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ANA TCRCJuly 20, 2015
rl Kieburtz MD MPHKarl Kieburtz MD MPHDirector, Clinical & Translational Science InstituteRobert J Joynt Professor of NeurologySenior Associate Dean, Clinical Research
National CTSA Directions
Revamped NCATS organization- P Kaufmann
National Steering Committee setting priorities
Site supplements to lead national joint efforts
Future areas of focus identified-RIC, TIC, CIN
Team science essential
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NCATS Transition
NCATS Office of Director Discovering New Therapeutic Uses for Existing Molecules (New Therapeutic Uses)Extracellular RNA Communication (exRNA)
Office of Rare Diseases Research (ORDR)
Small Business Innovation Research (SBIR) / Small Business Technology Transfer (STTR)Tissue Chip for Drug Screening
Division of Preclinical Innovation
Assay Development and High Throughput ScreeningBridging Interventional Development Gaps (BrIDGs)Chemistry Technology
Molecular Libraries Probe Production Center (MLP)NIH Chemical Genomics Center (NCGC)RNA Interference (RNAi)Therapeutics for Rare and Neglected Diseases (TRND)Toxicology in the 21st Century (Tox21)
Division of Clinical Innovation
CTSA Program (69% of NCATS budget)
• 2006 CTSA program starts at NCRR-12/23/2011: NCATS formed; NCRR disbanded
• NCATS Purpose: advance translational sciences by
• coordinating resources that leverage basic research in support of translational science
• developing partnerships to foster synergy in ways that do not duplicate or compete with industry activities.
• Leadership• Interim Director Tom Insel (Director of NIMH)
• Chris Austin named as Director Sep 2012
• Divisions of Preclinical Innovation and Clinical Innovation had interim directors, Petra Kaufmann now Clinical Innovation Director
IOM Report – released 6/25/2013
Suggested vision:A “tightly integrated network that works collectively to enhance the transit of therapeutics, diagnostics, and preventive interventions along the development pipeline; disseminate innovative translational research methods and best practices; and provide leadership in informatics standards and policy development to promote shared resources.”
Recommendations (roughly in order of prominence):
• NCATS should take a more active leadership role as the principal party in cooperative agreements
• Greatly streamline committee structure
• The consortium should work more cohesively together and with external partners toward carefully chosen strategic goals
• Establish a cross-consortium “Innovation Fund”
• Tighten up the evaluation program
• CTSAs should be allowed more freedom to capitalize on institutional strengths
• CTSAs should concentrate efforts toward innovative education programs
• CTSAs should continue to lead efforts in child health research
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Deconstruction of CTSA Consortium
Before
Oct 2013
• CTSA Consortium Steering Committee – 60 PIs + a dozen NCATS staff + other NIH staff
• CTSA Consortium Executive Committee – 25 PIs + assorted NCATS staff• CTSA Consortium Child Health Oversight Committee• 5 Strategic Goal Committees• 15 key function committees• Numerous other task forces and interest groups
Nov-Dec 2013
• All former committees and groups were disbanded; coordinating center support was withdrawn
• A new CTSA Steering Committee was created• Chair – Elaine Collier (NCATS)- now Petra Kaufmann• Vice Chair – Nora Disis (PI, U. Washington CTSA), now Alan Green (Dartmouth)• 11 other PIs (including Karl Kieburtz, Rick Barohn)• Chris Austin• Walter Koroshetz (NINDS)
NCATS Response to the IOM Report
NCATS Advisory Council Working Group on the IOM Report: The CTSA Program May 2014
Workforce Development-Goal: The translational science workforce has the skills and knowledge necessary to advance translation of discoveries.
Collaboration/Engagement-Goal: Stakeholders are engaged in collaborations to advance translation.
Integration/Lifespan-Goal: Translational science is integrated across its multiple phases and disciplines within complex populations and across the individual lifespan.
Methods/Processes-Goal: The scientific study of the process of conducting translational science itself enables significant advances in translation.
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Project Development
Going forward, the Consortium will operate through time-limited projects, approved by the Steering Committee,
with explicit planned outcomes.
