But remain wary about expansion, economic recoveryBy Karyn Korieth and Annick Anderson
Part one of a two-part series
G lobal investigative sites saw encour-aging signs of financial recovery dur-ing the past year, according to new
CenterWatch data, with the average site re-porting growth in clinical trial activity, site staff, patient volume and revenue. While clinical trial activity is expected to increase another 10% in 2012, sites remain wary about the lingering effects of the global eco-nomic crisis and the majority won’t expand operations this year.
Sites report clinical research activity has begun to rebound after a couple of difficult years brought about by the downturn in the global economy and the fallout from merger and acquisition (M&A) activity in the bio-pharmaceutical sector.
“In 2011 we had a strong financial year, and we are off to an even better start in
2012,” said Michael Good, COO of Kansas-based Via Christi Research. “We’ve had a couple of good years.”
Survey data also found improvement in site cash flow, and the majority of sites can pay their bills promptly, usually no later than 45 days.
But even though the investigative site landscape has seen growth during the last year, survey data indicate the outlook for
recovery remains fragile. Global sites report their profitability suffered during the past year, and only one-third of respondents believe economic conditions for sites will improve this year. More than half of sites are not planning to hire in 2012.
“At this point, caution is key for many sites,” said Kathy Jones Beals, vice presi-dent of business development and COO of
Global sites see growth in trials, revenue, staffing
Industry struggles with prospect of trials leaving U.S.
April 2012 A CenterWatch Publication Volume 19, Issue 04
see Trials on page 14
Must grapple with issuesof quotas, populations,differences in dosingBy Tamara Lytle
A s the clinical trials industry continues to expand around the globe, some in-dustry leaders have begun question-
ing whether action is needed to keep more trials in the United States.
Should the FDA have a quota for what percent of trials are conducted in the U.S.? Should other regulations or incentives be used to staunch the flow of trials to develop-ing nations? Does it matter whether or not the patient population comes from the U.S.?
“Rescuing Clinical Trials in the U.S.: A Call for Action,” a meeting organized by Duke University last October, was an effort to spur the conversation among high-level industry, academic and government leaders.
A series of white papers are expected to come out of the gathering.
“This is not a group that is against global clinical research,” said Dr. Robert Harrington, M.D., chairman of the department of medi-cine at Stanford University and former direc-tor of the Duke Clinical Research Institute. “But we want to make sure the U.S. remains a part of the global clinical research, particular-ly if we’re studying an intervention that might
Global investigative site staffing Mean number of employees
Source: CenterWatch, 2012 Survey of 257 Global Investigative Sites
Portals can bring social media benefitsBy Susan MH Lewenz
Here comes the Sun(shine Act)By Samuel Whitaker
21 Pipeline News
Grant Lead Opportunities
Eye On Lundbeck
Coming in MaySite financial checkupPart two of CenterWatch’s 2012 review of site health looks at profitability by size.
Risky businessWhile the industry endorses risk-based monitoring, CROs grapple with the possible loss of revenue it could mean.
Eye On Millennium
April2012
Dear Readers,
This past month I spent three days in Orlando at the Institute for International Research’s Partnerships in Clinical Trials conference. Among the food, drink and conversation was a most enthusiastic group of pharmaceutical, biotech, academic, CRO, niche providers and investigative site research participants, all dedicated to the long-term benefits of drug development.
I met with CROs, IRBs, technology companies, clinical supply vendors and more, each more excited than the last about their roles in helping to bring new medications to patients more quickly.
I made new contacts, gleaned new industry insights and even ran a sunrise race to benefit the Rock CF Foundation for Cystic Fibrosis. That last activity made me feel the best—aside from having the privilege to travel and attend the conference, it was great to be able to do some good at the same time.
Having the opportunity to travel and be away from the office and connecting with other professionals in the industry can be just what the doctor (or the researcher) ordered to reinvigorate and motivate us. It provides a fresh perspective and reminds us of why we entered this industry in the first place.
In this issue of The CenterWatch Monthly, we examine the perspectives of 257 global investigative sites with the results of our newest survey, which shows encouraging signs of financial recovery over the past year. The average site reported growth in clinical trial activity, site staff, patient volume and revenue. But while clinical trial activity is expected to increase another 10% in 2012, sites remain wary about lingering economic effects and most won’t expand operations this year.
In our second news feature, we look at the continuing expansion of clinical trials around the globe. Some industry leaders have begun questioning whether action is needed to keep more trials in the U.S., as they grapple with issues of quotas, target patient populations and dosing requirements in different countries.
Also this month, we’ve enhanced our Pipeline News section. Investigative sites have told us they rely on CenterWatch for study grant leads. New this month, we are proactively using our drug intelligence service to provide advance notice of trials that soon should be entering the next phase of clinical development. As part of this Grant Lead Opportunities service, if you are a sponsor or CRO and would like to list your upcoming trial in The CenterWatch Monthly or initiate a search to identify sites for your upcoming trial, or if you are a site and would like your profile included in our database, contact Claire Gross, (617) 948-5121, [email protected]. We hope both the sponsor/CRO and site communities will make this added resource an integral part of the ongoing site selection process.
For inquiries on multi-reader and corporate subscription rates and article reprints:Sales, Tel: (617) 948-5100Email: [email protected]
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April 2012 | The CenterWatch Monthly 3
CenterWatchInformation ServicesCWWeeklyA newsletter that reports on breaking news in the clinical trials industry. Available every Monday in a digital format, annual subscriptions are $249. Contact Sales, (617) 948-5100, or [email protected].
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CW Publicationsl Global Regulatory Systemsl The CRA’s Guide to Monitoring
Clinical Research - NEW EDITIONl The CRC’s Guide to Coordinating
Clinical Research - NEW EDITIONl Becoming a Successful Clinical
Research Investigatorl Protecting Study Volunteers in
Researchl A Guide to Patient Recruitment
and Retentionl Global market intelligence reports
Good guidance practices
At the close of 2011, as part of its Trans-parency Initiative, the FDA announced the availability of a report titled Food and Drug Administration Report on Good Guidance Practices: Improving Efficiency and Trans-parency (GGP Report). This GGP report was prepared in response to an earlier report (FDA Transparency Initiative: Improving Transparency to Regulated Industry, dated January 2011), which contained several ac-tion items and draft proposals to make the FDA’s operations and decision-making pro-cesses more transparent and foster more effi-cient and cost-effective regulatory processes.
In response to one action item in the earlier report, FDA Commissioner Dr. Margaret Hamburg called for an agency working group to prepare a report identifying the FDA’s “best practices” and making recommendations to streamline guidance document development, reduce the time between issuing draft and final guidance documents and make it easier to find guidance documents on the FDA’s web site. More information about the FDA Transparency Initiative is available at www.fda.gov/AboutFDA/Transparency/TransparencyInitiative/default.htm.
The follow-up GGP report identifies cur-rent “best practices” and recommends strat-egies to make the FDA’s guidance processes more efficient and transparent. These “best practices” and strategies are critical to the FDA because developing and issuing guid-ance documents is an enormous undertak-ing and critical to fulfilling the FDA’s mis-sion. In fiscal year 2009, the FDA issued approximately 124 guidance documents. Since then, guidance activity has been trending upward, with the FDA issuing ap-proximately 133 guidance documents in FY 2010 and 144 in FY 2011. These numbers include draft and final Level 1 and Level 2 guidance documents.
