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S P R I NG 2010

Worldwide Demand for More Clinical Trials Spawns New Ethics Committee Manual In response to “large worldwide demand for educating ethics committee members on how to review clinical trial protocols,” the publisher of Clinical Trial Magnifier has issued a new research ethics manual, with the assistance of AAHRPP and funded by Pfizer, Inc. Reviewing Clinical Trials: A Guide for the Ethics Committee is now available in printed and electronic form from the Clinical Trials Centre (CTC) at The University of Hong Kong, China. Written by Johan P.E. Karlberg, M.D., Ph.D., Professor of Pediatrics and Director of the CTC, and coedited by Marjorie A. Speers, Ph.D., President and CEO of AAHRPP, the manual promotes protection of participants in countries where clinical trials are being conducted outside leading academic institutions, such as Brazil, China, India, and Russia, as well as in other locations outside Western Europe, Canada, and the United States. Around 25 percent of all research sites involved in industry-sponsored clinical trials in 2009—or 12,500 sites, each conducting 50 ethics reviews a day—are located in developing countries, according to Dr. Karlberg. Pfizer asked Dr. Karlberg to produce the manual because of the influence of Clinical Trial Magnifier in Asia and other developing regions, Dr. Karlberg said. Company

Around 25 percent of all research sites involved in industry-sponsored clinical trials in 2009—or 12,500 sites, each conducting 50 ethics reviews a day—are located in developing countries, according to Dr. Karlberg.

executives met with him to discuss overall objectives and provided nonconditional comments on the final product, he said. The manual will be translated into a number of languages and will provide the focus for educational programs provided by academic institutions around the world, according to Dr. Karlberg. However, he said, “we must stress that nothing in this manual overrules local laws, regulations, and guidance. It has been developed to provide a general, theoretical background for clinical trials following the general principles spelled out in the Declaration of Helsinki and the ICH GCP (E6) Guideline.” The manual draws on practical experience, concluding with 50 scenarios for committees covering the majority of ethical areas in human research. Dr. Karlberg said that most of those scenarios have been tested and used successfully in educational activities for ethics committee mem-

bers. “They have proven exceptionally helpful in translating theory into practice, especially for novice clinical trial research professionals,” he said.

VOLUME 7 • NUMBER 2

3 4 6

FDA Continues to Find Fewer Problems Harvard Streamlines Research Review Pharma Summit Urged To Use One Set of Standards, Worldwide


Compliance, Collaboration, Competitiveness, … and Accreditation This spring edition of the AAHRPP Advance highlights the value of the three major benefits of accreditation to our clients: compliance, collaboration, and competitiveness.

Compliance Data from the FDA’s Center for Drug Evaluation and Research (CDER) continue to show that accredited organizations fare better in FDA inspections of compliance than nonaccredited ones. (See facing page.) When an organization considers the value of accreditation, it is important to factor in the results of such inspections. We will continue to track the number of “no action indicated,” “voluntary action indicated,” and “ordered action indicated” findings from the FDA when they become available next year.

Data from the FDA’s Center for Drug Evaluation and Research (CDER) continue to show that accredited organizations fare better in FDA inspections of compliance than nonaccredited ones.

activities that will take place at each institution. Barbara E. Bierer, M.D., Senior Vice President for Research at Brigham and Women’s Hospital and Director of Harvard Catalyst’s Regulatory Knowledge and Support Program, says that “with this reliance agreement in place, we hope we can reduce duplicative IRB review and promote, even accelerate, collaborative research efforts among investigators at the participating institutions.”