Initial Project #1: Development of a Cross-CTSA IRB
Reliance Agreement
Initial Project #2: Increasing Accrual
to the Nation’s Highest Priority Clinical Trials
Project Development
Additional projects now funded via supplemental grants to the leading institutions with subcontracts to the
participant CTSA hubs
Initial Project #3: Development of Cross-CTSA Clinical research training processes and
competencies
Initial Project #4: Development of Cross-
CTSA process for scientific review of
materials prior to IRB submission
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Current CTSA developments
RFAs for:
Collaborative Innovation Networks
Recruitment Innovation Centers
Trial Innovation Centers
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Targeted Outcomes-UR CTSI Goals-
• Clinical and translational research educationprograms produce skilled multidisciplinary research team members
• Local, regional and national partnerships support and enhance clinical and translational science
• Researchers and research teams advance clinical and translational science
• Clinical and translational research and supporting services are organized within a URMC academic home
• A diverse spectrum of community members and organizations are engaged in the research process
Clinical and translational research education programs produce skilled multidisciplinary research team members
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KL2 Career Development Program
• Institutional K-award program
• 2 years, 75% effort
• Salary support
• Some support for other costs
• Research project costs
• Travel
• Competitive application process
• RFA released in July
• Applications due ~ October
• Awards announced ~ March
• Two or three awards each year
Mentor-Protégé Curriculum
• At beginning of program year, protégés develop a Research Career Development Plan with their mentors
• Mentoring workshops for mentors and protégés
• Mentor group meeting
• Protégé group meeting
• Fall – a member of the Core meets with each protégé
• Spring – meeting with mentor-protégé dyad
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TL1 Predoctoral Training Program
• Institutional training grant linked to CTSA award
• Three types of trainees
• Academic Research Track for medical students (year-out program)
• PhD students in the Translational Biomedical Sciences Program
• MD/PhD students with an interest in translational science
• Each trainee receives a stipend and may receive some support for other costs
• 10 trainees per year
• Mentors and trainees supported by CTSI Mentor Development Core
TL1 Predoctoral Training Program
• Academic Research Track
• 1 year of support
• Medical students apply in December and are selected in February
• Options• Pursue MPH or other research-related masters’ degree
• Gain hands-on experience in a lab or research center
• PhD-TBS students
• Multi-year support is possible
• MD/PhD students
• Multi-year support is possible
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PhD - Translational Biomedical Science
• One of the first of its kind anywhere
• Goal: prepare individuals for academic and clinical careers involving the translation of basic biomedical research into clinical strategies to improve health
• Required and elective coursework in diverse disciplines
• Epidemiology• Biostatistics• Microbiology
• Immunology• Neuroscience• Pharmacology
• Biochemistry• Physiology• And more…
• Skill-building workshops and seminars
• Research rotations (3 in first year) leading to selection of thesis topic
• BWF-supported Infection/Immunity Concentration
Other Education Programs
• Research Masters’ Degrees (provided by Dept. of Public Health Sciences)
• MS – Translational Research
• MS – Clinical Investigation
• MPH
• Non-degree programs
• Certificates of Advanced Study (eg Biomedical Informatics)
• Academic Core Curriculum - fellows and residents – year-long program, weekly meetings
• Junior Faculty Academic Core Curriculum – one-week intensive course
• Skill-building training
• Online training in Comparative Effectiveness Research
• Online training in FDA regulatory fundamentals
• eRecord for research
• REDCap
• i2b2
• Annual Scientific Symposium
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CTSI Research Resources
• Web-hosted information for easy reference
http://www.urmc.rochester.edu/ctsi/research-help/
• Find a range of resources and services to support each stage of research development and operations
• Research Help Desk
• Functions as an information hub, supporting research teams
� Questions Answered
� Resources Identified
� Support for study design
� Mentors, collaborators and a range of institutional services
� Shared resources to include in research plan
� Guidance and assistance to navigate regulations and policies
CTSI Voucher System
In some cases, affiliated consultation services may have service-specific fees.
Limited financial assistance, to fund consultation fees, is available to researchers conducting clinical and translational research.
�Issued to eligible researchers to fund limited hours of fee-based consultation services
�Default limit of one voucher for the lifetime of a specific project
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CTSI Project Funding Programs
• Pilot Studies• Goal: facilitate new research and future project funding
• 1 year, $50,000
• Trainee Pilots• Goal: support trainee research
• 1 year, $25,000
• UNYTE Pilots• Goal: stimulate new cross-institutional collaborations
• 1 year, $50,000, two or more UNYTE institutions
• Novel Biostatistical and Epidemiologic Methods• Goal: stimulate new methods to improve validity, accuracy, scope or speed
• 2 years, $20,000
• Incubator Program• Goal: accelerate innovative scientific discovery leading to new research programs
• 2 years, $125,000, two or more linked projects
Clinical Research Center
The CRC provides support for patient-oriented research:
• Welcoming In- and outpatient facilities located within the Medical Center (G-5035) and in the Saunders Research Building (1.302)
• Experienced assistance in Research Nursing, Bionutrition, and Clinical Research Coordination
• The Center accommodates pediatric to adult research subjects.
