on the UCSF E-Value platform, and currently plays a lead role in the NIH National Research Mentoring Network (NRMN). We will work with each CTST training program to ensure mastery of best practices for being both a superb mentee and mentor by: • Working with the CTSI Online Education program to create a Web-based Mentor Training Program (MTP).

The online MTP will be based on our successful in-person course that has trained >100 mid-level faculty. We will also work with the NRMN to develop and include modules on “Mentoring Across Differences” that focus on mentoring women and underrepresented minorities.

• Collaborating with the UC Office of the President, and with start-up funds from the NRMN (Feldman; PI), we will form a UC-wide “Mentoring Advisory Group” with representation from all 10 UC campuses (including the 5 UC CTSAs) to identify mentoring best practices, with a special focus on URM mentees.

• Expanding use of the electronic mentor evaluation tool at UCSF and making the tool available to other CTSA hubs at UC BRAID and national CTSA networks.

• Enhancing the UCSF Profiles mentoring “gadget” to streamline the ability to find appropriate mentors; the tool is already freely available to other CTSA hubs using Profiles.

D.1.d. TWD Leadership Kirsten Bibbins-Domingo, MD PhD MAS, Professor of Medicine and CTST Director provides direction and leadership to all activities of the CTST and its Program Directors, overseeing academic, research, and service functions, and ensuring that program goals are met on time. Dr. Bibbins-Domingo will act as MPI of the KL2 and TL1 awards, facilitating integration and synergy of these core programs into the broader CTST activities. Douglas Bauer, MD, Professor of Medicine and KL2 Director provides leadership for all KL2 activities, overseeing selection, training, and mentoring of scholars and programmatic goals. Joel Palefsky, MD, Professor of Medicine/Laboratory Medicine and TL1 Director provides leadership for all TL1 activities, overseeing selection, training, and mentoring of trainees, and programmatic goals. Alison Huang, MD MCR, Associate Professor of Medicine and Director of the Resident Research Training Program oversees all activities of the RRTP and ensures that goals are met on time. Peter Chin-Hong, MD, Professor of Medicine and Director of the Pre-Health Undergraduate program oversees selection, training, mentoring, and program evaluation. Deborah Grady, MD MPH, Professor of Medicine and Co-Director of CTSI leads the CTSI Online Education Program and is responsible for content, format, and quality of online offerings. Mitchell D. Feldman, MD MPhil, Professor of Medicine and Director of the Comprehensive Mentoring Program is Associate Vice Provost for Faculty Mentoring and an internationally respected expert on mentoring. D.1.e. TWD Evaluation and Tracking. We will adhere to NCATS common metrics as these are developed and finalized.

Aim / Milestone Metric for Assessment / Frequency Aim 1. Continue and expand didactic and degree-granting programs Training in Clinical Research

# of students in the 1-year ATCR # of students in the 2-year Master’s # of students in new courses: precision medicine, informatics, special populations (annual)

Aim 2. Continue, expand, and enhance level-specific training in C&T sciences KL2 program #/% of junior faculty scholars completing KL2

#/% of successful transitions from KL2 to NIH individual K and from KL2 to R01 # of publications/ # in precision medicine, multisite trials, special populations

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#/% of URM junior faculty scholars #/% in academic medicine or other research career

TL1 program # of predoctoral students and fellows completing Master’s #/% or URM predoctoral students and fellows # of publications/ # in precision medicine, multisite trials, special populations #/% in academic medicine or other research career

Other CTST Programs # of trainees completing training by level (undergraduate, resident, fellow) # of trainees retained in research following program # of publications (abstracts and full publications) #/% of URM trainees by program

Aims 3-4. Expand investigator and staff training, online education, and just-in-time training Ethics and regulatory training

# of investigators and staff completing Responsible Conduct of Research and CITI GCP and other training # of investigators and staff participating in online course and just-in-time trainings

Aim 5. Develop a diverse scientific workforce Workforce diversity % of URM UCSF faculty C&T researchers (C&T researcher defined based on application to IRB)

% of UCSF Department Chairs who are women Aim 6. Support a culture of level-specific mentoring Comprehensive Mentoring Program

# of mentors enrolled in Mentor Development Program at UCSF and outside UCSF (annual) # of KL2 and TL1 scholars completing Web-based training (annual)

D.2. PILOT TRANSLATIONAL AND CLINICAL STUDIES (PTC) D.2.a. Overview and Innovation The CTSI Pilot Translational and Clinical Studies program (PTC) has had a transformational impact on the way intramural funding is provided at UCSF. When PTC began, there were multiple pilot funding sources, and each had different timing, application, review, and evaluation processes. PTC created the organization and infrastructure that now supports the UCSF Resource Allocation Program (RAP), which uses a uniform and unbiased application and review process to award almost all intramural funding at UCSF (Figure, right). RAP issues semi-annual calls for applications, organizes expert faculty scientific review committees, and facilitates a standardized NIH-style review. After scientific review, the PTC Steering Committee conducts a second round of evaluation to determine which high-ranking proposals best fit our funding priorities as described below. The RAP system for centralized administration and review of pilot funds has become a model for other CTSAs across the nation. D.2.b. PTC Achievements PTC applications have included a wide variety of clinical and translational research, as well as novel technologies and methods. Between 2007 and 2015, PTC received 1,518 applications and granted 320 awards to PIs from all 4 UCSF professional schools, from a total of 38 departments (Table 1). These awards have resulted in 222 publications and 154 subsequent awards resulting in over $150 million in new extramural funding. In the past 5 years, PTC also introduced 2 new funding mechanisms to further CTSI aims: Digital Health (2011) and Team Science (2014).

Table 1. Pilot Grants Funded 2007-2015 Category Awards Amount

Awarded Subsequent Funding

Publi-cations

Example Project

Junior Faculty Pilot Award

239 $6,997,440 $130,475,594 187 Targeting histone H3.3-K27M mutation for treatment of diffuse intrinsic pontine gliomas (PI: R. Hashizume)

URM Faculty Award

41 $1,216,925 $8,139,662 29 Adapting the Coronary Heart Disease Policy Model to Address Disparities in Heart Disease (PI: K. Bibbins-Domingo)

New Child/Family Caregiving

14 $413,753 $4,270,000 2 Identification of Biomarkers for Heart Failure in Children (PI: H. Bernstein)

Digital Health Research Award

20 $716,112 $7,527,712 4 Improving Physical Activity Adherence with Mobile and Social Media (PI: D. Schlosser)

Team Science Award

6 $399,303 n/a n/a Development of Small Molecule Therapeutics to Prevent Hemorrhagic Strokes (PI: D. Gould)

D.2.c. Approach to PTC We will continue PTC funding for cutting-edge clinical and translational research by junior faculty (especially

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studies aimed at testing new methods, measurements, and tools), URM investigators, those developing multidisciplinary teams, and funding for researchers returning after the birth or adoption of a child or struggling with family caregiving responsibilities. We will expand our Digital Health award to include technology-enabled research and informatics. In addition, to support our overall aims to promote precision medicine (Part H2) and research in special populations (Part F.1), we will introduce 2 new pilot awards in these domains (Table 2). For all PTC award categories, we prioritize research that includes multidisciplinary teams and diverse investigators. We will use RAP to solicit (twice per year), review, and score applications for PTC awards. Following NIH-style review and scoring by standing committees of UCSF faculty with appropriate scientific expertise, proposals that receive a high scientific score undergo a second review by the PTC Steering Committee (Sec. D.2.d, below), which then applies criteria specific to the grant mechanism. For example, in addition to proposing sound science, the Team Science Award requires investigators from diverse fields; descriptions of the responsibility and unique contributions of team members and organization of the team; and degree of multidisciplinary/multisite involvement.

PTC Aim 1. Advance new translational research methods, tools and infrastructure. • Informatics and Research Innovation (IRI) Pilot Award Program. In collaboration with the CTSI IRI program,

we will develop an award designed to support demonstration projects and pilots based on strong science that plan to use innovative informatics and technology-based approaches to conduct research, have a high likelihood of demonstrating efficiency and cost-effectiveness and are likely to develop methods and approaches generalizable to other studies. Approaches might include new technologies for secure identification of potential participants, direct-to-participant approaches to informed consent or randomization, novel uses of free commercial technologies such as Apple’s ResearchKit, working with UCSF informaticists to streamline ways to input high quality research data into the EHR, or ways to link disparate technologies to support research. Our IRI Award program will: Learn what works. A requirement of these awards will be that investigators provide a quarterly progress

report focused on opportunities and obstacles related to the research processes being tested, and work closely with IRI to assess cost, efficiency, cost-effectiveness, and potential generalizability of the tools.

Make success available. The most successful approaches used in these pilot projects will be further developed by IRI and UCSF Academic Research Systems, supported, and made available broadly to researchers at UCSF and our affiliates. These projects will result in an ever-growing set of technology-enabled research processes supported by CTSI.

PTC Aim 2. Promote multisite collaboration and team science. • Team Science Pilot Award Program. In collaboration with the CTSI Team Science Working Group (Section

C.2), we will continue to provide pilot funding for collaborative research teams. The goal of the TS Pilot Award is to stimulate new collaborations of scientists from diverse fields, including basic, clinical, and behavioral and social research, that address clinical and translational research questions requiring an innovative, multidisciplinary approach. We strongly encourage teams that are diverse based on gender, ethnicity, and race. In the coming years, to improve and expand our TS Award program we will: Encourage collaborations outside UCSF. The current Team Science Award has focused on development of

teams across UCSF schools and departments. Going forward, preference will be given to proposals that include investigators from our collaborators, including UC Berkeley, Kaiser Permanente, UCSF Benioff Children’s Hospital Oakland, UC Fresno, the SFBay Community Research Network, and UC BRAID.

Table 2. Proposed PTC Awards and Purpose of Award Proposed Awards Purpose of Award Informatics and Research Innovation Award

Demonstration projects and pilots that use innovative informatics and technology-enabled approaches to conduct research and push the boundary of the possible

Team Science Award Research that supports new collaborations of multidisciplinary teams, especially those that include investigators outside UCSF

Precision Medicine Award Support demonstration projects and pilots that use social, behavioral, biologic and other phenotypic data and biospecimen measures to test the feasibility of disease-focused projects in precision medicine

Underrepresented Minority (URM) Award

Pilot funding to support URM and investigators from disadvantaged backgrounds to advance the research agenda and enable them to remain in academic research

Special Populations Award Pilot funding to support research in special populations (children, elderly, vulnerable), especially if designed to develop critical measurement domains that span all 3 populations

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Provide team consults. In addition to funding, we will provide expert consultants from the UCSF Research Development Office staff to meet regularly with teams to provide advice on team leadership, diversity, organization, communication, mutual fair recognition, and conflict management.

Extend funding. The initial round of single-year awards resulted in the development of projects with high potential, but recipients reported that 1 year was inadequate to mature successful teams. In response, we plan to allow teams to apply for a second year of funding, dependent on meeting specified deliverables.

Learn what works. To learn from the experience of funded teams, we will require teams to prepare a semi-annual written report on challenges and opportunities for team development and operation, and meet with the Team Science Working Group to discuss these reports.

PTC Aim 3. Support research that advances precision medicine. • Precision Medicine Pilot Award. We will collaborate with the Precision Medicine (PM) team (Part H2) to

develop an award to support demonstration projects and pilots that use a variety of social, behavioral, biologic, and phenotypic data and biospecimen measures to test the feasibility of disease-focused projects in precision medicine. Proposals will be judged on: 1) potential to develop and demonstrate the promise of precision medicine in a specific disease area; 2) existing strength, resources and opportunities (e.g., ability to obtain molecular measurements, collect behavioral or other data, subtype the disease, link genomic data to EHR; access to existing biobanks; databases; an engaged participant community); 3) likelihood of improving health outcomes; 4) likelihood of engaging patients to build trust, improve the consent process or privacy, etc.; and 5) likelihood of developing generalizable infrastructure and tools, e.g., physical capacity, new consortia, personnel competencies, software/computational development, patient cohorts, and participant communities and networks.

PTC Aim 4. Advance research in special populations. • Special Populations Pilot Award. In collaboration with the Special Populations Initiative (SPI) and Community

Engagement Program, we will develop an award that directly advances the goals of the SPI (Part F.1). The aim of this award will be to encourage research in children, the elderly, and vulnerable populations, especially when focused on developing or advancing critical measurement domains that span all 3 populations: function and cognition, caregiver burden and context, family dynamics and social support, poverty, and health literacy. Priority will be given to junior investigators, multidisciplinary teams (especially those with team members outside UCSF), and URM investigators.

PTC Aim 5. Support underrepresented minority clinical and translational researchers. • Underrepresented Minority (URM) Pilot Award. In collaboration with the UCSF Vice Chancellor for Diversity

and Outreach, we will continue to provide the URM Pilot Award, which is designed to encourage URM fellows and faculty and those from economically or educationally disadvantaged backgrounds who conduct clinical and translational research, to remain in academia and thus increase the diversity of our faculty. We will enhance this award by working with the CTSI Mentoring Program to ensure that each awardee has active and culturally competent career and research mentoring, and with the UCSF Research Development Office to ensure that all funded investigators are fully aware of funding and research opportunities.

D.2.d. PTC Leadership Director: Kristine Yaffe, MD, Professor of Psychiatry, Neurology, and Epidemiology & Biostatistics, Vice Chair for Research in Psychiatry, Chief of Neuropsychiatry, and Director of the Memory Disorders Clinic at the SF VA Medical Center, will provide leadership to ensure that goals are met and resources are used efficiently. PTC Steering Committee: representatives from each School, with expertise in research on special populations or informatics. The Steering Committee is comprised of Dr. Yaffe, Steering Committee Chair (School of Medicine; research focus: aging and dementia); Fran Aweeka, PharmD (School of Pharmacy: vulnerable populations); Christine Miaskowski, RN PhD FAAN (School of Nursing: aging and pain); Andrew Auerbach, MD (School of Medicine: informatics and patient safety); Thomas Lang, PhD (School of Dentistry; radiology); Bertram Lubin, MD (Benioff Children’s Hospital of Oakland; pediatrics and vulnerable populations). D.2.e. PTC Evaluation and Tracking. We will adhere to NCATS common metrics as these are finalized.

Aim / Milestone Metric for Assessment and Frequency (all measured annually) All Aims. Advance new translational research methods focused on informatics and technology, multi-site collaboration and team science, and precision medicine; promote URM faculty and support family caregivers

• # proposals submitted and funded by category • Return on Investment measured as subsequent extramural funding • # publications resulting from pilot funding • # awards with URM PI • Surveys of Team Science awardees to assess impact

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References for Part D. Translational Endeavors

1. Johnson, M.O., et al., An innovative program to train health sciences researchers to be effective clinical

and translational-research mentors. Academic medicine: journal of the Association of American Medical Colleges, 2010. 85(3): p. 484.

2. Feldman, M.D., et al., A mentor development program for clinical translational science faculty leads to

sustained, improved confidence in mentoring skills. Clinical and translational science, 2012. 5(4): p. 362-367.

3. Feldman, M.D., et al., Training the next generation of research mentors: the University of California, San

Francisco, clinical & translational science institute mentor development program. Clinical and translational science, 2009. 2(3): p. 216-221.

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Part E Research Methods: Consultation Service (BERD) and Regulatory Knowledge and Support UCSF CTSI Research Methods consists of a Consultation Service (CS) and a Regulatory Knowledge and Support (RKS) program. The CS was built on domains of established expertise in biostatistics, epidemiology, and research design (BERD); it has evolved to include 72 consultants with wide expertise to support the design and conduct of high quality clinical and translational research. CS will continue and extend its services by adding new consultants with expertise to address technology-enabled research methods (including access to EHR data, integration of data from mobile devices and wearable sensors, and direct-to-participant research) and research across the lifespan, including health disparities. CS will also collaborate with the CTSI Team Science Working Group (Part C.2), UCSF Center for the Health Professions and the Research Development Office to add consultants with expertise in development and management of multidisciplinary teams. CS also plans to make some of the unique expertise provided by CS available to regional and national partners and to catalyze the development of novel clinical and translational research methods through funding to CS’s cadre of consultants by addressing the following Aims: CS Aim 1. Enhance the expertise provided by the Consultation Service by adding new consultants or training current consultants to provide expertise related to technology-enabled research and research across the lifespan; CS Aim 2. Extend the reach of the consultation services to partner with institutions locally, across UC BRAID, and across the CTSA consortium; and CS Aim 3. Support development of novel methods with small methodology grants to foster innovative and multidisciplinary team science approaches to solving clinical and translational research problems. The Regulatory Knowledge and Support (RKS) program has worked to streamline IRB processes, provided investigators with education, advice, and support for efficiently and accurately completing IRB applications, consent forms, and regulatory documents, developed IRB reliance across the UC Biomedical Research Acceleration, Integration and Development (UC BRAID) and NCATS Accrual to Clinical Trials networks, and developed agreements to use central and commercial IRBs. RKS will develop uniform electronic consent processes for use of biospecimens and clinical data across UCSF, monitor and facilitate clinical trial recruitment, establish a UC-wide Food and Drug Administration (FDA) Regulatory Unit, and provide just-in-time training for investigators and staff by addressing the following Aims: RKS Aim 1. Develop and implement the UCSF Biospecimen and Clinical Data eConsent system - a patient-centered portal for obtaining and documenting consent to use biospecimens and clinical data for research; RKS Aim 2. Monitor and facilitate success for studies that are not meeting recruitment goals; RKS Aim 3. Establish a UC-wide Food and Drug Administration (FDA) Regulatory Unit; and RKS Aim 4. Develop and implement embedded real-time IRB application support materials to improve investigator and staff understanding of the components of the IRB application and reduce time to approval.

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SPECIFIC AIMS The UCSF CTSI Consultation Service (CS) was built on domains of established expertise in biostatistics, epidemiology, and research design (BERD); it has evolved to include 72 consultants with a wide range of expertise to support the design and conduct of high quality clinical and translational research. The Regulatory Knowledge and Support (RKS) program has worked to streamline IRB processes, provided investigators with education, advice, and support for efficiently and accurately completing IRB applications, consent forms, and regulatory documents, developed IRB reliance across the UC Biomedical Research Acceleration, Integration and Development (UC BRAID) and NCATS Accrual to Clinical Trials networks, and developed agreements to use central and commercial IRBs. CONSULTATION SERVICE (CS) We will continue to support our very active and successful Consultation Service and extend our services by adding new consultants with expertise to address issues related to technology-enabled research methods (including access to EHR data, integration of data from mobile devices and wearable sensors, and direct-to-participant research), research across the lifespan and team science. We also plan to make some of the unique expertise provided by CS available to regional and national partners and to catalyze the development of novel clinical and translational research methods through funding to our CS cadre of consultants. CS Aims CS Aim 1. Enhance the expertise provided by the Consultation Service. In addition to supporting our current active Consultation Service, we will add new consultants or train current consultants to address CTSI’s focus on technology-enabled research, research across the lifespan and team science. CS Aim 2. Extend the reach of our consultation services to partner institutions locally, across UC BRAID, and across the CTSA consortium. CS Aim 3. Support development of novel methods with small methodology grants to foster innovative and multidisciplinary team science approaches to solving clinical and translational research problems. REGULATORY KNOWLEDGE AND SUPPORT (RKS) RKS will continue to use Lean Six Sigma approaches to maximize the efficiency of IRB and other regulatory processes and to facilitate multisite studies by promoting IRB reliance and use of central and commercial IRBs. In the next funding period, we will develop uniform electronic consent processes for use of biospecimens and clinical data across UCSF, monitor and facilitate clinical trial recruitment, establish a UC-wide Food and Drug Administration (FDA) Regulatory Unit, and provide just-in-time training for investigators and staff. RKS Aims RKS Aim 1. Develop and implement the UCSF Biospecimen and Clinical Data eConsent system - a patient-centered portal for obtaining and documenting consent to use biospecimens and clinical data for research. RKS Aim 2. Monitor and facilitate success for studies that are not meeting recruitment goals. RKS Aim 3. Establish a UC-wide Food and Drug Administration (FDA) Regulatory Unit. RKS Aim 4. Develop and implement embedded real-time IRB application support materials to improve investigator and staff understanding of the components of the IRB application and reduce time to approval.

Part E. Research Methods: Consultation Service (BERD) and Regulatory Knowledge and Support

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RESEARCH STRATEGY E.1. CONSULTATION SERVICE (CS) E.1.a. Overview and Innovation The CTSI CS currently includes 2 General Consultation Units (Biostatistics and Bioinformatics; Epidemiology and Research Design) and 6 Specialized Units (Figure). The CS includes 65 faculty and 7 staff consultants, largely supported by fees. Over the past 4 years we have provided more than 3,200 hours of consultation for approximately 500 unique projects per year, with very high ratings for both the quality and impact of our services. We propose to continue providing timely, efficient, and high quality consultation services, and to expand these services with the addition of experts skilled in CTSI’s new areas of focus – technology-enabled research, research across the lifespan, and team science. We will extend the reach of our consultation service to our partner institutions, the UC BRAID network of 5 UC medical campuses and the broader CTSA consortium. Finally, we will support novel methodology projects to drive research innovation and promote collaborations and team science. E.1.b. CS Achievements The CTSI CS has developed a multi-specialty program that is the “front door” for investigators to request expert advice on a wide range of topics (Part 1.Sec. 4.A). In response to investigator needs, we have added 6 specialized units to our 2 general CS units (Biostatistics and Bioinformatics, Epidemiology and Research Design). These specialized units provide expertise on database development and management (e.g., MyResearch, REDCap, OnCore, etc.); community-engaged research (employing members of the CTSI Community Engagement program); implementation sciences (employing members of the CTSI Training Program Implementation Sciences Program); regulatory support (e.g., IRB applications, consent forms, INDs, NDEs, adverse event reporting, etc.); participant recruitment (employing members of the CTSI Participant Recruitment Unit and experienced Clinical Research Coordinators); and scientific writing (abstracts, manuscripts, posters, proposals). Each unit includes several faculty and staff consultants. Using an online portal, clients enter a consultation request. Within 24 hours of submission, the CS administrator triages the request to the unit director or directly to a consultant, and enters the project into our tracking database. The consultant alerts the administrator to accept or decline the consultation, then communicates directly with the client to arrange an initial consultation. This approach works well, with an average time between initial consultation request and the first face-to-face meeting of approximately 7 days. After the initial client meeting, the consultant records the time expended in preparation for and at the face-to-face meetings. After an initial free hour of consultation per project from any unit, faculty consultations are charged at $175/hour and staff at $85-$110/hour. Consultants are paid based on percentage effort or by the hour. Allowing consultants to be paid by the hour makes it possible for us to vastly enlarge the number of consultants and the specificity of expertise. An important challenge, however, is to find ways to meet the fluctuating demand for services. We have maximized the efficiency of our investment in salary support for a core group of consultants in biostatistics, study design, and data management, and closely monitor our monthly costs per salaried consultant against hours reported. We continue to look for new hourly consultants, particularly in biostatistics, and have recently engaged several faculty from the UC Berkeley School of Public Health.

