Institutional Review Boards

History of IRBs in the United States

Recognizing that review by impartial others might mitigate conflicting differences in the ethical responsibilities of physician-investigators to research subjects from those of physicians to their patients and, thus, help to protect the rights and welfare of research subjects, James Shannon, MD, Director of the National Institutes of Health (NIH), in 1965 proposed that all NIH research involving human subjects be evaluated by an impartial panel of peers to ensure its ethical integrity. His idea derived, at least in part, from a model that began at the NIH Clinical Center when it opened in 1953, which was a model of group peer review for research involving healthy volunteers.¹ In 1966, US Public Health Service policy requirements for ethical review, which were expanded to all Department of Health Education and Welfare (the DHHS predecessor) research by 1971, were not well enforced.¹ Regulations for the protection of human subjects for DHHS, published in 1974 (45CFR.46), included a requirement for group ethics review and the term “institutional review board” was introduced. The World Medical Association also introduced review by an independent committee for oversight of science and ethics into the 1975 revision of the Declaration of Helsinki.⁸ The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, established by the US Congress after revelations of the US Public Health Service syphilis studies at Tuskegee, authored the Belmont Report which explicated ethical principles underlying the conduct of human subjects research.⁹ The Commission’s contributions, including integration of the Belmont principles, were incorporated into updated US regulations in 1981. The 1981 DHHS regulations were subsequently adopted by 16 federal agencies (not including the FDA) in 1991 as the Common Rule. The FDA required an IRB beginning in 1981 (Title 21 Code of Federal Regulations, part 56), although some investigators funded by pharmaceutical companies already used oversight committees.¹⁰ The most extensive proposed changes to the Common Rule since 1991 were issued by the DHHS in an Advance Notice of Proposed Rule Making in 2011 in an effort to enhance protections and efficiency.^11,12 Public comments were solicited and a Notice of Proposed Rulemaking is under development, but as of this writing has not been published (Fig 1).

US regulations at 45CFR.46 subpart E and 21CFR.56.106 require IRBs to be registered with the DHHS Office of Human Research Protections (OHRP), which is responsible for monitoring compliance with the Common Rule. Research institutions that receive DHHS funds file with OHRP an assurance that the institution will comply with federal regulations, called a Federal Wide Assurance.¹³ Each assurance has to include at least one internal or external IRB registered with OHRP. The FDA requires registration of IRBs but does not require prospective assurances of compliance; sponsors and investigators include evidence of IRB review when they submit data to the FDA.

Changes to Research

At the time that IRBs were codified in regulation, single-site clinical research was the predominant paradigm. Advances in knowledge, technology, and resources over the subsequent decades have significantly changed the face of research. Growth in public and private spending^14,15 as well as evolving scientific opportunities have created novel challenges for IRBs. The majority of clinical trials are now multisite, and some include > 100 sites, often with sites in multiple countries.¹⁶ In addition to multicenter and multinational research, IRBs review, for example, proposals for research with stored samples and data, cell-based and stem cell therapies, emergency research, social science research, and community-based research. IRBs operate under the same regulatory structure and use similar procedures despite a wide range of types of research posing disparate risks to subjects’ rights and welfare. Furthermore, the complexity of oversight has changed with the development of new entities involved in clinical research, such as contract research organizations, data and safety monitoring committees, clinical trial coordinating centers, accrediting associations, and commercial IRBs, among others.

Changes to IRBs

Concurrently, the number of, investment in, and responsibilities of IRBs have continued to increase. Most research institutions, universities, and health-care facilities have at least one IRB, and the majority has more than one.¹⁷ In addition, there are a number of independent or commercial IRBs.¹⁸ Increasingly, IRBs are tasked with responsibilities beyond those required by federal regulation, including, for example, review of conflicts of interest, compliance with privacy regulations, training of investigators, scientific review, and monitoring of clinical trial registration, among others. IRBs do indeed have responsibility for reviewing the science to assess the soundness of the design and the risks and benefits of the proposed research, however, many institutions have a separate scientific review process that precedes and complements IRB review.

Dissatisfaction and concern about what is perceived as an expansive mission and bureaucracy of IRBs has also mounted. Investigators and others criticize the IRB system as dysfunctional and “more concerned with protecting the institution than research participants.”¹⁹ Some claim that IRBs are overburdened²⁰ and overreaching. Researchers, institutions, and some IRB members complain about burden: excessive paperwork, inflexible interpretation of regulatory requirements, attention to inconsequential details, and “mission creep”—the expanding obligations of IRBs that seem to have little to do with protection of research participants.²¹ Fear of regulatory admonition has fueled a focus on compliance with regulations.²² Some perceive the excessive or “hyper” regulation as seriously affecting or stifling research productivity and adding cost without adding meaningful protections for participants.^23,24 Clinical investigators complain that the IRB review process is inefficient and delays their research for what seem like minor modifications.²⁵ The public hears about problems and fears that research might be unsafe and existing protections ineffective or inadequate.^26,27

Charles McCarthy, the first director of the US Office for Protection from Research Risks (the OHRP predecessor) noted, “[IRBs] have become more insightful and sophisticated…But unless [the Human Research Protection System] is considered to be an evolving and expanding mechanism, adapting to the problems of each period of history, it is in danger of becoming fossilized and ineffective.”²⁸ Flexibility and adaptability are important characteristics not usually attributed to IRBs. The challenge is how to evolve, expand, and adapt IRBs to the current exigencies of research in a rational and meaningful way. As noted by Cohen and Lynch,²⁹ the system is “ripe for a major course correction.”

