require special efforts to include members POLICY FORUM of those populations in research” (9), and by the World Medical Association Declaration ETHICS AND DIVERSITY of Helsinki, which states, “Groups that are underrepresented in medical research should be provided appropriate access to Justice, diversity, and research participation in research” (10). Therefore, consideration of diversity is essential to the question of fairness in subject selection and ethics review to IRB review. Diversity in is respon- It is time for institutional review boards and research ethics sive to the principle of , which committees to address the ethics of inclusion places priority on the welfare of research participants and creates the obligation that research presents a favorable balance of By David H. Strauss1,2, Sarah A. White1,3, serve efforts to address mistrust of research benefit to risk, after risks and burdens have Barbara E. Bierer1,3,4 and health care (6, 7). Responsibility to the been minimized. In calling for “maximiza- goals of diversity lies with all stakeholders tion of benefits” in the research, Belmont he disproportionate impact of in the clinical research enterprise (6), and directs attention to both individual benefit COVID-19 on certain populations, a commitment to diversity, individually and to the broader value of research to so- Downloaded from such as Black, Latinx, and Indigenous and collaboratively, by research sponsors, ciety. A clinical research enterprise that is populations in the United States, has funders, academic institutions, contract re- not inclusive does not adequately address focused attention on inequalities in search organizations, study sites, investiga- the health needs of a diverse society. Group health and on the need to increase en- tors, and IRBs is necessary. differences in susceptibility to disease and Trollment of racial and ethnic minorities and in treatment outcome can only be identi- other underrepresented groups in biomedi- RESPECT, BENEFICENCE, JUSTICE fied when those groups are studied. It is cal research (1). Yet too often, in the United Most regulated clinical research undergoes the obligation of an IRB to maximize ben- http://science.sciencemag.org/ States and globally, participant enrollment obligate review and approval by an IRB. efits through the inclusion of understudied in research has not reflected the demo- IRBs are charged with safeguarding the groups in a manner that is consistent with graphic composition of the general popu- rights and well-being of human partici- the study aims and does not introduce un- lation, those affected by the health condi- pants in accordance with the foundational acceptable harm or burden. tions being studied, or those for whom the tenets of , beneficence, Belmont describes two ethical convic- investigational product is intended (2), with and justice, as described in the Belmont tions in relation to respect for persons, racial and ethnic minorities and the young Report (8). An IRB’s ethical responsibilities self-determination, and decision-making: and the elderly, among others, being con- with regard to diversity derive from these the obligations to treat individuals as au- sistently underrepresented (3). Underlying and other principles, guidelines, and stan- tonomous agents and to protect those with causes for this underrepresentation have dards (9, 10). diminished autonomy. IRBs provide ad- on March 19, 2021 been described (4, 5), but change has been The discussion of justice in Belmont ditional safeguards for research involving slow. Notwithstanding the roles of other cites “moral requirements that there be participants with compromised voluntari- stakeholders in addressing this issue, we fair procedures and outcomes in the selec- ness (e.g., prisoners) or impaired compre- maintain that the specific value of institu- tion of research subjects.” As Belmont and hension. With regard to the inclusion of tional review boards (IRBs) and research other codes of ethics emerged from a his- diverse populations, respect for persons ethics committees (RECs) in promoting di- torical backdrop of abuse and injustice in demands efforts to foster informed and versity has been underrecognized and their research, “fair procedures” have been ap- autonomous decision-making and, there- authority underutilized. Here, we substanti- plied by IRBs largely (and, we believe, too fore, to address common barriers posed ate the role of and outline practical steps narrowly) to ensure that subjects are not by age, language, culture, and educational for the IRB and REC (hereafter “IRB”) to exploited and enrolled as a matter of con- disadvantage. Respect for persons requires help achieve greater diversity in clinical venience. The idea of justice within the the identification of opportunities and re- research. also includes the notion sources to engage understudied popula- The appropriate inclusion of diverse pop- of access to the benefits of research (i.e., tions and to enhance awareness, access, and ulations in clinical research is necessary if knowledge gained); this has direct implica- inclusion in research (4, 6). It also demands we are to understand how biological vari- tions for populations that have been under- modification of those aspects of research ability and social determinants of health studied, whether incidentally or systemati- and of consent that inadvertently limit the contribute to disease prevalence, transmis- cally. Subject selection cannot be equitable, participation of understudied populations. sion, course, experience of illness, and treat- and the requirements of justice cannot be For example, although inclusion of non- ment outcome. The inclusion of understud- met, when there is de facto exclusion of un- English speakers in a study may involve ad- ied and underserved groups informs clinical derstudied populations. ditional expenses of translation and/or in- decision-making and health policy and can This notion of justice is supported by the terpreters, it strengthens the commitment World Health Organization’s International to autonomy and justice. 1Multi-Regional Clinical Trials Center of Brigham and Ethical Guidelines for Health-related The ethical positions presented above Women’s Hospital and Harvard University, Cambridge, Research Involving Humans, Guideline 3, compel attention to inclusion of diverse MA, USA. 2Vagelos College of Physicians and Surgeons, which states, “In cases where the underrep- populations in clinical research and define Columbia University, New York, NY, USA. 3Brigham and Women’s Hospital, Boston, MA, USA. 4Harvard Medical resentation of particular groups results in or a specific duty for the IRB. In a 2019 sur- School, Boston, MA, USA. Email: [email protected] perpetuates health disparities, equity may vey (11), a majority of IRB chairs, IRB ad-

