Summary

Prescription drugs1 provide great benefit to the public’s health. However, most drugs also pose risks to health, and often these risks cannot be identified or fully characterized until after a drug has entered the marketplace. Because the US Food and Drug Administration (FDA) is the agency responsible for ensuring that the benefits of a prescription drug outweigh its risks, the timely identification of and response to risks from marketed drugs are central to its mission. Before 2007, FDA’s options in responding to risks of concern that emerged postmarketing were limited. It could either withdraw a drug from the market altogether or negotiate with sponsors to get them to accept a change in its regulatory status with regard to labels, warnings, and the like. The FDA Amendments Act of 2007 (Public Law [PL] 110-85; FDAAA) provided FDA with new postmarketing regulatory tools to better protect the health of the public, including the authority to require an industry sponsor to conduct a clinical trial or other research study in the postmarketing setting (called postmarketing requirements).2 That expanded authority brought a new set of ethical and scientific questions for FDA to consider; FDA asked the Institute of Medicine (IOM) to conduct a study to address these questions.

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1For simplicity, the committee uses the term drugs throughout this report, but similar considerations would apply to biologics. The committee’s charge is related to the Food and Drug Administration’s regulation of the drug and biologics supply. When discussing FDA’s regulatory authority and mission, therefore, the committee does not address FDA’s roles related to other products, such as tobacco, medical devices, veterinary medicines, the food supply, and animal feed.

2A postmarketing requirement (PMR) is an FDA-required research study that a sponsor must conduct after a drug has been approved and is released on the market.



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Summary Prescription drugs1 provide great benefit to the public’s health. However, most drugs also pose risks to health, and often these risks cannot be identified or fully characterized until after a drug has entered the marketplace. Because the US Food and Drug Administration (FDA) is the agency responsible for ensuring that the benefits of a prescription drug outweigh its risks, the timely identification of and response to risks from marketed drugs are central to its mission. Before 2007, FDA’s options in responding to risks of concern that emerged postmarketing were limited. It could either withdraw a drug from the market altogether or negotiate with sponsors to get them to accept a change in its regulatory status with regard to labels, warnings, and the like. The FDA Amendments Act of 2007 (Public Law [PL] 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).2 That expanded authority brought a new set of ethical and scientific questions for FDA to consider; FDA asked the Institute of Medicine (IOM) to conduct a study to address these questions. 1 For simplicity, the committee uses the term drugs throughout this report, but similar considerations would apply to biologics. The committee’s charge is related to the Food and Drug Administration’s regulation of the drug and biologics supply. When discussing FDA’s regulatory authority and mission, therefore, the committee does not address FDA’s roles related to other products, such as tobacco, medical devices, veterinary medicines, the food supply, and animal feed. 2 A postmarketing requirement (PMR) is an FDA-required research study that a sponsor must conduct after a drug has been approved and is released on the market. 3

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4 STUDYING THE SAFETY OF APPROVED DRUGS CHARGE TO THE COMMITTEE In April 2010, FDA asked IOM to “convene a committee to evaluate the sci- entific and ethical issues involved in conducting studies of the safety of approved drugs”. The five specific questions posed by FDA appear in Box S-1. In response to FDA’s request, IOM convened a committee of 12 members who have expertise in bioethics, biostatistics, clinical trials, epidemiology, health policy, law, patient safety, pharmacoepidemiology, and regulatory science. FDA requested two reports: a letter report due in July 20103 and this final report. 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. COMMITTEE’S APPROACH TO ITS CHARGE The committee met in person six times, including two open information- gathering sessions. The committee used the conceptual framework in its letter report as a starting point for this final report but conducted further research and deliberations related to its full charge. The following underpinnings of that con - ceptual framework, as well as additional themes that emerged as the committee deliberated its full charge, shaped this report: (1) an understanding of FDA’s public health mission; (2) the importance of adopting a lifecycle approach to drug safety and benefit–risk assessment; (3) FDA’s ethical obligations in making regulatory decisions, including the centrality of transparency and communication to those decisions; and (4) a commitment to using best practices in regulatory science and high-quality evidence in regulatory decision-making. BENEFIT–RISK ASSESSMENT AND MANAGEMENT THROUGHOUT A DRUG’S LIFECYCLE In Chapter 2, the committee explains the need for FDA to adopt a consistent process for factoring in different evidence in the making of regulatory deci - sions throughout a drug’s lifecycle. Using a consistent framework for regulatory decision-making will facilitate stakeholder understanding of decisions and the process by which decisions are made, emphasize the dynamic nature of benefit and risk assessments, provide an opportunity to consider the value of additional 3 FDA requested that IOM complete the letter report before a July 13–14, 2010, joint meeting of FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee on rosiglitazone.

