Institutional Review Boards: What’s Old, What’s New, What Needs to Change?

Abstract

Institutional Review Boards (IRBs) have come under fire for being burdened with work, causing delays in the progress of human subject research without improvements in the protection of human subjects. Over the years, there have been increases in the numbers of clinical trials, the use of multi-site studies, and the amount of bureaucracy, but no changes to the system to accommodate these advancements. Proposed changes include the use of a centralized IRB for multi-site studies and harmonization of reporting requirements amongst agencies. The purpose of this paper is to review the history, structure, and purpose of the IRB, to assess the criticisms of the current system, and to discuss solutions for improvement.

Critics of the Institutional Review Board (IRB) system have argued that research has changed, whereas the structure of the IRB has not. IRBs were formed to ensure the critical ethical, regulatory, and scientific oversight of human subject research. Compared to when IRBs were formed, there is now more clinical research, and more research involving multiple, collaborating sites, some of which may be international. Others have raised concerns that IRB members are burdened with work, including the review of minimal risk research. The Institute of Medicine (IOM) was commissioned to assess the national system for human subject protection in research. They found that “dissatisfaction with the current system is widespread.”¹ Although waiting for IRB approval can be bothersome, the importance of the question is more than that. There must be a balance between protecting human research subjects without hindering the progress of research. The purpose of this paper is to review the history, structure, and purpose of the IRB, to assess the criticisms of the current system, and to discuss solutions for improvement.

History

A history of the major events to enforce protections for human subjects in research is provided in Table 1. Prior to 1991 and the adoption of the Common Rule (which documents the requirements for IRBs), federal departments and agencies involved with human subject research used a variety of policies and procedures to protect subjects. Institutional Review Boards have jurisdiction over “all research involving human subjects conducted, supported, or otherwise subject to regulation by any federal department or agency…”² Definitions of commonly used terms are included in Table 2.

Table 1.

History of Human Subjects Protections^3,14

Year	Act	What it Did
1947	Nuremberg Code	Developed basic principles governing the ethical conduct of human subject research.
1964	Declaration of Helsinki	Provided recommendations to guide medical doctors in biomedical research involving human subjects. Further distinguishes therapeutic from nontherapeutic research.
1974	National Research Act	Created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission). The Commission identified basic ethical principles for human subject research and developed guidelines to assure that research is conducted in accordance with these principles.
1979	Belmont Report	Identified three fundamental ethical principles for all human subject research—respect for persons, beneficence, and justice.
1991	Federal Policy for the Protection of Human Subjects (Common Rule)	A uniform set of rules for the protection of human subjects was adopted by federal departments. The Common Rule requires that federally funded investigators obtain and document informed consent and describes the requirements for Institutional Review Boards.

Table 2.

Commonly Used Terms and Definitions

Term	Definition
Research	“A systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.”3
Human Subjects	“Living individual(s) about whom an investigator (whether professional or student) conducting research obtains (1) data through intervention or interaction with the individual or (2) identifiable private information.”3
Minimal Risk	“Where the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater, in and of themselves, than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.”3
Adverse Event	Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research (modified from the definition of adverse events in the 1996 International Conference on Harmonization E-6 Guidelines for Good Clinical Practice). Adverse events encompass both physical and psychological harms. They occur most commonly in the context of biomedical research, although on occasion, they can occur in the context of social and behavioral research.19
Unanticipated Problem	Any incident, experience, or outcome that meets all of the following criteria:19 unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied; related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

The composition of an IRB is mandated by Federal Policy.³ IRBs are required to have at least five members with varying backgrounds to provide adequate review of the types of research commonly conducted by an institution. The IRB must include at least one member whose primary concerns are in scientific areas and at least one member whose primary concerns are in nonscientific areas. It must also include at least one member who is not otherwise affiliated with the institution (drawn from the local community and knowledgeable of that community). An investigator can be an IRB member, but he/she cannot participate in the review and approval process for any project on which he/she could have a conflict of interest. Likewise, any member of the IRB cannot participate in the review of any project in which there is a conflict of interest. The IRB may not consist entirely of men or women but selections must not be made on the basis of gender. An institution may have more than one IRB. Although the IRB may work in coordination with other research committees, such as those that determine whether an institution should support the proposed research, it functions independently to determine whether or not to approve of a research protocol based on whether or not human subjects are adequately protected. IRB members may be paid for their time and expenses to attend the meetings.⁴

The main job of the IRB is to protect human subjects. Federal regulations do not require IRBs to review the scientific validity of the research design, but they do require that subject risks are reasonable in relation to the importance of the knowledge that may result. Thus, generalizable knowledge is not likely to result from a poorly conceived study.³ If subjects have been exposed to risk or have volunteered their time for a study that does not produce any useful data, the study is unethical.¹ Rigorous review of the science is usually left to the funding agency’s peer review process.³ However, when a study does not have federal funding, the scientific review may be provided by a review from an internal funding source. The IOM states, “Scientific review of a protocol should be particularly rigorous at the local level if the study will not be submitted for federal funding and/or will not be subjected to a peer review process similar to that of the National Institutes of Health or the National Science Foundation.”¹ Sometimes the IRB has limited understanding of the research that is being proposed, causing it to be unapproved. This often leads to frustrations for the research investigator. The IOM recommends that the IRB be restructured to focus on ethics review, and be renamed “Research ERB” (Research Ethics Review Board). Scientific and financial conflicts of review would be completed by separate divisions and then “feed into” the Research ERB’s comprehensive review.¹