• Access to the Center requires a short application and IRB approval.
• Modest fees are charged for services.
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Clinical Research Center
Resources:
• Telemetry
• Muscle testing
• Glucose clamps
• Serial and/or non-serial blood collections
• Short-term freezer storage
• Anthropometric measurements including DEXA
• Specimen processing
• Assessment and sophisticated analysis of dietary intake
• Research kitchen for preparation of controlled diets
• Nutrition education
• Research coordination services tailored to PI or project needs
• Childcare services
Improving the health of our community(s)
Healthcare delivery will change, driven by ACA and financial forces
URMC is committed to its Community mission
Health should improve as healthcare changes
We need to measure what is of most importance to the health of the community and target change in healthcare to the community needs
The CTSI wants to be sure that the community’s needs for healthcare change, and measuring the impacts on community health are a URMC priority
We organize how that input is structured so that it is consistently heard and acted upon
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Expanding the reach and efficiency of
clinical trials through technology
21st century technology and methodology should expand the availability of clinical research
Clinical trials of new interventions (drugs, devices) will likely benefit the most from these new methods
Using remote access (things like Skype) will permit research participants to be seen at home
Using remote data sensing (like via smart phones) will simplify getting information
Better planning of studies will allow them to be smaller and more efficient
Clinical Trial Methods and Technologies for the 21st Century
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Outline
• Clinical trials of the future
– Disease modeling
– Virtual visits
– Remote measures
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Future clinical trials will differ substantively from
current trials
Characteristics 20th Century 21st Century
Study design Randomized, double-blind,
parallel-group, placebo-controlled
trial
RCT, double-blind, parallel-group
Adaptive designs
Study population All-comers with a given disease Individuals selected based on
disease models and genetic results
Study recruitment Clinical practices Global clinical trial registries
Social networks organized by
individuals affected by disease
Trial visits In-person, phone In-person, phone, videoconferencing
Data management Paper and electronic forms Solely electronic
Participant feedback Limited; delayed Almost universal; approx. real time
Outcome measures Insensitive
Episodic
Subjective
Provider-centered
In-clinic
Unidimensional
Sensitive
Frequent or continuous
Objective
Patient-centered
Remotely
Multidimensional 28
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Pharmacology is increasingly including disease
modeling
Pharmacokinetics Pharmacodynamics Disease Modeling
What the body does to the drug
What the drug does to the body
The time course of disease progression
Source: Charles Venuto, Pharm.D; CHET29
DoseDrug
Concentration
Biomarker or
Clinical
Outcome
Clinical
Endpoint
Disease models can help identify appropriate
populations and outcome measures for trials
PK
Model
PK-PD
Model
Disease
Model
� What is the shape of the time course of disease progression?
� How does progression differ among population(s)?
� Can we predict trial participants who are most likely to drop-
out of a study?
Source: Charles Venuto, Pharm.D; CHET30
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Model-based drug
development was one
of the goals defined in
FDA’s 2004 Critical
Path Initiative report,
and this new tool sets
the stage for applying
new technologies to
accelerating medical
product development.
- Janet Woodcock, MD,
Director of the Center
for Evaluation and
Research, FDA
Disease models are important tools for drug
developers and regulatorsAlzheimer’s disease progression and trial simulation model deemed “fit-for-purpose” by
the FDA and EMA for clinical trial planning (2013) P
red
icte
d A
DA
S-C
og
Years
(MMSE = 20)Mild
(MMSE = 20)(MMSE = 26)Normal
(MMSE = 26)
Progression of ADAS-cognition scores over time:
� Described by nonlinear curves
� Rate of progression fastest in those with higher cognitive impairment at
baseline as measured by Mini-Mental State Examination (MMSE)
� Probability of drop out highest among ADAS-cog “fast progressors”
(MMSE = 14)Moderate
(MMSE = 14)
Source: Coalition against major diseases (CAM-D)
Modeling Initiatives of Neurodegenerative
Diseases at the Center for Human Experimental
Therapeutics
• Parkinson’s disease
1. Advancement of a quantitative disease
progression model of Parkinson’s disease
(Michael J. Fox Foundation)
2. Modeling Parkinson’s disease and
Understanding Progression (IBM)
• Huntington’s disease
3. Huntington’s disease Progression Model
of Total Functional Capacity Scores
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DATATOP Model (Holford et al.)
