4

Selection and Oversight of Required Postmarketing Studies

In keeping with a commitment to a lifecycle approach to benefit–risk management, Chapter 2 offered recommendations related to how the US Food and Drug Administration (FDA) should decide among multiple regulatory actions when conducting periodic assessments of the benefit–risk profiles of marketed drugs. Deciding which regulatory action to pursue takes on particular importance when new information about a benefit–risk profile emerges. The present chapter focuses on one of FDA’s possible regulatory actions: to require that the manufacturer conduct postmarketing research.1 It assumes that FDA has determined that it is appropriate to require postmarketing research.2 The committee recommends that FDA use the framework presented in Chapter 2 to make this determination. However, regardless of how the decision is reached, this chapter provides guidance to FDA in deciding what types3 of study designs should be required and in meeting its ethical responsibilities in making that determination and in providing

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1The committee includes clinical trials, observational studies, and meta-analyses in the terms study and research. That is in contrast with the Food and Drug Administration Amendments Act (FDAAA) of 2007, in which study is used to refer to “all investigations other than clinical trials”. FDAAA defines a clinical trial as “any prospective investigation in which the sponsor or investigator determines the method of assigning the investigational product or other interventions to human subject(s)”.

2This judgment by FDA presupposes that it has already determined that it cannot get the information it needs from additional surveillance activities, such as using Sentinel.

3It is important to note that FDA could require multiple investigations or a staged approach, in which it could start by requiring an observational study and then require a randomized controlled trial if the observational one does not produce sufficient evidence for decision-making. Because FDA could require multiple postmarketing studies in response to concerns about a particular drug, the committee refers to the “types” of research design that FDA might require. Use of the plural does not mean that FDA would never require a single investigation of some type.



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4 Selection and Oversight of Required Postmarketing Studies In keeping with a commitment to a lifecycle approach to benefit–risk man - agement, Chapter 2 offered recommendations related to how the US Food and Drug Administration (FDA) should decide among multiple regulatory actions when conducting periodic assessments of the benefit–risk profiles of marketed drugs. Deciding which regulatory action to pursue takes on particular importance when new information about a benefit–risk profile emerges. The present chapter focuses on one of FDA’s possible regulatory actions: to require that the manufac - turer conduct postmarketing research.1 It assumes that FDA has determined that it is appropriate to require postmarketing research.2 The committee recommends that FDA use the framework presented in Chapter 2 to make this determination. However, regardless of how the decision is reached, this chapter provides guid - ance to FDA in deciding what types3 of study designs should be required and in meeting its ethical responsibilities in making that determination and in providing 1 The committee includes clinical trials, observational studies, and meta-analyses in the terms study and research. That is in contrast with the Food and Drug Administration Amendments Act (FDAAA) of 2007, in which study is used to refer to “all investigations other than clinical trials”. FDAAA defines a clinical trial as “any prospective investigation in which the sponsor or investigator determines the method of assigning the investigational product or other interventions to human subject(s)”. 2 This judgment by FDA presupposes that it has already determined that it cannot get the information it needs from additional surveillance activities, such as using Sentinel. 3 It is important to note that FDA could require multiple investigations or a staged approach, in which it could start by requiring an observational study and then require a randomized controlled trial if the observational one does not produce sufficient evidence for decision-making. Because FDA could require multiple postmarketing studies in response to concerns about a particular drug, the committee refers to the “types” of research design that FDA might require. Use of the plural does not mean that FDA would never require a single investigation of some type. 169