Collaboration An innovative model for increasing collaboration, by providing efficient and effective review of multi-site studies, is now in place among nine Harvard and Harvard-Affiliated institutions (see page 4)—thanks to the work of Harvard Catalyst, the Clinical and Translational Science Center, an NIH-funded initiative based at Harvard Medical School. To help investigators from multiple institutions apply for a single IRB review, Harvard Catalyst developed a Cede Review form that investigators will be able to use to describe their proposed studies and detail the

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Competitiveness Pfizer, Merck, Novartis, and other companies are working together to explore ways to improve human participant protection and data integrity for transnational clinical trials. They are considering encouraging the accreditation of human research protection programs globally. (See page 6.) In order to compete to conduct or oversee clinical trials for the pharmaceutical companies, research sites, IRBs, and clinical research organizations worldwide would be encouraged to become accredited

to the same set of standards. One way to help IRBs and ethics committees meet such standards where clinical trials are being conducted outside the United States is to provide them with a manual on how to review clinical trial protocols. I have been working with my colleague, Johan P.E. Karlberg, M.D., Ph.D., Professor of Pediatrics and Director of the Clinical Trials Centre at the University of Hong Kong, China, on just such a manual entitled, Reviewing Clinical Trials: A Guide for the Ethics Committee. (See front cover.)

New Accreditations And finally, we are happy to announce that the Council on Accreditation awarded accreditation to organizations at its March meeting. (See page 7.) They bring the number of accredited organizations to 207, with more than 1,000 entities. — Marjorie A. Speers, Ph.D.


LETTER FROM OHRP

OVER PAST TWO YEARS

FWA, IRB Not Required for Institutions With No Active Role in Research

FDA Continues to Find Fewer Problems with Accredited Organizations

Dear Mr. Ward, We read with interest the article entitled “To Check or Uncheck the FWA Boxes” in the winter 2010 edition of AAHRPP Advance. In reading the article, we noted the following paragraph: “Checking Subpart A adds greater burden, for example, when it requires an assurance of compliance and IRB review of any school, nursing home, community center, or other venue where the organization has no active role in the research study other than to provide access to the study population.” We believe this statement is inaccurate for two reasons. First, as explained in our guidance on engagement of institutions in research, institutions (e.g., schools, nursing homes, community centers, or businesses) that permit use of their facilities for intervention or interaction with subjects by investigators from another institution would not be considered engaged in research, even if the research is conducted or supported by the Department of Health and Human Services. Therefore, a school, nursing home, community center, or business that has no role in the research study—other than to provide access to the study population—would not be considered to be engaged in the research and would not be required to hold an FWA or have an IRB designated under its FWA review and approve the research. This would be the case even if the institution that is engaged in the research checked the box extending the applicability of its FWA to all its non-exempt human subjects research, regardless of the source of support. Second, when an institution that voluntarily extended its FWA to apply to all research regardless of the source of support becomes engaged in non-exempt human subjects research that is not federally conducted or supported, a collaborating institution (including a school, nursing home, community center, or business) that also is engaged in that same research (e.g., employees of a collaborating school or nursing home intervene or interact with subjects for the purposes of the research) would not be required to hold an FWA and have an IRB designated under its FWA review and approve the research. One institution’s commitment to extend the applicability of its FWA to all non-exempt human subjects research conducted by the institution does not apply to other collaborating institutions. We hope these clarifications are helpful. Sincerely, Michael A. Carome, M.D. Captain, U.S. Public Health Service Associate Director for Regulatory Affairs (Editor’s note: When Dr. Carome contacted AAHRPP President and CEO Marjorie A. Speers, Ph.D., about the article “To Check or Uncheck the FWA Boxes” in the winter 2010 edition of the AAHRPP Advance, she suggested he write a response to the article. Dr. Carome submitted this letter to the editor. AAHRPP encourages individuals and organizations to send us their responses to our articles. They advance knowledge and improve human research protections.)

Federal inspectors continue to find fewer problems in research conducted by investigators at organizations accredited by AAHRPP than in research conducted by investigators at nonaccredited organizations, according to an ongoing evaluation project conducted by AAHRPP. The evaluation had previously found that a higher percentage of inspections of investigators at organizations accredited or seeking accreditation by AAHRPP resulted in no action indicated from the Food and Drug Administration in 2008, compared with FDA inspections of investigators at nonaccredited organizations, according to AAHRPP President and CEO Marjorie A. Speers, Ph.D.

