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Institute of Medicine (US) Committee on Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Ethical Issues in Studying the Safety of Approved Drugs: A Letter Report. Washington (DC): National Academies Press (US); 2010.

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Ethical Issues in Studying the Safety of Approved Drugs: A Letter Report.

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In the context of FDA-required randomized controlled trials, the need for a well-designed randomized controlled trial to determine the proper policy decision in response to a new drug-safety concern is a necessary but not sufficient condition for a trial to be ethically acceptable. Obligations to protect the rights and welfare of participants in a trial—to whom special duties of care and compassion may be owed because of illness, disability, or threat of illness—should be respected.

The general ethical principles governing research that involves human participants are well established and apply to the postmarketing context as they do to all human research (Council for International Organizations of Medical Sciences, 2002; DHEW, 1979). In the present letter report, the committee specifies aspects of those principles that have particular relevance to postmarketing research. In a postmarketing study, the risks to participants should be kept to the minimum that can be achieved while the trial is still able to answer the motivating policy question. The risk–benefit balance should be judged to be acceptable by FDA, participating IRBs, and the DSMB before initiation and throughout the course of the trial. That balance should also be acceptable to trial participants. To ensure that patients view the risks as acceptable in relation to any potential benefits, the trial should include a meaningful informed consent process that continues over the course of the trial and that includes prompt communication to participants of relevant new evidence or developments in clinical practice or professional standards that might affect their evaluation of the risks and benefits associated with continued participation.

Although the risks to research participants in randomized controlled trials are expected to be reasonable in relation to anticipated benefits, there is substantial consensus in both domestic regulatory and other guidance documents that different ways of balancing risk and benefit can be ethically justified. For example, both FDA regulations (21 CFR 50/56) and the Common Rule (45 CFR 46 Subpart A) distinguish among research that does not present greater than minimal risk, research that involves greater than minimal risk but offers the prospect of direct benefit to individual subjects, and research that involves greater than minimal risk and no prospect of direct benefit to individual subjects but is likely to yield scientific knowledge about the subjects’ disorder or condition. A trial in which the risks to participants are not outweighed by the prospect of direct medical benefits to participants may be justifiable if a question of pressing public health importance cannot be properly answered without the conduct of the trial and if other conditions intended to safeguard the rights and interests of participants are satisfied. Those conditions include but are not limited to determination by appropriately constituted review committees that the risks are small enough to make it ethically acceptable to ask people whether they are willing to be exposed to the risks in the service of contributing to the public good, minimization of the risks through careful study design and a robust monitoring plan that is in place throughout the course of the trial, and implementation of a thorough informed consent process that adheres to the highest standards of respect for participants.

The informed consent process should provide an accurate, comprehensible explanation of the available knowledge about the risks and benefits associated with being assigned to the treatment and control groups. It is a bedrock principle of research ethics that participants who put themselves at risk in human research should receive an understandable, unbiased, accurate, and comprehensive disclosure of the potential benefits and risks attached to study participation (DHEW, 1979; ICH, 1996). A comprehensive disclosure is important to fulfill the substantive moral requirement of informed consent that participants have a meaningful understanding of what is being asked of them, including the risks and benefits (if any), not merely that information is provided to them (Faden and Beauchamp, 1986).

When a substantial amount of information indicating that a drug to be studied may involve serious safety risks has already accumulated, there are heightened obligations to ensure that potential participants understand the risks posed by study enrollment. Those obligations may include special efforts to communicate complex risk information clearly and to establish that participants have sufficient understanding of what the risks mean to them.

The emphasis given to risk information in the consent process should increase with the severity of risk and the level of certainty about the causal association between the drug and the adverse outcome. At a minimum, risks that should be disclosed should include any black-box warnings, the “major statement” currently listed in television advertisements, any adverse-event findings of an FDA advisory committee, and a summary of evidence from published peer-reviewed studies.

Communicating complicated risk information and research findings to participants poses challenges. It is critical that the information be conveyed in a manner that can be understood and weighed by participants. A “kitchen sink” approach to consent-form drafting, in which voluminous information is included with little attempt to distill it into a short format that is useful to participants, is unfortunately increasingly common in clinical trials and should be avoided. Participants are likely to be overwhelmed by a long and complex form and unable to weigh conflicting study findings or findings about different types of risk.

Verbal disclosures and written consent documents (both consent forms and information sheets) should help potential participants to understand how experts weigh the available evidence about the safety profile of the drug being studied. Moreover, there is a growing set of additional resources (for example, decision aids, videos, and interactive electronic presentations) to supplement written materials that may enhance participants’ understanding of complex clinical information. Although evidence about the effectiveness of techniques designed to improve and document understanding among potential research participants is mixed (Kass and Taylor, 2008), such interventions as engaging in additional interpersonal conversations with potential participants and asking them to explain the study to a friend have been shown to be helpful (Flory and Emanuel, 2004; Kass and Taylor, 2008; Lindegger et al., 2006). Whatever efforts are employed to communicate with potential participants, it is key that they include information that is useful to participants about where the weight of the evidence falls with regard to serious risks and the level of confidence that experts have in drawing conclusions about the risks. A statement that “Some studies have found that the drug causes X, whereas others have not” may be true but misleading if nearly all well-designed studies have reached the same conclusion and there is little or no reliable evidence on the other side.

In addition to safety risks, people who are considering participation in research need to know how the care that they will receive in a protocol may differ from the care that they would ordinarily receive. Thus, information about “Alternatives to Participation” should convey the current standard of care for the health condition that the study drug targets. That is particularly crucial in cases in which medical practice has shifted away from prescribing the study drug because accumulating evidence from passive surveillance, observational studies, and small trials or meta-analyses suggests that another therapy is as effective and has a more favorable safety profile. A statement that if a potential participant does not enroll in the trial, he or she is more likely to have a different drug prescribed should be communicated in this situation. If clinical practice continues to shift during the trial period, the statement should be strengthened; researchers have an ethical obligation to disclose all new developments that may affect a person’s willingness to continue to participate in a research study.

Comprehensive informed consent processes can help ensure that trial participants understand the potential consequences of study participation in addition to what they are contributing to the advancement of public health in the regulatory arena. They cannot, however, serve as an exclusive or sufficient ethical justification for conducting a postmarketing trial. The other ethical bases for initiating a trial should be independently satisfied. People should not be asked to assume risks that are not justified in light of the benefits of the trial to participants or society. Particularly in research settings in which participants have low literacy, low income, and poor access to modern health care and medicines, even a robust consent process may do little to countervail the pressures that lead people to participate in research. Regulators, IRBs, and DSMBs should serve as particularly strong bulwarks against unethical experimentation in such settings.

Copyright 2010 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK209935
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