Unfortunately, lapses in human subject protection have resulted in dire consequences. In 2001, a young, healthy research subject died at Johns Hopkins University. The research subject died a month after inhaling an unapproved drug as part of a research study to examine the causes of asthma. As a result, a federal oversight agency suspended almost all of the university’s federally-funded human subjects research.⁵ Although the IRB can be blamed for tragedies such as this, the ultimate responsibility for ensuring patient safety lies with the primary investigator. Proper enrollment, reporting of adverse events, and study monitoring are the responsibilities of an ethical investigator.⁶

Criticisms of the Current System

There has been an explosion in the workload of IRBs since their formation. One reason is because over the past few years, the number of clinical research studies has increased by leaps and bounds. As of May 2013, there were over 146,000 clinical trials registered on clinicaltrials.gov.⁷ This number is up from 5,645 studies that were registered in 2000, when the website debuted. “Applicable clinical trials” that are required to register for this site include interventional studies of FDA-regulated drugs, biological products or devices. Other studies may voluntarily register, and registration of clinical trials in some type of public registry has become a requirement for publication by the International Committee of Medical Journal Editors.⁸ Although the increase in registered clinical trials over time is due to new registration requirements, there has undoubtedly been an increase in the number of trials conducted. Total spending on health-related research and development by pharmaceutical companies and the federal government is estimated to have tripled since 1990.⁹ This increase translates into an increase in the workload for IRBs.

Critics of the IRB system argue that the bureaucratic procedures of the IRB consume resources of time and money without translating into better human subject protection. One investigator stated, ‘The IRB, with all its work, dreams up corrections.’¹⁰ Similarly, one editorial stated, “IRB members spend too much time editing documents, marking typos, and asking for more details.”¹¹ Research may be hindered if time is lost because the IRB is focusing on issues that are unrelated to human subject protection. Also, the public may not be willing to participate if they do not feel adequately protected.¹² If the available study sample is reduced or otherwise biased, especially because of differences in consent forms among study sites, this can reduce the likelihood of a study producing meaningful results which also reduces its ethical integrity.¹³

Other causes of increased IRB workload include the requirement that continuing review of protocols and most amendments are conducted in fully convened IRB meetings. On July 26, 2011, the United States Department of Health and Human Services (HHS) issued an advance notice of proposed rulemaking to revise and strengthen the regulations for protecting human research subjects.¹⁴ The notice was opened to comments but has not yet been finalized. One reform proposal under this notice is to eliminate continuing review for all minimal risk studies that underwent expedited review, unless there is a need for continuing review to protect the subjects. Similarly, the notice recommends eliminating continuing review for studies that were initially reviewed by a convened IRB once the study reaches the data analysis stage or is accessing clinical data from procedures that are part of a subject’s standard care.

Another reason for increased workload is that IRBs are required to monitor adverse events. Unfortunately, there is no common definition of an adverse event, but a broad definition is provided in Table 2. Furthermore, investigators have to identify whether the adverse event is an unanticipated problem (also defined in Table 2). Figure 1 shows a flow diagram to determine whether an adverse event is an unanticipated problem (the majority are not). Some feel that the responsibility for reporting should be shifted from IRBs to data monitoring committees (DMCs) or data and safety monitoring boards (DSMBs).^11,15,16 DMCs are generally groups of individuals who are appointed by a sponsor and have pertinent expertise to a clinical trial. The DMC reviews the accumulating data on a regular basis and advises the sponsor on the safety of the recruited subjects and those yet to be recruited as well as the validity and scientific merit of the trial.¹⁷ Although there may be multiple IRBs in a multi-site study, there is only one DMC. In our 21-site study, “Wrist and Radius Injury Surgical Trial,”¹⁸ a 6-member DSMB was appointed by the funding agency, the National Institutes of Health. This DSMB consists of a biostatistician, three orthopaedic surgeons, and a gerontologist/clinical trialist (this study is restricted to patients 60 years and older). One member serves as the chairperson and one other member serves as the safety officer. Monthly reports are submitted by the coordinating site to the DSMB that summarize the current and projected enrollment, patient demographics, missing visits or data, protocol deviations and adverse events overall and by site. The DMSB meets every 6 months to review the reports. Serious adverse events, such as deaths, are immediately reported to the site-specific IRB as well as to the DSMB. Currently, investigators often have to submit adverse event reports to multiple agencies: the local IRB, the DMC (if applicable) and the sponsor. HHS states, “… most IRB members, investigators, and institutional officials understand the scope and meaning of the term adverse event in the research context, but lack a clear understanding of…what, when, and to whom adverse events need to be reported as unanticipated problems.”¹⁹ HHS has proposed a single web site for electronic reporting that would decrease administrative burdens and enhance the ability to identify and respond to risks from research interventions.¹⁴ The IOM proposes that the definition of an adverse event, the reporting format, the report recipients, and reporting timelines all be clarified and harmonized among federal agencies in order to enhance compliance.¹ Furthermore, the IOM recommends ongoing continuing education programs for clinical investigators with specific instructions about assigning a causal relationship of the adverse event to the drug, biologic, or device under investigation. Clinical trial participants also need education on how to recognize and report adverse events to the study personnel. To effectively protect study participants, the DMC must advise the IRB as to whether new adverse event information affects the safety of participants and if so, the information needs to be conveyed to the participants.¹