Trend continues from 2008 In 2009, the FDA’s Center for Drug Evaluation and Research (CDER) conducted 211 inspections. Sixty-five percent of the 17 inspections of investigators in accredited organizations indicated no action, while 54 percent of 194 inspections of investigators in nonaccredited organizations had similar results. Of the 219 inspections conducted in 2008 by CDER, 73 percent of the 30 inspections of investigators in accredited organizations indicated no action, while 53 percent of 189 inspections of investigators in nonaccredited organizations had similar results. In 2009, 35 percent of investigators from accredited organizations took voluntary actions to correct problems, while 44 percent of those from nonaccredited organizations took voluntary actions. C O N T I N U E D O N PA G E 5

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Harvard Streamlines Research Review IRBs affiliated with nine Harvard University and Harvard-affiliated institutions may now utilize one master reliance agreement by which they decide whether one IRB can review a protocol from investigators working in more than one of their research centers. Researchers from the different academic institutions will be able to reduce duplicative review and promote collaborative research efforts, according to an agreement now in place at Harvard. The following institutions participating in the partnership are currently accredited: ■

Beth Israel Deaconess Medical Center.

Brigham and Women’s Hospital (BWH).

Massachusetts General Hospital.

Children’s Hospital Boston.

Dana-Farber/Harvard Cancer Center.

Harvard Medical School.

Harvard Faculty of Arts and Sciences (FAS).

The institutions have collectively committed to trying to reduce multiple IRB review requirements when it is reasonable and feasible. The decision is handled by the IRBs on a case-by-case basis. The acceptance of reviewing responsibilities is not limited only to studies involving no greater than minimal risk studies but applies to all levels of risk and review categories.

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The Common Reciprocal IRB Reliance Agreement is the product of Harvard Catalyst, the Clinical and Translational Science Center, an NIH-funded initiative based at Harvard Medical School. “The agreement illustrates what can happen when people from multiple institutions and backgrounds come together,” Barbara E. Bierer, M.D., Senior Vice President for Research at BWH and Director of Harvard Catalyst’s Regulatory Knowledge and Support Program, told Harvard Medical School’s Focus newsletter. Dr. Bierer praised the efforts of regulatory and legal officials across the Harvard medical community for streamlining the review process for human studies. “The IRBs and regulatory and legal offices of the participating institutions worked tirelessly to bring this mechanism about and will continue to do so to make sure that it really works for the Harvard research community,” Dr. Bierer explained. “With this reliance agreement in

place, we hope we can reduce duplicative IRB review and promote, even accelerate, collaborative research efforts among investigators at the participating institutions,” said Dr. Bierer. “Not all studies will be eligible for ceded review, but each will be considered as long as the principal investigator requests it.” To help investigators apply for a single IRB review, Harvard Catalyst has developed a Cede Review form. Investigators will be able to use the form to provide the IRBs a snapshot of their proposed studies and detail the activities that will take place at each institution. The Cede Review form is available to all Harvard investigators and can be found on the Web sites of Harvard Catalyst and Harvard Catalyst institutions. The procedure for requesting ceded review begins when the researcher with overall responsibility for the study collaborates with colleagues outside of his or her primary institution. Instead of the IRB at each participating institution conducting a separate review of the IRB application, the lead investigator can request that a single IRB review the study. The IRBs for the institutions where the various collaborators are employed discuss whether the proposed study warrants individual review by separate IRBs, or if review by one IRB would suffice. The IRBs determine which IRB is

The institutions have collectively committed to trying to reduce multiple IRB review requirements when it is reasonable and feasible. The decision is handled by the IRBs on a case-by-case basis. The acceptance of reviewing responsibilities is not limited only to studies involving no greater than minimal risk studies but applies to all levels of risk and review categories.


appropriate to review the study, based on a number of criteria, such as: ■

Location from which all or most of the study participants will be recruited.

Specifics about study population.

Where most of the study procedures or interventions with study participants will be performed or occur.

Institution where the lead primary researcher is employed or draws a paycheck, regardless of appointment.