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5 SUMMARY BOX S-1 Charge to the Committee The US Food and Drug Administration (FDA) has requested that the Institute of Medicine convene a committee to evaluate the scientific and ethical issues involved in conducting studies of the safety of approved drugs. 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? 2. 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? 3. Considering the speed, cost, and value of studies, what types of follow-up studies are appropriate to investigate different kinds of sig- nals (detected pre-approval or postapproval) and in what temporal order? 4. Under what circumstances should head-to-head randomized clinical trials for safety be required? 5. How should FDA factor in different kinds of safety evidence in consid- ering different kinds of regulatory actions? postmarketing studies, and minimize delays and increase transparency in the agency’s decisions. The committee proposes a three-stage framework that FDA could apply to regulatory decisions prompted by new information that could affect a drug’s benefit–risk profile, and to use for periodic re-evaluations of the benefit–risk profile during a drug’s lifecycle.4 Central to the framework is the importance of eliciting and incorporating the perspective of the patient. 5 In the first stage (Stage I) of the framework, FDA should define the public health ques - tion that prompted the need for a regulatory decision, including identifying the specific characteristics of the drug and health problem at issue, available informa- tion about the drug, alternative treatments that are available, and plausible regula- tory actions and their potential consequences. In the second stage (Stage II) of the framework, FDA should evaluate the quality of evidence on both the benefits 4 Given its charge, the committee focuses on the use of the framework in the postmarketing setting, but it could also be useful in the premarketing setting. 5 FDA should ensure that patient advocacy groups represent the views of patients rather than the views of commercial entities that provide funding to the organizations.

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6 STUDYING THE SAFETY OF APPROVED DRUGS and the risks associated with the drug, including any new information that has triggered the need to consider regulatory action. The output of this stage includes estimates of the likelihood and magnitude of a drug’s benefits and risks and a characterization of the scientific evidence on which the estimates are based. The third stage (Stage III) of the framework is the stage in which regulatory decisions are made and implemented. This stage involves synthesizing and integrating the estimates of benefits and risks and the quality of the evidence on which these are based (from Stage II) with the public health question (as specified in Stage I); deciding on the appropriate regulatory actions, including whether further study should be required; communicating the decision; implementing the regulatory actions; evaluating the effects of the regulatory actions; and, particularly in the case of complex or difficult decisions, evaluating the decision-making process and the impact of the action taken on the public’s health. In order to formalize and make concrete a commitment to a lifecycle approach to drug oversight and benefit–risk management, the committee proposes that FDA develop and make public a living document, which the committee calls a Benefit and Risk Assessment and Management Plan (BRAMP), that FDA would update whenever it re-evaluates a drug’s benefit–risk profile. The document would serve as a guide that supports organizational adherence to the lifecycle approach, increases the transparency of FDA’s decisions, and fosters collabora - tion between FDA and drug sponsors. In light of its charge, the committee focuses on the ethical and scientific issues associated with one of the regulatory actions available to FDA: impos - ing a postmarketing requirement on a drug’s sponsor to conduct additional research, including studies that employ observational and RCT designs. 6 When FDA imposes a postmarketing requirement, it is expressing not only scientific uncertainty about the harms or benefits of a drug but a judgment that the public health interests served by requiring additional research outweigh the burdens placed on pharmaceutical manufacturers and—more important from an ethical standpoint—any risk of harm to or burdens on research participants. 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. Thus, as the committee uses the term studies, it applies to both clinical trials and non–clinical-trial investigations, such as observational investigations. When referring specifically to either observational designs or randomized controlled trial (RCT) designs, the committee uses those specific terms.

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7 SUMMARY design and conduct of the study adequately protect the rights and interests of research participants. FDAAA provides FDA the authority to require postmarketing research under specific circumstances, and FDA has interpreted its authority in guidance to industry about postmarketing requirements. The committee identifies, more specifically, circumstances that typically increase the uncertainty surrounding the benefit–risk profile of a drug under which FDA should seriously consider requir- ing postmarketing studies and, if it decides not to require research, it should make public its reasoning for that decision. EVIDENCE AND DECISION-MAKING FDA’s drug-related regulatory decisions are based, to a large extent, on scientific evidence. Statistical inferences must be made in order to use scientific evidence in decision-making. The two main approaches to statistical inference are the standard “frequentist” approach and the Bayesian approach. The frequentist approach to statistical inference is familiar to medical researchers and is the basis of most FDA rules and guidance. The Bayesian approach is less widely used and understood, and it has many attractive properties that can both elucidate the reasons for disagreements and provide an analytic model for decision-making that can allow decision-makers to combine the chance of being wrong about ben- efits and risks with the seriousness of those errors to support optimal decisions. Bayesian, frequentist, and other relevant methods can be useful for integrating new information about a drug into our current understanding about its association with harms or benefits to inform decisions, and FDA should develop a sufficient body of internal expertise of these approaches. Scientists and technical experts often disagree about the available evidence. 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, differ- ent 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. Decisions where scientists and technical experts disagree about the available evidence, such as in the case of rosiglitazone (Avandia®), are often the most difficult ones that FDA must make. If the underlying reasons for disagreements are not properly expressed or elicited, however, it will be difficult to reach a consensus on the appropriate regu- latory action. A lack of clarity about those disagreements makes it extraordinarily difficult for those involved in the decision-making process to understand the reasons for the disagreements, adjudicate them, and make decisions. The nature