Regulatory UpdateInReview
4 The CenterWatch Monthly | April 2012
Guidance documents are prepared for FDA staff, regulated industry and/or the public, and describe the FDA’s interpretation of or policy on a regulatory issue. The regu-lations are written in Title 21 of the Code of Federal Regulations (21 CFR), in Part 10.115. Unlike statutes (laws) and regulations, guid-ance documents do not establish legally enforceable rights or responsibilities. There are two types of guidance documents. Level 1 guidance documents are those that (1) set forth initial interpretations of statutory or regulatory requirements, (2) set forth chang-es in interpretation or policy that are of more than a minor nature, (3) include complex sci-entific issues or (4) cover highly controversial issues. Level 2 documents set forth existing practices or minor changes in interpretation or policy. Level 2 includes all guidance docu-ments that are not classified as Level 1.
The FDA’s GGP regulations govern how guidance documents are developed and is-sued and give interested persons a number of opportunities to provide input into the development process. Generally, the FDA solicits public input on Level 1 guidance documents before implementation. It posts draft Level 1 guidance documents on its web site with a Notice of Availability (NOA) posted in the Federal Register. Generally, the FDA accepts public comments on the draft for 60 days. In some instances, it also may hold public meetings or workshops on draft Level 1 guidance documents to solicit addi-tional comments or present the draft Level 1 guidance document to an advisory com-mittee for review. Once the comment period has closed, the FDA reviews the comments and considers them as it prepares the final guidance document. The FDA also posts fi-nal Level 1 guidance documents on its web site with an NOA in the Federal Register.
Generally, the FDA does not solicit public input on Level 2 guidance documents or on Level 1 guidance documents intended “for
immediate implementation,” i.e., for which “prior public participation is not feasible or appropriate” before implementing the guid-ance document. However, the FDA publish-es an NOA in the Federal Register for Level 1 guidance “for immediate implementation.” The FDA also posts both Level 2 and “for immediate implementation” Level 1 guid-ance documents on its web site. The public may comment on them at any time after they have been issued and the FDA will re-view the comments and consider them for document revision, as appropriate.
This streamlined approach permits the FDA to issue Level 1 guidance documents “for immediate implementation” and Level 2 guidance documents more quickly than standard Level 1, while still providing stake-holders with an opportunity to comment. Importantly, the additional administrative steps required for standard Level 1 guidance documents (i.e., issuing a draft, providing a comment period and issuing a final guid-ance document) generally make their re-lease a longer process.
In addition to the opportunity to com-ment on guidance documents themselves, interested persons have opportunities to provide input to the FDA on topics for guid-ance documents. The FDA publishes an an-nual guidance agenda, listing possible topics for future guidance document development or revision during the next year. Interested persons may submit comments on the top-ics listed or comments suggesting additional topics for guidance. Interested persons also may identify issues in citizen petitions the FDA may decide to address through a guid-ance document. The procedures for filing citizen petitions are in 21 CFR 10.30.
Requests for guidance documents also come to the FDA informally. Frequently, in-terested persons identify issues that would benefit from guidance at advisory commit-tee meetings, industry meetings, round-tables and listening sessions, or by contact-ing the appropriate FDA office. Interested
April 2012 | The CenterWatch Monthly 5
Month in ReviewHere are the top headlines from the past month’s CWWeekly feature stories:
l ACRO lobbying against Sunshine Act’s inclusion of reporting research payments to physicians
l Calls to CISCRP rise as patients seek human touch
l Unreported trial data becoming a hot-button issue for government, business boon for service providers
l Icon acquires health consultancy PriceSpective, as trend toward post-approval market access grows
l Synteract founder launches first nonprofit CRO, PHACT, to focus on trials for neglected diseases
l Report: Over one-third of clinical trials are outsourced
l Survey: Sponsors, CROs making changes to their business models to demonstrate value to payers
l Cegedim ranks top pharma companies on their use of, and success with, social media
Topics of the past month’s Pulse columns:
l The Pulse on Recruitment: How innovation is driving patient recruit-ment; Sites’ catch-22 of tracking the status of referred patients
l The Pulse on Latin America: Ethical issues in choosing countries in which to conduct studies
l The Pulse on Multinational Studies: The reasons for and means to ad-dress study delays
Executives interviewed in the past month’s Insider Insights columns:
l Patricia Leuchten, chief executive officer of Avoca Group
l Edward J. Stepanski, Ph.D., chief operating officer of Acorn Research
For more information about any of the above articles, please refer to Volume 16, Issues 7-9. To subscribe to CWWeekly, visit http://store.centerwatch.com, or contact: Emily Greenwell, (617) 948-5152 or Susan Dancewicz, (617) 948-5120, or [email protected].
persons sometimes submit a proposed draft guidance document to the FDA. Submitting proposed draft guidance documents, rather than topics, enables the FDA to approach a topic with a better understanding of the issues that interest the stakeholder. This may expedite the guidance document de-velopment process, particularly if the topic involves novel scientific issues. The FDA so-licits proposed draft guidance at a variety of different venues, such as trade association meetings and on its web site. Interested per-sons may submit proposed draft guidance documents on unsolicited topics as well.
All guidance topic suggestions and pro-posed draft guidance documents will be considered, but the FDA might not respond to or take action on every suggestion.
Access to data
The FDA has announced the availability of the report “Food and Drug Administration Transparency Initiative: Exploratory Program to Increase Access to the Agency’s Compliance and Enforcement Data” as another part of the Transparency Initiative. This report includes eight initiatives adopted by the FDA Com-missioner to explore avenues for making the FDA’s publicly available compliance and enforcement data more accessible and user-friendly. The FDA is responsible for a broad range of compliance and enforcement activi-ties. Increasing their transparency enhances the public’s understanding of the FDA’s de-cisions and promotes accountability of both the FDA and regulated industry. The current report incorporates public comments received to an October 2011 Federal Register notice that presented these eight initiatives in draft form.
Final guidance for knee products
The FDA has announced the availability of a final guidance document titled “Guidance
for Industry: Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage” dated December 2011. The guidance provides sponsors of investigation-al device exemption (IDE) or investigational new drug (IND) applications recommenda-tions about certain information that should be included in a submission describing a product intended to repair or replace knee cartilage. This guidance document does not apply to prostheses such as unicondylar or total knee implants, or meniscus replace-ment products. Human cells, tissues and cel-lular and tissue-based products are beyond the scope of this document.
A product intended to repair or replace knee cartilage may include a biologic, medi-cal device or combination product (com-prised of two or more different types of regulated constituents) whose components would individually be regulated by the FDA’s biologics or medical device review centers (the Center for Biologics Evaluation and Research, or CBER, and the Center for De-vices and Radiological Health, or CDRH). This guidance document addresses issues that may arise in the development of articu-lar cartilage repair or replacement products. The guidance supplements other FDA publi-cations on IDEs and INDs that may be rele-vant to development of these products. It also makes final the draft guidance document of the same title dated July 2007.
The FDA received numerous comments on that draft. In response, changes incorpo-rated in the final guidance include adding new sections and clinical study schedules, elaborating on nonclinical data consider-ations and updating the references. Some terminology was changed to harmonize terminology within the FDA and does not change the intent of the guidance. The guid-ance also reflects input received from the public and the Cellular, Tissue and Gene Therapy Advisory Committee meeting held May 15, 2009.
Interested persons may submit either electronic or written comments on final
guidance documents at any time. Send only one set of comments. Submit electronic comments to www.regulations.gov. Submit written comments to the Division of Dock-ets Management (HFA-305), FDA, 5630 Fishers Lane Room 1061, Rockville, MD 20852. All comments should be identified with Docket No. FDA-2007-D-0020 (for-merly Docket No. 2007D-0249).
Live biotherapeutic products
The FDA has announced the availability of a final guidance document titled “Guid-ance for Industry: Early Clinical Trials With Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information” dated February 2012. This guidance docu-ment provides certain IND sponsors with recommendations on submitting INDs for early clinical trials with live biotherapeutic products (LBPs) in the U.S. The guidance focuses on the chemistry, manufacturing and control information that should be provided in an IND for early clinical trials evaluating LBPs. The guidance is applicable to INDs of LBPs, whether clinical trials are conducted commercially, in an academic setting or otherwise. This final guidance makes final the draft guidance of the same title dated September 2010.