Whether another IRB is more properly constituted to review a certain scope or topic of work given expertise or composition.

Participating institutions may forgo the opportunity to rely upon the designated IRB and conduct their own IRB reviews. Once the determination is made, the investigator is informed about whether a single IRB will review the multi-site study and, if so, which IRB will provide that review. If one IRB provides review, the collaborating investigators at each site are responsible to the lead investigator for coordinating research activities among their institutions and for reporting incidents such as adverse events and unanticipated problems involving risks to participants or others. In addition, all investigators cooperate and comply with the reviewing IRB’s policies and procedures regarding such issues as: ■

Conflict of interest review and management.

Continuing review.

Post-approval monitoring.

Audits.

Reporting and managing noncompliance.

Initiating changes in the study protocol.

A relying IRB, with notice, may attend the meetings of the reviewing IRB. In addition, a reviewing IRB may require a relying IRB to send a representative for the review of a ceded study to ensure adequate consideration of conditions local to the institution. Upon request, relevant meeting minutes of the reviewing IRB will be made available to relying IRBs.

The reviewing IRB informs the lead investigator of its decisions regarding: ■

Decision to approve or disapprove a study.

Any modifications required to secure approval of a study.

The date when renewal of an approval is required.

If requested, the reviewing IRB may inform IRBs and organizational officials from participating institutions as well. You may contact Dr. Bierer at bbierer@partners.org.

FDA Finds Fewer Problems with Accredited Organizations C O N T I N U E D F R O M PA G E 3

In 2008, 27 percent of investigators from accredited organizations took voluntary actions to correct problems, while nearly half of those from nonaccredited organizations took voluntary actions.

Accreditation a marker “The trend is holding that investigators from accredited organizations perform better in an FDA inspection than those from nonaccredited

organizations,” Dr. Speers said. “Accreditation continues to be a marker for regulators, indicating that organizations accredited by AAHRPP maintain better documentation and have higher-quality research programs,” Dr. Speers said. Dr. Speers said AAHRPP would continue to monitor outcomes of government inspections and to work with the FDA to recognize the value of accreditation.

Clinical Investigator Findings Year

Accreditation Status

NAI

VAI

OAI

Total

Accredited or In Process

65%

35%

0%

17

Nonaccredited

54%

44%

2%

194

2009

211 2008 Accredited or In Process

73%

27%

0%

30

Nonaccredited

53%

46%

<1%

189 219

NAI—no action indicated VAI—voluntary action indicated OAI—ordered action indicated

Source: Clinical Investigator Inspection List, Center for Drug Evaluation and Research, Food and Drug Administration, 2009 and 2008

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University, described to the meeting how the globalization of clinical research has tested, challenged, and exposed assumptions and flaws in the way such research has been conducted in the past.

Wilenzick reminded the group that since 1995, “the number of countries hosting drug and device trials has doubled, while the number of research studies conducted in the United States has fallen by 8 percent and in Western Europe, by 2 percent,” according to a 2009 analysis published in the New England Journal of Medicine (NEJM, “Ethical and Scientific Implications of the Globalization of Clinical Research,” 360:816-823 [Feb. 2009]).

A Multi-Regional Trials Project

Sponsors committed to consistent global standards

Eighty participants from pharmaceutical companies, clinical research organizations (CROs), ethics committees, academia, and nongovernmental organizations, including AAHRPP, met to discuss an initiative begun by Pfizer last year named the Multi-Regional Clinical Trials Project (MRCT). MRCT is exploring ways to improve human research participant protection and data integrity for multi-regional clinical trials involving resource-constrained and economically deprived regions of the world, according to Wilenzick. “We are extremely pleased to see companies and institutions thinking about using one set of standards, worldwide,” remarked Marjorie A. Speers, Ph.D., President and CEO of AAHRPP, who attended the meeting. Those attending the summit, in addition to participants from Pfizer, Novartis, Western IRB, and Harvard, included representatives from: AAHRPP; Amgen; Anapharm; Biosource Corporation; Bristol-Myers Squibb; Genzyme; Glaxo Smith Kline; i3 Research; Johnson & Johnson; Manipal Acunova; Merck & Co.; PARAXEL International; Pharmaceutical Product Development; Quintiles; RapidTrials Inc.; The Johns Hopkins University; The National Institutes of Health; Tufts University; and the University of Pennsylvania.