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Published by AAAS INSIGHTS | POLICY FORUM ministrators, and investigators During review, an IRB should agreed that “IRBs should play consider the feasibility of study a key role in ensuring diversity Institutional review board oversight: methods that seek to identify, among participants in terms of Points to consider by reviewers recruit, and retain underrepre- gender, ethnicity, and language.” sented populations. Research Despite this, there has been INITIAL REVIEW team partnerships with pa- scant regulatory consideration, Study aims and subject selection tients and their families, ad- and little formal discussion • Do the demographics of the proposed sample reflect those vocacy groups, and commu- within the field, as to whether of the population affected by the condition or for whom the nity representatives have been diversity falls within the IRB’s intervention is intended? shown to be effective in inform- remit. There are also little data • When they do not, is the deviation adequately justified? ing recruitment and retention as to whether and when IRBs • Is planned under- or overrepresentation by age, race, strategies (12) as well as in exercise this authority, but the ethnicity, sex, gender, or social determinants of health in the providing input on study ques- observed underrepresentation sample scientifically justified? tions and participant-relevant in completed studies suggests endpoints, study conduct, and • Is there a statistical plan for examining heterogeneity in that IRBs do not consistently culturally and linguistically ap- outcome or across subgroups? attend to this responsibility. propriate communications. The Further questions relate to re- Criteria for inclusion and exclusion IRB should require a statement cent U.S. regulation and policy • Will inclusion and exclusion criteria inadvertently or in the study proposal summa- requiring a single, designated rizing the nature, process, in-

unnecessarily result in under- or overrepresentation of Downloaded from IRB to serve as the IRB of record understudied subgroups? put, and impact of such patient for multicenter research and • Have alternative approaches to minimizing risk that do not rely and community engagement whether this will offer benefit in on exclusion been considered? and how this information has consistency and reach with re- shaped the study itself and the gard to diversity and inclusion. Recruitment recruitment plan; simply ask- • Have recruitment procedures considered specific approaches to ing the question will prompt INCLUSION AND PROTECTION engage underserved populations? consideration by investigators. http://science.sciencemag.org/ In the face of the persistent The IRB can review and pro- Study conduct problem of underrepresenta- vide specific feedback to facili- • Are study procedures flexibly organized to accommodate the tion in clinical research, institu- tate successful recruitment of needs of underrepresented groups? tions should establish policies specific populations, includ- and provide necessary resources • Do all participant-facing materials conform to health ing language use, translation, at all institutional levels to en- literacy principles? placement of advertisements, sure that reviewing IRBs fulfill • Are participant materials translated? Is back translation and workforce characteristics. this obligation. The specific ap- necessary? If not, why not? The IRB should also ensure proaches we outline here will that all study materials adhere Payment serve to help incorporate the to health literacy principles on March 19, 2021 • Is payment sufficient to cover costs of participation? ethical oversight of diversity in and that user-testing is uti- IRB procedures, deliberations, lized where indicated. The IRB and expectations (see the box). • Are study results intended to be returned in a manner that should identify factors, such as An IRB has authority to re- meets the needs of populations studied? excessive time commitment, re- quire that a research protocol stricted clinic hours, the costs details study elements relevant CONTINUING REVIEW of travel, and inadequate com- to considerations of diversity. A • Has the study fulfilled its recruitment and accrual goals? pensation, that have a foresee- description and justification by able and negative impact on the • Is demographic distribution on track to approximate the investigator of the demo- enrollment of an appropriately the study goals? graphics of the intended study representative sample (13). sample (e.g., by age, sex, race, • If not, are adequate corrective actions described, sufficient, and IRBs should require inves- ethnicity, social determinants likely to be successful? tigators to detail study inclu- of health) and a description of sion and exclusion criteria either the demographics of the and, when not self-evident, to condition or those using or intended to use and phase of the study, the study’s specific provide a rationale for exclusion. Review of the product in the general population per- aims, and the study location, as discussed eligibility criteria should ensure that under- mit the IRB to make