Interested persons may submit either electronic or written comments on final guidance documents at any time. All com-ments should be identified with Docket No. FDA-2010-D-0500.
The Regulatory Update is excerpted from Research Practitioner, Volume 13, Number 2, March-April 2012.
Correction: In the graphic “Major CRO proclivity to acquire companies” on page one of the March 2012 CenterWatch Monthly, the year given as Parexel’s incorporation was incorrect. Parexel was incorporated in 1982.
Regulatory Updatecontinued from page 5
CRO Industry UpdateData and analysis provided by Plutus Capital Partners.
A boutique advisory firm that provides investment banking services including M&A, private placement and drug licensing to the global healthcare and life sciences industry, Plutus assists global CROs with their growth, acquisition and exit strategies.PLUTUS Global Thinking.
Local Solutions.
CRO PartnershipsFebruary was a busy month for CROs. The key theme was geographic expansion, with an intent to acquire service capability or client pipeline.
Date Category Partnering companies DescriptionFeb. 28 Globalization Quintiles/Russian Venture
Company (RVC)To strengthen Quintiles’ service capability in Russia, which it believes will experience rapid growth in the coming years.
Feb. 28 CRO services Charles River/Millipore An exclusive licensing arrangement to use Millipore’s TrueSpike Technology to enhance Charles River’s viral clearance studies offering.
Feb. 23 Globalization Inclinix/JSW Life Sciences To strengthen Inclinix’s patient recruitment capabilities in Europe.
Feb. 23 Globalization Frontage/Fanghui Pharma Frontage will provide support in infrastructure, development, regulatory and facility consultation to Chinese pharma companies in a $10 million agreement.
Feb. 16 Globalization Quintiles/Dayarn Pharma To strengthen Quintiles’ service offerings in the Middle East and North Africa (MENA), a region witnessing annual pharma growth rates of 12%-15%.
Feb. 7 CRO services ESTERN Medical/Nextrials ESTERN’s clients will be able to access Nextrials’ EDC system that enables EHR integration. Nextrials will be able to provide services in Latin American markets.
Feb. 1 Globalization Parexel/ASAN Parexel has collaborated with South Korea-based ASAN Medical Center to provide early-phase clinical trial services to sponsors in Asia.
Feb. 1 CRO services PPD/VirtualScopics Alliance expanded (formed in October 2010 focused on Oncology) to include clinical and medical imaging services across CNS, Cardiovascular, general medicine and medical devices.
CRO services: collaboration with the objective of strengthening the clinical service offerings of both companies. Research collaboration: partnership with the objective of building research capabilities. Globalization: partnership with the intent to gain access to clients in new geographic regions.
MultiplesPlutus tracks trading multiples of public CROs.
Company Ticker Revenue EBITDA Market Cap EV EV/Revenue EV/EBITDA P/E (Forward)
In millions, except multiples data. Data as of Feb. 29, 2012.
M&A TrackerThis table tracks the private equity and M&A activity in the CRO space for February 2012. Private equity interest in the CRO space continues, with the acquisition by Linden Capital Partners of SeraCare. Please email news of M&A transactions or CRO partnerships to [email protected].
Type Rationale Acquirer Target DescriptionCRO expansion Strengthen existing
capabilityVenn Life Sciences/Encorium Merger of the two CROs will be headquartered in Ireland and
have additional working capital for growth.
CRO expansion New service offering Ockham Nexus Oncology CRO Ockham has acquired Nexus Oncology to gain capability in regulatory and EMEA pharmacovigilance services.
PE investment Linden Capital Partners SeraCare SeraCare has accepted an $82 million offer from Linden, a Chicago-based, healthcare-focused private equity fund.
CRO expansion: acquisition by a CRO with the objective of strengthening existing capability, adding new service offerings or gaining access to new geographic markets. Business expansion: strategic acquisition by a healthcare-focused entity. PE investment: recapitalization or private placement by a PE fund.
The latest “hot” topic in clinical tri-als is how social media is a “must”
for patient recruitment. There is little doubt this new public forum holds an important place in patient enroll-ment and participation. But what about using similar, albeit private, social media tools with “communi-ties” that already exist internally to clinical trials—those between spon-sors/CROs and their sites?
Few sponsors recognize these pri-vate communities, let alone garner their benefits. A Clinical Trials Com-munity Portal (CTCP), which plugs in to existing systems through web services, is relatively simple to add. The CTCP’s primary function is im-proved communication between the
sponsor/CRO and sites. The opera-tional benefits, savings and efficien-cies come from features including:l Send/Receive/Track documents electronically
l 21 CFR Part 11 compliant signa-tures
l Immediate and secure commu-nications via secure Live Chat
l News and alertsl 24/7 online training availablel Enrollment tracking—sites can see how they are doing vs. oth-ers; sponsors can evaluate site performance over time.The community component of the
CTCP also can have a great impact on trials. Private and secure forums, blogs and image galleries can moti-vate CTCP usage and, by extension, keep sites focused on the objectives.
The investigator’s involvement in the day-to-day operation of a trial can be critical to recruitment success. The CTCP enables the physician to pro-vide insights, opinions and input on his schedule on any device. Accord-ing to Frost & Sullivan, 70% of health-care professionals use social media to communicate with other profession-als. By using a CTCP, sponsors save sites time and provide motivational tools, including the sharing of ideas and best practices with colleagues in a private, moderated forum.
Sponsors and CROs can harness the power of social networking to change how their own clinical op-erations teams interact with their sites, facilitating the flow of com-munication. The key to improv-ing trial quality will be engaging the trial community in dialogue throughout the duration of a study.
By Samuel Whitaker
A s pharmaceutical, biotechnol-ogy and medical device manu-
facturers are discovering in the wake of 2010’s Patient Protection and Affordable Care Act (PPACA), big legislation can mean big chang-es for clinical trials. As the industry mobilized to comply with immedi-ate changes, preparation for later provisions was deferred. But time moves quickly, and now a tiny stat-ute comprising about 1% of the PPA-CA’s text and receiving even less attention from policy analysts has become increasingly prominent.
As 22 short pages tucked neatly into PPACA, the Physician Payments Sunshine Provision—the Sunshine Act—mandates that drug, biological supply and medical device manufac-
turers annually track all payments of over $10 made to investigators and research sites. Penalties of up to $10,000 per omission mean sponsors need robust methods to manage in-vestigator, vendor and site payments.
Whether in-house or outsourced, global clinical payment tradition-ally has been undertaken manually, with limited use of automated re-sources. This drives payment distri-bution through several sources and makes consolidation for disclosure purposes difficult, if not impossible. Given the scale of modern clinical trials, delivering, tracking and re-porting thousands of these transac-tions can drive significant adminis-trative costs; in light of the Sunshine Act, payment management also is emerging as a regulatory liability.
But just as technology has en-
hanced other aspects of clinical trials, clinical technology develop-ers recently have shifted toward streamlining payment delivery and management processes. By central-izing global payments through a web-based system, technology en-ables detailed tracking, reporting and financial analytics across mul-tiple CROs, vendors, sites and in-vestigators, for which manual pro-cesses would be prohibitively costly and alarmingly unreliable.
Efficiently and accurately tracking and reporting payments is no longer the purview of only internal account-ing and finance departments; con-formity with the Sunshine Act will demand the attention of compliance, regulatory and top management.
In advance of the Sunshine Act, forward-thinking executives should capitalize on technology-based so-lutions for clinical payments.