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8 STUDYING THE SAFETY OF APPROVED DRUGS of scientific differences should be identified and explicitly stated so that all par- ticipants in the decision-making process—including scientists, technical experts, patients and other stakeholders, and the decision-makers themselves—understand the underlying sources of scientific disagreement. To maintain the public’s trust in the agency, it is important that the public can understand how FDA weighs the factors that lead to disagreements in its decisions. FDA’s handling of its recent regulatory decision to place restrictions on the distribution of rosiglitazone pro - vides a good example of how it can make public both the disagreements among agency scientists about evidence and how those disagreements were considered in the agency’s decision. The three-stage framework discussed above provides a process for eliciting and resolving those differences, and the BRAMP document constitutes a mechanism to provide transparency to the public about the disagree- ments and how they affected the decision. The reanalyses of data from rosiglitazone trials revealed discrepancies and judgment calls that occurred from ascertaining clinical events through data analysis that affected the interpretation of the evidence and, later, the regulatory decision. That example highlights the importance of adherence to principles of reproducible research, that is, presenting analyses in such a way that the reader of results can understand most of or all the process that occurred from the gather- ing of the data to the reporting of specific analyses. At a minimum, that requires provision of study protocols with statistical-analysis plans, statistical code, and information about how decisions were made to produce the analytic dataset from the raw measured data. Optimally, it involves some form of data sharing. Adher- ing to those principles, for both premarketing and postmarketing data, would facilitate a better understanding of FDA’s decisions by the public and allow analysts both in and outside FDA to investigate the sensitivity of conclusions to different analytic approaches. SELECTION AND OVERSIGHT OF REQUIRED POSTMARKETING STUDIES As a public health agency, FDA has ethical obligations both to protect the public from unsafe drugs and to safeguard the rights and interests of participants in the research that supports the agency’s decisions about drug benefits and risks. 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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9 SUMMARY when a question of pressing public health importance is at stake, no other design with a better benefit–risk balance for participants could supply the evidence needed for a responsible regulatory response to that question, FDA uses the find - ings of the research in formulating its regulatory response, and special safeguards are in place to protect the rights and interests of the research participants. As discussed in Chapter 4, FDAAA allows FDA to require an RCT only when observational studies are not sufficient to provide the information the agency needs. The challenge for FDA is to determine when one or more postmar- keting 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 disadvan- tages of observational studies and RCTs in the postmarketing setting, which poses distinct scientific and ethical challenges. In contrast to the premarket context, the drug of interest, once approved, will be in general use, making observational studies feasible, and patients will have access to it without having to participate in FDA-required research. After approval, evidence about the drug’s benefits and risks can be generated by multiple investigators, supported by various funders, and generated from a wide variety of observational studies and RCTs. Concerns about a drug’s benefit–risk profile are likely to involve comparisons with other active treatments that are considered to be therapeutic alternatives. In theory, an ideal RCT could provide the evidence that regulators need to identify the best regulatory response to a public health question of interest. In practice, however, a number of constraints can make the ideal trial infeasible and increase the potential for imprecision, bias, and decreased transportability 8 of results: patients may refuse to participate, making the study population less representative of the target population taking the drug; adherence may not reach desired levels; and patients may withdraw from the trial. Other practical consid - erations can limit an RCT or observational study’s ability to address the public health question. Those limitations include the ability to measure the endpoints of primary interest, the determinants of drug choice, timeliness, the quality of available data sources or easily obtainable information for observational stud - ies, the frequency of the endpoint being studied, the availability of participants, and the effect size of interest. The public health question also greatly affects the choice of design, with RCTs having advantages over observational studies when the public health question focuses primarily on a drug’s benefits or a relative effect size is likely to be small; observational studies have some advantages over 8 The term transportability is used in this report, rather than external validity or generalizability, because the committee thinks that it reflects a nonbinary characteristic better. Different effects can occur in a variety of settings, and study results may be transportable to some populations or settings but not others, so transportability may not be a simple binary property.