The number of projects supported by CS has grown while maintaining a high level of client-reported quality and impact over time (Table). Cost recovery from revenue generated now covers approximately 82% of overall consultation costs.

Vignette: CS advice and support impact research at every stage of a study and at every stage of a research career. A junior investigator in Pulmonary Medicine had a project that required CS data management to merge 3 datasets from 4 different clinical centers. He noted that with help from CS consultants, “in building this dataset, I was able to publish the first study to evaluate the impact of frailty on disability and risk of de-listing or death in lung transplant candidates. Our paper was accepted into a top pulmonary journal which will provide important preliminary data for an R01 grant I am working on now.”

Consultation Service Metrics from 2011 - 2015 *Scale = 1 to 5 (best) 2011-12 2012-13 2013-14 2014-15 Consultation hours 3413 2661 3298 3578 New Projects 491 630 604 500 Quality rating by client* 4.7 4.7 4.7 4.7 Impact rating by client* 4.1 4.3 4.3 4.0

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The Biostatistics and Bioinformatics Unit is our most utilized service. It consists of 1 faculty, 1 staff and 16 hourly consultants who provide a wide range of consultation, including refining study hypotheses, sample size estimates, statistical analysis plans, data monitoring plans, cutting-edge approaches such as causal inference, Bayesian statistics, statistics for medical image analysis, mixed-effects/hierarchical modeling, pharmaco-economic analysis, data-mining, reliability analysis, and statistical methods for bioinformatics. E.1.c. Approach to CS CS Aim 1. Enhance the expertise provided by the Consultation Service. In addition to supporting our current active Consultation Service, we will add new consultants or train current consultants to address CTSI’s focus on technology-enabled research, research across the lifespan and team science. Technology-enabled research. In collaboration with our proposed Informatics and Research Innovation (IRI) program (Part B), the UCSF Institute for Computational Health Sciences (led by Atul Butte, MD IRI Co-Director) and the Center for Digital Health Innovations (led by UCSF Chief Medical Informatics Officer and IRI Steering Committee member, Mike Blum), we will add consultants with expertise in: • Accessing electronic health record (EHR) data for research. We will partner with UCSF Enterprise

Information and Analytics Team and Academic Research Systems (ARS) to assist investigators in obtaining access to and manipulating EHR data from UCSF Medical Center, SF General Hospital, SF VA Medical Center, SF Bay Area Community Research Network, the Bay Area Accountable Care Network, as well as from “derived” research data models supported by networks such as NCATS ACT, UC ReX, and PCORnet housed in our Clinical & Research Data Warehouse (CRDW, see Part B, IRI Aim 1). ARS provides data access and secure hosting services (MyResearch) as well as analysts who help researchers access data. To complement this service, CS will enlist consultants from the other healthcare institutions (e.g., SF General Hospital, SFVA) with knowledge of the different research data models and population/condition-specific data marts. We will also expand the Data Management Unit to provide expertise in converting clinical datasets into analytic datasets. Finally, we will enlist “clinical champions” with deep expertise in the use of Epic to support clinical workflows to consult on designing interventions for research.

• Research informatics and big data management. We will expand our Bioinformatics/Data Management Unit with expertise in management of large datasets, data harmonization, curation, and visualization, and data reduction methods. We will extend our Biostatistics expertise to include natural language processing, machine-based learning, complex network analyses, and other big data analytic methods.

• Integration of data from mobile devices and wearable sensors. While CTSI already enjoys significant expertise using newer methods of incorporating data from mobile applications, remote sensors, and social networking platforms, we will expand expertise in these and other Web-based methods of data collection, and develop expertise to support investigators using the efficient trials platform infrastructure envisioned by IRI (Part B, IRI Aim 2).

• Direct-to-participant research methods. We will identify consultants with expertise in direct-to-participant methods, including Web-based recruitment, identity confirmation, data collection, and randomization. UCSF has several pioneering studies using these methods (Health eHeart, ADAPTABLE aspirin trial, PRIDEnet/PRIDE study; Section B.2, IRI Aim 4).

Research across the lifespan. We will collaborate with the UCSF Department of Pediatrics (Chair: Donna Ferriero, MD, Member, CTSI Internal Advisory Board) and Division of Geriatrics (Chair: Louise Walter, MD, Member, CTSI Internal Advisory Board) to add consultants who have expertise in pediatric and geriatric research. We will also work with Dean Schillinger, MD, Director of the new CTSI Special Populations Initiative (Part F.1) to add expertise on research in vulnerable populations. These specialty consultants will assist with study design and appropriate use of measurements related to function and cognition; caregiver burden and context; family dynamics and social support; poverty; and health literacy. They will advise regarding analytic issues relevant to these populations, and provide practical participant recruitment and retention expertise. Team science. We will collaborate with the CTSI Team Science Working Group (Part C.2), UCSF Center for the Health Professions and the Research Development Office to add consultants with expertise in development and management of multidisciplinary teams, including issues such as team leadership, diversity, organization, communication, mutual fair recognition, and conflict management. CS Aim 2. Extend the reach of our consultation services to partner institutions. All CTSAs provide core expertise in biostatistics, epidemiology, and research design. However, our partner CTSAs in the UC BRAID network can bring expertise that is not available at all institutions. BERD Directors at the 5 UC campuses are eager to engage in cross-institutional consultations for specialized areas, and we plan to develop this

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collaboration in the next funding period. In preparation, we have developed an intercampus recharge mechanism among the 5 UC BRAID hubs that avoids overhead costs for consulting. Our initial cross-campus services will be a UC-wide FDA regulatory consulting unit (see Part E.2; Aim 3) and providing access across BRAID to the UCSF Catalyst Advisors (Part H1; Aim 3). After testing and refining processes with the UC BRAID sites, we will expand to other areas of expertise, and make our specialized consultation services available to other CTSA hubs. CS Aim 3. Support development of novel methods. We will continue to offer competitive, small methodology awards to our consultants to foster the development of novel tools and methods. Most of these awards are based on difficult methodologic issues encountered during consultations that require novel methods and tools to solve. We will expand these awards to foster multi-investigator team collaboration among UC BRAID and other institutional consultants to further innovation in research methods and tool development. We will be regularly updating information of all BERD consultants from the UC BRAID sites for Aim 2. We will use this group of consultants to promote these multidisciplinary team science focused grants.

E.1.d. CS Leadership Director Alka Kanaya, MD, Professor of Medicine, provides direction and leadership to all activities of the CS program and its Unit Directors, overseeing academic, research, and service functions, and ensuring that program goals are met on time. John Kornak, PhD, Biostatistics Unit Director, Dr. Kornak, Associate Professor of Biostatistics, supervises faculty consultants and staff analysts and recruits consultants to ensure that expertise matches needs. Anthony Kim, MD, Epidemiology and Research Design Unit Director: Dr. Kim, Associate Professor of Neurology, supervises faculty consultants, recruits new consultants as needed, and assists in project assignment for specialized expertise. Jennifer Creasman, MSPH, Data Management Unit Director: Ms. Creasman, biostatistician and CTSI Senior Manager, supervises staff analysts and system development and recruits new data specialists as needed. E.1.e. CS Evaluation and Tracking

Aim / Milestone Metric for Assessment and Frequency Aim 1. Support and extend expertise provided by the Consultation Service Support high quality, timely consultation services to the UCSF research community (metrics tracked using OpenAir/Netsuite client relation management software)

Mean time from request to first meeting (quarterly) # of consultations hours; # new projects by unit (quarterly) Mean quality and impact rating by unit (quarterly) # of publications, # of collaborations as a result of consultation (annually) % of CS costs generated from recharge of services (annually)

Extend expertise provided by the CS # of new consultants added by area of expertise (quarterly) # of consultation hours; # of new projects by area of expertise (quarterly) # of consultants who have taken additional training per year

Aim 2. Extend the reach of our consultation services to partner institutions Extend consultations to partner institutions # of consultation hours; # of new projects to partners (quarterly)

Mean quality and impact rating for consultation to partners (quarterly) Aim 3. Support development of novel methods Promote novel methods development with small methodology grants to solving clinical and translational research problems

# of methodology grants funded (annually) # of publications generated by these grants (annually) # of methodology grants that include partners from other CTSAs

E.2. REGULATORY KNOWLEDGE AND SUPPORT (RKS) E.2.a. Overview and Innovation The Regulatory Knowledge and Support (RKS) program has streamlined IRB processes; provided education, advice, and support regarding regulatory issues; developed IRB reliance across UC BRAID and the NCATS Accrual to Clinical Trials consortium; and developed agreements to use central and commercial IRBs. In the

Vignette: CS methods grant supports software improvement. A biostatistics consultant redesigned and greatly improved R.rsp software with a CS novel methods grant. Released in fall 2013, approximately 35 publicly available R tools spanning various fields of academia and industry utilize R.rsp directly and ~7,000 indirectly. The R.rsp package is one of the most downloaded R packages. At UCSF, R.rsp helps to develop and share standardized protocols and to produce static and interactive reports in microarray and high-throughput sequencing studies.

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next funding period we will build on these efforts, focusing on development of consent processes for use of biospecimens and clinical data, monitoring and facilitating clinical trial recruitment, establishing a UC-wide Food and Drug Administration (FDA) Regulatory Unit, and providing just-in-time training for investigators and staff. E.2.b. RKS Achievements Over the last 4 years, RKS efforts have resulted in a 32% decrease in the number of days-to-approval, from 84 in 2011 to a current estimate of 57 days for full IRB review; notably, the number of IRB applications has increased by 8% in this same time period.

Achievements Benefit to Clinical and Translational Research Enabled IRB analysts to approve low-risk applications. Decreases time-to-approval for low-risk applications. Instituted IRB “pre-review” with “Minimal Submission Standards” to identify missing/incomplete components.

Applications promptly returned to investigators for completion with checklist of needed items and fields.

Allowed IRB staff to hold certain stipulations until after committee review.

Allows all stipulations to be sent to investigator at once, reducing the number of times the application is returned for revision.

Simplified IRB application for social/behavioral studies, and added a separate review committee.

Decreases investigator’s time to complete IRB application, providing appropriate expertise for review, unclutters biomedical IRB committees.

Revised IRB fields, order, and format based on survey of items commonly completed incorrectly.

Makes it easier to complete a high quality application.

Using Lean/Six Sigma techniques (led by CTSI’s Program Evaluation Team), we continuously measure and improve IRB and other regulatory processes. Recent results suggest that prolonged time to IRB approval is strongly associated with the need for investigators to revise applications. We have implemented approaches to decrease the number of revisions (Table above) and will continue this process in the next funding period. RKS has worked to ensure that regulatory approvals are pursued in tandem and to expedite ancillary approvals.

We have addressed investigator and staff training for regulatory issues in a number of ways, including formal courses on research ethics and responsible conduct of research (TICR Course EPI 201; completed by 2,209 students, trainees, faculty, or staff over the last 4 years), regular seminars led by IRB staff focused on the IRB process and consenting, and over 1,283 hours of expert advice over the last 4 years from the Consultation Service (CS) Regulatory Support Unit. RKS developed Web-based tools and guidance for organizing and managing Data Safety Monitoring Boards (DSMB) with links to NIH and FDA policies and instructions and a library of DSMB protocols. We developed tools to support accurate posts on ClinicalTrials.gov and created short online videos on conflicts of interest. RKS also developed an interactive online Research Compliance Handbook that describes regulatory requirements and sources of training and support. To assist researchers in complying with FDA guidance for drug and device development, RKS partnered with the CS Regulatory Support Unit to provide expert consultation on submitting INDs and IDEs, and developed an online Regulatory Binder Toolkit. With UCSF Chief Ethics and Compliance Officer (Theresa O’Lonergan) and IRB Director (Christopher Ryan, PhD, RKS Director), RKS worked to implement reciprocal IRB approval across UC BRAID. UCSF was an initial member of NCATS’ Accrual to Clinical Trials (ACT) consortium, which developed an IRB reliance agreement signed by 21 CTSA Hubs. CTSI participates on the ACT Regulatory Group and the NCATS IRB Regulatory Committee. In the past 4 years, UCSF has relied on another UC hub for IRB approval for 85 studies, and other UC campuses relied on UCSF for 165 studies. UCSF also contracted with the Western IRB (WIRB) to act as the IRB-of-record for industry-sponsored phase III and IV studies. WIRB has supported 13 late phase trials at UCSF. E.2.c Approach to RKS RKS will continue to work with the CTSI Program Evaluation Team to streamline processes and reduce time to approval. We will develop an eConsent portal for biospecimens and EHR data, provide just-in-time training for investigators and staff, monitor and facilitate clinical trial recruitment, establish a UC-wide Food and Drug Administration (FDA) Regulatory Unit, and provide just-in-time training for investigators and staff.

Vignette: To expedite ancillary approvals, RKS supported the development of a Radiation Dosimetry Calculator. The Calculator provides an accurate estimate of radiation exposure and has reduced time-to-approval at the Radiation Safety Committee. The Web-based tool is populated with UCSF-specific dose estimates for common procedures and produces a sentence for the consent form that relates dose to annual background radiation. The tool allows other sites to input site-specific estimates. It is being tested by UC BRAID hubs, with plans to share with other CTSA hubs next year.

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RKS Aim 1. Develop and implement the UCSF Biospecimen and Clinical Data eConsent system - a patient-centered portal for obtaining and documenting consent to use biospecimens and clinical data for research. We aim to enable the UCSF EHR (Epic) patient portal, MyChart, to allow patients to securely, conveniently, and easily express their preferences for use of biospecimens and clinical data obtained in the course of clinical care. Our efforts will be informed by experts at UCSF and across the CTSA network, but specifically by EngageUC and the Platform for Engaging Everyone Responsibly (PEER). EngageUC,1 a UC-wide project funded by NCATS, engaged stakeholders and demonstrated acceptability of a simplified consent for biobanking (Table below).

Lessons Learned from EngageUC Engaged stakeholders across California

• Investigators, biobankers, patient communities, and institutional officials used Deliberative Community Engagement to identify, develop, and refine community-informed strategies for informed consent.

• Research and regulatory stakeholders to develop guidelines for consent processes, EHR documentation, and infrastructure for sharing biobank samples and data.

Engaged patients with various conditions

• Healthy volunteers donating blood, patients facing a serious illness, patients with chronic conditions, and surrogates

Developed a simplified consent form

• Legal experts supported development of a simplified biobanking consent form that met all federal, state, local, and institutional requirements, yet was only 2-3 pages long

Conducted a pilot RCT of simplified consent

• In 3 clinics at UCSF and UCLA, demonstrated feasibility and acceptability and non-inferiority to a standard consent for patient understanding and for obtaining consent to donate for future unspecified research

Developed an educational video

• Presents and explains biobanking procedures and consent issues • Acceptability demonstrated in its pilot RCT

PEER is a project of the non-profit organization, Genetic Alliance, which has already managed the development of portals for a wide array of disease registries. We became aware of PEER through our work with the Community Engaged Network for All (CENA), a PCORnet PPRN. PEER creates a highly engaging, intuitive, privacy-assured, and customizable participant portal. Using PEER, participants can set data sharing, privacy, and access preferences, and manage their health information in a dynamic and granular system. We will: • Draw on the expertise of leaders of EngageUC (Daniel Dohan, PhD; Part E.2.d), UCSF Center of

Excellence in ELSI Research (Barbara Koenig, PhD; Part E.2.d), leaders of Genetic Alliance (Sharon Terry; see Letter of Support), and other CTSA hubs working on this issue (Medical University of South Carolina; UC San Diego) to vet, compare, and tailor an ethical, efficient, and patient-engaged eConsent system.

• Ensure technical feasibility of integration with the UCSF EHR-based patient portal (Epic/MyChart), our LIMS software that supports the new Biospecimen Resources Program and virtual Biobank (LabVantage) (see Part H2), and the UCSF Clinical and Research Data Warehouse in collaboration with our Informatics and Research Innovation Program (IRI; Part B).

• Ensure compliance with local, state, and federal (DHS and FDA) regulatory standards. • Focus on patient engagement and control, learning from the experience of EngageUC and PEER. • In collaboration with UCSF IT experts, from whom we have strong leadership and institutional support,

implement prototyping and testing in pilot projects (e.g., remnant blood from the UCSF Clinical Laboratories, the Athena Breast Health Network (Part G.1) and the Integrated Risk Prediction Model for Prostate Cancer (Part H2).

• Gather feedback from clinicians, administrators, researchers, patients, and regulators. • Improve and refine before final launch. • Make the UCSF Biospecimen and Clinical Data eConsent system available to other CTSA hubs using Epic

and MyChart. RKS Aim 2. Monitor and facilitate success for studies that are not meeting recruitment goals. If a study fails to reach recruitment goals, it may be impossible to answer the research question. In this case, it is not ethical to continue to expose participants to risk or burden. To address this problem we will: • Use data from required annual IRB recruitment reports to identify clinical trials with low enrollment. • Allow investigators of low enrolling trials to justify low enrollment (e.g., delayed funding). • Refer investigators without satisfactory explanations for recruitment delays to the CS Participant

Recruitment Unit (see Part G.2) for advice and support to develop a recruitment remediation plan. • Require investigators of trials that do not remediate failing recruitment goals to meet with the IRB Director

and relevant parties to discuss next steps, which may include denial of IRB renewal and trial closure.

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• Create a working group composed of senior investigators, research coordinators, and community members to establish and periodically revise specific parameters for taking these measured steps.

RKS Aim 3. Establish a UC-wide Food and Drug Administration (FDA) Regulatory Unit. Each of the UC BRAID hubs provides advice on core FDA requirements, but does not have adequate expertise on certain specific FDA regulatory issues, such as investigational device exemptions and orphan drug applications. In collaboration with UC BRAID, we propose to create a UC-wide consultation service to provide expertise on FDA-regulated drug and device studies (see UC BRAID LOS). We will: • Work with UC BRAID representatives to survey and catalogue the specific expertise related to FDA

regulatory affairs at each of the 5 UC BRAID campuses. • Work with RKS programs at each campus, and the UCSF-Stanford Center of Excellence in Regulatory

Science and Innovation (CERSI: a joint effort with the FDA designed to promote regulatory science) to identify gaps in expertise (see Giacomini [CERSI Co-PI] and Weichold LOS, Director of FDA Office of Critical Path Programs LOS).

• Work with CERSI staff and FDA visiting scientists at UCSF/Stanford to fill gaps in expertise by training appropriate campus-based RKS consultants (see Giacomini and Weichold LOS).

• Work with CTSI CS Regulatory Unit (Section E.1,above) and the BERD programs at the other UC campuses to operationalize the cross-campus FDA Regulatory Unit. CS has already developed a cross-campus recharge mechanism and has tested several cross-campus consultations.

RKS Aim 4. Develop and implement embedded and real-time IRB application support materials to improve investigator and staff understanding of the components of the IRB application and reduce time to approval. Conventional didactic training is often time-consuming, too broad, and disconnected from the immediate “need to know.” We have tracked fields of the IRB application associated with the highest proportion of errors and identified a set of common IRB stipulations that require revision of applications. In addition to RKS courses and consultation, we will: • Simplify IRB fields associated with errors, and add “pop-up” instructions on the electronic form. • Create voice-over animated and video materials for the 10 components of the IRB application that are most

commonly completed incorrectly. • Embed links to audio and video materials providing examples and acceptable language, and to the CS

Regulatory Support Unit in the IRB application form using hover-over access. • Evaluate changes in the rate of stipulations per application and time to IRB approval. E.2.d. RKS Leadership Christopher Ryan PhD, is Director of the UCSF IRB and previously served as Director of the University of Pittsburg IRB and Co-Director of its RKS Core. He will provide direction and leadership for all RKS activities and ensure that goals are met on time and resources are used efficiently. Barbara Koenig, PhD, is Professor in the School of Nursing, Director of the CTSI Responsible Conduct of Research course (Epi 201), and Research Ethics consultant to the CS Regulatory Unit. Daniel Dohan, PhD, is Professor of Health Policy and Deputy Director of the Philip R. Lee Institute for Health Policy Studies, Co-PD of EngageUC, Chair of the UCSF Precision Medicine Regulatory/Policy Workgroup, and Co-Director of the UCSF/UC Hastings Consortium on Law, Science, and Health Policy. E.2.e. RKS Evaluation and Tracking. We will adhere to NCATS common metrics as developed and finalized.

Aim / Milestone Method and Frequency of Assessment Aim 1. Develop and implement the UCSF Biospecimen and Clinical Data eConsent system • Vet, compare, and tailor eConsent systems • Time to selection of eConsent system (6 months) • Ensure technical feasibility and legal compliance • # of participants completing survey (2nd yr) • Prototype and test with pilot projects; Launch • Consent form content developed based on survey (3rd yr) Aim 2. Monitor and facilitate success for studies that are not meeting recruitment goals • Monitor IRB annual recruitment data • #/% of clinical trials with low recruitment (annual) • Refer investigators of low enrollment trials to CTSI CS

Participant Recruitment Unit for expert advice • # of clinical trials obtaining advice from CS • % of low enrollment trials closed/meet goals (annual)

• Revise criteria for referral to CS and for denial of approval • Revision completed (annual) Aim 3. Develop UC BRAID FDA Regulatory Consultation Service

Conduct FDA expertise and needs assessment across UC BRAID • # of cross-5 UC campus consultations (annual) Aim 4. Develop and implement embedded real-time IRB application support materials to improve IRB applications • Embed voice-over, animated & video materials for top 10 items • Reduction in # of IRB stipulations (annual)

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References for Part E. Research Methods

1. Garrett, S.B., et al., EngageUC: Developing an Efficient and Ethical Approach to Biobanking Research at the University of California. Clinical and translational science, 2015.