Susan MH Lewenz is CEO of Axxiem, creator of the AxxiTRIALS CTCP, a core platform that can be customized and branded to each company’s needs, with motivating features for both sponsor and study site participants. www.axxitrials.com
Sam Whitaker is founder and CEO of Greenphire, a provider of clinical payment technology solutions. Sam has developed and deployed two global clinical payment technolo-gies at Greenphire designed to automate site payments, patient payments and vendor payments. Previously, Sam was a vice president in Citigroup’s prepaid card division, where he developed new payment technology platforms.www.greenphire.com
Here comes the Sun(shine Act)
Portals can bring social media benefits
8 The CenterWatch Monthly | April 2012
Georgia-based NeuroTrials Research. “But I see indicators that things are coming back in a healthy way. I don’t think we will be there this year. But certainly all of the signs, such as inquiries for new projects, are coming in. Hopefully we will see a nice, healthy econo-my for our industry next year.”
Increased level of activity
During January and February, Center-Watch conducted its most extensive study of investigative site operations in a decade. In the survey, 257 global investigative sites with an average of 14 years experience in clinical research provided detailed infor-mation about their staffing levels, level of research activity, financial operations and
outlook for the future. The data establishes industry benchmarks for site operations and gives sponsors and CROs a chance to better understand the overall health and structure of this landscape.
More than four-fifths (81%) of clinical tri-als managed by the typical site are industry
sponsored, which isn’t surprising given that pharmaceutical and biotechnology com-panies account for 90% of clinical research spending. The typical respondent conduct-ed an average of 12 industry-sponsored tri-als and 2.7 government-sponsored trials in
Surveycontinued from page 1
April 2012 | The CenterWatch Monthly 9
see Survey on page 10
Investigative site plans to hire personnel in 2012
Source: CenterWatch, 2012 Survey of 257 Global Investigative SitesPlan to hire Do not plan to hire
2011, representing a nearly 6% increase in the total number of trials per site. Sites are expected to conduct an average of 16.2 trials each this year, a 10% increase from 2011.
Globally, the size of a typical site increased 8% last year, reaching an average of 12 employ-ees. This growth was driven mainly by add-ing investigators/subinvestigators or study coordinators to the staff. At SDS Clinical Trials, a dedicated research site in Southern California, CEO Nanci Hook-Seid hired four new coordinators during the past six months and has plans to hire two more to help orga-nize an influx of new studies. “When I first started in this industry in 1993, you could have one coordinator for three or four stud-ies. Now, the way our studies enroll quickly, you need one coordinator designated for each study when they are enrolling,” she said.
Overall, the typical site across the globe enrolled an average of 220 patients in 2011, a 7.3% increase from 2010. Sites in North America enrolled an average of 246 patients in 2011, compared to 151 per site in Europe and 200 in other regions surveyed.
Sites’ financial health
Although clinical grant spending overall has increased, sites are being forced to do
more with fewer dollars. In 2011, the typi-cal global site received $534,210 in clinical grant revenue, representing a 5.8% increase from 2010. Yet, at a time when protocols have become more complex and require a greater number of procedures, the size of an individual clinical grant for an industry- sponsored study remained unchanged in 2011 at about $43,650. With increasing com-petition for studies and tight budgets, the per-trial amount for industry-sponsored grants is expected to fall to $42,490 this year.
“The budgets have definitely not kept pace with the complexity or the labor in-tensity of these studies,” said NeuroTrials’ Jones Beals. “When there are fewer oppor-tunities, as there were a year or two ago, that puts the sponsor completely at an ad-vantage. If they don’t offer a grant that is as healthy as it might have been, the sites are more accepting than they might have been
before the downturn in the economy.”Meanwhile, federal grant funding has
not kept pace with the for-profit sector. The average individual grant for a government-sponsored trial dropped to $13,170 last year, less than a third the size of the average in-dustry grant. Although the grant amount for government-sponsored trials is expected to increase 14.5% this year, government- sponsored grants represent only about 6% of total clinical trial revenue for the average sur-vey respondent. Most sites see little value in going after federal funds when the resources invested in competing for them nearly cancel out the revenue they might receive.
Via Christi Research has government grant specialists on its staff, for example, but it no longer aggressively pursues NIH funding opportunities. “The funds have dried up, so the competition is a lot more in-tense,” said Good. “We have people looking at what is available to compete for and every now and then we will pick one. But we don’t chase them anymore. We let them fit with what we need. If we get the grant, fabulous. If we don’t, it’s a system or program we need to put into place anyway.”
Significantly, survey data found sites overall no longer depend on clinical re-search for their main source of revenue; more than 60% of site revenue globally comes from other sources. In the U.S., the percentage of income sites receive from clinical research has reached its lowest point in a decade. In 2007, sites received 76% of their revenue from clinical trial grants.
Surveycontinued from page 9
IndustryNews
10 The CenterWatch Monthly | April 2012
Distribution of total investigative site expenses
Source: CenterWatch, 2012 Survey of 257 Global Investigative Sites
Other expenses
General site marketing initiatives
Patient recruitment support
Information technology
Regulatory fees/protocol amendment fees
Training and certi�cation
All other sta� salaries
Rent
Study coordinator salaries and fees
Investigator fees 24%
18%
9%
9%
7%
6%
5%
5%
3%
14%
Global investigative site mean revenue and profitabilityIn U.S. dollars
Clinical grant revenue 2010 2011 Percent change
Average revenue per investigative site $504,938 $534,207 +5.8%
Profit 2010 2011 Percent change
Average profit per investigative site $50,724 $50,144 -1.1%
Percent of gross clinical grant revenues (based on average profit)
10.0% 9.4%
Source: CenterWatch, 2012 Survey of 257 Global Investigative Sites
see Survey on page 12
That amount dropped to 37% for U.S. sites in 2010 and remained unchanged for 2011. A U.S. site’s average revenue from industry-sponsored trials is less than half what it was a decade ago, falling from $1.3 million in 2001 to $631,000 last year.
Dedicated sites typically must derive all of their revenue from clinical grants, al-though some earn a small portion of income from activities such as consumer product research. But private-practice physician in-vestigators can fall back on their practice revenue if clinical research becomes too difficult or less profitable. The survey data suggests experienced private-practice in-vestigators may have less of an incentive to stay in the clinical research business if they continue to lose studies to lower-cost, nov-ice sites and if the increasing complexity of studies makes it difficult to find patients eli-gible to participate in their trials.
“If the studies they select are not a profit-able use of their and their staffs’ time, they will increase their appointment schedules on the practice side to compensate at the expense of the sponsors’ clinical research objectives. It’s really difficult to be a practic-ing physician researcher today and be prof-itable in both endeavors,” said Daniel Ulrey, president and CEO of MCSI, a U.S.-based site network with 391 independent sites.
As for how the grant dollar is spent, sala-ries consume 51% of revenue for global sites: investigator fees across all countries com-prised nearly a quarter of the budget, while study coordinator and other staff salaries comprised another fourth. While salaries still make up the largest portion of the bud-get, the percentage of money spent on salaries has dropped 26% during the past five years as other expenses, including rent, training, cer-tification and regulatory fees, have increased. In addition, sites in Europe tend to allocate
a higher percentage of clinical research rev-enue to regulatory fees and global marketing initiatives than sites in other regions.
At Meridien Research, which operates four dedicated research centers in the Tam-pa Bay, Fla., area, a tiered-employee support system has been developed to help manage higher salary costs. “Trials have become more complex, so you have to be smarter about how you do business,” said CEO Cathy Collins. “One of the ways we’ve been
April 2012 | The CenterWatch Monthly 11
C
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CM
MY
CY
CMY
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04_TrafalgarEthicsBoard_3p.pdf 1 3/15/12 3:47 PM
Perceived economic conditions2012 compared to 2011
Note: Percents rounded to nearest whole numberSource: CenterWatch, 2012 Survey of 257 Global Investigative Sites
successful is to segregate out functions that higher-level employees don’t necessarily need to do. Our coordinators are not doing regulatory, laboratory, phone screening or data entry work. Instead of having a high-level employee doing all of these ancillary activities, we have support employees that don’t make as much money. The model is efficient, effective and economical.”
