Ethical and Scientific Issues in Studying the Safety of Approved Drugs (2012) / Chapter Skim
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Pages 3-28
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From page 3... ...
110-85; FDAAA) provided FDA with new postmarketing regulatory tools to better protect the health of the public, including the authority to require an indus try sponsor to conduct a clinical trial or other research study in the postmarketing setting (called postmarketing requirements)
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In its letter report, Ethical Issues in Studying the Safety of Approved Drugs: A Letter Report, released on July 9, 2010, the committee addressed the first question of the committee's charge by presenting a conceptual framework for analyzing the ethics of postmarketing randomized controlled trials required by FDA. In this final report, the committee addresses all five specific questions posed to the committee by FDA.
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Questions to be explored by a committee include 1. What are the ethical and informed consent issues that must be con sidered when designing randomized clinical trials to evaluate potential safety risks?
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Because it has required the studies, FDA bears a measure of ethical responsibility for any adverse outcomes that research participants experience. When requiring postmarketing research, therefore, FDA should be confident that the information from the study is necessary to answer the public health question that prompted the consideration of a regulatory action, that the required study is designed and conducted in such a way that it can provide the necessary information, that it will use the study findings in a timely manner in its regulatory decisions, and that the 6 In this report, the committee uses the term studies, in accordance with ordinary usage in the scientific literature, as a parent or generic term that encompasses research projects of all types regardless of design.
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Those disagreements can result from different prior beliefs about the existence of a given benefit or risk, different opinions about the quality of a new study, different opinions about the relevance of the new evidence to the public health ques tion, and different ideas about how to synthesize and weigh all evidence relevant to the public health question. In addition, even if scientists do not make the final decision about what regulatory action FDA should take, they often have opinions about what level of certainty there should be for a given regulatory decision, and that opinion can shape their assessment of the strength of the evidence.
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Once it has decided to require postmarketing research, FDA must balance those two obligations when determining what type of study or studies to require. FDA may be justified in requiring studies that might expose participants to more net risk than they would probably face in regular clinical practice, that offer partici pants no reasonable expectation of clinical benefit, or both.7 This is only justified 7 Although there may not be any potential clinical benefit from the drug, research participants could benefit from participation through improved clinical care and being provided at no cost a drug that they could not afford.
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The challenge for FDA is to determine when one or more postmarketing observational studies are necessary and adequate to inform its regulatory decision, when one or more postmarketing RCTs are necessary and adequate, or when some combination of studies are required. To make that decision, FDA should consider the advantages and disadvantages of observational studies and RCTs in the postmarketing setting, which poses distinct scientific and ethical challenges.
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However, the ethical obligation to obtain prior informed consent is not applicable to all required postmarketing research. There are not always ethically relevant distinctions between some kinds of observational research that FDA could require manufacturers to conduct and FDA surveillance activities that are classified as public health practice.
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To ensure the public that such activities are being conducted with appropriate controls and protections, an independent review body should be formed to advise FDA on the ethics of the postmarketing research and surveillance activities involving large datasets that it conducts or requires. With regard to required RCTs, there are specific aspects of informed consent that are more salient in the postmarketing setting than in the premarketing set ting.
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adhere to the principles of reproducible research. What are the strengths and weaknesses of various approaches, including observational studies, including patient registries, meta-analyses, including patient-level data meta-analyses, and randomized controlled trials, to generate evidence about safety questions?
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The public health question that underlies FDA's regulatory decisions in the postmarketing setting is most likely to be addressed by comparing the drug at issue with the therapies likely to be used if the drug were removed from the market or its use were restricted. That is, it is most likely to be addressed by a head-to-head trial involving a comparison of two active treatments that are both indicated for the same patients who have the same condition.
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FINDINGS AND RECOMMENDATIONS Finding 2.1 FDA's current approach to drug oversight in the postmarketing setting is not sufficiently systematic and does not ensure consistent assessment of benefits and risks associated with a drug over its lifecycle. Use of a standardized regulatory decision-making framework that is flexible enough to adapt to decisions of dif ferent complexity could make FDA's decision-making process more predictable, transparent, and active, allowing FDA to better anticipate postmarketing research needs and to plan for such research early when more design options with fewer ethical tensions might be possible.
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The document should include a description of: any public health questions raised during the drug's lifecycle; the benefit and risk assessment specific to each public health question; key stakeholder input specific to each question; any regu latory decisions or actions and the rationale for each decision, including requirements for postmarketing research or a risk evaluation and mitigation strategy (REMS) ; a schedule for future assessments of benefits and risks; and plans for and results of evaluating the effectiveness of any regulatory decisions or actions.