2. Adamo, J.E., et al., A roadmap for academic health centers to establish good laboratory practice-compliant infrastructure. Academic Medicine, 2012. 87(3): p. 279.

3. Berro, M., et al., Support for investigator-initiated clinical research involving investigational drugs or devices: the Clinical and Translational Science Award experience. Academic Medicine, 2011. 86(2): p. 217-223.

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Part F Hub Research Capacity Abstract The UCSF CTSI is committed to supporting clinical and translational research involving all populations, including children, the elderly, and medically and socially vulnerable persons. CTSI will create a Special Populations Initiative (SPI) to promote translational research in these populations, with an emphasis on diversity and health disparities across the lifespan by addressing the following aims: SPI Aim 1. To create a UCSF-wide Special Populations Initiative (SPI) that provides a platform for translational collaboration and multidisciplinary teamwork between programs previously focused on a single population and that catalyzes research on special populations across UCSF and the San Francisco Bay Area; SPI Aim 2. To enrich and expand research networks to practices and settings where special populations disproportionately receive care; and SPI Aim 3. To strengthen UCSF research capacity by developing tools and communication expertise for research in special populations across the lifespan. In supporting Participant and Clinical Interactions, CTSI recognizes that many clinical studies require participant visits sited in appropriate research space, supported by trained and experienced staff, with in-person measurements and core services such as phlebotomy and biospecimen handling and processing. The CTSI Clinical Research Service (CRS) will be restructured to increase efficiencies, and facilitate access to clinical research services across UCSF and in support of NCATS’ clinical trials network initiative by addressing the following Aims: CRS Aim 1. Streamline CRS operations to enhance study initiation and conduct by implementing efficient electronic systems for research planning, budgeting, scheduling, and billing; and CRS Aim 2. Provide highly trained research staff to support clinical research efforts by establishing a Clinical Research Coordinator Core to optimize deployment of skilled human resources, and establishing a training program for CRS staff.

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SPECIFIC AIMS The UCSF CTSI is committed to supporting clinical and translational research involving all populations, including children, the elderly, and medically and socially vulnerable persons. We will create the CTSI Special Populations Initiative to promote translational research in these populations, with an emphasis on diversity and health disparities across the lifespan. Many clinical studies require participant visits sited in appropriate research space, supported by trained and experienced staff, with in-person measurements and core services such as phlebotomy and biospecimen handling and processing. We will restructure the CTSI Clinical Research Service to support Participant and Clinical Interactions, increase efficiencies, and facilitate access to clinical research services across UCSF and in support of NCATS’ clinical trials network initiative. SPECIAL POPULATIONS INITIATIVE (SPI) We will focus our Special Populations Initiative on vulnerable populations across the lifespan, building on strong multidisciplinary teams and multiple organizations at UCSF that conduct translational research in vulnerable populations. This focus brings together pediatricians and child health advocates, geriatricians, and researchers with expertise in vulnerable adult populations to strengthen and disseminate methods and measurements common to all – function and cognition, caregiver context, social determinates of health, family dynamics, socioeconomic status, and health literacy. Our SPI Aims are to: SPI Aims SPI Aim 1. Create a UCSF-wide Special Populations Initiative (SPI) that provides a platform for translational collaboration and multidisciplinary teamwork between programs previously focused on a single population and that catalyzes research on special populations across UCSF and the San Francisco Bay Area. SPI Aim 2. Enrich and expand our research networks to practices and settings where special populations disproportionately receive care. SPI Aim 3. Strengthen UCSF research capacity by developing tools and communication expertise for research in special populations across the lifespan. PARTICIPANT AND CLINICAL INTERACTIONS: CLINICAL RESEARCH SERVICE (CRS) The Clinical Research Service (CRS) provides the essential infrastructure and services needed to carry out high quality clinical and translational research – well-designed and safe space, highly trained research nurses and staff, scientific oversight, and administrative expertise. We have streamlined, integrated, and improved CRS services, including the introduction of a fair and transparent recharge model. In the next funding period we will further streamline and integrate CRS services, drive cost-efficiency, provide professional development and research training for staff (in coordination with efforts in Translational Workforce Development, Part D.1), and facilitate “sharing” of clinical research coordinators among investigators from different departments. CRS Aims CRS Aim 1. Streamline CRS operations to enhance study implementation by implementing efficient electronic systems for research planning, budgeting, scheduling, and billing. CRS Aim 2. Provide highly trained research staff to support clinical research efforts by establishing a Clinical Research Coordinator Core to optimize deployment of skilled human resources and initiating a training program for CRS staff.

Part F. Hub Research Capacity: Special Populations Initiative and Participant and Clinical Interactions

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RESEARCH STRATEGY F.1. SPECIAL POPULATIONS INITIATIVE (SPI) F.1.a. Overview and Innovation UCSF has a long record of conducting seminal research to understand and improve the health of children,1-3 the elderly,4-6 and vulnerable populations.7,8 Our overarching objective is to promote translational research in these “special populations (SPs)” with an emphasis on diversity and disparities related to socioeconomic status and race/ethnicity. SPs share common attributes that highlight the significance of this initiative: 1) a higher likelihood of social and environmental exposures leading to increased morbidity, mortality, and costs9; 2) greater cumulative risk exposures over the lifetime,10 highlighting the importance of a life-course trajectory, and 3) significant under-representation in clinical and translational research. To tackle these issues, we will launch the UCSF Special Populations Initiative (SPI) to promote cross-fertilization among researchers across these demographics and provide unique expertise in critical measurement domains that span all 3 populations: function and cognition; caregiver burden and context; family dynamics and social support; and social determination, poverty, and health literacy. F.1.b. SPI Achievements SPI coalesces an outstanding cadre of accomplished research centers and their investigators, representing an unprecedented coalition of research teams with expertise and accomplishments in their respective fields.

SPI Achievements UCSF Center Research Focus Major Accomplishments Center for Vulnerable Populations at SF General Hospital (PIs: Bibbins-Domingo/Schillinger)

• Social determinants of health

• Illness in low-income adults • Interventions for vulnerable

patients • Health communication

• Seminal work on health literacy and food insecurity9,11,12 • NIDDK P30 Center for Diabetes Translation; NIMHD P60 Chronic

Illness Risk in Minority Youth; NIH U54 BUILD grant • Bigger Picture social media campaign to prevent diabetes in youth • IOM work to integrate social determinants of health into EHR • Lead AHRQ PHoENIX research network of 21 public hospitals

UCSF Division of Geriatrics and NIA Pepper Center (PIs: Covinsky/Walter)

• Geriatric functional measures

• Cancer screening in elderly • Geriatric diabetes care • Geriatric medication

management

• Role of medical and social vulnerability in disability among elders13 • Career development and pilot studies on care for older patients in

medical and surgical subspecialties • Beeson-funded research on functional status and frailty measures to

improve selection of older patients for liver transplant

NIA Center for Aging in Diverse Populations (PIs: Perez-Stable/Napoles-Springer)

• Faculty development • Healthy aging in minorities • Health disparities

• Over 50 junior faculty supported with research funding and mentoring

• Novel measures of interpersonal processes of care for ethnic minorities developed

• AHRQ EXCEED Center grantee UCSF Memory and Aging Center (PI: Miller)

• Causes and cures for degenerative brain diseases

• NIH Alzheimer Disease Research Center • Consortium for Frontotemporal Dementia (FTD) Research • Multiple NIH trials of treatments for Alzheimer’s disease and FTD

UCSF Asian Research Center for Health (PI: Nguyen)

• Promote health and health equity

• NCI-funded Center to Reduce Cancer Disparities

• NIH Promoting Colorectal Screening in Asian Populations; NIH- Preventing Diabetes in Filipino Americans; PCORI - Patient-Centered Interventions to increase screening of Hep B and C

• NIEHS Reducing chemical exposure in nail salon workers UC BRAID Child Health Initiative (UCSF Leader: Keller)

• Research consortium of the 5 UC medical campuses to promote child health and lifespan research

• Autism Consortium - organized UC-Wide Autism Spectrum Disorders summit to develop a strategic plan for multisite research

• Challenges of recruiting highly vulnerable populations (premature newborns) and unmet need for rare disease therapies addressed

UCSF Newborn Brain Research Institute (PI: Ferriero)

• Defining patterns of injury in the newborn brain

• Defining role of stem cells in the developing brain

• Discovery of surfactant, CPAP, neonatal resuscitation, fetal surgery • Neurological Intensive Care Nursery established • Brain biobank for a pediatric neuropathology research established • Multiple completed and ongoing NIH-funded clinical trials

Benioff Children’s Hospital Oakland Research Institute (Leader: Lubin)

• Pediatric research with focus on hemoglobinopathies, nutrition/obesity, immunology, critical care

• Top 10 US pediatric research center with NIH funding > $40 million • Seminal work on vaccine development, breakthroughs in sickle cell

and thalassemia treatment and cures, bone marrow transplants; source of most pediatric tissue in Human Genome Project14-17

Benioff Children’s Hospital Oakland FQHC Research Network (Leader: Lubin)

• Asthma, vaccines, traumatic stress

• Marginalized populations

• CTSI created a CTSI satellite at UCSF Benioff Children's Hospital Oakland's high volume primary care clinic, which has led to its participation in 5 NIH clinical trials in the last 5 years

Center for Community Heath & Engagement (Leader: Lubin)

• Pediatric health inequities, social determinants of health

• Bay Area Consortium on Toxic Stress • Focus on adverse childhood events & social determinants of health

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F.1.c. Approach to SPI A core of accomplished investigators from the UCSF Center for Vulnerable Populations (Schillinger, Bibbins-Domingo), Geriatrics Pepper Center (Covinsky, Walter), Benioff Children’s Hospital Oakland Research Institute (Lubin), Center for Community Heath and Engagement (Lubin), and UC BRAID Child Health (Keller) have come together across 4 UCSF campuses to catalyze this cross-cutting translational research initiative. SPI Aim 1. To create a UCSF-wide Special Populations Initiative (SPI), we will: • Stimulate and deepen collaborations across the fields of geriatrics, pediatrics, and vulnerable populations, as

well as create multiple opportunities for other translational researchers to integrate these populations into their research; capitalize on the unique methodologies SPs require to improve health across the lifespan.

• Create SPI section on the CTSI Web site with resources and tools to develop community and facilitate engagement of CTSI investigators in SP research. The Web site will include information and references on population-specific recruitment and retention strategies, measurement tools with instrument forms,13 documentation, interviewer guides, and an open community-wide discussion forum.

• Sponsor an annual SF Bay Area-wide Translational Research Symposium on SPs that involves researchers, community members, public health department leaders, and policymakers. The symposium will feature a nationally renowned expert on SPs, platform presentations, a poster session, and one-on-one mentoring opportunities for fellows and junior faculty.

• Partner with CTSI Training Program faculty to provide expert mentoring to trainees in the Pre-health Undergraduate Program (PuP), Resident Research Training Program, TL1, and KL2 who are considering research in SPs; via the CTSI Consultation Service, provide expert consultation to experienced investigators conducting research in pediatrics, geriatrics and vulnerable populations.

• In collaboration with CTSI Pilot Translational and Clinical Studies (Part D.2), we will create a Special Population Pilot Award Program to encourage research in children, the elderly, and vulnerable populations, with preference for projects focused on developing or advancing critical measurement domains that span all 3 populations - function and cognition, caregiver burden and context, family dynamics and social support, poverty, and health literacy. Priority will be given to junior investigators, multidisciplinary teams (particularly those with members outside UCSF) and underrepresented minority (URM) investigators.

SPI Aim 2. To enrich and expand our research networks to practices and settings where SPs disproportionately receive care, we will: • Collaborate with UC BRAID Child Health on planning and implementation of multisite studies in pediatric

populations (including rare diseases). UC BRAID Child Health is a research consortium across the 5 UC medical campuses (each with a CTSA award) to promote child health and lifespan research. UC BRAID Child Health has working groups on autism, neonatal conditions, and rare diseases.

• Capitalize on the new affiliation between UCSF Benioff Children’s Hospital SF and UCSF Benioff Children’s Hospital Oakland by creating opportunities for collaborative research on problems that affect large populations of vulnerable children in the Bay Area. The Oakland campus has a pediatric Federally Qualified Health Center with 36,000 visits/year for children with Medicaid.

• Develop a consortium involving pediatric investigators at UCSF Benioff Children’s Hospital Oakland, SF General Hospital (SFGH), and UCSF Benioff Children’s Hospital SF campuses that addresses trauma in children, develops biological procedures to quantify impact, and develops strategies to address these challenges and improve health.

• Leverage the AHRQ-funded PHoENIX network (Public Hospital Evidence Network and Innovations Exchange, co-coordinated by Dr. Schillinger) of California’s 21 public hospital systems, which provide >13 million visits/year, to catalyze translational research across the lifespan for low-income populations.18

• Extend CTSI efforts to include researchers and populations at UCSF Fresno, a large medical system that serves >200,000 people in one of California’s most underserved regions. Fresno has been shown to have the worst health metrics in the nation in a number of areas, including obesity and Type 2 diabetes.

• Expand research into social service settings, such as food banks and food pantries, via a new network operated by UCSF and Feeding America, a national advocacy and advisory group.

• Enrich UCSF Pepper Center efforts to develop research networks focused on frail older patients: the National Home Care Network; On Lok Health services for disabled elderly; and the Goldman Institute on Aging, which provide an extensive array of community-based long term care services.

SPI Aim 3: To strengthen UCSF research capacity by developing tools and communication expertise for research in SPs across the lifespan, we will:

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• Work with the CTSI Consultation Service Participant Recruitment Unit (PRU) and the CTSI Community Engagement (CE) program to improve recruitment and retention of SPs. We will conduct community-based focus groups, poll investigators who have been successful in recruiting SPs, solidify relationships with our networks, provide expertise and training in cultural competency, and ensure that PRU includes consultants with deep expertise in SPs.

• Promote bioethical standards and create best practices for informed consent for those with cognitive impairment, limited literacy, or English proficiency19, and for caregivers, surrogates, and proxies.

• Develop and share resources related to measurement of important predictors and outcomes in SPs research, such as measurement of literacy, food insecurity, stress, allostatic load, caregiver burden, family-centered outcomes, functional status, cognitive status, and sensory impairment. These resources will be accessed via the CTSI Web site and from research design experts in the Consultation Service, and will also be available to our collaborators in UC BRAID and across the CTSA network.

• Expand access to functional status, socioeconomic variables, and literacy measures by supporting ongoing initiatives at the Pepper Center and the Center for Vulnerable Populations to integrate such measures into EHRs, and use natural language processing to abstract information from medical records on functional status and to estimate patient literacy.

• Disseminate methods relevant to SPs to KL2 and TL1 scholars during works-in-progress and seminars. In addition, we will develop, along with Dr. Bibbins-Domingo, didactic education related to SP research and collaborate on the content for the Health Disparities Track in the CTSI Master’s Program.

F.1.d. SPI Leadership Dean Schillinger, MD, Director; Chief of UCSF Division of General Internal Medicine; renowned health communication scientist; founder of UCSF Center for Vulnerable Populations at SF General Hospital. Bertram Lubin, MD, Associate Director; Associate Dean, UCSF Benioff Children’s Hospital Oakland; UCSF and hemoglobinopathy researcher and founder of UCSF Benioff Children’s Hospital Oakland Research Institute (CHORI). Kenneth Covinsky, MD MS, Associate Director; Professor of Geriatrics and a nationally recognized expert on determinants and measurement of geriatric disability; director of UCSF Pepper Center to promote UCSF research on the prevention and amelioration of disability in older persons. Louise Walter, MD MS, Chief of UCSF’s Division of Geriatrics; KL2 Associate Director; expert preventive services for the elderly. Roberta Keller, MD, Associate Professor of Pediatrics; Vice Chair, Pediatrics Clinical Translational Research; expertise in implementation of trials in critically ill infants and long-term follow-up. Kirsten Bibbins-Domingo, MD PhD, Director of CTSI Training Program with research expertise in cardiovascular epidemiology, health disparities, and cardiovascular disease (CVD) prevention. F.1.e. SPI Evaluation and Tracking. We will adhere to NCATS common metrics as these are finalized.

Aim / Milestone Metric for Assessment and Frequency Aim 1. To create a UCSF-wide Special Populations Initiative • Provide expert mentoring to junior

investigators • In collaboration with the Pilot CT Studies

Program, create a Special Populations pilot

• # of Assistant Professor faculty with primary focus on research in SPs • # of research projects and proposals that represent collaborations between

pediatric, geriatric and/or vulnerable populations. • # of funded CTSI pilot projects on research in SPs; ROI as follow-on funding

Aim 2. To enrich and expand our research networks • Harness and extend existing networks focused

on research in SPs • # of studies involving new SPI networks, e.g., BRAID, PHoENIX, Feeding

America, UCSF Fresno, Frail Elder Network • # of collaborative studies between UCSF Benioff Children’s Hospital SF and

Benioff Children’s Hospital Oakland Aim 3. To strengthen research capacity, develop tools and communication expertise • Develop processes and tools for informed

consent, recruitment, retention, and measurements in SPs

• IRB pre-approved language for informed consent from surrogates and proxies • IRB pre-approved language for informed consent for patients with low literacy • # of investigators using CTSI Participant Recruitment Unit expertise to recruit

SPs

Vignette: Social vulnerabilities affect risk for chronic disease. As a result of their observations while delivering primary care for low income populations, UCSF investigators developed groundbreaking research showing how social vulnerabilities, e.g., limited literacy, intimate partner violence, and food insecurity, profoundly affect risk for chronic disease and impede disease control.20-23 They created the Center for Vulnerable Populations to translate research discoveries into meaningful interventions to improve health.

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F.2. Participant and Clinical Interactions F.2.a. Overview and Innovation CTSI’s Clinical Research Service (CRS) provides the essential infrastructure, administrative expertise, coordination, and research personnel to conduct high-quality clinical research requiring human subjects participation. A wide range of services are available to investigators, including both inpatient and outpatient specialized adult and pediatric nursing support; phlebotomy; customized specimen processing, including peripheral blood mononuclear cells, blood, urine, and cerebrospinal and other body fluids; tracking and inventory; body composition and exercise physiology consultation and services; and pediatric neurodevelopmental testing. We provide access to commonly needed services at economies of scale. CRS’s aims are designed to eliminate barriers and enhance the quality and efficiency of human subjects research. F.2.b. CRS Achievements Approximately 360 studies are carried out in the CRS annually. In the last funding period CRS conducted an extensive program review, implemented a recharge model of cost-recovery, piloted a mobile nursing program, and improved efficiencies by consolidating operations and expanding outpatient facilities in coordination with the opening of UCSF’s new Mission Bay Hospitals (see Resources and Environment). CRS Core services, including Sample Processing Core Laboratories (SPL), Body Composition, Exercise Physiology and Energy Metabolism Core, and Neurodevelopmental Testing Core, have been reorganized to meet the evolving needs of UCSF investigators. CTSI collaborated with the Medical Center on the design of 2 new outpatient research clinics for adults and children, which doubled the available clinical research space at UCSF (left: new Adult CRS unit Parnassus campus; center and right: new Pediatric CRS unit Benioff Children’s Hospital SF).

Achievements in Participant and Clinical Interactions (Clinical Research Services) Supported wide range of clinical and translational research

• Average of 360 studies carried out in the CRS annually • Approximately 1,900 clinical trials conducted at UCSF in the past 4 years

Extensive program review to prioritize CRS services

• Online user and non-user surveys conducted • Internal review: CRS Taskforce • External Advisory Board review (CTSAs, industry)

Streamlined efficiencies across UCSF campuses

• Reduction from 8 to 4 CRS sites (SFGH, VAMC, UCSF-Parnassus, UCSF-Mission Bay) • Access to in-patient beds on an as-needed basis with reduced costs successfully negotiated • Coordinated with malignant hematology infusion center to maximize access/reduce

redundancies for specimen processing on Parnassus campus Moved clinical research centers out of costly hospital space

• New adult Clinical Research Center in 2500 sq. ft. of outpatient space at Parnassus with offices; conference, exam, and procedure rooms; drug infusion and phlebotomy space

• New Pediatric Clinical Research Center in 3080 sq. ft. of outpatient space at Benioff Children’s Hospital SF; state-of-the-art research facility with child interactive features including a neurodevelopment suite. Pediatric mobile research nursing staff are deployed from this unit to complete research procedures/data collection at inpatient pediatric units.

Expanded, consolidated, or sunset cores

• Increased sites and capacity of SPL, supporting >200 clinical research protocols annually • Merged Body Composition, Exercise Physiology, and Energy Metabolism Core with Dr. John

Shepherd’s research group to form consolidated core with full-cost recharge model; offers expert consultation and access to state-of-the-art Hologic Horizon™/A DXA

• Moved Neurodevelopmental Testing Core under the direction of Dr. Tom Boyce to provide study design consultation and psychological and behavioral assessments for pediatric clinical research studies with full-cost recharge model

• Planned closure of the bionutrition core due to under-utilization and high costs Created clinical research coordinator professional series with unique job classification

• Consolidated clinical trial coordination staff across UCSF into a single Clinical Research Coordinator (CRC) professional track, including CRC, Senior CRC, and CRC Supervisor. Senior CRCs and CRC Supervisors require certification through Society of Clinical Research Associates or the Association of Clinical Research Professionals

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F.2.c. Approach to CRS Clinical trials requiring CRS services are carried out at a number of sites across UCSF including Parnassus, the Mission Bay Hospitals, SFGH, the SFVA, and UCSF Benioff Children’s Hospital Oakland. Clinical research is critical to the UCSF mission and in order to accommodate the new NCATS rules restricting the use of CTSA funds in the context of clinical trials, we are focused on improving efficiencies and reducing costs, and have secured institutional commitments to ensure that clinical investigation at UCSF continues to thrive. CRS Aim 1. Streamline CRS operations to enhance clinical trial implementation: • Implement efficient electronic systems for research planning and budgeting, scheduling, and billing to

support clinical research studies. We are partnering with the Medical University of South Carolina (MUSC) to adopt their Web-based, open-source software tool, “Services, Pricing, & Application for Research Centers” (SPARC), a centralized electronic research service request and pricing portal that will enable investigators to initiate the budget planning process early in the study design phase. Investigators (or staff) are able to browse a catalog of resources and research services and obtain standardized and up-to-date cost estimates regardless of funding source. We will share our SPARC enhancements and best practices with MUSC and the CTSA community.