Waning profitability
Globally, survey results show sites strug-gle with profitability. The average profit for global sites dropped 1.1% in 2011, allow-ing sites a profit margin of 9.4%. In North America, profit margins dropped slightly to 12% in 2011, while European respondents reported profits fell to 8% last year.
Site profitability has been negatively im-pacted by a new budgetary practice recently adopted by some drug sponsors and CROs. Many sites receive a total budget number for a clinical research project that doesn’t delineate what is included, such as wheth-er it covers study start-up costs or specific amounts for each procedure. Sites must
determine whether the total amount will meet their study costs and defend any re-quest for an increase.
“We go back and ask for specific details as to what they have ‘bundled’ into a fee and often find out there are a lot of very expen-sive procedures,” said Aspen Clinical Re-search CEO Jon Ward. “Once highlighted, the sponsors/CROs are not delighted to pay for the procedures, but they usually will pay for or revise and remove the specific items from the protocol. This, of course, is another cost, due to the waiting and entire amendment process.”
In addition, sponsors and CROs typically don’t give sites completed protocols and budgets until after they have invested a sig-nificant amount of time preparing for the study. Sites generally must complete feasi-bility questionnaires, go through pre-study site visits, submit IRB and regulatory docu-ments and attend investigator meetings be-fore they see budget figures.
“The average site spends from $8,000 to $10,000 in direct and lost opportunity costs preparing for a study,” said Ulrey. “After they have invested their time and money, they are offered a budget. Because of the increasing complexity of the protocols offered today a lot of experienced PIs and administrators are
saying, ‘I need to know what the budget and the timelines are going to be beyond com-pleting the feasibility before we invest further time.’ Many sponsors understand this and say they will do their best to give the information to the sites. But many sponsors start the pro-cess of site identification months in advance of the protocol being completed, internal and FDA approval or a budget being finalized.”
To improve their profit margins, sites in general are becoming more business savvy. Experienced sites increasingly turn down complex protocols they won’t be able to execute. They also apply tighter scrutiny to budgets, pushing sponsors to pay costs that aren’t always reimbursed such as start-up fees, screen failures, document storage and travel for training.
Some sites are diversifying to make up for waning profitability. Via Christi Re-search, for example, which started in the industry three decades ago as a psychiatric research institute, now runs clinical stud-ies in 16 therapeutic areas, most recently adding specialties in rheumatology, oph-thalmology and endocrinology. The facil-ity also has aggressively pursued work from smaller biotech firms and has begun devel-oping relationships with large pharmaceuti-cal companies in China that might want to bring studies to the U.S. for FDA approval. “It’s very much a rollercoaster,” said Good. “Five to eight years ago our profit margins were probably higher, but we weren’t doing the dollar volume. Overall, the margins are tighter. But we have to make that up with more studies and more volume.”
As profitability has fallen, many sites have become more careful about working with fi-nancially risky companies. Some sites insist on monthly payments, rather than quar-terly, from single-asset biotech companies. Others decide against working with riskier venture-backed companies altogether. As a result, bad debt write-off in 2011 was only about 5%, unchanged from 2010.
“We’ve become more selective on agree-ing to take on new clinical trials,” said SDS
Surveycontinued from page 11
12 The CenterWatch Monthly | April 2012
IndustryNews
Profit expectations for 2012
Note: Percents rounded to nearest whole numberSource: CenterWatch, 2012 Survey of 257 Global Investigative Sites
Rest of worldOverall
29%
6%
44%
19%
22%
8%
40%
9%
17%4%
North America
8%
42%
26%
19%
Europe
47%
19%4%
30%
4%
Stay thesame
Increasesomewhat
Increasegreatly
Decreasesomewhat
Decreasegreatly
Clinical Trials’ Hook-Seid. “If it’s a new spon-sor, I will research that sponsor or CRO and make sure they have good financial backing.”
Sponsor payment improved
Although slow payments and reimburse-ments from sponsors has been a long-stand-ing problem for sites, survey data indicates cash-flow issues improved last year. The ma-jority of sites pay their bills promptly, typi-cally no later than 45 days. About one-third of sites report sponsors pay their invoices within 60 days; the average receivable days for work performed reached an all-time high in 2003 when sites waited more than 140 days for payment.
Payment schedules have improved as some sponsors have adopted monthly, as opposed to quarterly, systems, and elec-tronic data capture (EDC) helps expedite
payment approval processes. Many sites also have modified their own practices to ensure they are paid promptly. Staff mem-bers track milestones in various contracts and follow up on outstanding invoices.
“We’ve gotten a lot better at monitoring and being able to head off problems early,” said Meridien Research’s Collins. “Sites that don’t have good financial management get themselves into trouble because the lon-ger you let an outstanding balance go, the longer it will take to collect that balance. We don’t let things go very long. We know how many accounts receivable we have in the 0-to-30-day bucket, the 30-to-60-day bucket and the 60-to-90-day bucket. We are instituting a new policy by which right at the 30-day mark, we are going back and saying, ‘We just wanted to confirm that you received our receipt and you have all of the information you need to pay the bill.’”
While sites often believe when a CRO manages a study they aren’t paid as prompt-ly or as well, the CenterWatch survey found CROs have become less of a factor in site profits. More than half of global sites sur-veyed (57%) said the promptness of grant payment was either about the same or faster when a CRO was involved in managing a study. In addition, almost half (44%) of U.S. sites reported study grants were the same or higher when a CRO was involved in manag-ing a study, compared to just 27% in 2002.
Looking ahead
The outlook for the clinical trials land-scapes mirrors the slow, cautious recovery seen across the global economy. Although survey data shows the financial situation improving, sites indicate concerns about
the stability of the environment. Only 30% of respondents believe economic conditions for sites will improve this year, while the ma-jority believe their financial situations will either stay the same (34%) or worsen (36%).
Although clinical grant spending has in-creased, sites across the globe have seen their profit margins shrink. Looking forward, sites are evenly split about their profit expectations for this year. About half of sites anticipate profits to increase in 2012, while the other half believes profits will either stay the same or de-crease. Sites in Europe are less optimistic than other countries about profit expectations for 2012, with 66% of sites believing profits will either stay the same or worsen.
As a result, despite an expected increase in clinical trial activity this year, sites are reluctant to build their infrastruc-ture—57% of global sites have no plans to hire in 2012.
“Certainly the economic downturn has taken its toll,” said NeuroTrials’ Jones Beals. “Caution is key. If they don’t absolutely have to replace someone who is leaving,
they probably aren’t hiring as much as they might have a couple of years ago.”
Coming next month: an in-depth analysis of profitability at sites by volume of clinical research activity and infrastructure.
Annick Anderson has been conducting mar-ket research since 1998 in both the healthcare and consumer packaged goods industries. She can be reached at [email protected].
Karyn Korieth has been covering the clinical trials industry for CenterWatch since 2003. Her 30-year journalism career includes work in local news, the healthcare industry and national magazines. She can be reached at [email protected].
Surveycontinued from page 13
Trialscontinued from page 1
be widely used in U.S. clinical practice.”For example, when Plavix was part of the
pivotal CURE trial, only 600 of the more than 12,000 patients were from the U.S., said Harrington. “That formed the basis of what we do in clinical practice. For a drug that’s going to be used as widely as that, why so few patients in the United States?”
Harrington and others raise questions of how globalization is affecting trials, wheth-er where patients come from makes a differ-ence and what solutions should be pursued. The questions echo through the larger clini-cal trials industry.
