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ABA Health eSource
October 2009 Volume 6 Number 2

Clinical Trial Compliance: New Focus on IRBs

By Saul B Helman MD, Carol Landsman MHS, Mary Ann Northrup RN, MSN,
Navigant Consulting, Inc., Chicago, IL

Background:

AuthorAuthorAuthorInstitutional Review Boards (IRBs) also known as an independent ethics committee (IEC) or ethical review board (ERB) is a committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans with the aim to protect the rights and welfare of research subjects. These committees are charged with ensuring that research studies involving human subjects comply with certain federal regulations as well as providing a general oversight of patient safety in clinical trials. In the United States, the Food and Drug Administration (FDA) and Department of Health and Human Services have empowered IRBs to approve, require research modifications or disapprove planned research. An IRB performs the critical oversight functions for research conducted on human subjects that are ethical, scientific and regulated.

In accordance with the Food and Drug Administration (FDA) regulations, IRBs are responsible for the continuing review of ongoing clinical research to ensure that the welfare and rights of human subjects are protected. This includes:

  • Annual reviews of research (or more regularly based on risk) 1
  • Determining if independent review of the investigator is required to determine if material changes have occurred since previous review 2
  • Ensuring that any changes to research plans are communicated to and approved by the IRB 3
  • Suspending or terminating approval of research that is being conducted outside of IRB requirements 4
  • Approval of informed consent documents 5

IRBs are subject to potential pressure from multiple stakeholders – by the sponsors and investigators to approve the research studies in a timely manner and by the public and government to protect the welfare of the subjects. The due diligence and commitment required to perform the duties of an IRB can be significant 6 . However, most IRB members are volunteers and not paid for the time they spend reviewing studies. In addition, many facilities are resource-constrained for IRB support services. For these reasons, independent or for-profit IRBs are playing an increasing role in the protection of human research subjects. There are however, growing concerns with the autonomy, oversight of, and the degree of due diligence these companies provide.

The need and opportunity for independent or for-profit IRBs is clear, and the opportunity for these organizations to play a significant role in the oversight of clinical trials on a global basis is promising. IRBs, whether for-profit or not-for-profit, have significant duties in the oversight of clinical trials and are subject to increasing levels of scrutiny. The level of risk is increasing, with ever increasing complexity in clinical trials: by the nature of the therapeutic area, product class/type, geography, patient complexity and scientific/clinical understanding. The need for IRBs to manage risk and ensure that appropriate controls are in place is evident.

During a House Energy and Commerce Committee Oversight Investigations subcommittee meeting in March, 2009, the US Government Accountability Office (GAO) released results of an undercover investigation 7 into IRBs that was completed at the specific request of the subcommittee. The GAO recently concluded an investigation of three key aspects of the IRB system:

  • The process for establishing an IRB,
  • The process through which researchers who wish to apply for federal funding assure the Department of Health and Human Services (HHS) that their activities related to human subjects are guided by ethical principles and federal regulations, and
  • The process that medical research companies follow to get approval for conducting research on human subjects.

Relative to the third aspect of the investigation, the GAO was able to obtain approval from Coast, an independent IRB for a clinical trial sponsored by a fictitious medical device company with a fictitious device and researchers. That fake IRB was also successfully registered with the Office of Human Subject Protection (OHRP); supporting the need for tighter controls of IRBs.

In summary:

  • IRBs must be mindful of the role they play in protecting human subjects; and
  • IRBs must carefully scrutinize the information they receive from research sponsors as it may be incomplete or even false.

Concerns about the rigor of IRB reviews are not new. The GAO noted in a 1996 report that some IRBs spent only one or two minutes reviewing each study, often focusing on the informed consent documents. In addition, the HHS Office of Inspector General (OIG) noted in 1998 that IRBs reviewed too many research protocols and reviewed them too quickly. Their follow-up report in 2000 showed minimal progress in easing the workload of IRBs. The Office for Human Research Protection (OHRP) noted in 2005 that IRBs lacked expertise and sufficient resources.

FDA Registration Rule

In response to some of these concerns, the FDA IRB Registration Rule 8 , effective July 14, 2009, was enacted to provide the FDA with a comprehensive listing of all U.S. IRBs that review FDA-regulated research as well as non-U.S. IRBs (or equivalent bodies) that review FDA-regulated research and choose to voluntarily register. Sp onsors and clinical investigators are required by FDA regulations governing the conduct of clinical studies 8 to use IRBs that comply with the new rule. Therefore, if a sponsor and/or clinical investigator submits a study for review to an unregistered IRB, that sponsor and/or clinical investigator could be considered noncompliant with FDA regulations. An IRB that fails to register could be considered noncompliant with these regulations. As part of FDA inspectional activities, FDA may conduct an inspection of an IRB to verify compliance with regulatory requirements, including the requirement for an IRB to register. The rule requires that all IRBs reviewing FDA-regulated research must register between July 14 and September 14, 2009. The FDA also plans to use the registration to distribute educational materials to IRBs, so IRBs that fail to register will also run the risk of not receiving valuable information.