• Improve scheduling for clinical studies. We are implementing the Harvard CTSI-supported Catalyst Scheduling System. This Web-based tool allows investigators and study staff to schedule research subjects for study visits. The system can capture data on usage and staffing to maximize available resources across all geographic CRS sites. A robust scheduling system will allow efficient scheduling of human resources, space, and procedures across CRS cores and locations and help expand our user base.

• Integrate our clinical trial management system, OnCore, with IRB submission and study management. OnCore enables the management of research, safety, regulatory, financial, biospecimen, and billing data in one system, and it is used for insurance coverage analysis to separate clinical from research charges. To date, investigators must enter the same research protocol information into OnCore and the IRB system (iMedris). To streamline trial processes, we will link IRB submission to OnCore data entry to eliminate duplicate efforts. CRS is also developing a secure and efficient tablet-based visit checklist form, for bedside use by nursing and other clinical research services staff to capture services rendered at the point of care; this will improve accuracy for billing, and can also be shared with other institutions.

• Establish an incentive voucher program for early-stage investigators conducting clinical research. Accessing clinical research services is a major challenge for early-stage investigators, yet critical to their ultimate success. Vouchers will be awarded for investigator-initiated protocols and pilot studies based on scientific merit as determined by our Scientific Review Committee (see below). Vouchers up to $5,000 may be used for nursing services, phlebotomy, DXA and body composition, laboratory and specimen processing, and consultation services. Vouchers will be requested through SPARC. Studies with successful recruitment and adequate progress toward goals may qualify for renewal (1 voucher per investigator/year; 2 vouchers total).

• Coordinate scientific review and ensure quality. Subsequent to IRB submission, an analyst will identify those protocols for which scientific review is lacking or inadequate (e.g., no external peer review) and refer these to the CRS Scientific Review Committee, composed of experienced investigators representative of all CRS sites. CRS will provide rigorous scientific review to ensure that a proposed study has a sound rationale, clearly stated objectives, and appropriate research design, and does not expose study participants to unnecessary risks. As noted above, CRS’s Scientific Review Committee will conduct reviews for the voucher program.

CRS Aim 2. Provide highly trained research staff to support clinical research efforts: • Establish a Clinical Research Coordinator (CRC) Core. Due to fluctuating research needs and funding,

investigators often find themselves overstaffed or understaffed, which results in inefficiencies and increased research costs. We will establish a CRC Core, which will function as a matching service to allow an investigator with a need for a short-term or part-time coordinator to contract with and share a coordinator with an investigator who has excess capacity. CRS will provide administrative infrastructure and will develop or reuse open source Web-based management tools for the program. We will pilot demonstration projects with the Department of Ophthalmology and the Division of Cardiology.

Vignette: Identifying Clinically Relevant Glioma Subgroups for Prognostication. UCSF investigators used the CRS to study patients with glioma, the most common and deadly brain tumor. They performed a GWAS of blood- or saliva-derived DNA to identify glioma-risk alleles near telomerase genes (TERT and TERC).24 In a follow-up validation study, also supported by CTSI/CRS, these investigators demonstrated a striking association of TERT promoter mutations with high-grade gliomas, poor prognosis of grade II and III gliomas and were able to define distinct groups of gliomas of varying clinical behavior.25 This work sets the stage for development of a molecular “precision medicine” diagnostic to inform prognosis and management of these tumors.

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• Develop a clinical research training program for clinical research coordinators and nurses. In addition to ensuring that all investigators and staff are trained in Responsible Conduct of Research and Good Clinical Practice (GCP), we will implement a comprehensive training program for CRCs and clinical research nurses (CRNs). In collaboration with the Medical Center we will establish a program to cross-train UCSF clinical nurses who are interested in clinical research and motivated to acquire research skills. The training program will be developed in conjunction with a parallel curriculum for the CRCs. Essential elements will include training in responsible conduct of research, GCP methods, IRB submission, study start-up, patient screening/tracking, participant recruitment, informed consent documentation, use of the EHR, adverse events tracking, audits, and study closeout. Some courses will be offered online, including “Designing Clinical Research” and “Responsible Conduct of Research” in coordination with TWD (Part D.1). Training of CRCs and CRNs will enable them to effectively staff the Trial Innovation Unit (TIU; Part G.1). CTSI will also host a UCSF Profiles Boot Camp for clinical research staff to help them search, discover, and network with the larger clinical research community at UCSF, across UC BRAID, and throughout the CTSA hubs. We expect that training and participation in the clinical research training program will improve skills and overall quality of clinical research personnel, enhance professionalism, facilitate networking, and mitigate “burn-out” and turnover.

F.2.d. CRS Leadership Director of Clinical Research Services, Henry F. Chambers, MD, Professor of Medicine, is responsible for management of the ongoing research and teaching mission, administration, and finances; interacting with other components of CTSI; and coordination of CRS activities with other UCSF research activities. Associate Director of Pediatric Research Services, Roberta Keller, MD, Associate Professor of Pediatrics; Medical Director for the CRS Unit at UCSF Benioff Children’s Hospital SF will expand her role to oversee all pediatrics CRS (UCSF Benioff Children’s Hospital SF and Oakland, Neurodevelopment Testing Unit). Associate Director of Adult Research Services, Annie Luetkemeyer, MD, Associate Professor of Medicine, will oversee adult research activities at the Cancer Center and Women’s Hospitals at Mission Bay, the SFVA, SFGH, and the Parnassus campus. Chair of CRS Scientific Review Committee, Philip Rosenthal, MD, Professor of Pediatrics, is a long-time user of CRS facilities and resources. He will coordinate with the Chairs of the IRBs to expedite the parallel review processes as described above. F.2.e. Evaluation and Tracking We will incorporate NCATS common metrics as they are developed.

Aim / Milestone Metric for Assessment and Frequency Aim 1. Streamline CRS operations to enhance clinical studies implementation Develop efficient electronic systems Improve scheduling for clinical studies

• # of protocols and investigators utilizing CRS services (annual) • # of participant visits for both inpatient and outpatient units (annual) • # of trials registered in clinicaltrials.gov

Integrate the CTMS (OnCore) with IRB platform • Time from IRB submission to study activation (semi-annual) • Proportion of CRS studies meeting target enrollment (annual) • Milestones for OnCore integration

Establish an incentive voucher program • Pilot protocols resulting in funded extramural grants (annual) Coordinate scientific review • # of protocols referred for CRS Scientific Review (semi-annual)

• % of protocols deemed scientifically inadequate by IRB • Time from referral for review to submission to IRB (annual)

Aim 2. Provide highly trained research staff to support clinical research efforts Establish a Clinical Research Coordinator (CRC) Core • # of investigators/studies utilizing CRC Core (annual)

• # of clinical coordinators participating in CRC Core (quarterly) • Efficiency rating – CRC cost/# of FTE CRCs

Develop clinical research training program for CRS staff • % and # of CRCs who are certified by Society of Clinical Research Associates or Association of Clinical Research (annual)

• % and # of CRCs who are promoted in professional track (annual) • # of nurses participating in research training program; total # of

trained nurses (annual) • # of inpatient and outpatient units with nurses who participate in CTSI

research training

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References for Part F. Hub Resource Capacity

1. Kwan, A., et al., Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA, 2014. 312(7): p. 729-738.

2. Boyce, W.T., Fostering Early Brain Development. JAMA, 2015. 313(15): p. 1564-1565. 3. Allen, L., J. Jones, and A. Wat, Transforming the Workforce for Children Birth Through Age 8: A Unifying

Foundation. 4. Walter, L.C. and K.E. Covinsky, Cancer screening in elderly patients: a framework for individualized

decision making. Jama, 2001. 285(21): p. 2750-2756. 5. Covinsky, K.E., E. Pierluissi, and C.B. Johnston, Hospitalization-associated disability: “She was probably

able to ambulate, but I’m not sure”. Jama, 2011. 306(16): p. 1782-1793. 6. Greysen, S.R., et al., Functional impairment and hospital readmission in medicare seniors. JAMA internal

medicine, 2015. 175(4): p. 559-565. 7. Hyman, A., D. Schillinger, and B. Lo, Laws mandating reporting of domestic violence: do they promote

patient well-being? JAMA, 1995. 273(22): p. 1781-1787. 8. Wang, E.A., et al., Engaging individuals recently released from prison into primary care: a randomized trial.

American journal of public health, 2012. 102(9): p. e22-e29. 9. Schillinger, D., et al., Association of health literacy with diabetes outcomes. Jama, 2002. 288(4): p. 475-

482. 10. Yourman, L.C., et al., Prognostic indices for older adults: a systematic review. Jama, 2012. 307(2): p. 182-

192. 11. Schillinger, D., et al., Functional health literacy and the quality of physician–patient communication among

diabetes patients. Patient education and counseling, 2004. 52(3): p. 315-323. 12. Seligman, H.K. and D. Schillinger, Hunger and socioeconomic disparities in chronic disease. New England

Journal of Medicine, 2010. 363(1): p. 6-9. 13. Lee, S.J., et al., Development and validation of a prognostic index for 4-year mortality in older adults.

Jama, 2006. 295(7): p. 801-808. 14. Hoppe, C., et al., A pilot study of the short‐term use of simvastatin in sickle cell disease: effects on markers

of vascular dysfunction. British journal of haematology, 2011. 153(5): p. 655-663. 15. Pino-Yanes, M., et al., Genetic ancestry influences asthma susceptibility and lung function among Latinos.

Journal of Allergy and Clinical Immunology, 2015. 135(1): p. 228-235. 16. Vichinsky, E., et al., Transfusion complications in thalassemia patients: a report from the Centers for

Disease Control and Prevention (CME). Transfusion, 2014. 54(4): p. 972-981. 17. Harmatz, P., et al., Enzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized,

double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension study. The Journal of pediatrics, 2006. 148(4): p. 533-539. e6.

18. Lyles, C.R., et al., Innovation and Transformation in California’s Safety Net Health Care Settings An Inside Perspective. American Journal of Medical Quality, 2013: p. 1062860613507474.

19. Sudore, R.L., et al., Use of a modified informed consent process among vulnerable patients: a descriptive study. Journal of General Internal Medicine, 2006. 21(8): p. 867-873.

20. Schillinger, D., et al., Effects of Self-Management Support on Structure, Process, and Outcomes Among Vulnerable Patients With Diabetes A three-arm practical clinical trial. Diabetes Care, 2009. 32(4): p. 559-566.

21. Brach, C., B.P. Dreyer, and D. Schillinger, Physicians’ roles in creating health literate organizations: a call to action. Journal of general internal medicine, 2014. 29(2): p. 273-275.

22. Schillinger, D., et al., Effects of primary care coordination on public hospital patients. Journal of General Internal Medicine, 2000. 15(5): p. 329-336.

23. Seligman, H.K. and D. Schillinger, Hunger and socioeconomic disparities in chronic disease. New England Journal of Medicine, 2010. 363(1): p. 6-9.

24. Walsh, K.M., et al., Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk. Nature genetics, 2014. 46(7): p. 731-735.

25. Eckel-Passow, J.E., et al., Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. New England Journal of Medicine, 2015. 372(26): p. 2499-2508.

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Part G Network Capacity Abstract The UCSF CTSI will efficiently execute all necessary steps to serve as an outstanding hub partner in the CTSA Trial Innovation Centers (TICs) multisite study network. CTSI has actively engaged key institutional stakeholders to improve clinical trial start-up at UCSF with an emphasis on increasing parallel, rather than sequential, approval processes. CTSI is committed to serving as a liaison to the TICS (LTIC) by carrying out the following Aims: LTIC Aim 1. Develop a Trial Innovation Unit that streamlines and facilitates clinical trial start-up and implementation at UCSF, with an emphasis on multisite studies; and LTIC Aim 2. Work in coordination with regional and national CTSA hubs to develop shared technology and tools that enable networks to improve multisite trial start-up and execution. In concert with our work in trial innovation, CTSI has built a successful Participant Recruitment Unit (PRU) that will be improved and expanded to act as liaison to NCATS’ Recruitment Innovation Centers (RICs). Improving the ability to recruit and enroll participants is a key accelerator to multisite trials - and to all types of human subjects research. CTSI has built a successful Participant Recruitment Unit (PRU) that will serve as a local/regional resource for investigators and a liaison to the NCATS Recruitment Innovation Centers (RICs). Working closely with the CTSI Informatics and Research Innovation program, recruitment will be streamlined using EHR data, enabling real time recruitment for studies that require enrollment of participants at the time of an event or procedure, and providing expert advice and support for recruitment. CTSI is committed to serving as a liaison to the RICS (LRIC) by carrying out the following Aims: LRIC Aim 1. Streamline the process for identifying potentially eligible participants, develop a “Do Not Contact” list; extend capabilities for “real time” recruitment; provide expert advice to investigators on developing and carrying out recruitment plans, and provide an easy, automated process for interested patients and the public to identify active clinical trials; and LRIC Aim 2. Contribute expertise, experience and tools to help NCATS develop efficient and effective networks of recruitment centers.

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SPECIFIC AIMS The UCSF CTSI will efficiently execute all necessary steps to serve as an outstanding hub in the CTSA Trial Innovation Centers (TICs) multisite study network. We have actively engaged key institutional stakeholders to improve clinical trial start-up at UCSF with an emphasis on increasing parallel, rather than sequential approval processes. We are committed to serving as a liaison to the TICS, including implementing IRB reliance, using central IRBs, and pre-negotiated master contracts and data sharing agreements. In concert with our work in trial innovation, CTSI has built a successful Participant Recruitment Unit (PRU) that will be expanded to serve as liaison to NCATS’ Recruitment Innovation Centers (RICs). Our commitment and capability in this role is evidenced by our participation in the ACT Recruitment Innovation Center application and other national initiatives. LTIC Aims Despite the advantages of multicenter trials, these studies are challenging to implement, and often suffer from a lack of harmonization of financial, ethical, legal, and regulatory processes and approvals. To expedite initiation and execution of multisite trials, we propose the following: LTIC Aim 1. Function as a highly efficient clinical trial site in NCATS’ nationwide efforts to create large-scale clinical research collaboratives, we will:

• Develop a streamlined Clinical Trial Unit to coordinate clinical trial implementation and conduct, track trial performance and metrics, and serve as a liaison to the CTSA TICs

• Convene a clinical research governance committee • Facilitate identification of a UCSF investigator to serve as local PI on multisite trials • Streamline and improve research billing procedures • Reduce time to execute multisite trial contracts • Increase use of IRB reliance and central IRBs

LTIC Aim 2. Work in coordination with regional and national CTSA hubs to develop shared technology and tools that enable networks to improve multisite trial start-up and execution. LRIC Aims The CTSI Patient Recruitment Unit (PRU) works with UCSF Academic Research Systems (ARS) to provide investigators access to EHR data to determine the number of eligible patients for specific studies and to act as an honest broker to contact patients to invite them to enroll in research. In the next funding period we will refine and expand our recruitment services and scale these for use in NCATS’ planned RICs, through the following: LRIC Aim 1. Enhance CTSI’s Participant Recruitment Unit to ensure successful recruitment for multisite trials and for all human research studies at UCSF.

• Streamline the process for identifying potentially eligible participants from EHR data • Develop a “Do Not Contact” list for patients who do not wish to be contacted for research • Extend capabilities for “real-time” recruitment • Provide expert advice to investigators to develop recruitment plans and assist in carrying them out • Provide an easy to navigate, up-to-date Web site with which interested patients and the public may

identify active clinical trials at UCSF LRIC Aim 2. Contribute our expertise, experience, and tools to help NCATS develop efficient and effective networks of recruitment centers.

Part G. Network Capacity: Liaison with Trial Innovation Centers and Recruitment Innovation Centers

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RESEARCH STRATEGY G.1. Liaison to Trial Innovation Centers (LTIC) G.1.a. Overview and Innovation Multisite studies have great potential to improve health by enabling enrollment of the targeted number of eligible participants, and by ensuring generalizability with the inclusion of diverse participants across geographic sites. Enrollment at multiple sites may have advantages for any study design, but is particularly important in clinical trials, where enrollment of an adequate number of participants at a single center is often not feasible. CTSI has led UCSF’s efforts to overcome the financial, ethical, legal, and regulatory challenges of efficiently initiating and carrying out multisite studies. We will develop a Clinical Trial Unit housed in the Clinical Research Service (Part G.2) to coordinate multisite trial implementation and execution and to serve as liaison to the Trial Innovation Centers (TICs). Working with our regional partners, UC BRAID (the 5 UC Medical Centers, each with a CTSA award) and other CTSA hubs in the Accrual to Clinical Trials (ACT) Network, we have demonstrated that we can utilize network-wide IRB reliances and central IRB agreements, master clinical trial and data use agreements, and electronic participant recruitment approaches. G.1.b. LTIC Achievements In 2014, UCSF completed a clinical research strategic plan to identify barriers and develop processes to eliminate obstacles to high quality, efficient clinical research. The process included interviews with UCSF clinical investigators, industry leaders, and peer institutions to assess current trends in clinical research. Many of the goals of the strategic plan have been accomplished, as described below.

Steps in Multisite Clinical Trials

Current Achievements and Gaps Addressed by LTIC

Identify collaborators • Optimized UCSF Profiles to identify PI-specific content expertise and trial experience based on publications and grants, using MESH terms, free text, and key words

• Developed clinical trial search tool UC TrialQuest to identify 4000 pending and IRB-approved trials across the UC BRAID network

Initiate clinical trial Scientific review • IRB now accepts external scientific peer review (e.g., NIH, AHRQ, PCORI, DOD, VA, American Heart

Association, etc.), which occurred for 163/216 trials submitted to IRB over 6 months in 2015 • Other trials reviewed by CTSI Clinical Research Service (CRS) Scientific Review Committee (Part F.2)

Budgeting • CTSI CRS provides budgeting support and is working to bridge identified gaps: 1) start budgeting earlier in study design; 2) lack of access to campus-wide research charges; 3) need to distinguish billing to insurance vs. research

Contracting • Contracting concurrent with other needed approvals, process improvement, and Master Contracts (30 new since 2011; 64 total) have decreased time to signing

• Master contracts across the 5 UC BRAID sites with 28 pharma/biotech companies. Working to bridge identified gaps: 1) need for ongoing process improvement; 2) increase number and use of Master Contracts, Subcontracts, and Data Use Agreement

IRB and regulatory approvals

• Approvals by UCSF IRB and ancillary committees (e.g., IACUC, radiation, conflict of interest) concurrent and process improvement has decreased time to approvals

• Since 2012; 500 studies using IRB reliance across 10 UC sites. Working to bridge identified gaps: 1) continued process improvement; 2) expanded IRB reliance; 3) development of UCSF central IRB

Conduct clinical trial Recruit participants • See LRIC (Section G.2 below). Randomize and follow participants

• Traditional methods available. • CTSI Informatics and Research Innovation (Part B) refining approaches to use the UCSF EHR and

direct to participant methods to randomize patients and obtain outcome measures. Biospecimen collection & management

• See CTSI Precision Medicine Function (Part H.2).

Analyze data & disseminate findings

• CTSI Consultation Service (CS) Biostatistics and Science Writing Units. • MyResearch, a secure, HIPAA-protected environment for data management with curated analytic tools.

Disseminate findings • CTSI CS Science Writing Unit, Community Engagement program, Special Populations Initiative.

CTSI was an inaugural member of NCATS’ Accrual to Clinical Trials (ACT) Network, a national network of 21 CTSA hubs. We met very short timelines to develop and test processes for multisite clinical trials, including governance and regulatory frameworks, network and data use agreements, cohort exploration, access to detailed data on potential participants who meet specific study entry criteria, a common technology platform, and a data harmonization schema. In addition to developing these tools for efficient start-up and conduct of multisite trials, UCSF has successfully and efficiently conducted

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a number of phase III trials (Tables G1 and G2: January 1-June 30, 2014). We anticipate that our efficiency will increase significantly by implementing effective accrual tools developed at UCSF (Sec. G.2), with our regional partners, the UC BRAID network, and other CTSA hubs in the ACT Network (see Approach). G.1.c. Approach to LTIC LTIC Aim 1. To function as a highly efficient clinical trial site in NCATS’ nationwide efforts to create large-scale clinical research collaboratives, we will: • Develop a streamlined Clinical Trial Unit (CTU) to coordinate trial start-up and implementation and track

performance and metrics. We will work with the CTSA network-wide initiative that is developing common metrics for the CTSA program and serve as a liaison to the CTSA TICs. The CTU will be housed in the Clinical Research Services (CRS) program, in 2500 sq. ft. of newly renovated, state-of-the-art outpatient research space and will be led by Dr. Laura Esserman, Director of the UCSF Carol Frank Buck Breast Care Center and an experienced multisite trialist. Skilled CTU staff will coordinate IRB activities, contracting, budgeting, recruitment, and project management. To identify and facilitate all multisite trials, CTU services will be triggered by: 1) investigator request, 2) IRB submission or reliance agreement, 3) confidentiality agreement with a trial sponsor, or 4) initiation of a clinical trial agreement from UCSF Industry Contracts.