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170 STUDYING THE SAFETY OF APPROVED DRUGS oversight once research is under way. This chapter thus expands the committee’s responses to Questions 1, 3, and 4 of its charge (see Box 1-1). The chapter begins with a discussion of relevant features of the complex postmarketing context that bear on the selection of the types of designs to require. It then puts forward two sets of considerations that frame the decision problem more specifically: the scientific and practical criteria for assessing the advantages and disadvantages of alternative research designs and the statutory conditions and ethical preferences that often favor observational designs over random- ized controlled trials (RCTs) in the postmarketing setting. It then identifies the conditions under which it is acceptable for FDA to require each. The committee then discusses factors that affect choosing among types of observational studies and RCTs, once it has been decided to require an observational design, an RCT design, or both. That discussion is followed by an analysis of the ethical con - siderations that should guide the design and conduct of postmarketing research, including issues related to informed consent and safety monitoring, and FDA’s ethical obligations in the postmarketing setting. THE POSTMARKETING CONTEXT Because concerns about a drug’s benefit–risk profile can emerge throughout a drug’s lifecycle, the decision by FDA to require a manufacturer to conduct postmarketing research can occur when the drug is first approved or at any time thereafter. In the premarketing setting, the RCT is the standard for providing the efficacy data used by FDA to make approval decisions, although occasionally less-well-controlled designs have been accepted if the effect is of sufficient magnitude. In contrast, population-based observational designs, which require drug use in larger clinical populations, play no role in approval decisions unless approval in other countries has provided opportunity for observational study. Over the years, the agency has amassed considerable expertise in the design and interpretation of RCTs and in the ethics of randomizing research participants to receive unapproved, investigational drugs. For example, FDA has provided guidance documents on good clinical practice, institutional review boards, and informed consent (FDA, 2011a), and FDA officials have opined on when it is ethically acceptable to use placebos, rather than active comparators, to evaluate an investigational drug (Ellenberg and Temple, 2000; FDA, 2001; Temple and Ellenberg, 2000). FDA has less experience in undertaking comprehensive assessments of the ethical and scientific issues arising in the postmarketing context, which differs from the premarketing context in several relevant respects. For example, in the premarketing context, a drug’s manufacturer sponsors all the research with the investigational drug and generally uses randomized controlled designs developed in consultation with FDA (after Phase 1 and early Phase 2 studies); in contrast,

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171 SELECTION AND OVERSIGHT OF REQUIRED POSTMARKETING STUDIES in the postmarketing setting, FDA may be responding to new information about a drug whose benefit–risk profile has been or is being studied by multiple inves - tigators, supported by various funders, using a variety of observational and RCT designs. FDA’s decision about what kinds of studies it should require to assess a drug’s benefit–risk profile after the drug is on the market may depend heavily on its critical assessment of the evolving evidence base and the evidential gaps that may remain. Because in the postmarketing setting patients may have been taking a drug for many years and others will continue to be prescribed the drug, FDA has the option of requiring observational studies that use existing or routinely collected patient information, an alternative that is not available in the premar- keting context. Another difference between the premarketing and postmarketing contexts is that after marketing FDA can require both observational studies and RCTs, either simultaneously or sequentially. Although in the premarketing set - ting FDA can require multiple research designs and studies, its process typically is to pursue the sequence and progression of research from Phase 1 to Phase 3. In the premarketing setting for a new molecular entity, access to the investi- gational drug by patients is possible only through participation in research con - ducted to satisfy FDA premarketing requirements or through a few other selected avenues that are also controlled by FDA, such as expanded access through “com- passionate use” (FDA, 2011b). In the postmarketing setting, physicians are free to prescribe a drug to any patient for whom they think it medically appropriate. In most cases, if a doctor and a patient decide that it is in the patient’s medical best interests to take the drug, the patient does not have to enter a research study required by FDA to have access to it. In the premarketing context, FDA regulators and the manufacturer typically focus on the drug’s benefit–risk relationship compared with a placebo and use active comparators less often, typically when it is either ethically or method - ologically necessary, such as to evaluate assay sensitivity. In the postmarketing context, concerns about a drug’s benefit–risk profile are more likely to involve comparisons with other active treatments. For example, although at the time of approval and for some time thereafter a drug that poses serious risks may have a favorable benefit–risk profile, the acceptability of its profile may come into question when a new drug becomes available and appears to offer comparable benefits with less severe risks. In the case of Avandia® (rosiglitazone), the presence in the marketplace of the clinical alternative pioglitazone, a similar drug with a purportedly more acceptable benefit–risk profile, affected the public controversy and FDA’s response to it. Although the remit of FDA is not to ensure that the drug supply contains only the comparatively “best” drugs for an indication, it has a duty to the public’s health to remove or restrict from the supply drugs that pose unaccept- able risks in relation to benefit. In this respect, FDA’s responsibility to ensure that drugs continue to have a favorable benefit–risk profile may on occasion move the focus of required postmarketing research more toward comparative-effectiveness