an assessment of the further below. studied populations are not inadvertently appropriateness of the recruitment plan. Note that inclusion of a demographically or unnecessarily excluded and that criteria When the makeup of the proposed sample diverse study population does not imply are only as restrictive as necessary for safety deviates substantially from that of the de- that statistical conclusions regarding het- and to minimize harm. For example, the ex- mographics of the condition being studied erogeneity of treatment outcome will be clusion of older populations with a specific in the general population or for whom the possible, but it may allow directional as- age criterion might be revised to exclude intervention is intended, and no valid sci- sessments of efficacy and safety that can individuals with specific health concerns entific justification is offered, the IRB can then be further investigated. Inclusion will, who would be at increased risk, regardless require modification of the study to re- at a minimum, address the equitable selec- of age. When laboratory measures serve as cruit a more representative sample. Such tion of participants and the principle of jus- the basis for eligibility criteria, they should requirements are tailored to the nature tice in research. be adapted to reflect known sex-, age-, race-,

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Published by AAAS or ancestry-specific normal values, when the findings are generalizable, and whether a condition of study approval, however, will failure to do so would unnecessarily de- an alternative recruitment strategy might give rise to necessary discussion and col- crease eligibility of some individuals (14). yield a more diverse or less burdened, stig- laboration between IRBs and among inves- IRBs should identify common practices that matized, or disadvantaged population. tigators and the evolution of best practices limit enrollment of immigrant or minority Flexibly adapting requirements to spe- in the field. Of course, the obligation to pro- language speakers in multilingual commu- cific study types will encourage dialogue mote diversity in clinical research does not nities, restrict the participation of women between investigators and the IRB. When rest solely on the IRB or REC or the inves- of child-bearing potential (when requiring an investigator faces particular challenges tigators. Sponsors, regulators, research and appropriate contraception would suffice), in the recruitment and retention of specific academic institutions, funders, patients and and introduce bias in participant selection populations, the IRB could offer guidance patient advocates, and others must build by using overly subjective criteria (such as or consultation on protocol revision. capacity and infrastructure in what, in the “investigator discretion”). The IRB itself should be diverse in com- end, must be a collaborative enterprise. In exercising the regulatory requirement position, with membership and input re- As entities that hold investigators ac- for continuing oversight of ongoing research, flecting the demographic compositions of countable, IRBs are themselves accountable the IRB should periodically review the demo- the communities and populations studied to their ethical and regulatory mandates graphic breakdown of the accrued sample in the research it reviews through the use and ultimately to those who serve as partic- by age, race, ethnicity, sex, and social deter- of ad hoc consultants and by appointing ipants in research. The duty of IRBs to view minants of health where applicable to the members with experience working with di- subject enrollment and retention beyond research. Along with these data, IRBs should verse communities. However, a recent study the lens of “protection,” to deliberate on require an explanation of any meaningful de- showed that 87% of IRB members and 91% the benefits and risks of greater inclusion, Downloaded from partures from the recruitment plan and re- of IRB chairs were white (11). A diverse IRB and to exercise their authority to promote quest, review, and approve proposed correc- will be better attuned to the experience and diversity should be recognized and actively tive action when indicated. Ongoing tracking needs of participants and better able to offer implemented as a matter of justice. j input from the perspective of varied popu- lations. At a minimum, training in cultural REFERENCES AND NOTES “Equitable subject selection 1. D. B. Chastain et al., N. Engl. J. Med. 383, e59 (2020). competence and implicit bias should become 2. T. C. Knepper, H. L. McLeod, Nature 557, 157 (2018). http://science.sciencemag.org/ requires the balancing of part of required ethics education for all IRB 3. U.S. Food and Drug Administration (FDA), “2015-2019 members and staff. Finally, IRBs should de- drug trials snapshots summary report: Five-year summary and analysis of participation inclusion and protection…” velop expertise in providing concrete recom- and demographics” (FDA, 2020); www.fda.gov/ mendations for investigators in methods and media/143592/download. of accrual by the IRB, as well as dialogue tools to achieve greater diversity (6). 4. S. George, N. Duran, K. Norris, Am. J. Public Health 104, e16 (2014). between the IRB and investigator, commu- Impediments to inclusion of underrep- 5. L. T. Clark et al., Curr. Probl. Cardiol. 44, 148 (2019). nicates the importance of diversity, promotes resented and underserved populations in 6. B. E. Bierer et al., “Achieving diversity, inclusion, and transparency with regard to progress or lack research are numerous and complex. There equity in clinical research,” version 1.0 (Multi-Regional of progress, provides a measure of account- are no specific regulatory mandates of the Clinical Trials Center of Brigham and Women’s Hospital and Harvard, 2020); https://mrctcenter.org/ ability, and, ultimately, will change behavior. kind that typically drive accountability in diversity-in-clinical-trials/.