• Convene a clinical research governance committee. As at most academic medical centers, the governance needed to make comprehensive decisions and plans to improve multisite trials is dispersed across UCSF. To address this problem, we will create a comprehensive governance committee composed of leading clinical investigators from UCSF and community sites, and decision makers from medical center administration and campus compliance, contracting, and research IT. The committee will meet monthly to identify and prioritize obstacles to rapidly opening, enrolling, and completing multisite trials and develop integrated plans to meet these challenges. Mapping study processes across UC BRAID will allow us to critically examine each step with a focus on continuous process improvement.

• Facilitate identification of a UCSF investigator to serve as local PI on multisite trials. In the absence of an established collaboration, implementing multisite trials requires readily available information to select the most appropriate site PI. The CTU leader and staff will use their broad knowledge of UCSF faculty and the UCSF Profiles tool to rapidly identify candidate PIs based on their publications and research funding. We will continue to develop, enhance, and share Profiles across the CTSA network and implement tools developed by other CTSAs to facilitate collaborator “matching.”

• Streamline and improve research billing procedures. We are working with the UCSF Medical Center to develop clear and transparent research chargemasters to facilitate rapid budgeting for clinical trials. The chargemasters will support billing coverage analysis required by the University of California to distinguish research from standard-of-care costs that can be billed to insurance. Ongoing efforts will clearly define the trials that require billing analysis, develop an efficient unit to perform the analysis, and permit simultaneous submission of a trial for coverage analysis, IRB review, and contracting.

• Reduce time to execute multisite trial contracts. CTSI participates in the UC BRAID Contracting Initiative, which aims to drive continuous process improvement. This group collected 18 months of trial contracting data from across the 5 sites, is developing benchmarks for comparison, and is identifying best practices. Data analysis is ongoing, but this exercise made it clear that the major factor that reduces time to contract execution is use of Master Contract Agreements (MCAs) – decreasing time to execution, on average, by 19 days. UCSF has successfully negotiated MCAs with 64 companies as well as master subcontracts and data use agreements with multiple academic institutions. We will continue to negotiate MCAs and data use agreements and pursue other best practices that emerge from the BRAID Contracting Initiative.

Vignette: Identifying opportunities to reduce time from protocol submission to study implementation. We selected an investigator-initiated multisite trial of immunotherapy for glioblastoma and assessed coordination of IRB, scientific review, regulatory committees, OnCore, and Industry Contracts. Processes that significantly decreased start-up delays included: aligning the timing of multiple review committees, allowing processes to happen in parallel rather than sequentially, and enhancing communication across diverse units. Optimizing coordination resulted in a start-up time of 60 days, compared with the historical mean of 120 days.

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• Increase use of IRB reliance and central IRBs. Use of IRB reliance can accelerate multisite study approval. The UC BRAID agreement uses a single “IRB of record” whereby any of the 5 institutions rely on 1 IRB to review, approve, and monitor the trial. The average time for reliance approval is 11 days. In addition, we will position UCSF to function as a central IRB (cIRB) for multisite trials led by UCSF investigators. As a cIRB, we will draw from and follow the National IRB Reliance Agreement and Standard Operating Procedures (SOPs) developed by the CTSA-sponsored initiative “IRBRely” to create UCSF-specific forms, SOPS, and supporting documents/processes. We have secured institutional support to hire a cIRB Coordinator to oversee these efforts and have identified 3 UCSF-led multisite studies to test a UCSF cIRB: Pacific Pediatric Neuro-Oncology Consortium (PI: Prados); Athena Breast Health Network - WISDOM study (PI: Esserman); and the Primary Immune Deficiency Treatment Consortium (PI: Cowan).

LTIC Aim 2. To work in coordination with regional and national CTSA hubs to develop shared technology and tools that enable networks to improve multisite trial start-up and execution, we will: • Collaborate to streamline multisite trial processes. We are eager to contribute UCSF’s experience, energy,

and expertise to help inform and improve processes for NCATS’ emerging TICs, as well as other clinical trial networks. Modeled on our success in UC BRAID and the Accrual to Clinical Trials (ACT) networks, we will partner with NCATS, other CTSA hubs, and potential sponsors to improve and streamline trial governance, master contracts and data use agreements, cohort identification, IRB reliance, and recruitment. UCSF also has experience in research networks supported by PCORI, hosting a PCORnet pScanner Clinical Data Research Network node, and 3 Patient-Powered Research Networks - the Health eHeart Alliance, PRIDEnet, and the Community Engaged Network for All.

• Share tools/technologies. UC BRAID has created a toolkit of SOPs, templates, workflow maps, and best practices that will be shared with trial networks. The value of these is evidenced by the fact that several other CTSAs, including Stanford, USC, and Oregon Health Sciences University, have expressed interest in joining BRAID, and BRAID processes played a major role in informing the ACT network. UC TrialQuest is a Web-based tool that provides real-time IRB information on pending and active clinical trials in the UC system. A query of 200 trials pending IRB approval revealed that 39 multisite trials were approved by a UC IRB but were not using IRB reliance. UC IRBs now check TrialQuest and direct eligible protocols to use IRB reliance. TrialQuest can be disseminated across CTSAs to avoid duplicate IRB applications.

• Track and eliminate duplicate processes. UC BRAID studied IRB metrics on >400 protocols across the UC system and found that ancillary reviews substantially delay study execution. To address this concern, we have mapped workflows for ancillary reviews, implemented pre-review of protocols, eliminated review of standard-of-care procedures, and standardized conflict-of-interest criteria. CTSI will work with the NIH and other CTSA hubs to ensure that reviews are comprehensive, transparent, and consistent. The planned CTSA Support Center (CT-SC) will help harmonize amendments, adverse event reporting, and protocol changes in multisite studies. Interactions with the CT-SC will be a natural extension of UC BRAID activities.

• Develop methods to coordinate contracting across CTSA hubs. Harmonizing contractual definitions and language and developing common metrics will speed contracting across CTSA hubs. The UC BRAID Contracting Initiative collected 18 months of clinical trial contracting data, has been working to harmonize contractual language, and has developed metrics and benchmarks for comparison across the 5 UC sites. We will continue this effort across BRAID and share this expertise and best practices with the CTSA TICs.

G.1.d. LTIC Leadership Director, Laura Esserman, MD MBA is Professor of Surgery, Director of the UCSF Carol Frank Buck Breast Care Center, PI of the UC-wide Athena Breast Health Network, and PI of a PCORI Pragmatic Trial (WISDOM). She will oversee all activities, ensure that UCSF trials meet highest standards of quality, efficiency, and ethics, and will be the main point of contact for NCATs TICs. Henry F. Chambers, MD, Professor of Medicine and Director of Clinical Research Services, will be responsible for ensuring the integration of the Clinical Trials Unit into CRS and that the unit is supported by experienced CRS research coordinators and other staff. G.1.e. LTIC Evaluation and Tracking We will incorporate to NCATS common metrics and our evaluation processes as these are finalized.

Vignette: Multisite trials to drive innovation in breast cancer. The Athena Breast Health Network, led by Dr. Laura Esserman, is a collaborative of the UC Cancer Centers and community-based organizations (19 centers in the US and Canada). In an ongoing series of adaptive trials, the network is studying novel agents for personalized breast cancer therapy (I-SPY). To date, there have been 14 adaptive amendments to the I-SPY Master trial design and 9 agents added, 3 of which have graduated – i.e., reached the threshold for 85% likelihood of success in a confirmatory phase 3 neoadjuvant trial of 300 patients.

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Aim / Milestone Metric for Assessment and Frequency Aim 1. Function as a highly efficient clinical trial site in NCATS’ clinical trial networks Coordinate clinical trial start up and track performance # of days from IRB submission to trial initiation; # of days to execute

contract (measured continuously) Streamline research billing # of days to assign appropriate charges to research accounts Expand # and use of Master Agreements Increase by 10% per year (add 39 new agreements in next 5 years) Increase # of studies using IRB reliance and cIRBs Increase by 10% per year # of studies using IRB reliance Aim 2. Coordinate with regional and national CTSA hubs Collaborate to streamline multisite trial processes # of Master Contracts and Data Use Agreements, cohort

identification, IRB reliance and recruitment in coordination with NCATS TICS

Share tools and technologies across CTSA hubs # of CTSA hubs using UC BRAID/UCSF tools (e.g. TrialQuest, Profiles, Open Proposals)

Track and eliminate duplicate processes # of ancillary reviews mapped; # reviews of SOC procedures eliminated; # of months to standardize conflict of interest criteria

G.2. Liaison to Recruitment Innovation Centers (LRIC) G.2.a. Overview and Innovation Improving the ability to recruit and enroll participants is key to the success of multisite trials - and to all types of human subjects research. CTSI has built a successful Participant Recruitment Unit (PRU) that will serve as a local and regional resource for investigators and a liaison to the NCATS Recruitment Innovation Centers (RICs). Investigators may access the PRU directly or via the CTSI Consultation Service (CS) portal (Part E.1); PRU activities are managed and tracked as a unit of CS. In collaboration with UCSF Academic Research Systems (ARS), PRU routinely helps UCSF investigators use the EHR to determine the number of potentially eligible patients for a specific study and to extract contact data to allow the PRU, as the honest broker, to invite patients to participate in research. PRU has also collaborated with UC BRAID to demonstrate that we can identify eligible patients using EHR data across all 5 UC medical centers. Working closely with the CTSI Informatics and Research Innovation (IRI) program (Part B), we will streamline recruitment using EHR data, expand our capabilities for real-time recruitment for studies that require enrollment of participants at the time of an event or procedure, and provide expert advice and support for recruitment. G.2.b. LRIC Achievements

Achievements of the Participant Recruitment Unit (PRU) Used EHR at UCSF and across UC BRAID (UC Research Exchange: ReX) to identify and contact potentially eligible participants

• Investigators without IRB approval can use the Research Data Browser (RDB), a software tool developed at UCSF with pull-down data menus, to quickly determine the number of eligible patients (de-identified data) at UCSF and across UC BRAID. In 2015, 252 uses of the RDB at UCSF.

• Investigators with IRB approval work with PRU to define eligibility based on EHR variables; ARS extracts a list of potentially eligible patients and provides contact information to PRU. PRU contacts these patients and invites interested patients to contact the study team. In 2015, PRU supported recruitment for 108 studies.

Facilitated “real-time” recruitment

• Partnered with PatientPrecision, Inc. to develop PatientLocate, a HIPAA-compliant system that uses HL7 real-time events with IRB approval to identify eligible patients in the hospital or clinics. In the past 5 years, PatientLocate has identified 5,100 potentially eligible patients. 1,2,3,4

Created IRB pre-approved recruitment materials

• Materials (letters, flyers, posters, advertisements) in an array of styles and images with standardized fields for enrollment criteria, disease, investigator, and study design. Used by 65 studies in the last year.

Applicant for 1st ACT RIC • CTSI recently participated in the ACT Recruitment Innovation Center (RIC) application, a supplement to the University of Pittsburgh CTSA (5UL1TR000005-09S1).

G.2.c. Approach to LRIC UCSF investigators can recruit participants directly from 3 UCSF adult hospitals (Moffitt-Long; Mt. Zion, Betty Irene Moore Women’s Hospital), 2 pediatric hospitals (Benioff Children’s Hospitals of Oakland and SF), the SF Health Network (San Francisco General Hospital, Laguna Honda Rehabilitation Hospital, and SF Department of Public Health Community Clinics), the SF Bay Area Collaborative Research Network (over 100 community health centers in the 9 Bay Area counties), and the Bay Area Accountable Care Network (see Part A. Sec. B.1).

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LRIC Aim 1. Enhance CTSI’s Patient Recruitment Unit to ensure successful recruitment for multisite trials and for all human research studies at UCSF. • Streamline the process for identifying potentially eligible participants from

EHR data. PRU helps investigators with IRB approval use EHR data for recruitment. Currently, PRU works with programmers in ARS to translate study enrollment criteria into code to interrogate the EHR, which generates lists of potentially eligible patients. Contact data is “pulled” by ARS, and PRU sends letters from UCSF, using IRB-approved language, inviting patients to contact the investigator if they are interested in enrolling in the study. This process is slowed by the need for multiple iterations to refine code and by investigators’ unfamiliarity with the structure and limitations of EHR data. To address this problem, we created the Research Data Browser (RDB), which allows investigators without IRB approval to familiarize themselves with EHR data by using pull-down menus to browse de-identified demographics, labs, and diagnostic and procedure codes. We will enhance the RDB by adding variables and accumulating code for common inclusion/exclusion conditions. PRU will also work closely with IRI (Part B) to create a de-identified version of the EHR-derived UCSF Clinical and Research Data Warehouse to allow refinement of recruitment criteria that are more sensitive and more specific. We will also facilitate recruitment across networks by querying EHR data through network-generated common data models (e.g., the PCORnet Common Data Model and i2b2 SHRINE) that are supported by IRI and ARS (Part B.). In collaboration with IRI, we will create a reusable code library for computable phenotypes to create an ever-growing inventory of reproducible enrollment criteria. To underscore the importance of enrolling in research and ensure patient privacy, we will use UCSF’s EHR patient portal, MyChart, to contact potentially eligible patients.

• Develop a “Do Not Contact” list. Currently, patients agree to be contacted for research when they sign UCSF’s “Terms and Conditions of Care.” To honor patients’ wishes, we will develop a “Do Not Contact” option, via preferences recorded on a survey in the EHR patient portal, MyChart, and a phone-tree system for patients without Internet access. Using these 2 systems, patients will specify contact/no contact preferences for all research or certain types of research and state whether they would like to periodically review their preferences. MyChart will be used to flag a patient’s EHR, and to create a database for cross-referencing when patients are identified as potentially eligible for research. The EHR is flagged if a patient dies in our hospitals, but to help avoid contacting the families of those who die elsewhere, we will also cross-match with the California Death Registry and the Social Security Death Index biannually. Finally, we will maintain a list of patients contacted within the prior 6 months to avoid repeated contacting.

• Extend capabilities for “real-time” recruitment. We currently use PatientLocate, a commercial system co-developed by PatientPrecision, Inc. and UCSF Emergency Medicine investigators. For studies with IRB approval, PatientLocate uses a HIPAA-compliant system based on real-time HL7 feeds and natural language processing to identify patients in our hospitals or clinics and notifies authorized staff of a patient’s location using secure smartphone messaging. We will extend current capability based on demographics, diagnostic codes and lab values, to include procedures, drugs, radiology, pathology and spirometry reports. We will also explore enhancing real-time feeds by linking to the CRDW to access data that might be relevant for recruitment, even though these data are updated only daily (see Part B).

• Provide expert advice to investigators to develop recruitment plans and assist in carrying them out 5. Even with optimal study design, investigators need a strong recruitment plan with multiple approaches targeted to the study population. PRU will provide expert advice on development of a multi-pronged, targeted and effective recruitment plan, and if needed, access to experienced staff to carry out the plan. Experienced recruiters drawn from across the UCSF research enterprise will share focused expertise on recruiting patients with specific conditions, and members of the Clinical Coordinator Core (Part F.2) with extensive recruitment experience will be available to carry out these plans. Working with the CTSI Special Populations Initiative (Part F.1) we will bring expertise in recruitment of children, the elderly, underrepresented minorities, and vulnerable populations. Recruitment plans will include advice on study design, tailored recruitment tactics, estimated recruitment budget, and methods for tracking and analytics. Recruitment approaches may include using the EHR, disease registries, ResearchMatch (Web-based nationwide participant registry), UC ReX Data Explorer, targeted mass mailings, enrollment by clinicians from disease-focused practices and trusted community partnerships, as well as advertising in local newspaper, radio, and TV, community fliers, social media, snow-ball sampling, random digit dialing, and direct-to-participant marketing. PRU will work closely with digital marketing and advertising experts like TrialSpark, StudyKIK,

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and Landers, and help researchers use search engine-optimized digital media campaigns. Three UCSF studies, Health eHeart (N>30,000 participants), the Brain Health Registry (N>28,000), and the PRIDE study (N>13,000) have demonstrated success using social media for direct-to-participant recruitment and consent.

• Provide an easy-to-navigate Web site for interested patients and the public to identify active clinical trials at UCSF. UCSF, with UC BRAID, developed TrialQuest, which automatically obtains up-to-date IRB data from each of the 5 UC Medical Centers to allow investigators to identify trials taking place at other UC campuses. We will leverage this work and reuse relevant IRB data to populate a consumer-friendly, search-engine optimized Web site for people to find trials and contact study teams across the UC system. Campuses will brand their own sites with a configurable template. At UCSF, clinical trials data will be integrated with Profiles so that investigators’ profiles will include active trials.

LRIC Aim 2. Contribute our expertise, experience, and tools to help NCATS develop efficient and effective networks of recruitment centers. Our shareable EHR-based tools for recruitment (LRIC Aim 1) and emerging recruitment networks will help inform the NCATS RICs and network-wide recruitment. Approaches developed at UCSF are being adopted across UC BRAID (e.g., UC ReX Research Data Browser, de-identified versions of EHR-derived data, “do not contact” approaches); UC BRAID is a perfect regional network in which to beta test, refine, and disseminate recruitment approaches that can inform national recruitment networks. • UCSF has experience in emerging recruitment networks supported by both PCORI and NCATS. We host a

PCORnet pScanner Clinical Data Research Network node and 3 Patient-Powered Research Networks - the Health eHeart Alliance, PRIDEnet, and the Community Engaged Network for All (CENA). CENA, led by the nonprofit agency Genetic Alliance, UCSF, and UC Davis, is a collaborative network of 10 disease advocacy organizations primarily focused on rare diseases, many of which are diagnosed initially in children. Through CENA, each organization has created an online registry for patients and families to participate in research. UCSF’s Open Proposals platform (see Part A Sec. B.2) has been adapted by CENA to engage members in online research and recruitment discussions with researchers. We will share these technical solutions and community engagement strategies through UC BRAID, PCORnet, and the CTSA consortium.

• CTSI was an early participant in the NCATS Accrual to Clinical Trials (ACT) network, a collaboration of 21 CTSA hubs that developed and tested a national network using EHR data for cohort exploration and patient recruitment. We signed network and data use agreements that allow identification of potential study participants and healthy controls across the 21 hubs. Finally, we participated in the first NCATS RIC application, in collaboration with 20 of the original ACT sites (U. Pittsburgh CTSA [5UL1TR000005-09S1]).

• PRU will be the main liaison for the CTSA RICs and multisite trial sponsors. PRU will provide data on numbers of patients meeting study entry criteria that can be used for site selection and recruitment planning. PRU will work with RICs and study sponsors to develop recruitment plans, both for UCSF as one site in the network and (when appropriate) for recruitment across a network. PRU will also be the unit at UCSF responsible for carrying out and tracking success of multisite trial recruitment plans.

G.2.d. LRIC Leadership Deborah Grady, MD, MPH, CTSI Co-Director, Professor of Medicine and Associate Dean for Clinical and Translational Research will act as the Faculty Director of the PRU of the Consultation Service. She will provide direction and leadership to all activities of the PRU program ensuring that program goals are met on time. Alka Kanaya, MD, MAS, Professor of Medicine and Director of the CTSI Consultation Service will act as Co-Director of the PRU, ensuring that PRU can identify Consultants and Clinical Research Coordinators who assist in PRU activities.

Aim / Milestone Metric for Assessment and Frequency Aim 1. Patient Recruitment Unit for multisite and all human research studies at UCSF Streamline process to identify potentially eligible participants # of studies using EMR for recruitment; # patients enrolled (monthly)

% of trials meeting recruitment goals (monthly) # of reproducible enrollment queries (monthly)

Develop a “Do Not Contact” list Implementation using MyChart; end of second funding year Extend capability for real-time recruitment # of studies using; # patients enrolled using PatientLocate (monthly) Help develop and carry out recruitment plans # of recruitment plans developed (quarterly)

% of studies using the service with on-time recruitment (quarterly) Provide automated process for public access to active trials # of studies posted on the site (monthly)

# of site visits; and # of visitors who enroll (continuous) Aim 2. Contribute to NCATS development of a network of recruitment centers Share programming documentation, standardized definitions, and other resources with other hubs in the network

# of multisite trials recruiting at UCSF (continuous) % of multisite trials at UCSF meeting recruitment goals (annual)

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References for Part G. Network Capacity

1. Quinn, J.V., et al., The San Francisco Syncope Rule vs physician judgment and decision making. The American journal of emergency medicine, 2005. 23(6): p. 782-786.

2. Quinn, J., et al., Death after emergency department visits for syncope: how common and can it be predicted? Annals of emergency medicine, 2008. 51(5): p. 585-590.

3. Stein, J., et al., Ultrasonographically guided peripheral intravenous cannulation in emergency department patients with difficult intravenous access: a randomized trial. Annals of emergency medicine, 2009. 54(1): p. 33-40.

4. Quinn, J., et al., Prophylactic Antibiotics for Dog Bites: A RCT with Refined Cost Model. Western Journal of Emergency Medicine, 2007. 8(3).

5. Nasser, M.N., D. Grady, and C.W. Balke, Commentary: Improving participant recruitment in clinical and translational research. Academic medicine: journal of the Association of American Medical Colleges, 2011. 86(11): p. 1334.