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10 STUDYING THE SAFETY OF APPROVED DRUGS RCTs when the primary focus is on rare or delayed risks, and the relative risks are moderate or large. Virtually every study type has tradeoffs dictated by either its design or its conduct. Regardless of the type of design chosen, the study should have pre- specified protocols, endpoints, analytic plans, and procedures in place to ensure adequate and uniform followup, ascertainment and adjudication of endpoints, and other steps to ensure data quality. While often methodologically superior to observational studies that use existing data, in the required postmarketing context a prospective cohort study that is designed so that followup starts at the initiation of drug treatment can raise some of the same ethical issues that are raised by an RCT, assuming both occur at the same time in the drug’s lifecycle. In these circumstances, there may be ethi - cal advantages to FDA’s requiring observational designs examining the effects of past exposures, which may yield results sooner and enable faster regulatory action to protect the public’s health. The ability of such designs to provide the information FDA requires for regulatory action rests not only on the availability of high-quality data but also on access to those data. Access is itself a function of ethical considerations related to privacy and authorization. In deciding what type of RCT to require, FDA should consider which RCT would best approximate the ideal hypothetical trial. As with observational stud - ies, the choice of a comparator for a drug is an important element in the design of an RCT. If an effective treatment is available for the same indication, an active-controlled design (a head-to-head trial, defined as a comparison of two active treatments indicated for the same patients with the same conditions) is often preferred on both ethical and public health grounds. It may be ethically acceptable, however, for FDA to require a placebo-controlled postmarketing trial under some specific circumstances even if an alternative treatment is avail - able—such as studies of interventions intended to provide symptomatic relief for minor, self-limiting, or reversible conditions and in short-term trials to evaluate surrogate endpoints. When FDA requires postmarketing research, it has an obligation to ensure that the research is conducted ethically. One component of that obligation is to ensure that, when appropriate, the study secures the voluntary informed consent of research participants. 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. It is unclear whether FDA’s human subjects regulation (21 CFR 50) or the Common Rule (45 CFR 46) is the operative regulation for FDA-required, postmarketing observa- tional studies, nor is it clear whether some or all types of observational designs qualify as clinical investigations under 21 CFR 50. It is important that FDA clarify whether its human subjects regulations govern required postmarketing observa-

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11 SUMMARY tional studies and, if so, how FDA will address and expect institutional review boards (IRBs) to address any differences between 21 CFR 50 and 45 CFR 46 in oversight and research participant protections for different observational designs. The desirability of linking datasets and of obtaining additional information from patients, or otherwise needing access to some identifying information about patients, will probably increase. That increase could lead to additional ethical questions about the adequacy of data-security practices, authorization for access to different datasets, and the difference, if any, between research and public health goals. To ensure the public that such activities are being conducted with appropri- ate 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. In postmarketing trials, patients may be asked to submit to a drug regimen when a safety signal has prompted concerns about risk and possibly about the acceptability of the drug’s benefit–risk profile. In that context, it is important to provide information to potential participants about why a new study is required and why it is still ethically acceptable to ask them to consider participating in the study. Provisions may need to be made to ensure adequate discussion of how well patients’ existing treatment is working for them. Potential participants also need to know how the care that they will receive in an RCT may differ from the care that they would ordinarily receive. If clinical practice shifts during the trial period, that should be communicated to participants. For all postmarketing research that it requires, FDA should provide the rel- evant oversight bodies, such as the IRB and data-monitoring committee (DMC), information about the public health question at issue; the specifics of the study design intended to address that question, including any design features that it views as necessary to the ethical justification of the study; and any changes in clinical practice or professional standards that arise over the course of the study that might affect the benefit–risk profile of a drug and influence a person’s deci - sion to join or remain in the study. The IRB should consider dissemination of that information to potential and current study participants. RESPONSES TO THE CHARGE QUESTIONS9 How should FDA factor in different kinds of safety evidence in consider- ing different kinds of regulatory actions? Since no single algorithm can determine how to factor different kinds of safety evidence into regulatory decision-making, the committee specifies pro - 9 The committee presents the questions in the order in which they are discussed in the chapters of the report, not the order in which they are presented in the charge.