Figure 1.

Reporting guidelines for adverse events/unanticipated problems (Adapted from¹⁹)

Improvements in collaboration, including studies with multi-center and international partnerships, have increased the complexity of IRB regulation. On clinicaltrials.gov, 6% of the registered studies have locations in both the U.S. and non-U.S.⁷ In these studies, each participating institution must obtain IRB approval which also means that each site has its own informed consent document. One study found that after local review of the informed consent document in a multi-center trial, some sites required minimal changes whereas others required up to 160 changes.²⁰ In our WRIST trial involving 21 study sites, the coordinating center’s IRB had to reach a final opinion on all study items before the other sites could initiate their IRB application. The DSMB required the inclusion of certain documents before IRB approval at the coordinating center was complete. Because of these delays, it took nearly a year for some sites to obtain IRB approval.¹⁸ Some IRBs in the WRIST study required that the site have two consent forms (one for patients in the surgical study arm and one for patients in the non-surgical study arm) while other sites only have one consent form for both study arms. In general, the concerns of one IRB are not necessarily relayed to the IRBs at the other participating sites. This can affect the protection of human subjects as well as the decision of subjects to enroll in the study depending on the wording of the informed consent document. Differing subject enrollment at each study site can lead to biases in the sample,¹³ reducing the likelihood that the study will produce quality results. The IOM stated that the variability produced by duplicative review of multi-center protocols may actually detract from human subject protection.¹ Many have proposed using a centralized IRB system. The National Cancer Institute, in consultation with the Department of Health and Human Services Office for Human Research Protections (OHRP), has created a Central IRB (CIRB) Initiative of multi-center cancer treatment trials.²¹ This process reduces the workload of local IRBs but still retains their authority to accept or reject the review provided by the CIRB. Local IRBs need to comply with OHRP guidance that if Institution A relies on Institution B for IRB review, Institution A still has the responsibility of ensuring that local research policies are being upheld. This is done by subsequent review by a designated official at Institution A. A centralized IRB can also reduce the possibility of having a conflict of interest because the IRB members are not at the same institution as the investigator.¹ Similar to the CIRB, a collaborative review model called IRBshare has been created.²² IRBshare uses a centralized, secure web portal to house the IRB documents in a multi-center study. The participating institutions can also have a shared review process, if they wish, whereby they rely on one full board review and then complete their own shared review (via a sub-committee) to address local issues. Participating institutions can also undergo a full review if they choose not to use a shared review. All post-approval documents (continuing review, local adverse events, amendments, etc) will be reviewed locally. The OHRP has acknowledged that IRBshare is permissible under the OHRP regulations.

Dr. Robert J. Levine from the Yale University School of Medicine states in an editorial that he would add an educational system for IRB staff and members followed by an accreditation system for IRBs and certification system for the staff.¹⁵ The IOM’s recommendations are similar. They recommend that the OHRP engages representatives to develop practical guides for risk classification. Because some IRBs are afraid of being noncompliant with federal guidelines, they are often too strict and do not allow exemptions from review or inconsistently allow for expedited review. The IOM states, “Review boards lack clear guidance about how to make these assessments and do not have sufficient educational materials available to assist in these determinations, which are key to ensuring adequate levels of protection.”¹ Educational resources provided by HHS include training videos, webinars, conferences and a Quality Assessment Program.²³ Public Responsibility in Medicine and Research (PRIM&R) is an organization dedicated to advancing the highest ethical standards in research through educational and professional development.²⁴ They offer certification for IRB professionals, conferences, and online training courses. The Association for the Accreditation of Human Research Protection Programs, Inc. (AAHRPP) is an independent, non-profit accrediting body for organizations involved in human research.²⁵

Human subjects are a valuable resource and their safety must be protected. Although it is easy to try to place any failures in the system on the IRB, there are multiple areas for improvement. One must remember that IRB members aim to protect the welfare of human subjects, and criticism will not improve their morale or the current system. When there are deficiencies in authority, Congressional action may be required.¹ However, some improvements can be made with enhanced communication between agencies and education on the part of IRB members and clinical investigators. Research has changed dramatically since the introduction of the IRB and it may be beneficial to all parties to re-evaluate the current system to determine whether certain concerns can be handled better by other agencies and/or by collaborations with the IRBs.