One solution popular with some research sites and their advocates is to require a
minimum number of U.S. patients for trials evaluated by the FDA. Dr. David L. Fried, M.D., F.A.C.P., chief principal investigator and medical director of Omega Medical Re-search in Rhode Island is in that camp along with owner Johnna Pezzullo, R.N. Pezzullo, whose site runs 20 to 25 trials a year, concedes she is biased: The downturn in the economy already has hurt sites, and now even more business is being lost to overseas locations.
But Alberto Grignolo, Ph.D., corporate vice president of Parexel, said there’s no turning back the clock on globalization. “The world is the stage,” he said.
The trend toward non-U.S. trials
Currently, more than half of all FDA- regulated principal investigators are in
North America, compared with more than 80% a decade earlier.
“We are increasingly seeing marked drop-off in U.S. enrollment,” added Har-rington. One example of that shift, he said, is the stark difference between the GUSTO trial in the 1990s, in which 50% of patients were from the U.S., and the PLATO trial reported in 2009, in which only 10% of pa-tients were from the U.S.
The number of U.S.-based principal investigators rose from 6,000 in 1991 to 14,000 in 2007, according to Grignolo. But the number for the rest of the world exploded during that time, from 500 to 12,000.
Jonathan C. Fox, M.D., Ph.D., vice presi-dent of the CVGI clinical therapeutic area for AstraZeneca, said costs are lower outside the
Sponsor payment promptness
Note: Percents rounded to nearest whole numberSource: CenterWatch, 2012 Survey of 257 Global Investigative Sites
Greater than 90 days Between 45-90 days Between 30-45 days
Rest of world
27%
28%
45%
Overall
37%
18%
45%
North America
13%
37%
49%
Europe
42%
34%
25%
To obtain a copy of the summary results report of the 2012 CenterWatch Survey of Global Investigative Sites, contact Steve Zisson at (617) 948-5142, [email protected].
U.S. “Rent, electricity, the doctors’ time, the nurses’ time, it’s all cheaper,” he said.
Mean patient costs in Eastern Europe are half of those in the U.S., and in Asia the fig-ure is 48%, according to TTC.
But labor costs change over time. They are lower when a country first begins to conduct clinical trials, then rise with the increased demand for workers, according to John Lew-is, vice president of public affairs at ACRO, the trade group representing the eight larg-est CROs. Indian labor costs, for instance, have risen to U.S. wage levels, he said. And labor savings have to be balanced against the costs of regulatory delays in those countries and expenses such as shipping medicines to a developing country or transporting tissue samples to a central lab in another country.
Mark Lacy, president of Benchmark Re-search in Austin, Texas, said sponsors are taking trials elsewhere for more than just
cost savings. “They are leaving the United States to get around rules and regulations.” In India, for instance, stipends can amount to a quarter of a patient’s annual income, which would not happen in the U.S.
But Lewis said evading good regulation only yields bad data—which would be a waste of money.
ACRO analyzed 22 multi-regional trials and found no statistical difference in qual-ity among the data from different countries, Lewis said.
Lewis, Grignolo and Fox agree there are important benefits to globalization.
“There are a lot of human beings living outside the United States on planet Earth, and we care about them, too,” Fox said. “It’s not all about us.”
Conducting trials in other countries helps sponsors with both regulatory ap-proval and sales in those countries. And it helps get medicines to patients faster. Lewis said, for example, phase III cancer trials
April 2012 | The CenterWatch Monthly 15
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would take on average nearly six years with U.S. patients only, compared with less than two years with a global patient base.
FDA Deputy Director Doug Throckmor-ton said, “Good data, whether it comes from the United States or other parts of the world, help us understand if a new drug works.”
And the global population makes it easier to fill studies. In the U.S., patients have oth-er treatment options and many aren’t inter-ested in participating, said Grignolo, while in countries with less modern medicine, pa-tients are more eager to enroll.
Population differences
Trials sites, academics and CROs differ on whether trial location makes a differ-ence. Some experts argue that demograph-ics, lifestyle and health systems are different in the U.S., so the impact of a drug can be different, too.
“You’d like enough patients in the U.S. to gain a sense of comfort that the results in the U.S. are consistent with what’s observed in the rest of the world,” said Harrington.
But CROs argue the location of the trial often does not affect the results. Grigno-lo said regulators can and should look at whether a drug works for their population, but it should be done on a case-by-case basis, not as a requirement that a certain percent-age of all trials be conducted in that country.
“A blanket requirement misses the point,” said Grignolo. “Every drug can be differ-ent. Every disease can be different. Medical practice may be different or similar.”
Throckmorton said the FDA looks at population differences in approving drugs. Genetics can mean some populations me-tabolize drugs differently. And practice pat-terns, lifestyle and other medications can have an impact on a drug’s effectiveness.
“We understand we are regulating the U.S. market,” he said. “We really do want
to make sure the medicines we approve do work in the U.S.”
But demographics may not be the best way to understand differences between popula-tions, said Grignolo. Scientific knowledge from the human genome is playing a role. In some cases, he said, differences between Northern and Southern European people may be more pronounced than differences between Asian and European populations.
Because of that, looking at biology and genomics is becoming more important than geography and ethnicity, he said.
But critics say when the U.S. is a smaller portion of the trial population, demograph-ic groups within the U.S. get even shorter shrift.
Systemic differences in the U.S. also raise questions.
Harrington said the U.S. practice of medicine can be very different than in other parts of the world when it comes to concur-rent medicines, different procedures and interventions for repeat symptoms. Disease prevalence and lifestyle also vary by region. U.S. patients, for example, typically have heavier body weight, he said.
And, he added, about 25% to 30% of U.S. patients in cardiovascular trials may have diabetes, compared with 15% in the rest of the world.
Fox said an arbitrary quota would hit tri-als where population differences affect the
trial as well as those that don’t. Instead, re-quiring U.S. patients be included in trials should have some scientific basis for that particular disease.
Solutions
Fried would like to see the FDA impose a minimum requirement for U.S. partici-pants in clinical trials for drugs it approves. “The FDA is the safeguard,” he said.
Fox warns that any quota would still leave U.S. patients as only a percentage of the trial. And under the laws of statistics, drawing conclusions from that smaller per-centage of the whole study will not always guarantee accurate results.
Lewis, of ACRO, said quotas are down-right impractical. If you designed trials to match U.S. demographics, he said, “you’d never finish the trial. It’s difficult enough to recruit patients now.” And who’s to say the real difference is not between countries but, say, between populations in Baltimore and rural Kentucky.
Sponsors and the FDA already can look at the global results to see whether there’s a difference in effectiveness among different populations. “That’s the current system and we think that works pretty well,” Lewis said. “That should be the presumption going in—that people are people.”
16 The CenterWatch Monthly | April 2012
IndustryNews
see Trials on page 18
Mean per patient costs 2008-2011 relative to North American ratesAll phases and therapeutic areas
Source: TTC, LLC
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Throckmorton said Congress already calls on regulators to look at the effects on the U.S. population. Only rarely is that ef-fect different than for the overall trial popu-lation. In those cases, the FDA can request the sponsor provide more information or conduct additional trials.
For example, he said, with the blood thinner ticagrelor, questions arose about whether it affected the U.S. population in the same way. When the FDA approved the drug, regulators modified how it was used for U.S. patients. The FDA, said Throck-morton, has other methods than quotas to achieve the same ends.
Lewis does not expect the FDA to adopt a quota. “In what is already a very compli-cated, not always transparent, approval pro-
cess… that everyone concedes takes too long and costs to much, we see no justification for complicating it with a quota,” he said.