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172 STUDYING THE SAFETY OF APPROVED DRUGS research or comparative-safety research, which entails the scientific and ethical challenges of doing research in the context of “regular” clinical practice. The public health question at issue in the postmarketing setting is typically what the effect will be of a regulatory decision to limit the use of or withdraw a drug from the market. To answer that question, studies must include the comparators that are most likely to be used in lieu of the drug. 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 research participants who participate in the research that supports the agency’s deci- sions about drug benefits and risks. In both the premarketing and postmarketing contexts, FDA must balance those potentially competing obligations. Difficult choices must be confronted when a study design that seems to offer the great- est potential for obtaining knowledge relevant to the public health question also involves the greatest burden on and risks to research participants. In the postmarketing setting, there may be circumstances in which it is ethically acceptable to ask patients to participate in research that exposes them to possible risks that are not likely to be outweighed by the prospect of clinical benefit to them, and that are readily avoidable if they use treatment options that are available outside research participation. Although the risks to research par- ticipants are required to be “reasonable in relation to anticipated benefits of the research to subjects and society”, there is substantial consensus in both domestic regulatory and other guidance documents that various ways of balancing benefit and risk can be ethically justified. An RCT that might expose research participants to more net risk than they would probably face in regular clinical practice or that offers participants no rea - sonable expectation of clinical benefit may be justifiable if 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 findings of the research in formulating its regulatory response, and special safeguards are in place to protect the rights and interests of the research participants. The safeguards should include (1) the determination by an appropriately constituted review committee that the additional net risk is small enough for it to be ethical to ask people whether they are willing to accept the risk solely to contribute to the public good, (2) the addi- tional net risk has been minimized by careful study design and implementation of a robust monitoring plan throughout the study, (3) special measures will be taken in the process of soliciting informed consent to confirm that patients understand and willingly accept that they are assuming a net risk beyond what they are likely to face in clinical practice solely in the interest of the public good, and (4) pro- cesses will be implemented 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 non–research-related clinical management.

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173 SELECTION AND OVERSIGHT OF REQUIRED POSTMARKETING STUDIES Given the complexity of the postmarketing background against which the determination of the types of studies to require must be made, the committee recognizes that there is no simple formula for making such decisions. Instead, it recommends that FDA use two sets of criteria to guide its decisions: general criteria for assessing the advantages and disadvantages of alternative research designs, and the statutory conditions and ethical preferences that favor observa - tional designs over RCTs in the postmarketing setting. REQUIRING OBSERVATIONAL STUDIES AND RANDOMIZED CONTROLLED TRIALS General Criteria in Selection of Required Postmarketing Studies In theory, and assuming that there is no public health need to obtain relevant evidence quickly, an ideal RCT would almost always provide the evidence that regulators need to identify the best regulatory response to the public health ques - tion of interest. The design of such an ideal hypothetical trial would be structured to be responsive to the scientific uncertainties that underlie the public health question that is the focus of the regulatory decision. For example, it would use standard therapy or placebo as the comparator, depending on which choice best suits the public health question; it would include patients who have severe disease if the public health question is about those patients; it would have a long duration if that was of interest from a public health standpoint; and so on. It would be designed to secure the best level of adherence that is achievable in a real-world setting. The hypothetical trial would also be designed to minimize bias, nontrans- portability, and random error. In practice, however, a number of constraints can make the ideal trial infea- sible. Ethical obligations to obtain informed consent mean that the patients in the trial are restricted to those willing to participate, which may not be representative of the source population in important respects, such as risk status. It may be diffi - cult to recruit sufficient numbers of willing patients. Adherence may not reach the maximum achievable. Patients can withdraw from a trial at any time, potentially losing outcome information. Information from studies published while the trial is going on may affect the willingness of patients or physicians to continue. All such departures from the ideal hypothetical trial contribute to imprecision, bias, and nontransportability of results. The challenge then is to design and conduct a postmarketing study or col - lection of studies that comes as close as possible to emulating the ideal hypo - thetical trial while accommodating important ethical and practical considerations. Depending on the circumstances, the type of study design that best approximates the ideal hypothetical trial may be an RCT, but it also may be an observational study, based either on existing data, or prospective data, with a protocol similar to an RCT, except for patient assignment. Deciding which design is better structured

