Ethical and Scientific Issues in Studying the Safety of Approved Drugs (2012) / Chapter Skim
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Appendix B: Committee's Letter Report
Appendix B: Committee's Letter Report
Pages 231-250
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From page 231... ...
FDA requested a final report on the five questions in 2011. In light of the scheduling of a joint meeting of FDA's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee on July 13–14, 2010, FDA further requested a letter report addressing question 1 of the charge -- "What are the ethical and informed consent issues that must be considered when designing randomized clinical trials to evaluate potential safety risks?
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From page 232... ...
In light of the scheduling of a joint meeting of FDA's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee on July 13–14, 2010, FDA requested a letter report addressing question 1 of the charge -- "What are the ethical and informed consent issues that must be considered when designing randomized clinical trials to evaluate potential safety risks?
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From page 233... ...
Given the short period available for preparing this letter report, the com mittee focused on identifying a conceptual framework to guide its analysis of the ethics of the design and conduct of postmarketing safety research required by FDA, including key issues that need to be taken into account in assessing ethics and informed consent in randomized controlled trials. In developing this framework, and in its explication in this letter report, the committee relied on the extensive body of codes, regulations and guidance on the ethics of research involving human participants, much of which is built around a commitment to several basic moral principles, including beneficence, respect for persons and their autonomy, and justice.
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From page 234... ...
It is appropriate for FDA to require that a randomized controlled trial be conducted to provide additional evidence about an approved drug's efficacy and safety only when (i) uncertainty about the risk-benefit balance is such that a respon sible policy decision cannot be made based either on the existing evidence or on evidence from new observational studies, and (ii)
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From page 235... ...
THE PUBLIC HEALTH CONTEXT OF DRUG SAFETY The ethics of any postmarketing study required by FDA, including random ized controlled trials, should be assessed in the context of FDA's mission to promote and protect public health. The safety of the US drug supply contributes to the nation's health, and FDA is the agency responsible for ensuring this safety.
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From page 236... ...
In making a decision whether to require a postmarketing study, however, FDA not only should consider the ethical issues that arise in obtaining information to clarify a policy decision2 but should bear in mind that such issues vary among types of studies. The committee concludes that for FDA-required postmarketing research to be ethical, a critical first step is the determination by FDA that it is facing a policy decision of importance to public health that cannot satisfactorily be resolved with existing evidence.3,4 2 When referring to a policy decision the committee means choosing among the range of responses available to the FDA when safety signals emerge -- including the decision to continue a drug's monitoring plan without modification, the decision to add a warning to a drug's label, the decision to require a postmarketing trial, and the decision to remove a drug from the market -- some of which are not mutually exclusive.
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From page 237... ...
Those principles and practices, sometimes referred to as the emerging field of regulatory science, 5 require that policy decisions reflect the best available scientific evidence and analytic techniques drawn from a wide array of disciplines and technical expertise, including decision sciences, behavioral economics, and cognitive psychology. Public accountability and transparency increase the likelihood that the perspec tives of stakeholders,6 who have kinds of knowledge different from those of technical experts, are included in the making of policy decisions.
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From page 238... ...
Judgments about the adequacy of available evidence for FDA decisions require input from a multidisciplinary team acting through a process that can integrate and take advantage of the different kinds of knowledge and perspectives that reside in clinical practice, biologic science, ethics, biostatistics, epidemiol ogy, and research design. The decision-making process should also minimize and correct for potential cognitive and intellectual biases that arise from previous policy decisions or strongly held opinions -- for example, the human tendency to focus on evidence that confirms a pre-existing belief or decision and to discount evidence that contradicts it.
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From page 239... ...
Without a reasonable prospect of contributing to scientific knowledge, the exposure of research participants to even minimal risk or inconvenience can never be justi fied. In the case of postmarketing clinical trials required by FDA, that ethical precept requires further specification and strengthening.
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From page 240... ...
New safety signals may arise from various sources: spontaneous reports of adverse events, safety-surveillance systems, observational studies, meta-analyses, and randomized trials. FDA can require new research to address key safety ques tions if the existing evidence is insufficient to infer causality or to characterize the frequency and severity of observed harms with adequate confidence or if such evidence is not complete enough to judge the acceptability of the risk–benefit profile for a drug's intended use.
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From page 241... ...
They can often be much larger than randomized controlled trials, involve longer patient followup, include a broader diversity of patients and care settings, and be completed more quickly. Because of those features, observational stud ies evaluating infrequent outcomes that occur long after exposure and in which confounding by indication is unlikely can sometimes provide higher-quality safety evidence than randomized controlled trials, if the trials were not optimally designed to capture such safety outcomes.
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From page 242... ...
Because observational designs usually generate fewer ethical concerns than randomized controlled trials, a decision to require a randomized controlled trial to resolve safety questions should be based on the determination that neither the existing evidence nor new, prospectively conducted observational studies can provide safety evidence sufficiently reliable for FDA to make a sound policy decision. If a randomized controlled trial is deemed necessary for an FDA-policy decision, its characteristics should include the following: 1.
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From page 243... ...
Every postmarketing clinical trial should have a properly qualified data-safety monitoring board (DSMB) in place with a written charter and a pre-specified data-monitoring plan, which includes statistical guidelines for stopping the trial 11 I fnew information raises substantial uncertainty about the appropriateness of the current product warning, suggesting that it may be in the interest of patients to have the warning removed, it may be ethically acceptable to mount a trial that involves patients who are the subject of the warning to resolve this question.
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From page 244... ...
ADDITIONAL ETHICAL OBLIGATIONS TO RESEARCH PARTICIPANTS In the context of FDA-required randomized controlled trials, the need for a well-designed randomized controlled trial to determine the proper policy deci sion 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 com passion may be owed because of illness, disability, or threat of illness -- should be respected.
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From page 245... ...
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 dif ferent ways of balancing risk and benefit can be ethically justified. For example, both FDA regulations (21 CFR 50/56)
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From page 246... ...
. 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.
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From page 247... ...
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.
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From page 248... ...
2004. Interventions to improve research participants' understanding in informed consent for research: A systematic review.
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From page 249... ...
2000. Placebo-controlled trials and active-control trials in the evaluation of new treatments.
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