IRB requirements with regard to study clinical research. Institutional commitment 7. R. C. Warren, M. G. Shedlin, E. Alema-Mensah, C. on March 19, 2021 demographics should be flexibly tailored to diversity is uneven, the research work- Obasaju, D. A. Hodge Sr., Ethics Med. Public Health 10, 128 (2019). to individual study purpose, phase, set- force itself is inadequately diverse, and re- 8. The National Commission for the Protection of Human ting, and size. For example, for some re- sistance from the research community to Subjects of Biomedical and Behavioral Research, “The search (e.g., phase 3 studies, comparative any additional oversight is likely. Further, Belmont Report: Ethical principles and guidelines for the protection of human subjects of research” (U.S. effectiveness research), an IRB may adopt expertise in the engagement and study of Department of Health, Education, and Welfare, 1979); the principle, as a rebuttable presumption, hard-to-reach populations is variable and www.hhs.gov/ohrp/regulations-and-policy/belmont- that a study sample should reflect the de- related infrastructure is limited. Finally, in report/read-the-belmont-report/index.html. 9. World Health Organization, Council for International mographic makeup of the condition being the United States, some question whether Organizations of Medical Sciences (CIOMS), studied or for whom the intervention is in- Belmont or the are appropri- “International ethical guidelines for health-related tended. Other studies, such as small explor- ately applied to matters of social justice. research involving humans” (CIOMS, ed. 4, 2016); https://cioms.ch/wp-content/uploads/2017/01/WEB- atory, proof-of-concept, early phase studies, Institutions should support, educate, and CIOMS-EthicalGuidelines.pdf. or research that seeks to learn about spe- resource IRBs, investigators and their study 10. World Medical Association, “WMA declaration of cific communities, would not be expected teams, and others in research so that they Helsinki—Ethical principles for medical research to be representative of those affected by the can give necessary attention to diversity as a involving human subjects,” 9 July 2018; www.wma.net/ policies-post/wma-declaration-of-helsinki-ethical- condition. Similarly, a local site in a multi- fundamental value in the ethical conduct of principles-for-medical-research-involving-human- site study may be selected because it pro- research. The application of diversity to re- subjects/. poses to recruit a specific racial or ethnic search review is neither simple nor without 11. S. H. Berry et al., “Profile of institutional review board characteristics prior to the 2019 implementation of the group to diversify a larger study population. risk, but we do not believe the requirement revised common rule” (RAND Coproration, 2019); Equitable subject selection requires the fundamentally differs from other compo- www.rand.org/pubs/research_reports/RR2648.html. balancing of inclusion and protection and, nents of IRB review. Overly prescriptive 12. T. Greenhalgh et al., Health Expect. 22, 785 (2019). 13. L. Gelinas et al., N. Engl. J. Med. 378, 766 (2018). like all aspects of research with human par- approaches by the IRB and REC, specific 14. D. A. Vyas, L. G. Eisenstein, D. S. Jones, N. Engl. J. Med. ticipants, grounding in good science. When mandates, or the application of quotas to 383, 874 (2020). a study proposes to recruit a sample that study samples will not serve the interests of is composed predominantly or solely of a science and would not be justifiable or pal- ACKNOWLEDGMENTS D.H.S. received consulting fees as a member of the Takeda racial, ethnic, or other minority, the IRB atable to the research community. Drawing Pharmaceuticals Advisory Council. might reasonably ask why the selection of attention to diversity and inclusion as a this sample is scientifically necessary, how goal and setting reasonable expectations as 10.1126/science.abf2170

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Published by AAAS Justice, diversity, and research ethics review David H. Strauss, Sarah A. White and Barbara E. Bierer

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