S(t) = S0 * e-kprog*t + Sss*(1 – e-kprog*t)
FS-TOO
FS1QE2
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1. How well does a previously developed disease
progression model describe newer clinical trial
data?
• Progression rates of disease
• Predicted clinical scores
• Drug/placebo effect estimates
Using DATATOP model to describe QE2 and FS1
Data
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QE2: Time vs. Observed and
Predicted UPDRS Scores
FS1: Time vs. Observed and
Predicted UPDRS Scores
Observed score
Predicted score
Disease Parameter Estimates by Study (average + standard deviation)
Baseline Disease Status (UPDRS) Steady-State Status (UPDRS) Progression half-life
DATATOP 21.8 94 117 years
QE2 22.4 + 9.1 88.9 + 19.0 117 + 21 years
FS1 21.6 + 8.6 83.2 + 22.4 114 + 32 years
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2. Can we identify patient-level factors which
explain Parkinson’s disease progression?
• Problem
– Factors responsible for variability are not
well understood and not taken into account
when designing clinical trials.
• Goal
– Build a model for predicting disease
progression and identifying patient
attributes which explain progression
patterns.
• Data
– Longitudinal data of early Parkinson’s
disease patients from clinical studies at
CHET
• Support and Approach
– IBM Advanced Care Analytics software to
develop predictive algorithms (big data
driven)
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Parkinson’s disease progression is characterized
by substantial degree of heterogeneity
3. Disease progression modeling in
Huntington’s disease (HD)
• The primary or secondary clinical endpoint in
many HD clinical trials is change in Total
Functional Capacity (TFC) score from baseline.
• No disease progression model to describe the
natural progression of TFC scores in HD
patients has been published.
– Scores range from 0 (worse) to 13 (normal)
• Goal: To develop a mathematical model
describing longitudinal changes in TFC scores36
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3. Disease progression modeling in
Huntington’s disease (HD)
METHODS
• Longitudinal clinical trial data
used to construct model (CARE-
HD)
• Linear model:
S(t) = S0 + α*t + ε
– S(t): expected TFC score at a
given point in time
– S0: baseline TFC score
– α: rate of TFC score decline
– ε: prediction variability
RESULTS
• Separate progression rates of TFC
decline estimated for active and
placebo treated patients
- 0.084 units/month (active)
- 0.097 units/month (placebo)
• Estimates of inter-individual and
prediction variability quantified (data
not shown)
PL
AC
EB
OA
CT
IVE
Abstract to be featured at 2014 MDS Congress: Venuto CS, Dorsey ER, Kieburtz K. Huntington’s disease progression model
of TFC scores. Abstract #592
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Office v. virtual visits at Kaiser Permanente Northern California, 2008-2013
Virtual visits are rapidly reshaping the way we
deliver care
Source: Pearl R Health Aff 2014;33:251-257
“I expect that by 2016, with the expanded use of video, the number of
virtual visits—including secure email, telephone, and video encounters—in
KPNC will surpass the number of in-person office visits.”
Robert M. Pearl, MD
Executive Director and CEO
Permanente Medical Group
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With 23andMe, we used virtual visits to marry
phenotypic data with genotypic information
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Study’s aims
1. To assess feasibility of recruiting participants for a remote research study
2. Assess ability to collect data remotely
3. Assess validity of self-reported data from individuals with Parkinson disease
Methods
One-time remote standardized assessment of individuals with self-reported
Parkinson disease who live in the U.S., have high speed internet access, and
may have at least one genetic risk variant for Parkinson disease
Outcome measures
1. Motor and non-motor characterization of participants
2. Validation of self-completed 23andMe Parkinson disease baseline survey
Sponsors/partners
Virtual research visits
Source: Marrying director to consumer genetic data with remote phenotypic assessments in Parkinson disease. American Academy of Neurology.
April 2014. Abstract.
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Remote recruitment and research visits in participants who
have pursued direct-to-consumer genetic testing is feasible
Map of research participants from a single site study
Source: Marrying director to consumer genetic data with remote phenotypic assessments in Parkinson disease. American Academy of Neurology.
April 2014. Abstract.
