Abstract: Clinical trials—medical research studies involving people—play an essential role in the advancement of medical science and technology. The information obtained from clinical trials is crucial to the discovery of safer and more effective methods to screen for, prevent, diagnose, and treat the numerous maladies that afflict the human population. For the past forty years, Institutional Review Boards (IRBs) have had the primary responsibility of conducting the ethical review of clinical trials. IRBs play a crucial role in protecting human participants from unethical medical research by ensuring that participants are adequately informed of any inherent risks associated with their participation in the trial and that they are willing participants. This article provides a general overview of IRBs, discussing what they do, who regulates them, and their relationship with state tort law. Clinical trial sponsors need to have an understanding of the IRB functions in order to ensure that their chosen IRB is operating effectively and is adequately protecting the rights and safety of human subjects.
During World War II, Nazi physicians and scientists performed medical research experiments on thousands of unwilling prisoners of war, many of whom died or were permanently injured as a result. For instance, individuals were submerged in vats of icy water to research diverse ways of treating hypothermia, injected with viruses to examine different treatments, and shot to test various blood clotting treatments. The callous disregard of human life demonstrated by these researchers in the name of medical research garnered international attention during the post-war trials at Nuremburg. It prompted the creation of a set of guidelines—later referred to as the Nuremburg Code—that outlined research ethics principles for experiments involving human subjects. The Code was one of the first authoritative legal attempts to create ethical standards for modern medical research involving human subjects.
The international adoption of the Nuremburg Code had little actual effect on the conduct of human experimentation in the United States in the years immediately following World War II. No formal committees to review medical research were established in the United States until 1953 when the National Institutes of Health (NIH) began requiring that all of its proposed clinical research projects obtain approval from a human subjects review panel. Over the next few decades other organizations and federal agencies adopted similar requirements, leading to the establishment of review boards at hundreds of institutions. IRBs, sometimes also referred to as “Ethical Review Boards,” soon became an integral part of the clinical trial process in the United States.
This article provides a broad overview of IRBs and their role in providing the ethical oversight of clinical trials. It examines what they are, what they do, their relationship to the Food and Drug Administration (FDA), and their potential liability under state tort law. A company’s failure to understand the important role of IRBs can cause their clinical trials to be suspended or terminated, and in worse case scenarios, can endanger the health and safety of the human subjects involved.
What is an Institutional Review Board?
An IRB is any board, committee, or group formally designated by an institution to review clinical trials involving human subjects. IRBs essentially act as the FDA’s surrogate to oversee the protection of human subjects in clinical trials. The FDA has granted them the authority to approve, disapprove, or require modifications to a clinical trial both prior to and during the trial. IRBs have traditionally been run by volunteer boards of clinicians and scientists working in the local investigator’s hospital or institution, but independent, for-profit IRBs do exist and are becoming more common.
FDA regulations for IRB membership state that IRBs must have:
- At least five members with varying backgrounds and experience,
- At least one member whose primary concerns are scientifically related and another whose primary concerns are non-scientific in nature,
- Both male and female members,
- At least one member who is not affiliated with the host institution,
- Members with no conflicts of interest, and
- Members who have knowledge pertaining to vulnerable populations, if necessary (e.g., children, pregnant women, prisoners, mentally disabled).
Before a clinical trial can commence it must be reviewed by an IRB. The purpose of an IRB’s review of a clinical trial is to assure that ethical principles are in place for patient selection criteria, and that participants receive adequate informed consent information necessary to understand the potential risks involved. During the initial application process, sponsors are required to submit necessary documentation for review, including protocols, informed consent forms, materials to be distributed to participants, and other related documentation as necessary.
The IRB reviews the material and its members meet to discuss and determine whether the trial follows the appropriate ethical standards and should be approved. If the trial is approved, the IRB monitors its progress as appropriate, typically on at least an annual basis. They also monitor any adverse events that occur during the course of the trial.