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12 STUDYING THE SAFETY OF APPROVED DRUGS cesses and principles to guide FDA in deciding among postmarketing regulatory actions. The committee identifies the following five actions FDA can take to improve its decision-making process for postmarketing regulatory decisions in response to different kinds of safety evidence: (1) adopt a specified decision- making framework; (2) create a BRAMP document for each drug; (3) character- ize the nature of any disagreements about scientific evidence; (4) create effective multidisciplinary teams with wide ranging expertise, including expertise in observational study design and interpretation, outcomes research and pharmaco - epidemiology, and Bayesian methods and modern causal inference approaches; and (5) 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 gener- ate evidence about safety questions? A wide variety of designs, data sources, and context-specific facts and priori- ties affect the strengths and weaknesses of studies, such as whether an adverse event is rare or common, mild or serious, or known or unknown and whether the relative size of risk increase posed by a drug is large or small. A clinical trial of too short a duration to find a delayed effect is going to provide less relevant safety evidence than a design based on patient registry data with long follow- up. These and other contextual and situation-specific factors can be expected to trump broad principles. The committee does, however, outline some general considerations that are important for evaluating the value of various designs for decision-making purposes. The initial considerations are how strong the signal that motivates the design is and whether it involves primarily an increase in risk, a decrease in benefit, or both, for either the general population or a definable subgroup. Second is how time-urgent the need for a regulatory response is on the basis of the nature of the signal. The third consideration involves how large the change in benefits or risks must be, on both relative and absolute scales, to justify a regulatory response. Fourth is what the other causes of a given adverse event (or failure of benefit) might be and how predictive they are. Fifth is the qual - ity of data likely to be gathered as part of any given design with respect to drug exposure, outcomes, confounders, and other relevant patient, disease, or contextual characteristics. Sixth is a judgment of how study design, conduct, or context is likely to affect the transportability of the study results. Seventh is what the logistical requirements of a design will be, including data access, cost, and feasibility. Finally, there are considerations of ethical burden, consent, confidentiality, and study oversight. These factors can lead to the choice of either a single design type or a combination of studies with counterbalancing strengths and weaknesses.

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13 SUMMARY Considering the speed, cost, and value of studies, what types of follow- up studies are appropriate to investigate different kinds of signals (detected pre-approval or postmarketing) and in what temporal order? All the issues listed in the preceding question about design choice also affect the optimal sequencing of study designs in response to a given signal. The main difference is that the outcome of one study may affect the design, conduct, or ini- tiation of subsequent studies. There are general principles to guide FDA beyond the statutory requirement in FDAAA10 to require a clinical trial only if sufficient information to address the public health question and the attendant decision can - not be obtained with an observational study. All research strategies will work best if anticipated and planned for early, even evidence synthesis. The committee identifies a number of characteristics—consistent with FDA’s authorities under FDAAA and with FDA guidance on postmarketing requirements—that, if evident in the premarketing phase, should cause heightened concern about the possibility that harm will outweigh benefit in the postmarketing context. Under what circumstances should head-to-head randomized clinical tri- als for safety be required? 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. However, for such a study to be scientifically valid and ethical, the active comparator must have a well-defined benefit–risk profile and be a clinically acceptable alternative to the drug being tested. If no comparator treatment exists or no comparator has a well-defined benefit–risk profile, typically at least one arm of the study should be some form of “usual care” or a placebo if usual care is not a proven or active treatment. If there are ethical reasons for not having a usual-care or placebo arm in the study—for example, if the treatment in question is for an irreversible and fatal disease—a treatment that does not have a well-defined benefit–risk profile might be the only ethically acceptable comparator. In such cases, FDA should take the questionable benefit–risk profiles of the drug and its comparator into account when interpreting the results of the study. What are the ethical and informed consent issues that must be considered when designing randomized clinical trials to evaluate potential safety risks? The ethical justification for FDA to require a trial to resolve a postmarket - ing benefit–risk profile question rests on the determination that (1) a responsible 10 2 1 USC § 355(o)(3)(2010).