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Part G Network Capacity Metrics

Agreement:

Agreement

Name

Principal

InvestigatorSponsor Study Location

Project Title

Contract

Received Date

Contract

Finalized Date

Date Submitted

to CHR

Date Approved

by CHR

Signed by

UCSF

Signed by

Sponsor

Date of First

Patient Visit

# of Patients

Approved

# of Patients

Enrolled

CA-0050738 Aaron Logan Astellas Pharma Inc. University of California San Francisco A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial 3/11/2014 6/16/2014 3/24/2014 6/13/2014 6/16/2014 6/20/2014 9/12/2014 20 13CA-0056883 Adam Boxer UC San Diego University of California San Francisco Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4 Study) 1/21/2014 1/21/2014 2/6/2014 4/8/2014 1/21/2014 1/21/2014 8/14/2014 86 43

CA-0056517 Adil I. Daud Merck & Co., Inc. University of California San Francisco A Multicenter, Randomized, Controlled, Two-Arm, Phase III Study to Evaluate the Safety and Efficacy of MK-

3475 Compared to Ipilimumab in Patients with Advanced Melanoma

1/7/2014 1/9/2014 8/22/2013 9/12/2013 1/9/2014 1/9/2014 1/9/2014 22 22

CA-0057115 Andrew H. Ko Celgene Corporation University of California San Francisco A Phase 3, Multicenter, Open-label, Randomized Study of nab-Paclitaxel Plus Gemcitabine versus Gemcitabine

Alone as Adjuvant Therapy in Subjects with Surgically Resected Pancreatic Adenocarcinoma

4/24/2014 6/5/2014 3/5/2014 6/11/2014 6/5/2014 8/7/2014 3/5/2015 15 2

CA-0053728 Byron Lee Boston Scientific

Corporation

University of California San Francisco SAMURAI STUDY 2/12/2014 2/13/2014 1/21/2014 3/4/2014 3/18/2014 3/19/2014 5/13/2014 10 4

CA-0060747 Charles Eichler Proteon Therapeutics, Inc University of California San Francisco Multicenter, Double-Blind, Placebo-Controlled Study of PRT-201 Administered Immediately after Radiocephalic

Arteriovenous Fistula Creation in Patients with Chronic Kidney Disease

4/30/2014 11/10/2014 5/6/2014 7/15/2014 11/13/2014 11/13/2014 1/2/2015 10 2

CA-0062856 Flavio Vincenti Alexion Pharmaceuticals,

Inc

University of California San Francisco Protocol ECU-DGF-201: A randomized, parallel-group, double-blind, placebo-controlled, multi-center study of

Eculizumab for the prevention of delayed graft function after kidney transplantation in adult subjects at increased

risk of dela

6/2/2014 8/22/2014 7/24/2014 9/3/2014 9/22/2014 9/25/2014 12/9/2014 20 9

CA-0062629 Hope Rugo PAREXEL International

Corporation

University of California San Francisco Multictr Randomized Double-Blind Placebo-Contr. Phase 3 Trial of Fulvestrant (Faslodex) w/ or w/out PD-

0332991 (Palbociclib) Goserelin in Women w/ Hormone Receptor-Positive, HER2-Negative Metastatic Breast

Cancer Whose Disease Progressed After Prior Endocrine Therapy

5/27/2014 5/30/2014 1/22/2014 4/22/2014 5/30/2014 6/5/2014 6/17/2017 10 6

CA-0059418 Jacque

Duncan

Pennsylvania State

University

NIH Natl Eye Institute Study of COmparative Treatments for REtinal Vein Occlusion 2 (SCORE2) 3/18/2014 8/28/2014 12/3/2014 1/7/2015 8/28/2014 8/29/2014 5/15/2015 5 2

CA-0059209 Matthew

Gubens

Novartis AG University of California San Francisco A phase III, multicenter, randomized, open-label study of oral LDK378 versus standard chemotherapy in adult

patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer who have been treated

previously with chemotherapy (platinum d

3/24/2014 3/25/2014 11/20/2013 2/10/2014 3/25/2014 3/29/2014 study closed

before anyone

enrolled

6 0

CA-0047660 Matthew

Gubens

Merck & Co., Inc. University of California San Francisco A Phase II/III Randomized Trial of Two Doses of MK-3475 (SCH900475) versus Docetaxelin Previously Treated

Subjects with Histology Non-Small Cell Lung Cancer (Protocol MK-3475-010)

4/17/2014 5/12/2014 2/6/2013 5/31/2013 5/14/2014 5/16/2014 6/19/2014 10 10

CA-0056673 Melvin Heyman AbbVie Inc University of California San Francisco A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Human Anti-TNF Monoclonal

Antibody Adalimumab in Pediatric Subjects with Moderate to Severe Ulcerative Colitis

1/16/2014 8/21/2014 6/23/2014 10/31/2014 8/21/2014 9/4/2014 2/18/2015 10 1

CA-0057959 Melvin Heyman Genentech, Inc. University of California San Francisco Hickory GA28950 - PHASE III, DOUBLE BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY OF

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PATIENTS WITH MODERATE TO SEVERE ACTIVE ULCERATIVE COLITIS WHO ARE REFRACTORY TO

OR INTOLERANT OF TNF INHIBITORS

2/18/2014 10/15/2014 9/23/2014 2/3/2015 10/22/2014 2/16/2015 no enrollment to

date

10 0

CA-0059372 Melvin Heyman Sucampo

Pharmaceuticals, Inc

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CA-0048479 Nitish Badhwar Boston Scientific

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University of California San Francisco ZERO AF Clinical Evaluation of the Blazer Open-Irrigated Ablation Catheter for the Treatment of Paroxysmal

Atrial Fibrillation

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CA-0053284 Norah A.

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Eisai Companies University of California San Francisco A Randomized, Global, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and

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Lebrikizumab In Patients With Uncontrolled Asthma Who Are On Inhaled Corticosteriods And A Second

Controller Medication

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before anyone

enrolled

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CA-0056593 Sandy Feng Novartis AG University of California San Francisco A 24 month, randomized, controlled, study to evaluate the efficacy and safety of concentration-controlled

everolimus plus reduced tacrolimus compared to standard tacrolimus in recipients of living donor liver transplants.

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CA-0058856 Sarah Arron Allergan Inc. University of California San Francisco A Long-term Safety and Efficacy Study of Oxymetazoline HCl Cream 1.0% in Patients with Persistent Erythema

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Older) With Atopic Dermatitis

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CA-0056453 Stephen M.

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CA-0056403 Teresa De

Marco

Lung Biotechnology Inc University of California San Francisco BEAT: A multicenter, double-blind, randomized, placebo-controlled, Phase 3 study to assess the efficacy and

safety of oral BPS-314d-MR added-on to treprostinil, inhaled (Tyvaso) in subjects with pulmonary arterial

hypertension

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CA-0056256 Teresa De

Marco

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CA-0056416 Anne

Luetkemeyer

Bristol-Myers Squibb

Company

San Francisco General Hospital Phase 3 Evaluation of Daclatasvir Plus Sofosbuvir in Treatment-naive and Treatment-experienced Chronic

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CA-0055871 Anne

Luetkemeyer

Gilead Sciences, Inc. San Francisco General Hospital A Phase 3, Multicenter, Open-Label Study to Investigate the Efficacy and Safety of Sofosbuvir/Ledipasvir Fixed-

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Actelion Pharmaceuticals

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CA-0047688 Sam James AbbVie Inc San Francisco General Hospital Clinical Study Protocol M11-352 A Randomized, Multicountry, Multicenter, Double-Blind, Parallel, Placebo-

Controlled Study of the Effects of Atrasentan on Renal Outcomes in Subjects with Type 2 Diabetes and

Nephropathy SONAR: Study Of Diabetic Nephrop

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CA-0055205 Anil Sapru Boston Children's Hospital University of California San Francisco HALF-PINT: Heart and Lung Failure - Pediatric INsulin Titration trial - CCC 5/12/2014 5/12/2014 11/16/2014 4/2/2015 no enrollment to date120 0

CA-0058382 Joel Palefsky EMMES Corporation, The University of California San Francisco HSIL Outcome Study (HOST) - AMC supplement 4/30/2014 4/30/2014 6/20/2014 9/3/2014 9/24/2014 340 44

CONFIDENTIAL

Part H1 Product Development Abstract The key objectives of CTSI’s Catalyst Program for Product Development (PD) are to expand investigator access to customized resources, including expert feedback, advice, and pilot funding, to drive promising early-stage research through the complex process of clinical translation. Catalyst proposes the creation of an innovative didactic and experiential curriculum on the principles of product development, and to further develop collaborations with industry partners. Program activities will be carried out at UCSF, across UC BRAID, and are designed to scale for the CTSA network. PD Aim 1:To address gaps in resources to enable product development at UCSF. Catalyst will: Create the Catalyst Early Therapeutics program to better support high-risk early therapeutics development, adding advisors with expertise in early drug discovery capabilities and partner with other UCSF drug innovation centers and the UCSF-Stanford Center for Excellence in Regulatory Science. Catalyst will pilot and refine the Early Therapeutics program in collaboration with the UCSF Comprehensive Cancer Center, thereafter expanding to other disease areas; Offer expanded project management resources to funded projects; Create an Entrepreneur-in-Residence program to support long-term relationships between experienced entrepreneurs and research teams developing technologies with potential to be commercialized; Expand access to Contract Research Organization services; Expand Catalyst’s Strategic Innovation Partnership Program through targeted “matchmaking” events for industry partners and UCSF researchers; Enhance funding sources through outreach to industry and venture partners. PD Aim 2: To build and scale product development education and training. Catalyst will: Expand the Catalyst Internship Program from 10 to 20 training slots and provide opportunities for industry externships; Implement a “Case-Based Learning Curriculum in Product Development” based on foundational case studies linked to core content and principles taught through online training and interactive learning modules available to UCSF, other CTSA hubs, and industry; PD Aim 3: To extend product development activities in collaboration with other CTSA hubs. Catalyst will: Facilitate access to the Catalyst advisor network throughout UC BRAID. After refining governance, organization and operating procedures across UC BRAID, UCSF CTSI will open the Catalyst advisor network to other CTSA hubs; Expand the UC BRAID Drugs, Devices, and Diagnostics Development group to focus on early therapeutics by developing an online resource (UC-CORE) to identify, describe, and link the drug discovery-related core facilities of the 5 UC campuses, with a specific core related to early therapeutics discovery. Catalyst will collaborate to enhance multi-campus industry partnerships with a unified contract negotiation process that identifies a single point of contact to enable industry partners to negotiate with the entire UC system. This will promote the development of meaningful industry collaborations across the UC system.

CONFIDENTIAL

SPECIFIC AIMS Academic investigators play a key role in early stage discovery work with potential for profound impact on patient care and human health. However, translation of discoveries into a drug, device, diagnostic, or digital health application is expensive and challenging. The key objectives of CTSI’s Catalyst Program for Product Development (PD) are to expand investigator access to customized resources, including expert feedback, advice, and pilot funding, all of which are required to drive promising early-stage research through the complex process of clinical translation. In addition, we propose the creation of an innovative didactic and experiential curriculum on the principles of product development and to further develop collaborations with industry partners. Program activities will be carried out at UCSF and across UC BRAID and are designed to scale for the CTSA network. PD Aims PD Aim 1. Address gaps in resources to enable product development at UCSF. We will: • Create the Catalyst Early Therapeutics program to better support high-risk early therapeutics development,

adding advisors with expertise in early drug discovery capabilities such as computational modeling, medicinal chemistry, and pharmacokinetics and partner with other UCSF drug innovation centers and the UCSF-Stanford Center for Excellence in Regulatory Science. Using the Catalyst approach of “identify, advise, and award” we will pilot and refine the Early Therapeutics program in collaboration with the UCSF Comprehensive Cancer Center, thereafter expanding to other disease areas.

• Offer expanded project management resources to funded projects. • Create an Entrepreneur-in-Residence program to support long-term relationships with experienced and

successful entrepreneurs available to partner closely with research teams that are developing technologies with the potential to be commercialized through stand-alone startup companies.

• Expand access to Contract Research Organization services. • Expand Catalyst’s Strategic Innovation Partnership Program through targeted “matchmaking” events that

bring together industry partners and UCSF researchers with shared interests. • Enhance funding sources through outreach to the panoply of available industry and venture partners.

PD Aim 2. Build and scale product development education and training. We will: • Expand the Catalyst Internship Program by increasing the number of training slots (from 10 to 20) and

provide a more immersive and intensive product development training experience with opportunities for industry externships.

• Implement a “Case-Based Learning Curriculum in Product Development” with a unique and widely accessible program based on foundational case studies linked to core content and principles taught through online training and interactive learning modules available to UCSF, other CTSA hubs, and industry.

PD Aim 3. Extend product development activities in collaboration with other CTSA hubs. We will: • Facilitate access to the Catalyst Advisor Network by our UC BRAID partners via applications submitted

through the CTSI Consultation Service (Part E.1). Each UC BRAID institution will manage and support the development of projects led by investigators on their own campus. After developing, testing, and refining governance, organization, and operating procedures across the BRAID network, we will open the Catalyst Advisor Network to other CTSA hubs.

• Expand the UC BRAID D4 to focus on early therapeutics by developing an online resource (UC-CORE), which will identify, describe, and link the drug discovery-related core facilities of the 5 UC campuses, with a specific core related to early therapeutics discovery. Using a Catalyst-like approach, D4 will organize drug discovery experts from the UC campuses and industry experts to identify, support, and guide early stage projects.

• Enhance multi-campus industry partnerships with a unified contract negotiation process that identifies a single point of contact to enable industry partners to negotiate with the UC system, rather than with individual campuses. This strategic endeavor will promote the development of meaningful collaborations across the UC system and with industry for projects that require multisite expertise, resources, and capabilities.

Part H1. Optional Function: Product Development (Catalyst Program)

CONFIDENTIAL

RESEARCH STRATEGY H1. PRODUCT DEVELOPMENT (PD): CTSI CATALYST PROGRAM H1.a. Overview and Innovation Entrepreneurship and commercialization are critical to facilitating the translation of discoveries made in academic research environments to products that improve health. The CTSI Catalyst Program is an internal accelerator that addresses key gaps in product development at UCSF and across the UC BRAID network. Organized to support 4 tracks (therapeutics, diagnostics, devices, and digital health), Catalyst identifies, advises, and supports promising projects with high likelihood of producing commercial products. Our innovative approach draws on an extensive network of industry experts with intellectual property, venture capital and financing, regulatory, and other relevant insights into product development. Catalyst combines customized feedback and advice from these volunteer advisors with competitive funding to translate promising early technologies into health products with meaningful clinical benefit. H1.b. PD Achievements Since its initiation 4 years ago, projects supported by the Catalyst program have resulted in 14 new start-up companies and 126 disclosures or patents. Catalyst’s return on investment (defined as the ratio of follow-on funding to the amount invested by the program) has been over 14-fold. The large and growing Catalyst advisor network is a tangible measure of our success with over 200 volunteers representing the Bay Area’s vibrant life sciences eco-system. The panel includes industry professionals with expertise in the development of therapeutics (~60%, small molecule and biologicals), diagnostics (~30%), devices (~35%), and digital health (~22%). The panel has experience in financing and venture capital, intellectual property, regulatory affairs, pre-clinical/clinical development, commercialization, and other domains relevant to product development. Most advisors have made long-term commitments to the Catalyst program under signed confidentiality agreements and are engaged on a project-by-project basis to precisely leverage their expertise to solve project-specific challenges. Catalyst has drawn the attention of other academic institutions, biomedical organizations, and industry, with the adoption of similar models at the University of Michigan, The Johns Hopkins Science and Technology Advisory Team, the new Dell Medical School at UT Austin, and the California Life Sciences/BayBio Fast Fellows Program.1-4 Catalyst has garnered significant support from industry partners including Genentech, MedImmune, Quest Diagnostics, and Sigma-Aldrich. Finally, Catalyst was used as a model for the NHLBI Center for Accelerated Innovation (CAI) Awards Program that identifies and supports product development across UC BRAID, the 5 UC Medical campuses. UCSF investigators have been successful in CAI, receiving 6 of the first 16 awards across the 5 campuses.

Achievements in Product Development Catalyst Award Program

• Over 200 expert volunteer consultants provided 3000+ consultation hours • Supported 69 therapeutics; 39 diagnostics; 24 devices, and 36 digital health projects • Provided $3M in competitive funding: $43M follow-on funding received • Developed 38 partnerships • 14 total start-up companies;126 disclosures/patents; 34 peer reviewed publications

Catalyst Internship Program

• Placed 10 interns each year on product development teams led by industry experts; exposed students to alternative career paths and teaches product development in a case-based manner

Catalyst Seminars • Explored issues with industry experts; e.g., digital heath intellectual property/copyright, repurposing of approved drugs, diagnostics commercialization and reproducibility in pre-clinical development

Catalyst Strategic Innovation Partnerships

• Targeted ”matchmaking” events that brought together industry partners and UCSF researchers • Successful launch of novel long-term collaborations with: − Quest Diagnostics ($140K to Catalyst + ~$1.95M project funding), with initial focus on autism, oncology,

neurology, and women’s health − MedImmune ($170K to Catalyst + $3.8M project funding in negotiation), the global biologics research and

development arm of AstraZeneca with initial focus on cardiovascular and metabolic disease; oncology; respiratory; autoimmunity; neuroscience; and infectious disease

− Sigma-Aldrich ($50K + $50K in-kind) and Surpass Awards (pre-clinical CRO, $20K/year in-kind) − Genentech $200K gift to Catalyst − Facilitated initiatives with Pfizer Center for Therapeutic Innovation, GSK (Pre-DPAC), Onyx, AbbVie

Innovation HUB “1.0”

• Supported development of an integrated innovation hub linking UCSF groups, including Center for Digital Health Innovation (CDHI), Quantitative BioSciences 3 (QB3), The Entrepreneurship Center, Innovation Technology and Alliances (ITA), Small Molecule Discovery Center (SMDC)

Entrepreneurship Center

• ~100 entrepreneur mentors • 33 teams in last 2 Lean Launchpad cohorts; ~50% of 2013 teams reached a significant product milestone,

e.g., getting into an accelerator or other program, raising angel or venture funding

CONFIDENTIAL

H1.c. Approach to PD The Catalyst Program bridges the existing gap between mainstream sources of funding for discovery research and support for commercialization. Investigators submit project ideas twice per year in response to an open call for proposals. The Catalyst panel of industry advisors reviews and evaluates proposals based on the following criteria: 1) unmet need, 2) scientific rationale, 3) development feasibility, 4) commercial attractiveness, and 5) intellectual property status and potential. Investigators with projects thought to have high potential are matched with advisors to address the gaps and risks identified in the review process to formulate a viable product development plan. Investigators subsequently present their revised proposals to the advisor panel, which again scores the projects. The top-ranked proposals receive funding to reach well-defined key milestones. Funding (generally $50K-$250K in cash or in-kind, according to the need and merit of the project) is administered by CTSI with resources coming from CTSI and industry partners. In the next funding period, we will expand the Catalyst program at UCSF, developing new strategic partnerships with industry, build and scale our training programs, and extend product development activities in collaboration with other CTSA hubs. PD Aim 1. Address gaps in resources to enable product development at UCSF. • Expand Catalyst to better support high-risk early therapeutics development – In an academic environment,

development of therapeutics (drugs) is generally much more challenging than development of diagnostics or devices because substantial resources are required to achieve early developmental milestones. About 90% of the therapeutics projects proposed for Catalyst support are too early to be evaluable or to secure funding for the next stage of development. This leaves a significant gap for support of highly innovative early therapeutic projects with significant potential but high risk, which currently struggle to progress.

To address this gap, we propose to create the Catalyst Early Therapeutics program. The Early Therapeutics program will link with NCATS resources, such as compound libraries, chemistry, and repurposing schemes. The program will use the Catalyst approach to product development and engage the existing Catalyst advisor network, but will require more focused expertise and resources and a different set of industry partners. We will add advisors with expertise in early drug discovery capabilities such as computational modeling, medicinal chemistry, and pharmacokinetics. We will also partner with other UCSF drug innovation centers, including the Small Molecule Discovery Center, Comprehensive Cancer Center Pharmacokinetic Group, Pre-Clinical Therapeutics Core, Computational Chemistry and Biology Center, and the UCSF-Stanford Center for Excellence in Regulatory Science. While there are established Pharma company collaborations at UCSF, including the Pfizer Center for Therapeutic Innovation (CTI) and the GSK pre-Discovery Partnerships with Academic Centers schema (pre-DPAC), these are restricted to the specific areas of interest of the companies and tend to focus on partially de-risked, later stage projects. Thus, we will also need to expand our industry collaboration to partners

Vignette: Accelerating the Commercialization of a Novel Chemotherapy Filtering Device. UCSF investigators had the idea to create a catheter-based filter that absorbs chemotherapeutic agents downstream of the target organ, minimizing systemic adverse events. Armed with promising in vitro data, Catalyst matched the investigators with a veteran catheter-based device innovator, an oncologist, and a biotech executive, and provided access to prototyping facilities. This team formed a start-up company and developed multiple prototypes used in animal studies. The device is currently being commercialized by a leading medical device company, which acquired the start-up.

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interested in early therapeutic development. Catalyst Early Therapeutics advisors, with our UCSF and industry partners will use the Catalyst approach of “identify, advise, and award” to support the most promising early translational therapeutics projects at UCSF. We will pilot and refine the Early Therapeutics program in collaboration with the UCSF Comprehensive Cancer Center (Cancer Center) to focus specifically on cancer target validation. The Cancer Center will bring faculty expertise as well as seed funding and project management. We will jointly issue a specific call for proposals for the Cancer Target Validation project. Awards will be based on the novelty of the molecular target, strength of supporting pre-clinical or clinical validation data, the availability or feasibility of an assay, and the potential for a biomarker or personalized medicine approach. A select set of Catalyst advisors and Cancer Center faculty with drug discovery and oncology expertise will select projects for funding. Once established and refined, the Catalyst Early Therapeutics program will be opened for application by investigators pursuing therapeutics for other diseases and conditions.

• Expansion of project management resources – In our experience with over 100 projects, the ability to manage communications, personnel, tasks, timelines, and milestones is critical for success. Catalyst Program personnel will provide oversight of project management and relationship management with key partners for every funded project. Catalyst personnel will also use this opportunity to train teams in project management, and will engage consultants from the UCSF Research Development Office to address problems related to team cohesion and effectiveness (Part C.2).

