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Ethical and Scientific Issues in Studying the Safety of Approved Drugs Abstract Pharmaceutical products are crucial for preventing and treating diseases, but they can also have harmful effects. Until a drug has been used by a large, diverse population of patients over time, substantial uncertainties about its benefits and risks will remain. The US Food and Drug Administration (FDA) has recently made progress in monitoring drug safety after approval, but the committee finds that FDA needs to embrace more fully a lifecycle approach to drug safety oversight. The lifecycle approach requires FDA to take an anticipatory role in shaping the directions of safety research, starting at the time of drug approval. The process should continue throughout the drug’s market lifetime, and its intensity should be dictated by the strength of signals that a drug’s risks might outweigh its benefits for everyone or for a definable subgroup. The committee recommends that FDA adopt a specified decision framework for evaluating benefit–risk information that addresses scientific and ethical disagreements and public values. The committee also recommends that FDA create, at the time of approval, a single, publicly available, living document to track its oversight of each drug across its lifecycle, called a Benefit and Risk Assessment and Management Plan (BRAMP). No general algorithm can dictate when FDA should require a postmarketing study or what type of studies to require if it makes that decision, but the committee identifies circumstances that should cause heightened concern about a drug and the scientific and ethical advantages of various study designs to resolve specific public health questions as they emerge. Circumstances under which postmarketing investigations should be required include not only those specified by the FDA Amendments Act (FDAAA) and the 2011 FDA guidance, such as accelerated approval using surrogate endpoints and new evidence about a drug’s benefit–risk balance, but such conditions as approval of first-in-class drugs on
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Ethical and Scientific Issues in Studying the Safety of Approved Drugs the basis of surrogate endpoints, and when surrogate indicators point to potential harms of a drug. The committee finds that although randomized controlled trials (RCTs) remain the gold standard for studying efficacy, there can be ethical and scientific reasons to prefer observational designs when the postmarketing research question focuses on a drug’s risks; such designs can often provide safety evidence of sufficient quality for decision-making. When requiring postmarketing RCTs, FDA has special obligations to protect patient-participants’ rights and interests, including working with relevant institutional review boards and data monitoring committees. FDA should also establish a new body to provide advice on the ethical challenges that can be posed by requiring observational studies and surveillance activities. For both ethical and scientific reasons, required postmarketing RCTs should include an accepted active treatment as at least one comparator if one is available that would probably be used if access to the drug in question were restricted. Finally, an increased monitoring role requires that FDA establish effective interdisciplinary teams with the expertise necessary to design safety research and interpret resulting data; the necessary expertise goes beyond that necessary for drug approval. The expanded expertise includes observational study design, analysis and interpretation, Bayesian and causal inference methods, ethics, pharmacoepidemiology, outcomes research, and the design and analysis of clinical trials for safety outcomes.