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In the postmarketing setting, however, evidence may be derived from surveillance, observational studies, patient registries, published and unpub lished clinical trials, meta-analyses, and relevant case reports or series. Data sources, study designs, and analytic approaches for the postmarketing context are evolving rapidly.
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Although FDA's decisions to require postmarketing research need to be made case by case, there are some identifiable conditions that are concordant with but more specific and detailed than those outlined in FDAAA and FDA guidance, which make information from additional postmarketing research important. Recommendation 2.4 FDA should prospectively determine and publicly identify specific condi tions, including drug characteristics and other features, that are associated with greater uncertainty about a drug's benefit–risk profile in the postmar keting setting.
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Finding 3.1 Some of FDA's most difficult decisions are those in which experts disagree about how compelling is the evidence that informs the public health question. Understanding the nature and sources of those disagreements and their impli
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on the basis of different assessments of prior evidence, the quality of new data, the adequacy of confounding control in the relevant studies, the transportability of results, the appropriateness of the statistical analysis, the relevance of the new evidence to the public health question, how the evidence should be weighed and synthesized, or the threshold for regula tory actions. Recommendation 3.1 FDA should use the framework for decision-making proposed in Recom mendation 2.1 to ensure a thorough discussion and clear understanding of the sources of disagreement about the available evidence among all participants in the regulatory decision-making process.
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In assessing the relevance of study findings to a public health question, the transportability of the study results is as important as the determinants of its internal validity. Recommendation 3.3 In assessing the benefits and risks associated with a drug in the postmarketing context, FDA should develop guidance and review processes that ensure that observational studies with high internal validity are given appropriate weight in the evaluation of drug harms and that transportability is given emphasis similar to that given bias and other errors in assessing the weight of evidence that a study provides to inform a public health question.
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Recommendation 3.6 For drugs that are likely to have required postmarketing observational stud ies or trials, FDA should use the BRAMP document to specify potential public health questions of interest as early as possible; should prospectively recommend standards for uniform definition of key variables and complete ascertainment of events among studies or convene researchers in the field to suggest such standards and promote data-sharing; should prospectively plan meta-analyses of the data with reference to specified exposures, outcomes, comparators, and covariates; should conduct the meta-analyses of the data; and should make appropriate regulatory decisions in a timely fashion. FDA can also improve the validity of meta-analyses by monitoring and encourag ing compliance with FDAAA requirements for reporting to ClinicalTrials.
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Finding 4.1 A decision by FDA to require postmarketing research can put research participants at risk. It can also put patients and the public at risk by delaying a regulatory decision that might be protective of public health.
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Recommendation 4.2 When deciding which type of research to require in the postmarketing setting, FDA should carefully weigh the strengths of potential observational studies for evaluating risks and their ethical and practical advantages, including the timeframe within which the data are needed, against the limitations of poten tial observational studies for generating the data needed to answer the public health question. An RCT should be required only if FDA has concluded that an observational study could not provide the necessary information, that an RCT is likely to generate the information within the necessary timeframe, and that the necessary RCT is ethically acceptable.
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, clarify whether its human subjects regulations (21 CFR 50) govern required postmarketing observational studies and, if so, how FDA will address and will expect IRBs to address any differences between 21 CFR 50 and other potentially applicable human subject regulations (45 CFR 46 Subpart A)
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, should clarify whether its human subjects regulations (21 CFR 50) govern required postmarketing observational studies and, if so, how FDA will address and will expect IRBs to address any differences between 21 CFR 50 and other potentially applicable human subject regulations (45 CFR 46 Subpart A)
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Finding 4.7 There are heightened informed consent concerns in the conduct of FDA-required RCTs in the postmarketing setting. FDA has an ethical responsibility to ensure that postmarketing clinical trials include appropriate informed consent processes and oversight.
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FDA's Office of International Programs, through its Harmonization and Multilateral Relations Office, is tasked with the responsibility of coordinating and collaborating with other agencies and countries on international standards and harmonization issues and is therefore well positioned to address these concerns. Recommendation 4.8 FDA should direct its Office of International Programs to include explicitly among its responsibilities working with counterpart agencies of other gov ernments and with industry to resolve concerns about the ethics and quality of evidence in the conduct of FDA-required postmarketing research outside the United States.
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