“Sponsors are increasingly involving qualified investigators and sites from the developing world in multiregional trials and are committed to ensuring that such research is consistently done to well established global standards,” he said. Wilenzick noted that challenges for sponsors, researchers, and the research community include making sure that:

Pharma Summit Urged to Use One Set of Standards, Worldwide Accredited sites for all multi-regional trials Industry sponsors can and should encourage accreditation of human research protection programs globally, representatives of major pharma and other research and oversight organizations proposed at a “summit meeting” hosted in January by Pfizer and Harvard University in Cambridge, Massachusetts. The proposal endorsed at the meeting included a recommendation that sponsors and other research companies and institutions could also make funding available to IRBs in the developing world in order to facilitate accreditation, according to Marc Wilenzick, Chief Compliance Counsel at Pfizer Research & Development, who helped organize the meeting. Participants in the meeting decided to finalize a draft report incorporating such recommendations and publish it in April.

An integrated, accredited research system At the meeting, Greg Koski, M.D., Ph.D., of the Clinical and Translational Science Center at Harvard University, also known as Harvard Catalyst, suggested building a fully integrated research system, using accredited sites that share data in real time—as well as standardized policies and procedures, across research sites, sponsors, and regions. The recommendation on accreditation was initiated by the Working Group on Enhancing the Quality and Efficiencies of Ethics Reviews, headed by David Forster of Western IRB and Susan D’Amico of Novartis Pharmaceuticals Corp. Dr. Robert M. Califf, Vice Chancellor for Clinical Research at Duke 6

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The results of studies are accurate, valid, and generalizable to patients in other regions.

Patients and communities benefit from being included in research, and that those benefits justify the risks that come with participating in a trial.

Patients, their physicians, local ethics committees, local governments, and sponsors decide about those benefits.

And most important, the research enterprise ensures that research participants in developing countries are treated fairly, safely, and responsibly.

Data and safety monitoring The Working Group on Enhancing Data and Safety Monitoring, chaired by Chuck Knirsch of Pfizer and Janet Wittes of the Statistics Collaborative, presented proposals for building the


capacity of Data Monitoring Committees (DMCs): ■

Developing a fellowship program to train promising new DMC members, where the fellow would serve on the DMC with experienced DMC members and gain experience. Developing sample DMC charters for multi-regional studies involving resource-constrained and economically deprived regions of the world.

Site selection and team expertise The Working Group on Enhancing Site Selection and Investigator Team Expertise, chaired by Linda Meyerson of Glaxo Smith Kline, Amir Kalali and Adam Chasse of Quintiles, and Tracey Blumenfeld of RapidTrials, presented proposals for enhancing global site selection, as well as training and education of investigators and site personnel, and made initial recommendations: ■

Developing a common framework for selecting study populations and sites could greatly improve siteselection activities and should be developed, along with a validated site-assessment methodology. Development of those tools could also facilitate better sharing of best practices for site selection among sponsors, CROs, and others. Exploring ways for sponsors to share information on site quality, in order to ensure industry-wide visibility on country-specific—and possibly site-specific—quality trends, as legally permissible, and ways to collaborate to improve the selection of high-quality sites should be pursued. Support should be undertaken for assessing the value of certification programs that are designed to enhance the knowledge, skills, and performance of investigators and

research coordinators. If validation can be demonstrated, industry should preferentially place trials with those sites that offer certified investigators (and consider other ways to promote certification).

Professionalism of monitors The Working Group on Enhancing the Professionalism of Monitors, chaired by Deborah Copeland of i3 Research and Craig Wozniak of Glaxo Smith Kline, presented proposals for supporting the professionalism of monitors and improving monitors’ understanding of, and influence on, the consent process. The group’s initial recommendations included: ■

Support professionalism of monitors with a recognition of the core competencies for monitors and improved training (including compiling an inventory of existing training programs, conducting a gap analysis, and developing an educational framework stipulating the characteristics of high-quality professional education programs).

