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Defining and Describing Benefit Appropriately in Clinical Trials

Published online by Cambridge University Press:  01 January 2021


Institutional review boards (IRBs) and investigators are used to talking about risks of harm. Both low risks of great harm and high risks of small harm must be disclosed to prospective subjects and should be explained and categorized in ways that help potential subjects to understand and weigh them appropriately. Everyone on an IRB has probably spent time at meetings arguing over whether a three-page bulleted list of risk description is helpful or overkill for prospective subjects. Yet only a small fraction of all the time and attention lavished on risk disclosure has been devoted to discussing whether and when potential benefit to subjects can reasonably be claimed and, if so, how it should be described in the consent form and process.

Traditionally, IRBs and regulators have worked to ensure that clear lines can be drawn between research that, by definition, carries no potential for direct benefit — because it uses healthy volunteers or because it is not foreseeably focused on the development of treatments — and research that does have the development of effective treatments as its goal.

Copyright © American Society of Law, Medicine and Ethics 2000

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This is the outdated but persistent distinction between “nontherapeutic” and “therapeutic” research. See, for example, World Medical Association Declaration of Helsinki, “Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects,” revised 1996, reprinted in JAMA, 277 (1997): 925–26; see also Capron, A.M., “Ethical and Human-Rights Issues in Research on Mental Disorders That May Affect Decision-Making Capacity,” N. Engl. J. Med., 340 (1999): 1430–34; Rolleston, F. and Miller, J.R., “Therapy or Research: A Need for Precision,” IRB, 3, no. 7 (1981): 1–3; Levine, R., “The Need to Revise the Declaration of Helsinki,” N. Engl. J. Med., 341 (1999): 531–34.Google Scholar
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The Common Rule is the shorthand name for the set of federal regulations that govern federally funded research with human subjects. The regulations, which implement Pub. L. 93–348 (the National Research Act of 1974), were harmonized into the Common Rule in 1991 for 17 federal departments and agencies, and are codified separately for each. The Common Rule itself was published in the Federal Register, 56 Fed. Reg. 28,012 (June 18, 1991). The codifications most familiar to those involved in research oversight are the U.S. Department of Health and Human Services regulations, 45 C.F.R. pt. 46, and the Food and Drug Administration regulations, 21 C.F.R. pts. 50 and 56. The FDA has not adopted the Common Rule; its regulations are somewhat modified, though overall quite similar.Google Scholar
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For example, a purpose statement that declares, “The purpose of this research is to develop a new kind of cancer treatment, which works by helping the body's immune system to attack cancer cells,” could be misleading in a consent form for a Phase I study when the intervention has not yet been tried in humans. Potential subjects could easily take this to mean that in this Phase I study they will receive a “new treatment” that “works.”Google Scholar
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For example, the guidance document provided for investigators preparing gene transfer research protocols (Appendix M of the NIH Guidelines, “Points to Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA Molecules into One or More Human Subjects”) requires “clear itemization” in the consent form of “types of adverse experiences, their relative severity, and their expected frequencies.” It suggests that risks of harm be categorized as mild, moderate, and severe, and that any verbal descriptions of frequency, such as rare, uncommon, or frequent, be explained. It also mandates mention of the possibility of unforeseen harms (Appendix M-III-B-1-e). See King, N.M.P., “Rewriting the ‘Points to Consider’: The Ethical Impact of Guidance Document Language,” Human Gene Therapy, 10 (1999): 133–39.Google Scholar
I am indebted to Dr. Jon Gordon for first calling my attention to this concern.Google Scholar
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All claims of benefit, including collateral benefit, should address all three dimensions of benefit. In some respects, collateral benefit claims may be questioned, but that discussion is beyond the scope of this paper.Google Scholar
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