• Development of an Entrepreneur-in-Residence program – Currently, Catalyst advisors are involved for a brief period to help select and advise promising Catalyst projects. However, some Catalyst projects could benefit from longer-term involvement from advisors with experience in business development, finance, and start-up processes. In fact, several Catalyst advisors are serial entrepreneurs who have expressed interest in partnering with Catalyst-supported teams to provide more extensive guidance. Such a collaboration has already occurred – see EIR Vignette below. While this process may happen organically, we propose to facilitate the process by developing the Entrepreneur-in-Residence (EIR) program. We will identify (and add) advisors who are capable of acting as EIRs, catalogue their interests and expertise, and pair them with selected Catalyst teams. We will also ensure that Catalyst teams understand the value that can be added by an EIR and any costs of engagement. There will be no commitment of IP to the EIR, but he/she may invest in the project. With proven entrepreneurs working alongside committed research teams, the likelihood of successfully transporting promising academic innovations into freestanding investable private companies will be maximized. Vignette: Catalyst EIR Proof of Concept. A successful entrepreneur, investor, and Catalyst advisor was introduced to a Catalyst team aiming to create a disruptive technology for the treatment of cataracts. He spent time working with the team to develop a business strategy through to Clinical Proof-of-Concept and has now taken on the role of CEO and principal investor for the newly created start-up company. The team is currently raising a successful Series A funding round and moving the project into the pre-clinical safety and pharmacology phases of development.

• Expand access to contract research organization services – To help support UCSF researchers in their drug and device development activities, we have assessed and pre-selected contract research organizations (CROs) that offer a broad range of key research and product development services not readily available in academic institutions. Our CROs are chosen for their proven technical expertise, flexibility, past experience in working with academic investigators, and price. These CROs have signed Master Service Agreements and non-disclosure agreements, facilitating a streamlined process for designing and conducting key pre-clinical studies, including high-throughput screening, ADME, pharmacokinetics and pharmacodynamics, toxicology, bio/analytical services, medicinal chemistry and custom synthesis, GMP manufacturing, and preclinical disease models. In the next funding period, we will select additional CROs to ensure that available services are inclusive of biocompatibility, prototype development, software application development and other capabilities to enable product development in devices and digital health tracks.

• Expand the Strategic Innovation Partnership Program – Leveraging academic-industry partnerships is critical for product development. Through targeted “matchmaking” events that bring together industry partners and UCSF researchers with shared interests, Catalyst has been successful at launching novel long-term collaborations that will enable product development with a focus on clinical and commercial viability. We now collaborate with Quest Diagnostics,5 MedImmune,6 Sigma-Aldrich, and others. Based on the initial success of this collaboration model, we propose to increase the number of such ventures by creating a Strategic Innovation Partnership Program that introduces specific companies to UCSF researchers interested in product development. Using our established network of industry contacts, we will

CONFIDENTIAL

“match” the interests of these companies with the work of UCSF researchers to support long-term translational academic research with the goal of commercialization. In collaboration with the new UCSF Office of Innovation and Partnerships, we will host discussions to define projects of mutual interest and tailored collaboration models to support product development.

• Enhance funding – The Catalyst Program has been successful by creatively using available funds to support promising projects. But there remains significant untapped potential to translate technologies that, due to resource constraints, have not received sufficient funding to achieve key strategic milestones. We have successfully worked with industry partners to garner almost 50% of the Catalyst funding awarded each year; we now propose to significantly expand our proven fundraising model and explore new partnerships in collaboration with the UCSF Office of Innovation and Partnerships, specifically targeting other industry partners (e.g., pharmaceutical, biotech, diagnostics, and medical devices companies, Health Management Organizations, CROs, IT/ Technology companies). In addition, we will continue exploring partnerships with philanthropic organizations including venture philanthropists, as well as angel investors, venture capitalists, and corporate venture funds (see Vignette, below).

PD Aim 2. Build and scale product development education and training. • Expand the Catalyst Internship program – The Catalyst Internship Program aims to train the next generation

of investigators on the process of translating academic discoveries into valuable clinical products. Interns can be students, post-docs, fellows, or faculty who express interest in the program. Interns are selected based on experience and expressed interest and are placed on a Catalyst product development team led by academic investigators and industry experts. They work with the team throughout the full Catalyst Awards cycle on product development. The internship exposes students to alternative careers, and familiarizes them with the product development pathway using a case-based approach. To date, the program has been extremely competitive – we are only able to accept 30% of those who apply – and has demonstrated success on key metrics including intern satisfaction, education, and peer referrals. We propose to double the number of training slots (from 10 to 20) and provide a more immersive and intensive product development training experience. Interns will be actively engaged with ongoing Catalyst-supported projects and also receive supplemented didactic education via in-person seminars and an online course (see Curriculum Table, below). We will also develop opportunities for industry externships with Catalyst advisors and local life science and technology companies. In collaboration with the UCSF-Stanford Center for Excellence in Regulatory Science and Innovation (CERSI), interns can take advantage of the CERSI lecture series on regulatory science and affairs (generally monthly in person and available on YouTube), the FDA visiting science program (weekly talks by FDA scientists on the UCSF campus), and the CERSI mini-course on Regulatory Framework for Mobile Medical Technologies.

• Develop a case-based curriculum in product development – Current training programs have limited utilization by faculty, fellows, and graduate students, primarily due to course format, content, and time requirements. Working with the CTSI Online Education program, we have developed pilot case studies for teaching key principles of translational research and drug development much the way case studies are utilized in a business school curriculum (e.g., Harvard Business School Case Studies7). We propose to develop, and make available to UCSF, other CTSA hubs, and the external community, a unique and scalable program that enables remote learning; curriculum is based on foundational case studies linked to core content and principles taught in an asynchronous online model with limited in-person or remote mentoring. We plan to identify and work with individuals in industry and academia who were involved in the specific cases to provide details, perspectives, and insights. Through compelling, real-world narratives that describe unmet clinical needs; clinical, regulatory, and reimbursement strategies; and market

Vignette: Enhancing Funding for Product Development. The Catalyst team has increased new project funding through novel partnerships with industry. For example, while serving on the Catalyst Diagnostics review panel, Quest Diagnostics’ Senior VP of Science and Innovation recognized the value of targeted industry participation at the earliest stages of academic innovation and worked with us to develop a partnership that provides significant funding to UCSF projects that align with Quest interests. In a different model, we worked with Surpass Inc., a pre-clinical CRO, to create a mechanism by which Surpass provides in-kind services to rapidly test medical device prototypes in animal models.

Product Development Case-based Curriculum Modular For self-guided and self-paced learning Individualized Enables user to select the most

relevant training material Contextualized Maximizes engagement through real

world examples Scalable Leverages online technologies

CONFIDENTIAL

and economic forces, the case studies will present complex aspects of healthcare product development and commercialization. Specific teaching points within each case will then be more fully explored through interactive learning modules. Private healthcare companies and government organizations, which depend on a well-informed research and administrative workforce to maximize the clinical and commercial value of innovative products and services, would also benefit greatly from such education.

PD Aim 3. Extend product development activities in collaboration with other CTSA hubs. • Facilitate access to the Catalyst advisor network by our UC BRAID partners – The Catalyst advisor network

has been very successful in helping UCSF investigators translate early stage technologies toward products and represents a tremendous intellectual resource. We propose to facilitate access to these advisors by other CTSA hubs in the UC BRAID network. Applications for access to the Catalyst advisor network will be submitted via the CTSI Consultation Service, which already receives requests for consultation from other UC campuses, and has processes in place to track and evaluate consultation services. The CS will ensure that applications are complete, and will then triage requests to the Catalyst team, who will direct requests to appropriate advisors. To ensure that advisors receive adequate information, we will create a structured application that includes a description of the problem, the current status of the project, target market, and the project team, and an approach consistent with existing application requirements for Catalyst funding. We will also require that applications document potential sources of financial support from the “home” CTSA hub, and agreement by the home CTSA to provide project management, tracking, and outcome data. Each UC BRAID institution will manage and support the development of projects led by investigators on their own campus. This resource will be advertised to the other UC BRAID sites via CTSA publications/contacts at each site. After developing, testing, and refining governance, organization, and operating procedures across the BRAID network, we will open the Catalyst advisor network to other CTSA hubs. This model has been successfully used by the Boston area Center for Integration of Medicine and Innovative Technology (CIMIT),8 composed of Boston’s leading teaching and research institutions, which have leveraged internal business development and project management capabilities to enhance product potential of the technologies at their institutions. Providing access to our expert advisors will facilitate product development across CTSA hubs.

• Expand the UC BRAID D4 to focus on early therapeutics – The UC BRAID Drugs, Devices, and Diagnostics Development group (D4), chaired by Catalyst Director, June Lee, MD, was created to coordinate the development of therapeutics, medical devices, and diagnostics across the 5 UC medical campuses. D4 identified drug and device development core services and resources at each UC campus, and created a centralized, Web-based description of available services with directions for access and use. Sharing of these translational resources will promote and support product development activities and training, facilitating cross-UC industrial partnerships and collaborations. The NHLBI-funded UC Center for Accelerated Innovation (CAI) grew out of D4. CAI identifies and supports product development related specifically to cardiovascular, pulmonary, and blood diseases. Projects are solicited from across the 5 UC Medical Campuses, with centralized review and selection of projects for funding. However, similar to the UCSF Catalyst experience, about 90% of the therapeutics proposals received by CAI are too early in development to be fully evaluated or to secure funding. We propose to work in concert with D4 to develop an online resource (UC-CORE) that will identify, describe, and link the drug discovery-related core facilities of the 5 UC campuses, with a specific core related to early therapeutics discovery. Using a Catalyst-like approach, D4 will organize drug discovery experts from the UC campuses and industry experts to identify, support, and guide early stage projects. At appropriate stages of development, these projects will leverage resources from UC CAI, UC-CORE, and other established industry collaborations at each campus. Organizing the UC-CORE facilities and providing coordinated access to expertise, resources, and funding to support the validation and translation of early therapeutics projects across the UC system will enable greater success in translation and an opportunity for the development of extensive academic-industry partnerships supporting development of therapeutics.

• Enhance multi-campus industry partnerships with a unified contract negotiation process – The UC system has a substantial basic and applied research portfolio with major potential, but as noted, translation to viable products often requires industry partners. A recent D4 survey of a broad range of life science companies in California confirmed their significant interest, particularly in the potential of collaborating across multiple UC campuses. However, the survey also revealed that the requirement to negotiate contracts with each of the 5 UC Medical campuses, even when Master contracts exist, is the single most significant deterrent to these

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potential industry partnerships. We will develop a contract negotiation process with a single point of contact that enables industry partners to negotiate with the UC system, rather than with individual campuses. The UC Office of the President is eager to establish such a process, and we have industry partners (Medimmune, Quest, Surpass) that have agreed to “pilot test” this process. We will expand our efforts in collaboration with UC BRAID D4, other UC campus stakeholders, and industry partners to proactively identify and formulate projects requiring multi-UC campuses with significant potential for synergy with industry partners. The overarching goal is to accelerate the development of meaningful collaborations across the UC system and with industry for projects that require multisite expertise, resources, and capabilities.

H1.d. PD Leadership June Lee, MD, Director, is Professor of Medicine (Pulmonary and Critical Care), and a member of the CTSI Internal Advisory Board. She has more than 2 decades of experience in clinical research in academia and industry. In her current role, she also oversees key strategic partnerships at UCSF. Dr. Lee will supervise all Catalyst program activities and ensure that goals and milestones are met on time. Aenor Sawyer, MD, is Assistant Professor Surgery and heads the Catalyst Digital Health track. She is the Associate Director of Strategic Relations for the Center for Digital Health Innovations at UCSF. Dr. Sawyer is an Advisor to Rock Health and mentors digital health innovators at CDHI and UCSF. She has over a decade of health technology innovations and is also a founder of Trinity, a digital health start-up company. Catherine Tralau-Stewart, PhD, is Head of the Catalyst Therapeutics track, and has 30 years experience in early drug discovery through to clinical Proof-of-Concept in industry and academia; she has been involved in the discovery and development of over 15 marketed drugs. Dr. Tralau-Stewart will supervise the Catalyst Early Therapeutics program and the UC BRAID D4 early therapeutics initiative. Kathleen Giacomini, PhD, is Professor in the Departments of Biopharmaceutical Sciences, Pharmaceutical Chemistry, and Cellular and Molecular Pharmacology at UCSF. She is Co-PI of the UCSF-Stanford Center of Excellence in Regulatory Sciences and Innovation (CERSI) funded by the Food and Drug Administration (FDA), which aims to advance the field of regulatory sciences and improve the development and evaluation of diagnostics, therapeutics and medical devices. She will coordinate with CTSI to make CERSI training opportunities available to UCSF trainees and faculty engaged in product development. H1.e. PD Evaluation and Tracking

Aim / Milestone Metric for Assessment and Frequency Aim 1. Address gaps in resources to enable product development at UCSF. • Expand Catalyst to better support early therapeutics

development • Expand project management • Develop Entrepreneur-in-Residence program • Expand access to contract research organizations (CRO)

# of early therapeutic projects supported (semi-annual) Amount of follow-on funding and ratio of award $/follow-on $

(annual) # of new IP generated (annual) # of Entrepreneurs-in-Residence (annual) # of CRO Master Service Agreements (annual) # of projects using CRO services (annual)

Aim 2. Build and scale product development education and training. • Expand the Catalyst internship program • Develop a case-based product development curriculum

# of interns and level of training (annual) Intern satisfaction/# of peer referrals (annual) # of students using curriculum/student satisfaction and confidence

(annual) Aim 3. Extend product development activities in collaboration with other CTSA hubs. • Facilitate access to the Catalyst advisor network • Expand UC BRAID D4 to focus on early therapeutics

# of projects at other CTSA hubs using Catalyst advisors (semi-annual)

Satisfaction of non-UCSF investigators with Catalyst advice (annual) # of UC-wide early therapeutics projects supported

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References for Part H1.Optional Functions: Product Development

1. Fishburn, C.S., Teaching translation. SciBX: Science-Business eXchange, 2014. 7(12). 2. Osherovich, L., Herding catalysts at UCSF. SciBX: Science-Business eXchange, 2014. 7(8). 3. Mullin, E. MedImmune, UCSF strike translational research deal. 2014 [cited 2015 Aug 27];

Available from: http://www.fiercebiotechresearch.com/story/medimmune-ucsf-strike-translational-research-deal/2014-02-12.

4. Walker, J. Quest Diagnostics, University to Develop Diagnostic Tools. 2014 [cited 2015 Aug 27]; Available from: http://www.wsj.com/news/articles/SB10001424052702304347904579308702500522072

5. UCSF Clinical & Translational Science Institute. Quest Diagnostics, UCSF to Develop Diagnostic Tools. 2014 [cited 2015 Aug 27]; Available from: http://ctsi.ucsf.edu/news/research/quest-diagnostics-ucsf-develop-diagnostic-tools.

6. UCSF Clinical & Translational Science Institute. UCSF-CTSI and MedImmune Make Notable Academic-Pharma Alliance List. 2014 [cited 2015 Aug 27]; Available from: http://ctsi.ucsf.edu/news/about-ctsi/ucsf-ctsi-and-medimmune-make-notable-academic-pharma-alliance-list.

7. Harvard Business Publishing. Case Method Teaching. [cited 2015 Aug 27]; Available from: https://cb.hbsp.harvard.edu/cbmp/pages/content/casemethodteaching

8. Parrish, J.A. and R.S. Newbower. CIMIT: A Prototype Structure for Accelerating the Clinical Impact of Research on Novel Therapeutics. [cited 2015 Sep 8]; Available from: http://cimit.org/images/cimit-model.pdf.

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Part H2 Precision Medicine Abstract The key objectives of CTSI’s Precision Medicine (PM) Optional Function are to integrate basic, biomarker, phenotypic, psychosocial and behavioral data, creating a massive computational knowledge network that enables prevention, diagnosis, and treatment decisions tailored to each individual. UCSF is home to a number of diverse precision medicine efforts that focus on specific diseases, populations and/or technological capabilities. For the precision medicine function, CTSI will steward and coordinate with the diverse precision medicine efforts at UCSF. CTSI will assume the primary responsibility for developing and expanding an infrastructure that centralizes and standardizes consents, collects high quality human biospecimens, and links these biospecimens with rich annotated phenotypic data to broadly support the creation and maintenance of research databases. CTSI will create avenues to couple these research databases with the EHR, thus enabling the true practice of PM through the following Aims: PM Aim 1. To support high-quality biospecimen consenting, acquisition, and biobanking from diverse patient populations, CTSI will: develop a centralized biobanking consent form; coordinate consenting for biospecimens to support precision medicine research; create a Research Specialist Core to coordinate biospecimen collection in clinics and operating rooms throughout the UCSF health system; build an infrastructure for optimized biospecimen collection, processing, and storage; develop scalable, compliant, biospecimen storage facilities to accommodate the needs of legacy and new biobanks; and develop processes to collect post-mortem specimens; PM Aim 2. To facilitate precision medicine research by creating a Biospecimen Resources Program, a richly annotated centralized, searchable, Web-based biospecimen database, CTSI will: implement a configurable, Web-based LIMS software platform to optimize specimen collection and management and develop processes to facilitate biospecimen sharing across UCSF and outside UCSF; and PM Aim 3. To enable the practice of PM by creating portals to integrate selected population and research data with the EHR, CTSI will: develop the tools and policies necessary to create portals to integrate population and research data to the EHR for point-of-care guidance; and support a series of demonstration projects across disease areas to explore both the mechanisms and implications of integrating selected population and research data into the EHR.

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SPECIFIC AIMS The UCSF CTSI has chosen Precision Medicine (PM) as one of its Optional Functions. This selection is based on a combination of unique opportunities and substantial prior experience. PM aims to integrate and analyze basic, biomarker, phenotypic and psychosocial data, creating a massive computational knowledge network that reaches toward prevention, diagnosis, and treatment decisions tailored to each individual. UCSF is home to a number of diverse PM efforts that focus on specific diseases, populations and/or technological capabilities. For our PM function, CTSI will steward and coordinate with the diverse PM efforts at UCSF. CTSI will assume the primary responsibility for developing and expanding an infrastructure that collects high quality human biospecimens and links these biospecimens with richly annotated phenotypic data to broadly support the creation and maintenance of research databases. When indicated, we will create avenues to couple these research databases with the EHR, thus enabling the true practice of PM. This vision has been significantly substantiated and promoted by the award, announced in August 2015, of 2 trans-UC projects that leverage CTSI investments in precision medicine, sponsored by the California Initiative to Advance Precision Medicine and hosted by UCSF. Both projects involve UCSF, and UCSF investigators lead one project (see Vignette in Research Strategy). These projects involve our UC BRAID partners, and best practices developed through this California initiative will be shared with other CTSA hubs. The theme of PM is woven throughout our CTSA proposal; the approaches described and supported by this PM function will dovetail with the other components, including Informatics and Research Innovation (Part B), Pilot Translational and Clinical Studies (Part D.2), and the KL2 and TL1 training programs (Parts I and J). Our overall goals are to: 1) optimize and centralize consenting for biospecimens in coordination with RKS (Part E.2); 2) improve the collection of high quality liquid and tissue biospecimens to drive PM research; 3) implement a centralized laboratory information management system (LIMS) to record and track biospecimens; 4) coordinate existing UCSF legacy biobanks and new biobanks to create a centralized “virtual” biobank to support both internal and external collaborations; and 5) create customized portals to introduce population data into the EHR to enable the practice of PM. PM Aims PM Aim 1. To support high quality biospecimen consenting, acquisition, and biobanking from diverse patient populations, we will: • Develop a centralized biobanking consent form. • Coordinate consenting for biospecimens to support PM research. • Create a Research Specialist Core to coordinate biospecimen collection in clinics and operating rooms

throughout the UCSF health system and at our regional partners. • Build an infrastructure for optimized biospecimen collection, processing, and storage. • Develop scalable, compliant, biospecimen storage facilities to accommodate the needs of legacy and new

biobanks. • Develop processes to collect post-mortem specimens. PM Aim 2. To facilitate PM research by creating a Biospecimen Resources Program, a richly annotated centralized, searchable, Web-based biospecimen database, we will: • Implement a configurable, Web-based LIMS software platform to optimize specimen collection and

management. • Develop processes to facilitate biospecimen sharing across and outside UCSF. PM Aim 3. To enable the practice of PM by creating portals to integrate selected population and research data with the EHR, we will: • Develop the tools and policies necessary to create portals to integrate population and research data to the

EHR for point-of-care guidance. • Support a series of demonstration projects across disease areas to explore both the mechanisms and

implications of integrating selected population and research data into the EHR.

Section H2. Optional Function: Precision Medicine

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RESEARCH STRATEGY H2. PRECISION MEDICINE H2.a. Overview and Innovation Precision Medicine (PM) aggregates, integrates, and analyzes information on biological events and processes, drawing on diverse data to produce a knowledge network with the potential to provide accurate health advice, predictions, diagnoses, and treatments tailored to the individual (see Figure 1). In a recent Science Translational Medicine article, UCSF Chancellor Sam Hawgood, and Vice Chancellor for Research Keith Yamamoto, describe PM as “harnessing the confluence of biological, physical, engineering, computer, and public and clinical health sciences to enable data-driven, mechanism-based health and health care for each individual”.1 UCSF has established a tri-pillar PM Platform Committee to coordinate and operationalize PM efforts across the institution. CTSI leads the Clinical Discovery pillar of the UCSF PM Platform (the other pillars are Basic Discovery and Social and Behavioral Discovery). PM requires both rich, phenotypic clinical data as well as general health data linked to biospecimens for genetic and epigenetic analyses. CTSI will direct and provide key elements of support for PM activities at UCSF in collaboration with our regional partners and national initiatives. These include: optimizing the consent process to allow data sharing across stakeholders; biospecimen collection, processing and storage; coordination of diverse biobanks across diseases and communities; and integration of selected population and research data with the EHR to enable the actual delivery of PM at the point of care. The overarching goal of these efforts is to enable data-driven, mechanism-based health and healthcare for each individual at UCSF, in coordination with our UC BRAID partners, and at other CTSA hubs. Our PM initiative will be supported by the CTSI Informatics and Research Innovation program (Part B) and will inform pilot studies (Part D.2), and the training of the next generation of clinical and translational investigators (Part D.1). H2.b. PM Achievements PM is a priority for the UCSF community, and CTSI has made a number of investments to support the UCSF PM Platform. CTSI PI Jennifer Grandis leads the Clinical Discovery arm of the UCSF PM Platform Committee (chaired by Vice Chancellor for Research, Keith Yamamoto), positioning CTSI to deploy its expertise and resources to facilitate clinical and translational research related to PM. CTSI has been instrumental in supporting research processes and infrastructure that will enable our proposed PM Aims.