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18 STUDYING THE SAFETY OF APPROVED DRUGS Finding 2.5 Some FDA decisions in response to postmarketing public health questions are controversial or difficult. Complex instances tend to occur when FDA must make a decision despite scientific disagreement about the relevant evidence or when the likely effects of a given regulatory action are uncertain. These cases serve as important opportunities for FDA, external scientists, and the public to learn about the complexities of the decision-making process and the consequences of a regulatory decision, and for FDA to improve its processes and practices. Recommendation 2.5 FDA should conduct after-action reviews of postmarketing drug-related deci- sions that are particularly controversial or difficult or when a major regulatory decision is made after marketing. Such a review should include an assessment of the decision-making process itself and the effects of the final decision on the public’s health. Finding 2.6 Surrogate endpoints are often relied on in the drug-approval process, and their use has been related to a number of high-profile drug-safety problems. The findings of postmarketing studies can be used to revise the approval process and improve the endpoints and methods used in it. Recommendation 2.6 As part of a continuing effort to improve regulatory science, FDA should maintain and annually update a list of surrogate endpoints allowed for use in the approval of drugs, the rationale for their use, the postmarketing expe - rience regarding their correlation with health outcomes of interest, and any revisions of approval requirements that may have been suggested by the results of the postmarketing studies. The list should accumulate the post - marketing experience of the successes and failures of various surrogates so that for each major drug class, the regulatory science related to approval methods can be modified and improved. FDA should also revise or develop guidance documents for the use of selected surrogate endpoints that, on the basis of postmarketing studies, appear to be inconsistently predictive of clinical outcomes. 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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19 SUMMARY cations for FDA’s decisions is key to improving the agency’s decision-making process. For example, experts can disagree about the plausibility of a new risk (or decreased benefit) 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. In the interest of transparency, FDA should use the BRAMP document proposed in Recommendation 2.2 to ensure that such disagreements and how they were resolved are documented and made public. Finding 3.2 Such methods as Bayesian analyses or other approaches to integrating external relevant information with newly emerging information could provide decision- makers with useful quantitative assessments of evidence. An example would be sensitivity analyses of clinical-trial data that illustrate the influence of prior prob - abilities on estimates of probabilities that an intervention has unacceptable safety risks. These approaches can inform judgments, allow more rational decision- making, and permit input from multiple stakeholders and experts. Recommendation 3.2 FDA should ensure that it has adequate expertise in Bayesian approaches, in combination with expertise in relevant frequentist and causal inference meth - ods, to assess the probability that observed associations reflect actual causal effects, to incorporate multiple sources of uncertainty into the decision- making process, and to evaluate the sensitivity of those conclusions to dif - ferent representations of external evidence. To facilitate the use of Bayesian approaches, FDA should develop a guidance document for the use of Bayes - ian methods for assessing a drug’s benefits, risks, and benefit–risk profile. Finding 3.3 Traditionally, the main criteria for evaluating a study are ones that contribute to its internal validity. A well-conducted RCT typically has higher internal valid - ity than a well-conducted observational study. Results of observational studies,

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20 STUDYING THE SAFETY OF APPROVED DRUGS however, can have greater transportability if their participants are more similar to the target clinical population than to the participants in a clinical trial. In some circumstances, such as an evaluation of the association between a drug and an uncommon unexpected adverse event, observational studies may produce esti - mates closer to the actual risk in the general population than can be achieved in clinical trials. In assessing the relevance of study findings to a public health ques- tion, 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. Finding 3.4 The principles of reproducible research are important for ensuring the integrity of postmarketing research used by FDA. Those principles include providing informa- tion on the provenance of data (from measurement to analytic dataset) and, when possible, making available properly annotated analytic datasets, study protocols (including statistical analysis plan) and their amendments, and statistical codes. Recommendation 3.4 All analyses, whether conducted independently of FDA or by FDA staff, whose results are relied on for postmarketing regulatory decisions should use the principles of reproducible research when possible, subject to legal con- straints. To that end, FDA should present data and analyses in a fashion that allows independent analysts either to reproduce the findings or to understand how FDA generated the results in sufficient detail to understand the strengths, weaknesses, and assumptions of the relevant analyses. Finding 3.5 The ability of researchers in and outside FDA to analyze new information about the benefits and risks associated with a marketed drug and to design appropriate postmarketing research—including conducting individual-patient meta-analy - ses—is enhanced by access to data and analyses from all studies of the drug and others in the same drug class that were reported in the preapproval process. Although disclosure of such information is likely to advance the public’s health, such disclosures raise concerns about the privacy of participants in the research

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21 SUMMARY that generated the information and may threaten industry interest in maintain - ing proprietary information, which is deemed important for innovation. New approaches to resolving this tension are needed. Recommendation 3.5 FDA should establish and coordinate a working group, including industry and patient and consumer representatives, to find ways that appropriately balance public health, privacy, and proprietary interests to facilitate disclosure of data for trials and studies relevant to postmarketing research decisions. Finding 3.6 The elements of the benefit–risk profile of a drug are best estimated by using all the available high-quality data, and meta-analysis is a useful tool for summarizing such data and evaluating heterogeneity. However, because the reporting of harms in published RCTs and observational studies is often poor or inconsistent and because there is often substantial publication bias in studies of drug risk, steps are needed to improve both the reporting of harms and the design of studies of harm. That can be done through prospective planning for selected meta-analyses and by monitoring compliance with the FDAAA requirement that summary trial results for all primary and secondary outcomes be published at ClinicalTrials.gov. 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. gov. Finding 3.7 FDA produced a high-quality guidance document on the use of the noninferiority design for the study of efficacy. Increasingly, FDA is using the noninferiority design to evaluate drug safety endpoints as the primary outcomes in randomized trials. The use of noninferiority analyses to establish the acceptability of the benefit–risk profile of a drug can take the decision about how to balance the risks and benefits