But other countries do impose require-ments that clinical trials be conducted on their populations. Grignolo, who is based in Japan, said Japanese regulators feel Cau-casian doses often are too high for their populations. One-third of drugs approved in Japan have an effective dose that is 50% of the Caucasian dose, he said. Sponsors must meet Japanese patient minimum levels in trials and show data comparing those pa-tients to the overall results.
And Grignolo said China (where Parexel has four offices), requires that some phase II and phase III data be produced in China. The exact percentage is negotiated between regulators and sponsors for each trial.
Other options are being discussed for en-couraging U.S. trials.
Fox would like the government to find ways to encourage community physicians to run trials and attract more American patients to participate. Harrington would like to see the National Institutes of Health use its funding and influence to encourage more U.S. universities to conduct trials.
And Fried would like to see private insur-ers require that drugs they cover have U.S. trials. “Who else can make a difference? The people who pay for drugs at the consumer level.”
But Lewis said government and private insurance programs just want to know if a drug is effective. “That has nothing to do with where the trial is conducted. I don’t see insurer interest there.”
Lewis said the way to keep more trials in the U.S. is to provide incentives to doctors to conduct trials. But he worries health care reform will do just the opposite. The new
18 The CenterWatch Monthly | April 2012
IndustryNews
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rules aimed at transparency, known as the Sunshine Act, require pharmaceutical firms to publicly disclose payments to doctors, including those for clinical trials. A recent survey conducted by ACRO showed 24% of investigators said they would be less likely to conduct research if that income was dis-closed to the public.
Lewis also would like to see tax law changes to allow sponsors and CROs to bring profits from overseas operations back to the U.S. to reinvest in more research without paying 35% tax rates.
Lacy said companies take advantage of all sorts of tax loopholes that encourage them to move trials out of the U.S. “The American sites, American people are being shortchanged.”
The U.S. unwittingly encourages com-panies to conduct trials elsewhere by doing much more auditing of U.S. sites than of
foreign ones, he said. The FDA should take a tip from the British system and charge drug companies for audits performed at sites outside the country. “We’re not asking for anything more than parity and equal treat-ment,” Lacy said. But he doubts anything will change because of the lobbying power of the pharmaceutical industry.
But Throckmorton said the U.S. has a different system—a single fee for trials does
go toward inspections, both foreign and domestic, among other things. Some au-dits are conducted abroad, but the choice of whether to audit is based on issues such as past record, size of trials and data anomalies detected. “I don’t see us making our choice based on geography,” he said.
FDA figures compiled by the Office of Biostatistics show that in 2008, 1.9% of
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Estimated time to enroll FDA-regulated phase III cancer studiesTotal FDA-regulated, actively enrolling phase III cancer trials worldwide
Source: VOI Consulting, based on data from American Cancer Society, Globocan and clinicaltrials.gov
1,218
Years to �ll trial withglobal patients
Years to �ll trial withU.S. patients only 1.95.8
Number of willing and eligiblepatients per study worldwide
Number of willing and eligiblepatients per study in the U.S. 357120
domestic sites were audited, but only 0.7% of foreign sites were audited. The FDA has access to audits the sponsors perform them-selves. “Whether or not we are in the door, there are other ways to get information,” Throckmorton said.
He said the FDA is working to improve the clinical trials infrastructure, which would help keep more trials in the U.S. The FDA is trying to clarify regulations for the adverse events reporting system, for in-stance, to make the process less time con-suming. And changing rules to make it eas-ier for clinical investigators to become part of trials also will help encourage domestic trials. Throckmorton said the Clinical Tri-als Transformation Initiative Program (CTTI) is an effort to improve the way clini-cal trials are conducted in the U.S.
“If we make it efficient, they will continue to want to have their trials in the U.S.,” he said.
Grignolo, an executive board member of CTTI, echoed the call for simplification. Bureaucracy and inefficiencies drive some trials out of the U.S. The average National Cancer Institute trial takes 800 days to en-roll, he lamented.
“That is a remarkable inefficiency that does not serve the patient well,” he said. He’d like to see academic centers agree on templates for contracts with sponsors, so sponsors don’t have to negotiate separately with each academic center for the same tri-al. Standardized case reporting forms and other documentations also would stream-line the process greatly.
Finding ways to keep trials in the U.S. is important for keeping the industry healthy, said Pezzullo of Omega Medical Research. “If big companies are allowed to run most of their trials outside the U.S., it’s going to hurt the industry. We have good safeguards,
quality data.”One thing people on all sides of the issue
agree on is that globalization will continue.Fox hopes the U.S. doesn’t leave all re-
search to other countries. “Society loses if we as citizens of the United States with a long history of successful innovation… don’t continue to make those kinds of in-novations.”
Tamara Lytle is a Washington, D.C.-based freelance writer. She has covered government policy, healthcare reform, politics and Congress for more than 20 years. She writes for newspapers, national magazines and web sites.
20 The CenterWatch Monthly | April 2012
IndustryNews
Trialscontinued from page 19
Global distribution of FDA-regulated clinical trialsTotal number of unique, active investigators
Source: Tufts CSDD; <csdd.tufts.edu>Other Western Europe North America
2006
16,239
4,072
6,787
2008
16,159
3,343
8,358
2010E
14,568
2,869
4,663
2000
18,401
3,578
3,578
2002
19,585
2,3193,865
2004
17,483
4,440
5,828
Global Issues in Patient Recruitment and RetentionDiana L. Anderson-Foster, Ph.D.
Not provided renal failure ProMedDx, LLC. Marion M. Santa Ines, MA, CCRA, [email protected] (508) 285-7877
CenterWatch analyzes data in its drug intelligence service to provide advance notice of clinical trials expected to be entering the next phase of clinical development soon. Contact information is provided to inquire about trials. If you are a sponsor or CRO and would like to list your upcoming trial here or initiate a search to identify sites for your upcoming trial, or if you are a site and would like your profile matched to sponsor and CRO requests, contact Claire Gross, (617) 948-5121, [email protected].
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suffering from disorders in these areas, by developing and providing innovative spe-cialty therapies. Its web site describes its core values as imagination, passion and re-sponsibility.
The company’s focused expertise, global resources, extensive academic and institu-tional research network, and reputation for effective partnering, make it a logical choice for other companies seeking mutually bene-ficial partnerships to advance clinical-stage and commercial pharmaceutical products.
Diseases targeted by Lundbeck include psychiatric conditions of depression and anxiety, psychosis, bipolar disorder, Al-zheimer’s disease and alcohol dependence. In addition, Lundbeck is involved in devel-oping treatments for neurological diseases including Parkinson’s disease, Hunting-ton’s disease, epilepsy, stroke and Lennox-Gastaut syndrome. Its state-of-the-art tech-nologies focus on mechanisms of synaptic transmission, neurodegeneration and neu-roinflammation.
Corporate development for this medium-sized pharmaceutical company is based in Copenhagen, with offices worldwide. Mul-tidisciplinary research teams in Denmark and in the United States integrate their ad-vanced knowledge in research and develop-ment disciplines with clinical and therapeu-tic expertise.
Lundbeck’s Psychiatry/Psychology pipe-line contains four drugs in phase III, one in phase II/III and three in phase II. In Neu-rology, Lundbeck has two drugs in phase III development.
A once-monthly, depot injectable for-mulation of aripiprazole, a dopamine D2 partial agonist for maintenance treatment
of schizophrenia, was co-developed with Otsuka Pharmaceuticals.
A phase III, multicenter, randomized, double-blind, placebo-controlled U.S. clini-cal trial assessed the efficacy, safety and tolerability of the intramuscular formula-tion. Although this study was originally designed to continue for 52 weeks, interim analysis showed the drug successfully met efficacy criteria and the study was stopped. In November 2011, the FDA accepted the New Drug Application (NDA) for aripip-razole depot formulation for maintenance treatment of adults with schizophrenia.