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The Connect.Parkinson study will connect patients with
Parkinson disease to a national network of providers
*
In collaboration with:
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Online recruitment for telemedicine studies is
successful and suggests latent demand
0
50
100
150
200
250
300
350
12-Feb 22-Feb 4-Mar 14-Mar
Tota
l co
mp
lete
d s
urv
ey
s
Completed interest surveys for Connect.Parkinson study, 2/12/14 – 3/12/14
Total study recruitment
target = 200
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Participants from all over the U.S. and abroad
have visited the Connect.Parkinson website
Source: Google Analytics, accessed 3/13/2014
Map of visitors to Connect.Parkinson
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Technological advancements have increasing
allowed for outpatient monitoringEmerging non-invasive, wireless ECG monitoring
• Recent development of wireless communications in Holter monitors allow
continuous, high resolution ECG data streams ranging from days to months
at a time
• Real-time transfer of ECG data encourages rapid analysis and timely
clinical interventions
• Long-term, high-yield Holter monitoring helps to detect more atrial
fibrillation episodes and arrhythmias with rare occurrence
Source: Rosero SZ, Kutyifa V, Olshansky B, Zareba W. Ambulatory ECG monitoring in atrial fibrillation management. Prog Cardiovasc Dis. 2013; 56: 143-52.
[photo] http://directorsblog.nih.gov/2014/01/16/move-over-holter-heart-monitoring-in-the-mhealth-era/
Traditional Holter monitorWireless adhesive patch
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Wireless remote monitoring reduces time to
clinical decisions in response to clinical events
Source: Crossley GH, et al. The CONNECT (Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision) trial: the value of wireless remote
monitoring with automatic clinician alerts. J Am Coll Cardiol 2011; 57: 1181-9.
Evaluation of clinician response to arrhythmias and cardiovascular disease in CONNECT study
fibrillation,
Study designIndividuals with ICDs were
randomized to remote v.
in-person evaluations of
arrhythmias
Study results•Arrhythmias were detected
and addressed by clinicians
17 days faster in the remote
monitoring group (p<0.001)
•For individuals with atrial
tachycardia or atrial fibrillation,
the median time to response
was 3 days in the remote arm
compared to 24 days in the
in-person arm
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Smartphones may also be able to measure
symptoms remotelyPilot smartphone study in Parkinson disease
Abbreviations: 3D = three dimensional; DFA = detrended fluctuation analysis; PD = Parkinson disease; SD = standard deviation; TKEO = Teager-Kaiser energy operator
Figure 1. Android smartphone
and software application
Figure 2. Analysis of acceleration time traces
Source: Arora S, Venkataraman V, Donohue S, Biglan KM, Dorsey ER, Little MA. Using smartphones to diagnose Parkinson disease: a pilot study (under review)
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Source: Arora S, Venkataraman V, Donohue S, Biglan KM, Dorsey ER, Little MA. Using smartphones to diagnose Parkinson disease: a pilot study (under review)
Smartphones can distinguish those with
Parkinson disease from those withoutGait and posture tests in Parkinson disease
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-2 0 2 4 6 8
x 10-4
0.8
1
1.2
1.4
Teager-Kaiser energy operator
Det
rended
flu
ctuati
on a
nal
ysi
s
a) Gait test
Participant with Parkinson desease
Control participant
Gait test
0 0.5 1 1.5
0.6
0.8
1
1.2
1.4b) Postural sway test
Teager-Kaiser energy operator
Det
rended
flu
ctuat
ion a
nal
ysi
s
Postural sway test
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Success of pilot study has resulted in an expanded
smartphone study of Parkinson disease Active and passive monitoring of disease
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Overview
• Six-month controlled study of ~2000 participants in U.S. and
U.K. will commence in early 2014
• All study activities will take place remotely, using electronic data
capture and videoconferencing
Outcome
Measures
• Feasibility: Individuals will download, install, and use an Android
application to complete movement tests in the home
•Active measures (twice per day) include voice, response time,
dexterity, postural sway, and gait
•Passive measures (continuous) include accelerometer, GPS, and
socialization (frequency of texts and calls)
Study Visits
• Study visits with 50 randomly selected participants will be
conducted using secure video conferencing software, allowing
participation from the home
• Visits will confirm presence or absence of Parkinson disease and
assess traditional clinical characteristics (motor rating scales and
cognitive testing
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Remote monitoring can fundamentally reshape
the way clinical trials are conductedMC10 BioStamp and the Reebok CHECKLIGHT
Source: http://www.mc10inc.com/digital-health/home-diagnosis/baby-temperature/ ; http://www.mc10inc.com/consumer-products/sports/checklight/
BioStamp
• Continuous health monitoring provides
high-resolution data which leads to better
assessments and timely interventions
• Minimally-disruptive technology which can
be easily integrated into the day-to-day lives
of prospective participants
MC10/Reebok CHECKLIGHT
• Consistent, reliable, and actionable
impact data collected in real-time
• Significant foray into linking
neurological disorders with remote
sensing, with potential implications for
Parkinson disease
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