Encourage professional certification of monitors.

Ensure that all monitor-training programs include a focus on the monitors’ role in assessing and maintaining a high-quality informed consent process, with greater clarity about how and where monitors should assess the quality of informed consent processes.

Contract transparency And the Working Group on Transparency of Contract Terms, chaired by Kate Heffernam of KGH Advisors and Mark Barnes of Harvard University, focused on clinical trial agreements and developing model terms for key provisions affecting research integrity, patient rights, and academic freedom. The group is exploring standards for model language regarding publication rights, confidentiality and non-disclosure, fair benefits, compensation for injury—including insurance and indemnity provisions— privacy and data use and sharing, secondary usage of tissue samples, and dispute resolution.

Three Universities, Two Independent IRBs,and A Teaching Hospital Achieve Accreditation AAHRPP went beyond 200 on its list of accredited organizations in March, awarding accreditation to three universities, two independent IRBs, and another community hospital system. The six organizations include 37 different entities, including major arts and sciences, medical and dental schools, hospitals, and other research and oversight centers, bringing the total number of entities covered by AAHRPP accreditation to over 1,000. Here is the list of newly accredited organizations: Full Accreditation: ■ Columbia University in the City of New York, New York, NY ■ Sterling Institutional Review Board, Atlanta, GA ■ The Greenville Hospital System, Greenville, SC ■ The Ohio State University, Columbus, OH ■ University of Illinois at Chicago, Chicago, IL Qualified Accreditation: ■ Harrison IRB, LLC, London, OH A A H R P P A D VA N C E

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ADVANCE

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AAHRPP

Published quarterly by the Association for the Accreditation of Human Research Protection Programs, Inc. President and CEO: Marjorie A. Speers, Ph.D. Editor: David Ward Design: Levine & Associates, Inc. Washington, DC Printing: Todd Allan Printing, Co., Inc. Beltsville, MD Contact AAHRPP: AAHRPP 2301 M Street, N.W., Suite 500 Washington, DC 20037 Office: (202) 783-1112 Fax: (202) 783-1113 accredit@aahrpp.org www.aahrpp.org

Learn from the Experts at AAHRPP about …

Checking or Unchecking the Boxes on the FWA AND

Organizational Conflict of Interest

Peter Vasilenko, Ph.D., Vice President of Accreditation, will host two webinars this spring—“Whether to Check or Uncheck the Boxes on the FWA,” on April 22, and “Managing, Minimizing, and Eliminating Organizational COI,” on June 17, both from 11 A.M. to 12:30 P.M. (ET). We welcome you and your colleagues to join him in these discussions, where you will learn how to apply two of the key changes in the

AAHRPP Accreditation Standards. Fill out the registration form at www.aahrpp.org and send one copy back for each computer you want to connect to the webinar. As many colleagues as you want may participate through that connection. Or, e-mail lcarmichael@aahrpp.org or call (202) 783-1112 to request a registration form. The fee is $90 per connection for organizations that have paid their application fee; $130 for others.

Begin Your Self-assessment with AAHRPP’s… Getting Started Webinar Most accredited organizations agree that the work you do on your selfassessment drives both the efficiency

and the effectiveness of the application process. Learn how to do it well, by scheduling a webinar tailored to your organization, conducted by Peter Vasilenko, Ph.D., Vice President of Accreditation at AAHRPP. If you need assistance initiating the accreditation process at your organization, this webinar explains the value and the process of accreditation, including how to lead your self-assessment, how to use the Evaluation Instrument for Accreditation effectively, and how to respond to accreditation standards organizations sometimes find difficult. Schedule your two-hour Getting Started webinar by contacting us at lcarmichael@aahrpp.org. The fee for this custom webinar is $50.


V7.2 - Advance - Spring 2010