Also in phase III testing for schizophre-nia is zicronapine (previously known as Lu 31-130), a monoaminergic agent that pref-erentially acts at the dopamine D4 recep-tors, with potent antagonistic effects at do-pamine D(1), D(2) and 5-HT(2a) receptors. Pharmacological data suggest zicronapine has antipsychotic activity as well as good tolerability. Findings from two randomized phase II clinical studies were significantly and strongly positive, with clear differences from placebo at zicronapine doses of 7mg and 10mg. In addition, efficacy and safety data were favorable in comparison to olan-zapine.
For schizophrenia and adjunctive treat-ment of major depressive disorder (MDD), Lundbeck and Otsuka Pharmaceuticals are in phase III development of OPC-34712, a novel psychotherapeutic agent intended to offer improved efficacy and tolerability with less akathisia, restlessness and/or insomnia than currently available agents. It affects multiple monoamine systems and has re-duced partial agonist activity at D2 dopa-mine receptors and enhanced affinity for specific serotonin receptors.
Also in phase III trials for depression and anxiety is Lu AA21004, a multimodal an-
tidepressant with reuptake inhibition and receptor activity as a 5-HT3 and 5-HT7 re-ceptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and in-hibitor of the 5-HT transporter. In nonclini-cal studies, Lu AA21004 has been shown to increase serotonin, noradrenaline, dopa-mine, acetylcholine and histamine in spe-cific brain regions.
Preclinical as well as clinical data suggest potential efficacy and good tolerability of Lu AA21004. All tested doses met the primary efficacy endpoint in a placebo-controlled, European study enrolling 560 patients with MDD. In addition, a relapse preven-tion study enrolling 639 patients showed Lu AA21004 had long-term efficacy in MDD maintenance treatment. Most adverse events were judged to be of mild to moder-ate severity.
Nalmefene (Selincro), a specific opioid receptor antagonist with a distinct mu, del-ta and kappa profile, is in phase II/III test-ing for pathological gambling and in phase II testing for smoking cessation. It has been evaluated for the past two decades as a po-tential treatment for substance use disor-ders, and it has been shown to help regulate alcohol intake through its activity at the cortical mesolimbic circuit.
Treatment, therefore, can be individual-ized to limit alcohol consumption rather than requiring full abstinence. In multi-center, randomized, double-blind, placebo-controlled, phase III trials, alcohol-depen-dent patients reduced their total alcohol intake by an average of two thirds after six months of treatment with 18mg nalmefene. The drug was safe and well tolerated, and ef-ficacy was maintained and even improved after one year of treatment.
For treatment of depression, Lundbeck is partnering with Takeda on phase II test-ing of Lu AA24530, a monoamine enhancer with reuptake inhibition at monoamine transporters and antagonist activity at 5-HT3 and 5-HT2c. Animal models showed increases in acetylcholine, noradrenaline,
Eye On
22 The CenterWatch Monthly | April 2012
April 2012 | The CenterWatch Monthly 23
dopamine and 5-HT levels in brain regions involved in mood regulation and suggested Lu AA24530 would have improved efficacy and more rapid onset of action in the treat-ment of depression. In a dose-finding, phase II clinical trial in patients with MDD, six weeks of treatment with Lu AA24530 was well tolerated and associated with statisti-cally significant improvements compared with placebo on the primary efficacy end-point and on key secondary endpoints.
For Alzheimer’s disease, Lundbeck is in phase II testing of Lu AE58054, a potent and selective antagonist of the 5-HT6 re-ceptor, which is mostly located in brain re-gions implicated in cognition. A long-term, multicenter, placebo-controlled trial of Lu AE58054 as add-on therapy to donepezil is underway in patients with moderate Al-zheimer’s disease.
In the Neurology arena, intravenous car-bamazepine is in phase III development for epilepsy. This sodium channel blocker is a novel injectable formulation of the oral antiepileptic drug, which has been in widespread use for nearly four decades for treatment of complex partial seizures. The intravenous formulation would be useful for patients who temporarily could not take carbamazepine by mouth because of sur-gery or for other reasons. A clinical trial is underway to assess bioequivalence of intra-venous and oral doses and to compare the safety, tolerability and pharmacokinetics of the two formulations.
Also in phase III trials is desmoteplase, a novel plasminogen activator and highly fi-brin-specific thrombolytic agent, licensed from Paion for treatment of acute ischemic stroke. When compared with alteplase, currently used to dissolve thrombosis in acute ischemic stroke, desmoteplase has high fibrin selectivity, no neurotoxicity, no apparent harm to the blood-brain bar-rier and a longer half-life (about four hours compared with about five minutes). The FDA has issued Fast Track designation to
Phase Drug Name Date
III OPC-34712 -depression Jun 2011 -schizophrenia Jul 2011III zicronapine Apr 2011III intravenous carbamazepine Jun 2010III Lu AA21004 -anxiety Jun 2008 -depression Dec 2007III Aripiprazole depot formulation Jul 2008III desmoteplase Apr 2005II/III nalmefene -pathological gambling Aug 2005II Lu AE58054 Dec 2009II Lu AA24530 Oct 2007II nalmefene Sep 2005 -smoking cessation
Pipeline activity—Lundbeck
Total revenue 2011: $2.9 billionTotal R&D spending 2011: $620 million
Pipeline activity by phase
Comparing phase I–III pipeline distribution
Distribution of drugs in development by primary therapeutic area focus
Date major drugs entered current clinical phase
100%50%
Phase II Phase II/III Phase III
Phase IIIPhase IIPhase I
40%30%
60%
39%
21%
Lundbeck Industry Benchmark
0%Ps
ychi
atry
/Psy
chol
ogy
Psyc
hiat
ry/P
sych
olog
y
Psyc
hiat
ry/P
sych
olog
y
Neur
olog
y
Neurology
Psychiatry/Psychology
2
8
see Lundbeck on page 24
24 The CenterWatch Monthly |April 2012
Lundbeckcontinued from page 23
desmoteplase, a genetically engineered ver-sion of a thrombolytic protein found in the saliva of the vampire bat. Studies to date have suggested desmoteplase was more ef-fective than placebo in patients with visible arterial occlusion or high-grade stenosis on baseline angiography, and these pa-tients had less severe strokes and smaller mismatch volumes when treated with des-moteplase.
Lundbeck’s long track record of suc-cess in the Psychiatry and Neurology fields should continue to apply to the drugs in its pipeline, which primarily target highly prevalent conditions including depression, Alzheimer’s disease, epilepsy and stroke. In the Psychiatry arena, most of Lundbeck’s candidates involve neurotransmitter ma-nipulation through receptor agonists or antagonists. In Neurology as well as in Psy-chiatry, some candidates are novel formula-tions of drugs with a long history of wide-spread use.
Laurie Barclay, M.D., is a neurologist who has published more than 60 peer-reviewed journal articles concerning her research on Alzheimer’s disease and other dementias. Following her medical internship and neu-rology residency at the New York Hospital-Cornell, her neurobiology fellowship was at the Burke Rehabilitation Center-Cornell, where she also served as chief of the Spinal Cord Trauma Unit and clinical director of dementia research. Dr. Barclay was an as-sistant professor of neurology at the New York Hospital-Cornell, 1983-1987, and at the University of South Florida, 1987-1992, and then went into private practice, medicolegal consulting and medical writing. She retired from practicing neurology in December 2005 to become a full-time medical writer and journalist, and to devote more time to professional ballroom dancing with her husband and partner, Richard Collett.
100%
Average number of countries,by phase, where clinical trialsare conducted
Phase II 21Phase II/III N/APhase III 54
Average Average number of sites
Phase Drug number of sites in the U.S. in W. Europe in E. Europe rest of world
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