IRBs- Are They Still Working?
Madeleine M. Jester, RN, JD

Abstract

There is no doubt that serious abuse of human research subjects is much less likely to occur today than in the past because of the institutional review board (IRB) oversight process. However, no oversight system can guarantee complete protection for each individual.

At the request of Congress, the Government Accounting Office (GAO) reviewed the existing systems for protecting human subjects, to assess how well IRBs are working to protect research subjects’ rights.¹ The GAO found that due to time constraints and lack of expertise on the part of the FDA inspectors, IRBs were not being properly inspected in a timely manner. The report also noted that some IRBs themselves were not consistently in conformance with FDA regulations, and that protocol reviews could be compromised by such factors as lack of procedures and too heavy a workload.

The report demonstrated that more still needs to be done, to ensure that the rights of research subjects will continue to be protected in an increasingly complex research environment.

This article discusses the findings of the GAO investigation, and offers some suggestions for sponsors and IRBs to manage their exposures in this area.

Findings on Oversight Responsibility

The report focused on the responsibilities of the FDA and the Office for Protection from Research Risks (OPRR) to protect the rights of human subjects participating in research on drugs, devices and biologics. The report noted that the bulk of the oversight activity within the FDA is carried out through the Center for Drug Evaluation and Research (CDER), although the same regulations apply to studies conducted for applications filed to the Center for Biologics Evaluation and Research (CBER) and the Center for Devices and Radiological Health (CDRH).²

The primary monitoring tool used by the FDA to oversee human subject protection is inspection of the IRBs that review research protocols and consent forms. These inspections include examination of the IRBs’ written procedures and minutes documenting initial and continuing review of studies.³

Limitations of FDA Inspections

There are about 1,200 IRBs overseeing drug research in the United States. The FDA has a formidable task in trying to inspect all of them in a timely manner, and significant gaps still exist in FDA’s IRB inspection system. For example, some inspectors do not have the expertise to understand the implications for human subjects participating in certain drug studies of innovative therapies, or to ask the right questions.

Also, although CDER’s goal is to issue 250 IRB inspection reports a year, it only issues about 150 such reports. The GAO investigation found that in one of FDA’s districts containing several major research centers, 12 IRBs had not been inspected in over 10 years by either CDER, CBER or CDRH. In addition, some IRBS found to have significant problems were not reinspected until 3 to 5 years later. This meant that these deficient IRBs received no timely feedback on how well they were correcting their problems.⁴ This is unfortunate, because according to researchers and drug industry representatives, FDA inspections help motivate IRBs and investigators to follow proper procedures for human subject protection.⁵

Factors Impacting IRB Review

The report found that there are a number of factors that reduce the effectiveness of IRBs. The sheer numbers of research studies some IRBs look at may mean that each study only receives a 2-3 minute review, which is not enough time to appropriately discuss the benefit/risk ratio for subjects in the studies as well as the adequacy of the consent form. At some IRBs the administrative staff, not the actual committee members, do the annual review of ongoing studies. Since the studies are reviewed to just make sure the basic required information about side effects has been reported, the implications of this information for the safety of subjects in the study may not be considered.

Sometimes committee members are reluctant to question leading scientists or they have financial or collegial ties to investigators, and this compromises the independence of the IRB review. Another factor that impacts the adequacy of review is the complexity and size of some studies, which makes it difficult for IRB members without technical expertise to assess the pertinent ethical issues and adequacy of human subject protection. Finally, pressures to recruit subjects can lead IRBs to overlook deficiencies in the informed consent documents.⁶

FDA Enforcement Activities

Between January, 1993 and November, 1995 the FDA issued 31 Warning Letters to institutions noting serious deficiencies in their IRBs’ performance. These deficiencies included researchers reviewing their own studies, IRBs conducting no review or expedited review of studies requiring full review, no tracking of ongoing studies, and failing to make sure that consent forms contained the required elements.⁷

According to a November 1997 article in the FDA Enforcement Manual, the FDA has recently begun to crack down on IRB related violations, having issued at least seven Warning Letters this year alone. The violations noted included inadequate safety records, lack of written IRB procedures, and inadequate records on patient informed consent.⁸ The FDA issued a December, 1997 Warning Letter to a hospital IRB in the South detailing such problems as failure to maintain adequate records and to document initial and ongoing review of studies. The hospital was subject to restrictions on new and continuing enrollment in research protocols until the institution’s procedures were brought into compliance with FDA regulations.⁹

Limiting Exposure

Much has been done to improve the protection of human subjects in recent years. However, the findings of the GAO report and the deficiencies found during FDA inspections discussed above demonstrate that no oversight system can guarantee complete protection for each individual. The report made the point that oversight systems by their very nature only minimize rather than eliminate the potential for things to go wrong.¹⁰

Sponsors and IRBs must continue to keep these factors in mind, and to develop procedures on both sides to make sure that protocols are being reviewed appropriately.

Sponsors must not assume that they do not have to think about human protection issues, because an IRB has approved their protocols and consent forms. They still have the ultimate responsibility to their study subjects, and an IRB’s review is only as good as the documentation it receives from the sponsor. Sponsors can also investigate the IRBs they are thinking of using for protocol review, and should look at such factors as whether or not the IRB consistently complies with FDA regulations, how impartial the IRB members are, how they track and review ongoing studies, and how thoroughly they review both the protocols and consent forms for the required elements.

IRBs can examine their internal policies and procedures, and also make sure that the IRB members have the expertise to review the increasingly complex protocols being conducted today. They can also try to manage the workload in such a way that the reviewers have the opportunity to give each study the thoughtful and thorough review it deserves. Many IRBs assign a few protocols to a primary reviewer, and that reviewer reports on those protocols to the rest of the committee. This can be more efficient than if each committee member is expected to review all the protocols on the agenda for a given meeting, but it also means that the other committee members are not well prepared to discuss potential problems with protocols they have not reviewed in depth.

These are just a few suggestions for ways that sponsors and IRBs can produce better protocol reviews and thus limit their exposure to liability. However, more still needs to be done to ensure that research subjects will be protected from unnecessary risks in an increasingly complex research environment.

Editor's note, 9/99: In June, 1998, the Office of Inspector General at the Department of Health and Human Services issued an in depth 4 part report on IRBs, that highlighted some of the deficiencies in the ability of IRBs to oversee the conduct of clinical trials. Congress and the FDA are continuing to investigate how well IRBs are functioning in today's complex research environment.

See also IRBs-The Basics, Balancing Benefit and Risk in Clinical Research

References

1. Letter Report to the Ranking Minority Member, Committee on Governmental Affairs, U.S. Senate, Scientific Research: Continued Vigilance Critical to Protecting Human Subjects, 3/8/96, GAO/HEHS-96-72

2. Id., p 2

3. Id., p 4.1

4. Id., p 5.3

5. Id., p 4

6. Scientific Research - Continued Vigilance Critical to Protecting Human Subjects, Statement of Sarah F. Jaggar, Director Health Financing and Public Health Issues, Health, Education, and Human Services Division, before the Committee on Governmental Affairs, March 12, 1996, GAO/T-HEHS-96-102, Chapter 0:4

7. Supra 3

8. "Seven Warning Letters Cite Violations of Institutional Review Board Requirements," FDA Enforcement Manual, Thompson Publishing Group, Inc., November 1997 Monthly Bulletin, pp7, 8

9. December 3, 1997 Warning Letter to St. Francis Hospital, Columbus, Georgia; from FDA web site http://www.fda.gov

10. Supra 1, p 5

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