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Letter Report
Pages 1-15

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From page 1... ... 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? Read the entire page →
From page 2... ... Given the short period available for preparing this letter report, the committee 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. Read the entire page →
From page 3... ... 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 responsible policy decision cannot be made based either on the existing evidence or on evidence from new observational studies, and (ii) Read the entire page →
From page 4... ... Under FDAAA 2007, FDA can require postmarketing studies and clinical trials under the following circumstances (PL 110-85) : "To assess a known serious risk related to the use of the drug involved." "To assess signals of serious risk related to the use of the drug." "To identify an unexpected serious risk when available data indicates the potential for a serious risk." The ability to require further study of a drug is a powerful tool for FDA to use in acquiring additional information to make informed, science-based decisions as part of its public health mission. Read the entire page →
From page 5... ... 7 Accurately assessing the risks posed by and the potential benefits of a drug requires the use of a wide variety of scientific data, including findings from animal studies of toxicology, basic research (for example, mechanistic studies and structure–activity relationships) , clinical trials, high-quality epidemiologic and health-services research (such as observational studies and meta-analyses) Read the entire page →
From page 6... ... In the case of postmarketing clinical trials required by FDA, that ethical precept requires further specification and strengthening. In particular, before a clinical trial is selected as the design of choice, it should be determined that no other research or information gathering effort -- including a new observational study -- can reduce the uncertainty about a drug's risk–benefit profile sufficiently to support a responsible policy decision. Read the entire page →
From page 7... ... 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 questions 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. Read the entire page →
From page 8... ... 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 studies 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. Read the entire page →
From page 9... ... 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. Read the entire page →
From page 10... ... It is never ethically justified to include in a postmarketing trial participants for whom the drug is contraindicated by the currently approved product label unless their involvement is necessary to answer a specific question and the risks to them posed by participation are acceptable. 11 The exclusion of participants for whom more moderate safety warnings or precautions have been issued presents a more difficult case and involves a tradeoff among several considerations: the prevention of possible harm to participants, the generalizability of the trial's findings to patient populations in which the drug is being used, and the ability to reach an answer to the study's safety questions more quickly (if the participants are likely to experience the outcome of interest at a higher rate) Read the entire page →
From page 11... ... 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) Read the entire page →
From page 12... ... . 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. Read the entire page →
From page 13... ... 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. Read the entire page →
From page 14... ... 2007. Making sense of noninferiority: A clinical and statistical perspective on its application to cardiovascular clinical trials. Read the entire page →
From page 15... ... Clinical Trials 4(3) Read the entire page →

From page 1...

... 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?

Letter Report Pages 1-15

Letter Report
Pages 1-15