Trends in Litigation

There have been a number of lawsuits alleging harm to research subjects 9 . While many of these lawsuits are aimed at investigators and manufacturers, research institutions and IRBs can also be targets as they play a critical role in protecting human subjects. However, before this rule was enacted, the data on file with the FDA on IRBs was suspect. The information that the FDA currently has on file is derived from research and marketing applications so that the FDA cannot be certain that it has current information on IRBs. For example, some drug and device studies are exempt from FDA submissions for clinical trials, so the studies are often conducted without FDA involvement. Many device studies are conducted with only IRB approval. Therefore the FDA does not have real-time information about these studies or the IRBs involved. While there have been several cases involving an IRB as a defendant, Robertson v. McGee (2002) 10 is currently the only case where individual IRB members were named as defendants. Lawsuits involving IRBs as defendants generally fall into four categories:

  • Failure to disclose risks (lack of informed consent),
  • Conflict of interest with the study sponsor or investigator,
  • Dignitary damages (failure to treat subjects with proper human respect); and
  • Privacy – specifically, the unauthorized release of protected health information (PHI).

Risk Mitigation

Using the standard OIG “seven elements” 11 approach, IRBs can mitigate their risk and liability while ensuring the appropriate level of oversight. This would include t he development of written policies and procedures; the designation of a compliance officer and other appropriate bodies; the development and implementation of effective training and education; the development and maintenance of effective lines of communication; the enforcement of standards through well-publicized disciplinary guidelines; the use of audits and other evaluation techniques to monitor compliance; and the development of procedures to respond to detected offenses and to initiate corrective action. IRBs must have effective policies and procedures to guide IRB contract requirements, FDA requirements and the general function of the IRB. Expertise must be sought for the review of every protocol – even if it means bringing in an outside reviewer for a particular study. Education of investigators and IRB members on their legal obligations is critical – not only for new members, but continuing education for existing members.

Effective compliance monitoring and auditing activities will identify gaps in the current process and areas for continuing education and improvement. The corrective action procedures will insure that identified issues are investigated and the associated risks mitigated.

Responding to allegations of misconduct may be the most important compliance program element. In 2008, the House Oversight and Investigations Subcommittee charged that Copernicus IRB (in addition to the trial sponsor) failed to report or investigate fraud committed in a clinical trial of Aventis’ antibiotic Ketek. While Aventis was under scrutiny, the founder and CEO of the Copernicus IRB, Sharon Hill Price, took the toughest criticism from the subcommittee 12 . This case led the subcommittee to begin investigating IRBs 13 .

Conclusion

It is clear that the role IRBs play in assuring that research studies involving human subjects comply with certain federal regulations as well as providing a general oversight of patient safety in clinical trials is a critical one. Recent legislation has been enacted to insure that IRBs conduct this critical role in an ethical, scientific and regulated manner. In order to accomplish this, IRBs must establish a balance of mitigating risk and liability, while ensuring the appropriate level of oversight. These risk mitigation activities, of course, require a commitment of time, money and oversight by the executive management of the IRB or the research facility. But given the level of scrutiny and the potential risk to human subject protection, facilities can’t afford not to invest resources in this area.


1 FDA21 CFR 56.108(a)(1) and 56.109(f)
2 FDA 21 CFR 56.108(a)(2)
3 FDA 21 CFR 56.108(a)(3-4)
4 FDA 21 CFR 56.108(b)(2) and 56.113
5 FDA 21 CFR 50.25, 56.1 09(b), 312.60, 163 312.66 and 812.100
6 Icenogle, DL. “IRBs, Conflict and Liability”; Clinical Research and Medicine; 2003 January, 63-8.
7 GAO report: Undercover Tests Show the Institutional Review Board System Is Vulnerable to Unethical Manipulation. March 26, 2009.
8 http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM171256.pdf
9 Hoffman, S, Berg, JW. The suitability of IRB liability. University of Pittsburgh Law Review; volume 67:365.
10 Robertson v McGee (2002)
11 OIG Compliance Program Guidance for Pharmaceutical Manufacturers. http://oig.hhs.gov/authorities/docs/03/050503FRCPGPharmac.pdf
12 http://archives.energycommerce.house.gov/cmte_mtgs/110-oi-hrg.021208.Ketek.shtml
13 Energy & Commerce Committee Oversight & Investigations Subcommittee “Institutional Review Boards that Oversee Experimental Human Testing for Profit”, Chairman Bart Stupak Opening Statement, March 26, 2009.

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