Abstract
Federal regulations for protection of human subjects in biomedical and behavioral research have been in place since 1974. Preceded by the Belmont Report, which described ethical principles for human research, regulations known as the Common Rule (common across federal agencies) followed. They may be found at 45 CFR 46 and are administered by the Office of Human Research Protections (OHRP). Updated regulations have been approved and are expected to be in effect by early 2018.
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Federal regulations for protection of human subjects in biomedical and behavioral research have been in place since 1974. Preceded by the Belmont Report , which described ethical principles for human research, regulations known as the Common Rule (common across federal agencies) followed. They may be found at 45 CFR 46 and are administered by the Office of Human Research Protections (OHRP) . Updated regulations have been approved and are expected to be in effect by early 2018.
Under these regulations, research is defined as a systematic investigation designed to produce generalizable knowledge; a human subject means a living individual involved in research (46.102). Each institution operates one or more institutional review board(s) (IRB) under policies approved by OHRP . They have the authority to approve, require modification, or disapprove research proposals; decisions are based on minimization of risk to subjects and weighed against anticipated benefits and fair subject selection. The Food and Drug Administration has similar guidelines. Detail of these requirements and description of alternative models for IRB review may be found in tables in Grady (2015). Other sources of guidance include International Ethical Guidelines for Health-related Research Involving Humans prepared by the Council for International Organizations of Medical Sciences (CIOMS ), the Declaration of Helsinki by the World Medical Association, and Good Clinical Practice Guidelines by the International Conference of Harmonization.
The goal of IRB review is to assure that subjects will be protected during research. A scoping review of empirical research related to quality and effectiveness of research ethics review found no controlled trials or an underlying framework of institutional review board (IRB) effectiveness, or a systematic research agenda by which to answer these questions (Nichols et al. 2015). Literature on informed consent for research found a similar story – lack of clear evidence of potential research subjects making an informed decision. Many were thought to be enrolling in trials without an adequate understanding of fundamental concepts such as voluntariness or risks of participation, although extended one-on-one discussions appeared helpful. There are few studies of potential subjects who chose not to enroll (Hallinan et al. 2016). Despite these limitations, programs of accreditation provide evidence of quality, widely sought by IRBs.
Many institutions/trials have additional review mechanisms to assure quality. Separate scientific review committees address quality of the science and work collaboratively with the IRB. Data safety monitoring boards (DSMBs) were developed to provide close oversight of the integrity of intervention trials by ensuring objective assessment of accumulating data, monitoring trial results and data quality and safety (DeMets and Ellenberg 2016), and potentially recommending early trial termination. Neither of these mechanisms appears in federal regulations, although DSMBs may be required by funders.
Subjects protection is surely one of the most basic elements of research integrity. It requires not only a virtuous investigator who can solve ethical problems as they arise during research, but as history has taught, an effective oversight system as described above, largely structured as a form of self-regulation by peers. Now 40 years later, it is clear that the system must accommodate new issues also essential to integrity of research. These include recognition of demand on the part of potential subjects for access to clinical trials, over-protection especially of vulnerable groups such as children or prisoners which has stifled research to the groups meant to be protected, and attention to basic constructs such as risk/benefit ratio which depend as much as possible on a stable and reproducible base of prior studies.
Advice: Be informed about the research review boards (IRBs ), animal care and use committees , conflict of interest, and biosafety committees in your institution. While your mentor will have had much experience with them, do not hesitate to approach IRB staff during proposal preparation with your unanswered questions. It is better to get their advice now rather than after your proposal could not be approved.
4.1 A Scoping Review of Empirical Research Relating to Quality and Effectiveness of Research Ethics Review
Stuart G. Nicholls, Tavis P. Hayes, Jamie C. Brehaut, Michael McDonald, Charles Weijer, Raphael Saginur, and Dean Fergusson
Nicholls SG, Hayes TP, Brehaut JC, McDonald M, Weijer C, Saginur R, et al. (2015) AScoping Review of Empirical Research Relating to Quality and Effectiveness of Research Ethics Review. PLoS ONE 10(7): e0133639. https://doi.org/10.1371/journal.pone.0133639. Copyright: © 2015 Nicholls et al.
4.2 Pharmaceuticalisation and Ethical Review in South Asia: Issues of Scope and Authority for Practitioners and Policy Makers
Bob Simpson, Rekha Khatri, Deapica Ravindran, and Tharindi Udalagama
Simpson, B, Khatri, R, Ravindran, D, Udalagama, T. Pharmaceuticalisation and ethical review in South Asia: Issues of scope and authority for practitioners and policy makers. Social Science and Medicine 131, 247–254 (2015). Crown Copyright © 2014 Published by Elsevier Ltd.
4.3 Understanding the Functions and Operations of Data Monitoring Committees: Survey and Focus Group Findings
Karim A. Calis, Patrick Archdeacon, Raymond Bain, David DeMets, Miriam Donohue, M. Khair Elzarrad, Annemarie Forrest, John McEachern, Michael J. Pencina, Jane Perlmutter, and Roger J. Lewis
Calis, K, et al. Understanding the functions and operations of data monitoring committees: Survey and focus group findings. Clinical Trials 14(1), 59–66 (2017).
Reprinted with permission of Sage Publications.
4.4 Women and Fetuses First? An Ethical Case for Giving Priority in Clinical Research Testing of Zika Vaccines to Pregnant Women
Kelly McBride Folkers and Arthur L. Caplan
Unpublished.
4.5 Rethinking the Belmont Report?
Phoebe Friesen, Lisa Kearns, Barbara Redman, and Arthur L. Caplan
Friesen, P, Kearns, L, Redman, B, Caplan, A. Rethinking the Belmont Report? American Journal of Bioethics 7, 15–21 (2017). (forthcoming) Friesen, P, Kearns, L, Redman, B, Caplan A. Rethinking the Belmont Report? The American Journal of Bioethics 17(7), 15–21 (2017). Copyright © Taylor & Francis Group, LLC.
Reprinted by permission of Taylor & Francis LLC (http://www.tandfonline.com).
References
DeMets DL, Ellenberg SS. Data monitoring committees – expect the unexpected. N Engl J Med. 2016;375(14):1365–71.
Grady C. Institutional review boards; purpose and challenges. Chest. 2015;148(5):1148–55.
Hallinan A, Forrest A, Uhlenbrauck G, Young S, McMinney R. Barriers to change in the informed consent process: a systematic literature review. IRB. 2016;38(3):1–10.
Nicholls SG, Hayes TP, Brehaut JC, McDonald M, Weijer C, Saginur R, Fergusson D. A scoping review of empirical research relating to quality and effectiveness of research ethics review. PLoS One. 2015;10(7):E013639.
Additional Suggested Reading
The Belmont Report: Ethical principles and guidelines for the protection of human subjects of research. 1979. (This is a foundational document which describes the ethical basis for human subjects protection in research.)
Grady C. Institutional review boards; purpose and challenges. Chest 2015;148(5):1148–1155. (Provides a clear description of institutional review boards and the policies under which they operate.)
Hallinan Z, Forrest A, Uhlenbrauck G, Young S, McKinney R. Barriers to change in the informed consent process: A systematic literature review. IRB. 2016 ;38(3):1–10. (Reviews research on informed consent in research and suggests steps to make it more robust.)
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Caplan, A.L., Redman, B.K. (2018). Human Subjects’ Protection. In: Caplan, A., Redman, B. (eds) Getting to Good. Springer, Cham. https://doi.org/10.1007/978-3-319-51358-4_4
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