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22 STUDYING THE SAFETY OF APPROVED DRUGS of two drugs out of the hands of regulators. Noninferiority trials also have the disadvantage of being biased toward equivalence when trial design or conduct is suboptimal; this is of particular concern when such trials are used to estimate risks. Recommendation 3.7.1 FDA should develop a guidance document on the design and conduct of noninferiority postmarketing trials for the study of safety of a drug. The guid- ance should include discussion of criteria for choosing the standard therapy to be used in the active-treatment control arm; of methods for selecting a noninferiority margin in safety trials and ensuring high-quality trial conduct; of the optimal analytic methods, including Bayesian approaches; and of the interpretation of the findings in terms of the drug’s benefit–risk profile. Recommendation 3.7.2 FDA should closely scrutinize the design and conduct of any noninferiority safety studies for aspects that may inappropriately make the arms appear similar. FDA should use the observed-effect estimate and confidence interval as a basis for decision-making, not the binary noninferiority verdict. 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 deci- sion that might be protective of public health. Some conditions are necessary but not sufficient for an FDA decision to require postmarketing research to be ethical. Recommendation 4.1.1 FDA should require postmarketing research only when (1) uncertainty about the benefit–risk balance is such that a responsible decision about the future regulatory status of the drug cannot be made on the basis of existing evidence; (2) it is expected that the research can be properly designed and implemented to reduce uncertainty about the benefit–risk profile to allow a responsible regulatory decision; (3) FDA has a plan for using the results of the research to make a regulatory decision in a timely fashion; and (4) the research can be conducted in a manner that provides sufficient protection of and respect for research participants. Finding 4.2 For postmarketing investigations authorized under Section 901 of FDAAA,12 FDA can require an RCT only if it is unable to obtain the data that it needs from an observational study or surveillance. Determining what kind of study will pro - 12 21 USC § 355(o) (2010).

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23 SUMMARY vide the information needed to answer FDA’s public health question, however, is complex. In the postmarketing setting, both observational studies and RCTs have advantages and disadvantages. In some circumstances, the evidence provided by an observational study may be as good as or better for informing a public health question than the evidence provided by a feasible clinical trial; that is more likely to occur when the magnitude of the relative risk is large in contrast with the potential for confounding, which occurs with many drug harms. Observational studies also have a number of ethical and practical advantages over RCTs. In other circumstances, however, the evidence available from an observational study would not be able to provide the necessary additional information to help answer the public health question. Those instances are more likely to occur when the public health questions are related primarily to a drug’s benefits. 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. Finding 4.3 When FDA requires a postmarketing RCT, the public health question is most likely to be properly addressed by a comparison of the target drug with the standard ther- apy for the condition involved—if there is a standard therapy. Such a trial would involve a “head-to-head” design, defined as a comparison of two active treatments that are indicated for the same patients who have the same condition. However, it is also important both scientifically and ethically for at least one clinically acceptable comparator in the required trial to have a well-defined benefit–risk profile. Recommendation 4.3 If FDA requires a postmarketing RCT for an indication for which there is an accepted active treatment that would probably be used if access to the drug under study were restricted, the alternative treatment should be used as at least one comparator in the trial. Finding 4.4 When deciding whether to require a postmarketing study, FDA must balance its ethical obligation to protect the public’s health with its ethical obligation to

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24 STUDYING THE SAFETY OF APPROVED DRUGS protect research participants. In some instances, FDA may be faced with a deci - sion to require an RCT that might expose participants to more net risk than they would probably face if decisions about their drug treatment were being made in the context of clinical practice or that offers no reasonable expectation of clinical benefit to participants although its results may benefit society. Requiring such a study may be ethically justifiable but only under special circumstances. Recommendation 4.4 FDA should require a postmarketing RCT that might expose research par- ticipants to more risk or less net clinical benefit than they would probably face if decisions about their drug treatment were being made in the context of clinical practice only if a question of pressing public health significance is at stake, if no other design with a better benefit–risk balance for participants could supply the evidence needed for a responsible regulatory response to the question, and if special safeguards are in place to protect the rights and interests of the research participants. Those safeguards should include the determination by an appropriately constituted review committee that the additional risk is small enough for it to be ethical to ask people whether they are willing to accept it solely to contribute to the public good; the minimiza- tion of additional risk by careful study design and implementation of a robust monitoring plan throughout the study; the inclusion of special measures in the process of soliciting informed consent to confirm that patients understand and willingly accept that they are assuming an additional risk, beyond what they are likely to face in clinical practice, solely in the interest of the public good; and the implementation of processes to ensure that over the course of the trial participants are regularly informed of any changes in clinical practice or the medical literature relevant to assessments of the comparative benefits and risks associated with trial participation and (nonresearch) clini - cal management. Finding 4.5 Although regulations governing human subjects research do not apply if an activ - ity is considered public health practice, as is the case with the Sentinel system, it is often not possible to draw a clear or ethically relevant distinction between some kinds of FDA-required observational research and public health practice. It is important that FDA, in conjunction with the Office for Human Research Protections (OHRP), 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) in oversight and research-participant protection, including consent requirements,