Achievements in PM

Tools and Models to Increase # of Biospecimens for PM Research

• Developed approach for efficient, transparent governance • Identified components of consenting process that require further clarity in outpatient settings • Determined the different approaches to best engage the general public, patients, biobankers,

researchers, institutional regulatory officials, and UC leaders to ultimately enhance acquisition and use of human biospecimens (Engage UC)2

• Developed model for transparent, equable and efficient, infrastructure to share biospecimens and clinical data across UC campuses (UC BRAID)

• UC BRAID-led biobanking group conducted 2 surveys to assess biobanking activities on 5 UC

Fig.1 Precision Medicine Ecosystem. Research data from a variety of sources (basic, clinical and social/behavioral) coupled with enabling tools (including eConsenting, virtual biobanks and “omics”) leads to layers of knowledge (Knowledge Network). Collected data then drive research and technology development, leading to improved preventions and treatments thereby allowing the physician to practice precision medicine.

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BRAID campuses and opportunities to create a UC-wide “virtual” biobank

Centralized Process for Biospecimen Acquisition and Tracking

• Collaborated with UCSF Project Management Services and convened biobanking stakeholders to determine specifications for a LIMS-based software platform to manage biospecimen collections and informatics

• Extensive evaluation of possible software systems and selection of configurable, Web-based LIMS software platform to optimize specimen collection and management, and to leverage the latest technologies to effectively share analytical data

Clinical Cancer Genomics Lab (CCGL)

• CCGL created to analyze tumors using targeted capture followed by NGS to screen for mutations and copy # of changes in 539 cancer related genes with parallel analysis of normal DNA samples and reporting on inherited cancer risk genes

• Supported 7 pilot PM studies leading to 4 peer-reviewed publications (to date) and additional NIH and industry funding

• CCGL integrated into UCSF Medical Center workflow Clinical Whole Exome Sequencing Collaboration with UCLA (in coordination with UCLA CTSI Precision Medicine Optional Function)

• Delivery of clinical whole exome sequencing data for inherited diseases • Collaboration with UCLA includes monthly clinical case sign-out for discussion of results of

findings with clinical presentation • During the 18-month collaboration, 115 patients without a diagnosis were sequenced, with an

approximate 30% diagnosis rate

Leadership of State and National PM Efforts

• UCSF leadership chaired 2011 IOM/NAS panel on PM and authored report • UCSF faculty members of 2015 NIH Precision Medicine Initiative Working Group • UCSF coordinated RFA and review of applications for statewide effort to identify 2

demonstration projects for State of California Initiative to Advance Precision Medicine • Hosted 2 day-long workshops on UCSF campus to engage stakeholders and focus objectives

of State of California PM Initiative • Administration of the 2 trans-UC collaborative projects funded

Creation of the Multiple Sclerosis (MS) BioScreen

• Developed tool to enable the dynamic management of MS that facilitates display, context, and management for patients and clinicians (see Vignette)

Facilitation of infrastructure for nationwide Health eHeart study

• Developed electronic study visits • Implemented use of sensors linked to mobile apps to monitor heart health • Enabled electronic recruitment through social media

Central IRB facilities and electronic informed consent (Engage-UC) for UC-wide Athena Breast Health Network

• Provided insight to utilize ‘opt-out’ informed consent for clinical data use of 150,000 breast cancer patient longitudinal cohort study

• Coordinated multi-campus IRB process utilizing IRBRely • Championed ethical considerations for healthy population breast cancer susceptibility genetic

testing

Vignette: MS BioScreen illustrates how Precision Medicine can rationalize therapeutic strategies for individual patients. Multiple sclerosis (MS) is a complex neurological disease with symptoms that vary from one person to the next, and over each patient’s lifetime. MS BioScreen accesses and integrates patients’ medical records with a superb reference database of prospectively followed patient cohorts in the modern treatment era, making it possible to optimize individual treatment. BioScreen reference data are derived from several actively-followed cohorts in the US and Europe, including MS-EPIC, a decade-long UCSF MS study that includes brain and spinal cord imaging, genetic, physiological, blood-chemistry, and environmental exposure data, as well as disease course and treatment. Using state-of-the-art informatics, the MS BioScreen software contextualizes the clinical course of an individual patient relative to others in the reference cohort, and supports clinicians in proposing treatment plans that have the highest chance of success based on the experience of MS patients whose disease has similar characteristics.3The MS BioScreen application illustrates the promise of Precision Medicine—how collection of various types of data can translate into knowledge that leads to more precise and effective therapies.

H2.c. Approach to PM Through the development of a PM function and a Biospecimen Resources Program, CTSI is poised to serve as the centralized, trusted steward at UCSF to broadly enable the practice of PM. PM requires high quality biospecimens, platforms to measure and record patient phenotypic data with linkage to the biospecimens, and pathways to make these data and specimens broadly available to researchers and at the point of care to inform clinical decision making. We will accomplish these goals through the following Aims: PM Aim 1. To support high-quality biospecimen consenting, acquisition, and biobanking from diverse patient populations, we will: • Develop a centralized biobanking consent form. To date, the lack of centralization/harmonization of

biospecimen collection at UCSF has led to a large number of consent forms for tissue collection (>1,500 IRB-approved biobanking consents), resulting in excess administrative burden, lost opportunities for specimen collection, and confusion among patients, staff, and investigators. We propose to develop a single central UCSF protocol and consent for the collection of discarded biospecimens (liquid and tissue), modeled

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on successful strategies employed at other CTSA hubs including Vanderbilt University (BioVU), the Mayo Clinic, Duke University, and UC Davis (for blood). CTSI will lead the harmonization effort by creating a single consent form for discarded blood and tissue biospecimens. We are in the process of surveying stakeholders at UCSF and will hold a Biobanking Symposium in early 2016 with leaders from institutions that have successfully implemented such central biobanking consenting; Vanderbilt, Duke, Toronto and Children’s Hospital of Philadelphia, have accepted our invitation to participate. In coordination with the UCSF IRB (Part E.2), we will also establish mechanisms to distribute de-identified tissue and data to other investigators under a blanket IRB protocol. This model has been successfully deployed by a number of legacy biospecimen banks to date. Such an approach will both increase assents for the donation of biospecimens and improve efficiencies in the design of successful research studies involving biospecimens.

• Coordinate consenting for biospecimens to support PM research. As an outgrowth of Engaging University of California Stakeholders for Biorepository Research (EngageUC),2 led by the UCSF CTSI in the current funding period, we developed and implemented exemplary procedures for biorepository collection and operations at University of California outpatient clinics. We propose to build on this accomplishment: EngageUC is now conducting a pilot clinical trial at UCSF and UCLA to compare standard consent procedures for obtaining tissue with a community-endorsed, simplified, electronic consent enhanced with video. Based on the results of this pilot study, and in coordination with RKS (Part E.2), we will develop an optimal centralized consenting process for biospecimens at UCSF. We will focus on electronic consenting (eConsent) procedures to support PM that optimize participant understanding, autonomy, and satisfaction. The electronic consent for biobanking will be embedded in the UCSF EHR Epic MyChart patient portal. Moving the biospecimen consenting process out of diverse clinic settings will improve patient education, increase the number of subjects consented, and streamline clinical workflows. Implementation of an eConsent strategy will integrate the consent into the EHR and eliminate the current requirements for scanning and uploading.

• Create a Research Specialist Core to coordinate biospecimen collection in clinics and operating rooms throughout the UCSF health system and at our regional partners. To date, each disease-working group has hired their own staff, when resources permit, to execute tissue collection. This has led to a lack of coordination around tissue collection, inadequate communication with key clinical units (e.g., anatomic pathology, cytopathology, lab medicine), excess burdens on some staff, underutilization of others, and no service for investigators who lack the resources to hire such staff. Under the auspices of the Biospecimen Resources Program, we are hiring a Research Pathologists’ Assistant who will work in coordination with the Gross Room supervisors and disease-team pathologist to oversee biospecimen collection and processing in the operating rooms at UCSF. This individual will train the members of this Core in SOPs and deploy them to collect biospecimens across the institution. This will further ensure that specimens are processed according to the customized needs of investigators. The Research Pathologists’ Assistant will also establish the SOPs for optimum biospecimen storage in accordance with best practices of custodianship, and will oversee the distribution of biospecimens according to the governance of the disease groups.

• Build an infrastructure for optimized biospecimen collection, processing, and storage directed by standardized SOPs to ensure optimum analyte quality and regulatory compliance to augment the scope, quality, and management of biospecimen banking. Implementation of standardized SOPs will allow us to share data with national and international consortia. The infrastructure has 3 major components: 1) the portals for coordinated informed-consenting, as described above; 2) the specialist Core for tissue biospecimen acquisition and the portals for non-tissue biospecimens; and 3) the biospecimen management platform described in Aim 2 that will encompass all aspects of the biospecimen life cycle, including operation under all federal and state statutes regulating biospecimens and linked clinical data. This is necessary to support translational research and precision medicine across the UCSF health system enterprise and beyond when appropriate. In coordination with the EVCP office, we have created a new Biospecimen Resources Program (directed by Scott VandenBerg, MD PhD) that will be responsible for executing this effort.

• Develop scalable, compliant, biospecimen storage facilities to accommodate the needs of legacy and new biobanks. This facility will be integrated into the biospecimen workflow infrastructure and will have the biospecimen management practices to meet or exceed requirements for CAP accreditation. These include biospecimen handling/processing annotation, custodial tracking and identification, biospecimen analyte quality assurance and control, histologic confirmation and consistency (FFPE), and documented compliance with standardized best handling practices.

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• Develop processes to collect post-mortem specimens. Post-mortem acquisition of normal and disease-related tissue biospecimens yields analytes of adequate quality and represents a unique opportunity to increase the number and variety of biospecimens available for PM research. We will start by establishing working groups to initiate a directed, rapid molecular post mortem biospecimen program to address: 1) creation of a post-mortem biospecimen consent document; and 2) determination of workflow patterns to optimize directed, rapid post-mortem tissue acquisition. Formulation of an optimal consenting process (language and approaches that yield a high rate of assents) will involve a multidisciplinary approach that will leverage the expertise in the CEER/CTSI RKS (Part E.2.). Establishment of effective work patterns, with attention to biospecimen quality (cold ischemic time) will impact the scope of the program. We will collaborate with our partners in UC BRAID and at other CTSA hubs to carry out demonstration projects to address issues specific to post-mortem biospecimen acquisition and processing.

Vignette: California Precision Medicine Initiative Award - Metagenomic deep sequencing tools identify any infectious cause of encephalitis. More than half of the 20,000 people hospitalized for encephalitis each year in the United States fail to have the cause of their brain inflammation identified. Using metagenomic deep sequencing tools, UCSF investigators, led by Joe DeRisi, PhD, and K Scholar Michael Wilson, MD and their team can identify any infectious cause of encephalitis and by analyzing the gene expression patterns of the patient, can better differentiate between patients suffering from infectious encephalitis and those suffering from autoimmune encephalitis. Working with a multidisciplinary team of experts in neurology, infectious diseases, bioinformatics and genomics, they have already begun to work with physicians to target therapies earlier in the disease course and improve outcomes4 for this rapidly progressive and frequently devastating condition. To facilitate this, they have initiated a first-of-its-kind Precision Medicine Board and consult service to place research-based findings in a clinical context.

PM Aim 2. To facilitate PM research by creating a Biospecimen Resources Program, a richly annotated centralized, searchable, Web-based biospecimen database, we will: • Implement a configurable, Web-based LIMS software platform to optimize specimen collection and

management and to leverage the latest technologies to effectively share analytical data. The availability of large numbers of human biospecimens with both suitable quality and full clinical and companion diagnostic biomarker annotation is crucial for PM research. UCSF currently houses numerous fragmented and uncoordinated biospecimen collection efforts that are costly, difficult to sustain, and challenged by increasing regulatory and compliance requirements. Each disease-working group has developed their own solution to annotation and record keeping and none are fully satisfied. Although they articulate diverse concerns, they all note that critical obstacles include the need to maintain a homegrown or purchased software platform and the lack of integration to the EHR. We recently led a campus-wide effort of diverse stakeholders, in collaboration with UCSF Project Management Services (and support from the EVCP and UCSF Information Technology Group Governance Committee), to identify the best LIMS software platform to support the new Biospecimen Resources Program. CTSI will promote broad campus buy-in and adoption of this enterprise software solution through communication and outreach efforts. Several large legacy biobanks including breast cancer, prostate cancer, and memory and aging have already committed to “buy in” to this model. We will develop detailed and individualized adoption plans for key stakeholders and guide the implementation of a biospecimen management and banking software platform that will include the availability of significantly richer datasets in support of banked biospecimens, improved regulatory compliance, improved operational efficiency, and enhanced technological sophistication for UCSF biobanks with complex workflows and informatics needs. All activities associated with research biospecimens will be managed by this system to enable comprehensive clinical and phenotypic annotation for the creation of a virtual biorepository. This cloud-based resource will feature a robust search engine to query the inventory for de-identified data elements involving biologic, clinical, and molecular phenotypes. Access to information linked to a subset of specimens will be broadly available, as well as information about how to secure centrally stewarded specimens (e.g., fat from bariatric surgeries or unused blood from the clinical labs). This resource currently does not exist at UCSF. We envision that this infrastructure will facilitate a UCSF enterprise-wide culture for the broader use of human biospecimens in diverse research settings. The availability of annotated human biospecimens will further promote sharing at the UC level by participation in the UC BRAID “virtual” biobank. We will follow up on phase I and phase II of the UC BRAID biobanking surveys to determine the necessary steps to “link” information about UC biorepository inventories.

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• Develop processes to facilitate biospecimen sharing across UCSF. Many biospecimens are collected under the direction of disease-working groups that are heavily invested in securing the tissue for their own research. Participation in the centralized, searchable, Web-based biospecimen database will only require that the information about the collection be made fully transparent (see Figure 2). Disease-specific investigators will retain the right to determine how they want to distribute the specimens acquired. CTSI will develop and encourage shared governance and data use agreements to stimulate collaborations. We have already used this approach successfully to provide UCSF investigators with access to the samples and rich phenotypic data, including GWAS and Geocoding, collected under the auspices of the Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH).

• Develop processes to facilitate biospecimen sharing outside UCSF, including our partners at UC BRAID and the CTSA hubs. To foster and support translational research collaborations, we will create an Index of biospecimens at UCSF. Access to the inventory will be open and available on the Biospecimen Resources Program website. Researchers will be encouraged to register their collections with the Index. Researchers in need of clinical biospecimens for their research can then search the Index looking for collections that meet their criteria. These researchers can request additional information or request to contact the PI of the collection. The Biospecimen Resources Program will facilitate these initial discussions.

PM Aim 3. To enable the practice of PM by creating portals to integrate selected population and research data with the EHR, we will: • Develop the tools and policies necessary to create portals to integrate population and research data to the

EHR for point-of-care guidance, with the goal of increasing physician understanding and patient education that both promote informed patient choices and permit more efficient disease management. These efforts will be carried out in coordination with key institutional stakeholders including bioethicists and chief genomics officers, among others. Such portals will: 1) integrate individual patients’ tissue phenomics and genomics data into both physician as well as patient portals of the EHR; 2) provide educational tools and resources to interpret the tissue phenomics and genomics data for all stakeholders; 3) interface tissue phenomics, genomics, and EHR data to establish new nodes and edges that comprise a continuously evolving knowledge network; 4) develop policies for clinical, translational, and basic research access; and 5) develop the policies and metrics to organize authorization and authentication of clinical, translational, and basic researchers to access and use the data generated. CTSI will ensure that the access is compliant with HIPAA, informed consent, and other applicable policies, and that patients engaged through an informed consent process. In coordination with the UCLA CTSI PM Optional Function, we will link genomics (WES and WGS) in the context of adults and children who present with undiagnosed diseases.

• Support a series of demonstration projects across disease areas to explore both the mechanisms and implications of integrating selected population and research data into the EHR. The ultimate goal is to create a self-learning health care system.5 Using the CTSI tool Open Proposals, we will annually solicit proposals to model the practice of PM (see MS BioScreen Vignette, above, and Vignette, Prostate Cancer Integrated Risk Prediction Model, below). In addition, in collaboration with the Pilot Translational and Clinical Studies Team (PTC) team (Part D.2), we will develop an award to support demonstration projects and pilots that use a variety of social, behavioral, biologic, and phenotypic data and biospecimen measures to test the feasibility of disease-focused projects in PM.

Fig. 2 Creation of a Virtual Biorepository. We will integrate the 150+ legacy biobanks at UCSF to create a single Virtual Biorepository that links to high quality phenomic data (research and clinical). This data will be made accessible to researchers and CTSA hubs to precision medicine collaborations.

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H2.d. PM Leadership Director: Scott VandenBerg, MD PhD, is Professor of Pathology in the UCSF School of Medicine and the Director of the UCSF Biospecimen Resources (BIOS) Program and the UCSF Helen Diller Family Comprehensive Cancer Center Biorepository and Tissue Technology Shared Resource. He is an experienced neuropathologist who optimized the biobank in the Brain Tumor Research Center at UCSF before developing a centralized biobanking enterprise at UC San Diego with an advanced tissue biomarker core. He was recruited back to UCSF to lead the central biobanking effort. He will provide direction and leadership to all activities of the PM function, ensuring that goals are met on time. Co-Director: Laura van ’t Veer, PhD, is Professor of Laboratory Medicine in the UCSF School of Medicine, the UCSF Helen Diller Family Comprehensive Cancer Center Associate Director Applied Genomics, and Program Leader Breast Oncology. She is a world-renowned molecular biologist and inventor of MammaPrint®. At UCSF School of Medicine she established in 2010 the CLIA laboratory for cancer diagnostics. She received the 2014 European Union second prize Women Innovator and received the 2015 European Inventor Award. She will co-direct the PM function with specific focus on PM clinical practice integration and data sharing with stakeholders. Peter Carroll, MD, is Professor and Chair of Urology at UCSF in the School of Medicine. He is an experienced physician scientist with expertise in precision medicine approaches to prostate cancer. He will oversee the committee who selects demonstration projects (Aim 3) and will help coordinate the integration of population and research data into the EHR. His group has pioneered the use of such data in the treatment of individuals with prostate cancer (see Vignette above). Barbara Koenig, PhD, is Professor in the School of Nursing and the Institute for Health & Aging at UCSF. Dr. Koenig is an anthropologist and bioethicist. Her current interests include characterizations of race in a genomics age, emerging genomic technologies, biobanking, and return of research results to participants. She is the co-director of the UCSF/Kaiser Center for Transdisciplinary ELSI Research in Translational Genomics and will contribute her expertise to development of eConsenting for centralized collection of biospecimens for precision medicine research at UCSF. H2.e. PM Evaluation and Tracking

Aim / Milestone Metric for Assessment and Frequency

PM Aim 1. Support high quality biospecimen consenting, acquisition, and biobanking from diverse patient populations • Develop centralized biobanking consent process • Coordinate biospecimen consenting • Build infrastructure for biospecimen collection,

processing, storage • Create research specialist Core to coordinately collect

biospecimens • Develop process to collect post-mortem specimens

• # of months for protocol/consent form development & IRB approval • # of subjects consented; # of legacy biobanking consents sunsetted • # of SOPs developed and # of months to SOP adoption • # of staff trained; participating; # of staff from legacy biobanks

participating • # of months for protocol/consent form development &IRB approval;

# of specimens collected PM Aim 2. Implement a richly annotated centralized, searchable, Web-based biospecimen database • Implement LIMS software platform • Develop process for sharing biospecimens

• # of legacy biobanks migrating data; # of new banks established • # of biospecimens shared across UCSF; # of biospecimens shared

with external collaborators PM Aim 3. Create portals to integrate selected population and research data with the EHR • Develop tools and policies to govern and facilitate use of

portals • Demonstration projects

• # of months for tool development; # of months for policy development and dissemination

• # of projects supported annually; process to incorporate lessons learned from projects into the SOP

Vignette: An integrated risk prediction model and decision aid for prostate cancer. Some prostate cancers remain localized without any intervention, whereas others progress and are lethal. There is currently no clinical tool to distinguish aggressive from indolent prostate cancers. The UCSF prostate cancer team led by Peter Carroll, MD is using a retrospective cohort to develop an integrated risk prediction model that includes relevant biomarker and lifestyle variables and combines this with genetic and tumor genomic classifier variables using the UCSF Urologic treatments and outcomes database and tissue bank. The goal is to use this model prospectively to guide clinical decision-making, provide decision support services and a patient portal for those diagnosed with prostate cancer. CTSI is coordinating the key stakeholders including clinicians, UCSF Academic Research Services, UCSF Data Warehousing and Analytics and EHR teams to develop a model of integrating these data into the EHR to iteratively guide therapy as well as advance patient education and information aiming to reduce morbidity associated with standard surgical and radiation therapies for indolent disease.

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References for Part H.2 Precision Medicine 1. Hawgood, S., et al., Precision medicine: Beyond the inflection point. Science translational medicine, 2015.

7(300): p. 300ps17-300ps17. 2. Garrett, S.B., et al., EngageUC: Developing an Efficient and Ethical Approach to Biobanking Research at

the University of California. Clinical and translational science, 2015. 3. Gourraud, P.A., et al., Precision medicine in chronic disease management: the multiple sclerosis

BioScreen. Annals of neurology, 2014. 76(5): p. 633-642. 4. Wilson, M.R., et al., Actionable diagnosis of neuroleptospirosis by next-generation sequencing. New

England Journal of Medicine, 2014. 370(25): p. 2408-2417. 5. Angus, D.C., Fusing Randomized Trials With Big Data: The Key to Self-learning Health Care Systems?

JAMA, 2015. 314(8): p. 767-768.