Case study: In August 2003, an IRB approved a device study in which the principal investigators (PIs) stated they did not have any financial conflicts of interest. The study was later approved by the FDA under the condition that the sponsor undertake a follow-up safety study. During the post-approval study, a newspaper reported that some of the investigators at other sites related to the trial had financial conflicts of interest. An independent auditor reported to the IRB that the PIs at the sites it was overseeing also had financial conflicts of interest. When one of the PIs failed to respond to IRB inquiries regarding the conflict, the board terminated its approval to conduct the trial, instructing that patients be transferred to medical care. The PI later admitted to receiving royalty payments on sales of the device; however, he argued the conflict did not occur until after the study began, making his initial claim of no financial conflicts true. The IRB eventually agreed not to terminate the site permanently after the sponsor showed that termination of the study meant less safety information would be available. A new investigator was assigned to the trial, and the IRB changed its renewal procedures to include a question that asks investigators whether new conflicts of interest have arisen.
If a trial appears to have strayed from its approved protocol or violated any ethical boundaries, the IRB has the power to withdraw its approval of the study. IRB withdrawal of a study can be detrimental to the progress of a new drug or device because the FDA cannot accept applications with clinical data from non-IRB-approved trials.
FDA Oversight of IRBs
The FDA and the Office of Human Research Protection (OHRP) are the two government agencies that generate the primary regulations for IRBs. The FDA has authority over most clinical trials for drug, biologic, and medical device products. (IRBs that review government-sponsored studies are additionally regulated by the OHRP). FDA regulations outline specific IRB requirements and functions. These include, but are not limited to, membership requirements, duties, informed consent requirements, records requirements, conflict of interest requirements, and administrative actions for noncompliance. The FDA has authority to conduct periodic inspections of IRBs to ensure that they are operating in compliance with current regulations, statutory requirements, and their own internal written procedures. Most FDA inspections of IRBs are either surveillance or directed inspections. Surveillance inspections are periodic, scheduled inspections to review the overall operations and procedures of the IRB. Directed inspections are unscheduled inspections focused on the IRB’s review of a specific clinical trial or trials, and generally result from a complaint, clinical investigator misconduct, or safety issues pertaining to a trial or site. During inspections, FDA personnel typically review:
- Records of IRB membership,
- IRB procedures and guidelines,
- Minutes of IRB meetings,
- Study-related documents sent to the IRB by the clinical investigator, and
- Study-related documents sent by the IRB to the clinical investigator.
If the FDA discovers that an IRB is not complying with the appropriate regulations, it can issue a Warning Letter. In the past five years, ten warning letters have been issued to various IRBs across the United States. The most common problems cited in these letters were the failure of IRBs to follow their own written procedures and the failure to have a majority of IRB membership present when reviewing trials. Other common problems cited include the failure to document IRB activities, informed consent-related issues, and the failure to review the studies at appropriate intervals. IRBs that fail to correct compliance issues outlined in Warning Letters may be disqualified by the FDA Commissioner. The FDA will not approve an application for a research permit or a market application in which the clinical investigation was under the review of a disqualified IRB.
IRB Registration & Accreditation
IRBs are required to register with the Department of Health and Human Services (HHS), which receives approximately three hundred IRB registration applications every month. This requirement allows the government to maintain current information on all clinical trials, including those that are exempt from FDA submission requirements. For example, some studies that involve non-significant risk are conducted with only IRB approval. The registration requirement allows the HHS to have real-time information about these studies and the IRBs that review them.
The registration process is fairly simple and consists of supplying basic information, such as the name of the institution or organization operating the IRB, the senior officer responsible for overseeing the IRB’s activities, the location of the IRB, the approximate number of active protocols it intends to review, and a description of the types of FDA regulated products it intends to review.