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25 SUMMARY in different observational designs so that its regulations are not a barrier to what would otherwise be ethically acceptable observational designs. FDA also needs to determine how best to ensure that it is feasible for drug companies and their contractors to conduct the postmarketing observational studies that it requires, in view of the Health Insurance Portability and Accountability Act of 1996 and other potential constraints, while protecting the privacy of the people whose data are used. It is also likely that the desirability of linking datasets and of obtaining additional information from patients or otherwise needing access to some iden - tifying information about patients will increase, whether studies are conducted under the auspices of FDA-supported surveillance systems, such as Sentinel and deemed public health practice, or conducted by manufacturers as required by FDA and interpreted at least by some to be research, raising additional ethical questions about the adequacy of data security, authorization of access to different datasets, and different research and public health purposes. Recommendation 4.5.1 FDA, in conjunction with the Office for Human Research Protections (OHRP), 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) in oversight and research-participant protection, including consent requirements. Recommendation 4.5.2 To assure the public that surveillance and required observational studies can proceed with appropriate controls and protections, and to facilitate the con - duct of ethically acceptable surveillance and required observational studies that are important to the public’s health, FDA should form an independent body to advise FDA, on an as needed basis, on the ethics of postmarketing research and surveillance activities that it conducts or requires. This advisory body should be positioned to provide guidance on emerging ethical chal - lenges, with particular focus on activities that are determined not to require IRB oversight. Finding 4.6 FDA has an ethical obligation to ensure that the rights and interests of participants in the postmarketing research that it requires are properly protected. IRBs and data-monitoring committees (DMCs) can play a critical role in assisting FDA with this obligation, but these bodies require information and guidance from FDA to be effective in their research-participant protection responsibilities.

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26 STUDYING THE SAFETY OF APPROVED DRUGS Recommendation 4.6 For all postmarketing research that it requires and that is subject to IRB or DMC oversight, FDA should provide each IRB (including centralized IRBs and multiple IRBs) and each DMC with the up-to-date BRAMP document for the study drug and sufficient information in writing for the IRB or DMC to provide appropriate oversight, including information about the public health question at issue, the specifics of the study design intended to address the question, design features that FDA views as necessary for the ethical justification of the study, and any changes in clinical practice or profes- sional standards that arise over the course of the study that might affect the benefit–risk profile of a drug and influence a person’s decision to participate or remain a participant in the study. 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. Recommendation 4.7 FDA should issue guidance for interpreting disclosure and informed consent requirements in applicable federal regulations in the context of postmarket - ing RCTs that it requires, using the authorities granted to it in Section 901 of FDAAA13 to help oversight bodies (such as IRBs) to ensure that such trials include a comprehensive informed consent process. The guidance should emphasize that, in addition to standard disclosure requirements, the follow - ing information of particular importance in the postmarketing setting should be communicated to research participants: why a new study of an approved drug is being required; salient risks posed by participation in required post - marketing research, including whether new information suggests that the drug under study may pose serious risks; and whether medical practice has shifted or is shifting away from prescribing the study drug. The guidance should make clear that participants must be informed of any substantial changes in clinical practice and professional standards over the course of the trial and informed of any new research findings relevant to their willingness to accept or to continue to accept the risks associated with the trial. And the guidance should identify the conditions under which consent processes should include measures to validate the adequacy of participants’ understanding, not only the adequacy of the disclosures made to participants. 13 2 1 USC § 355(o) (2010).

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27 SUMMARY Finding 4.8 During the last two decades, the volume of clinical trials conducted outside the United States has increased dramatically, and this has led to concerns about the quality, reliability, and transportability of research results and about the adequacy of protections for research participants. Those concerns apply as well to FDA- required postmarketing research that uses research sites outside the United States. 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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