Reform: Needs, Attempts, and Challenges

Recognition of the need for a robust system of protecting human research subjects within the changing research landscape has led to various proposals for reform and suggestions for alternative models.^30‐35

Reform proposals offer changes to address some of the various factors that are problematic for IRBs and for those who use them. Yet, reform efforts have been somewhat paralyzed by the tension between those who find the current system inadequate and those who find it too overreaching.^36,37 Nonetheless, many grant that multiple reviews for a single study are duplicative, lead to significant delays in research without adding meaningful protections, and can result in inconsistencies that bias the science.^38,39 Additional reasons for considering reform of the current oversight system include inherent conflicts of interest, inadequate resources, the emergence of new research methodologies, and insufficient expertise of members, among others.⁴⁰ IRBs also grapple with how to respond to evolving research methods, and high profile cases in which regulators disagree with or disapprove of IRB decisions can fuel uncertainty and anxiety.^41,42

Various systems of pre-IRB review have gained traction as a way to improve IRB efficiency: Major issues and gaps can be identified and corrected through prereview before an IRB sees the proposal. Institutions are also adopting a framework that more explicitly recognizes the essential roles of the institution, investigators, and research teams in addition to IRBs in protecting human subjects.⁴³ Several alternatives to the traditional model of single IRB review or review at each site of a multisite study have been developed and tried (Table 2).^44‐53 Proposed revisions to the Common Rule include a recommendation for a single IRB of record for domestic multisite trials.⁹ More recently, the NIH called for comments on a draft proposal for a single IRB review for NIH-funded multisite trials.⁵⁴ NIH is also currently funding several empirical studies of central IRBs with the goal of informing policy development relevant to central IRBs.⁵⁵ Despite these significant efforts, many challenges remain in changing the process of IRB review, including questions of liability, cost structures, and incentives, and uncertainty about the relative merits of proposed models.⁵⁶

Need for Evidence

Reform proposals often recognize the need for data about what works and for creative and testable ways of achieving the appropriate combination of protecting the rights and welfare of participants with meaningful and efficient IRB review that promotes high quality, relevant, and timely research. Evidence about how well IRBs are functioning, how effective they are, and how they could be more efficient would provide useful guidance for reform efforts.⁵⁷ Existing studies describe IRB structure, process, or outcomes and show that IRB judgments are inconsistent, as is their application of a standard set of regulations.^58,59 Practices and decisions vary between and within IRBs often without justification, including determinations about risk level, inclusion criteria, and the appropriateness of methods of recruitment and consent.^55,60 Despite complaints about inconsistency, independence and local evaluation make some IRB variation inevitable. Moreover, it is difficult to find a study or to identify metrics able to measure how effective IRBs are at ensuring the ethical conduct of research or protecting research participants.⁶¹ Improving effectiveness requires clear and measurable goals for IRBs and ethical justification for regulatory requirements.⁶²

Many of these factors converge for critics of the IRB system: growing requirements and costs,^63,64 bureaucratic burden, vague goals, and limited evidence of effectiveness.

“The available evidence indicates that there are substantial direct and indirect costs associated with IRB oversight of research. IRBs also operate inconsistently and inefficiently, and focus their attention on paperwork and bureaucratic compliance. Despite their prevalence, there is no empirical evidence that IRB oversight has any benefit whatsoever—let alone benefit that exceeds the cost.”⁶⁵

Both normative analysis and empirical evidence are needed to understand how to improve the current system and optimize protections for contemporary research. If the goal is primarily to protect research participants from risk, for example, then more analysis of what risks count and more empirical evidence about research risks would provide direction for how we are doing and where the gaps are. As Taylor⁶⁶ notes, “whether and how to protect is inescapably normative and inescapably empirical.” In its 2011 report Moral Science: Protecting Human Participants in Human Subjects Research, the President’s Commission recommended that federal agencies involved in the funding of human subjects research “develop systematic approaches to assess the effectiveness of human subject protections and expand support for research related to the ethical and social considerations of human subject protections.”⁶⁷

Centralizing IRB Review

Primarily driven by concerns about redundant review, burden, and delay, much attention has been given to the idea of single or central IRB review for multisite studies as an alternative to local IRB review at each site. Multiple reviews also have the possibility of jeopardizing the science by introducing bias.³⁷ Institutions participating in multisite studies are permitted by federal regulations⁶⁸ to use arrangements that centralize or share reviews, yet relatively few employ these options. Many proposals for reforming or updating guidance and regulations have recommended single or central review for multisite studies.^{10,28‐31,35} Lingering resistance to adopting central or single review for multisite trials appears to be based on concerns about the importance of local context, local accountability and liability, discomfort with relinquishing control over the review, uncertainty about the quality of review by other IRBs, and logistical concerns such as cost-sharing.^30,54 There is a paucity of data evaluating how single or central review compares to review at local sites regarding quality of review, satisfaction, resource use, or efficiency.

Conclusions

IRBs have an important role in protecting human research participants from possible harm and exploitation. Independent review by an IRB or equivalent is an important part of a system of protections aiming to ensure that ethical principles are followed and that adequate and appropriate safeguards are in place to protect subjects’ rights and welfare while they contribute to ethically and scientifically rigorous research. Over the four decades since IRBs were codified into regulations, IRB review and oversight has developed and matured as part of a robust system that provides “substantial protections for the health, rights, and welfare of research subjects.”⁶⁹ However, during that same period, research methods and opportunities have evolved, the domains of oversight have expanded, and the research enterprise has grown and diversified. The rules, norms, procedures, and even articulation of the goals of IRB review have not kept pace. Although ethical principles underlying research with human subjects have not changed, their implementation and actualization requires refinement and adaptation to respond to changing scientific and social contexts. Data, creativity, regulatory flexibility, and continued dialogue are needed to optimize the implementation of principles and to help shape the future structure, organization, processes, and outcomes of review and oversight by IRBs and related players. These efforts will support progress in clinical research, public trust in the enterprise, and protection of the participants that make research possible.