Case Study: In 2008, the GAO created a phony study involving a fictitious adhesive gel and submitted it to Coast IRB (Coast)—an independent, for-profit organization—for review. The fake gel matched several examples of “significant risk” devices from FDA guidance. Coast reviewed and approved the phony study. In March 2009, the GAO issued its report and in April the FDA directed Coast to suspend review of all new clinical trials as well as further enrollment of any new subjects in current trials. Coast transferred its studies to other IRBs and ceased operations in June. Approximately 300 trials involving as many as 3,000 researchers were affected by the closure.
It is important to emphasize that, HHS registration alone does not guarantee an IRB is in compliance with government regulations. In March 2009, the Government Accountability Office (GAO) created a fake IRB and succeeded in registering it with the HHS. When HHS was later questioned, the HHS director stated that the current regulations do not charge HHS with approving IRB registrations, rather they are intended simply to make it easier for the government to stay in contact and inspect IRBs.
Because registration does not guarantee regulatory compliance, sponsors should take care to do some due diligence into their IRBs prior to commencing a study. Sponsors who fail to do so put at risk the future of their products and may expose human subjects to danger or harm.
Sponsors can minimize concerns over their trial’s IRB practices by choosing IRBs that are accredited. The Association for the Accreditation of Human Research Protection Programs, Inc. (AAHRPP) is an independent, non-profit accrediting agency for human research protection programs, including IRBs. While accreditation is not an FDA requirement, it is a signal to research participants, researchers, sponsors, government regulators, and the public that the IRB has committed to a thorough compliance review and that the research program is of quality. In order to be accredited, an IRB must provide evidence of its commitment to scientific and ethical research. This evidence may include IRB policies, procedures, and practices. While accreditation may not be an easy process, it does provide an additional assurance that an IRB conducts reliable research reviews.
IRBs and State Tort Law
IRB compliance with federal regulations unfortunately does not shield the IRB from potential liability through state tort law. IRBs—and, in some cases, individual IRB members—are sometimes listed as defendants in state tort lawsuits. While this is relatively uncommon, it does occur and the question of whether IRB organizations should be somewhat shielded from liability actions (i.e., by creating a rebuttable presumption of due care for IRBs who are complying with regulations) has increasingly been a topic of discussion in the legal community over the past few years.
Case Study: In July 2000, research was suspended at the University of Oklahoma Health Sciences Center because it failed to give adequate protections for research participants during a study that tested a vaccine for melanoma. Amongst the OHRP’s findings was that the IRB approved inadequate informed consent documents, did not satisfy continuing review requirements, and failed to ensure that additional safeguards were used on the terminally ill subjects. This study became the subject of litigation and all of the IRB members were individually named as defendants. Plaintiffs argued that the defendants failed to notify them of their failure to comply with federal regulations, which amounted to the plaintiffs being involved in the study without their consent. The case was eventually dismissed on other grounds.
Those who oppose legal presumptions that help shield IRB members from liability argue that the risk of liability prompts more careful reviews. They also argue that the risk of liability encourages positive changes in the regulatory oversight of IRBs by increasing public exposure of IRB problems, which can lead to positive changes in the law. However, as the potential for IRB liability increases it will be harder to get members to serve on IRBs, many of whom offer their service on a voluntary basis. IRB members also may engage in defensive practices in response to an increase in potential liability. Both of these increase research costs, which are already extremely high, and drive trials outside of the United States where ethical oversight is more difficult to regulate.
IRBs sometimes seek to avoid potential liability by asking their sponsors to indemnify them. Sponsors who agree to indemnify their IRBs from liability associated with clinical trials should examine carefully their insurance policies to ensure that any indemnification promised does not exceed the limits of their policies. If the indemnification promised an IRB is broader than what is granted under the sponsor’s insurance policies, the sponsor will be held responsible for any liability that is not covered under their insurance policies.
While IRBs play a small role in clinical trials, they are a crucial part of the research process. Clinical trial sponsors should take care to ensure that their IRBs are complying with the appropriate regulations as well as acting as responsibly as possible in order to avoid tort liability. A sponsor’s careful attention to matters involving the IRB helps ensure the safety of their trials as well as the safety of the human subjects involved.
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