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174 STUDYING THE SAFETY OF APPROVED DRUGS to generate the evidence needed to answer the public health question turns on a number of considerations, including • how strong the safety signal is that motivates the design, and whether it primarily involves an elevation in risk, a decrease in benefit, or both, for either the general population or a definable subgroup. • time-urgency of the regulatory response. • how large the change in risks or benefits must be, on both relative and absolute scales, to justify a regulatory response. • the potential for and likely magnitude of confounding. • the quality of data to be used in any given design on drug exposure, out- comes, confounders and effect modifiers. • how study design, conduct or context are likely to affect the transport- ability of the study results. • the logistical requirements of a design, including cost, data access, patient availability, and other determinants of feasibility. • ethical dimensions, consent, confidentiality, and study oversight. The first consideration is whether resolution of the public health question requires new evidence primarily on a drug’s benefits, its risks, or on both. In some cases, the benefit–risk profile is close enough to an unacceptable threshold that obtaining high-quality evidence on both in the same population, in the same study is critical for resolving the public health question. Questions about clinical benefit can arise either because original approval was on the basis of surrogate endpoints, or because a group is subsequently found in whom reduced or absent benefit is suspected. The latter situation falls under a “failure of expected phar- macological action of the drug”, which constitutes an adverse drug experience under FDAAA.4 These situations favor conduct of a large, high-quality RCT with a sufficient followup period to assess longer-term outcomes of interest and sufficient power to detect a risk elevation of public health importance. But if the benefits of a drug are well-characterized and a concern emerges about a new risk, there can be advantages to a broader range of designs, contingent on the other considerations listed. Combination strategies can be optimal for assessing both benefits and risks (Vandenbroucke and Psaty, 2008). The time interval over which the harms or ben- efits occur also will affect design. The latent period of some adverse effects (such as cancer) may be too long to ascertain prospectively, requiring retrospective designs examining patients in whom these outcomes that have already occurred. Observational designs that rely on electronic health records or claims data can be used to assessing such risks, whereas small, short-term RCTs can be used to 4 FDAAA (PL 110-8521) §§ 901(b), 905(a) (2007), USC §§ 355-1(b)(1)(E), (b)(4), and (b)(5) (2010).

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175 SELECTION AND OVERSIGHT OF REQUIRED POSTMARKETING STUDIES assess certain benefits detectable in that time frame, for example, symptom relief, physiologic effects, or biomarker effects. Second, timeliness is an important practical consideration in deciding among study designs. If a signal is of a serious, unexpected adverse event that gains public notice, the need to take action quickly can be paramount, requiring designs such as case-control studies or case-series with population controls or those based on administrative data, with potential for confounding. At the time of approval, large observational studies may not be feasible until a sufficiently large number of patients start to use the drug. As time passes, however, and more patients are using the drug, such studies become feasible. At that point, experimental studies may take more time to conduct than do observational studies that use existing data sources (such as a health-plan database). In some cases, the decision to require an RCT necessitates a tradeoff between a delay in generating high-quality evidence and a more rapid return of findings that are potentially confounded. As previously noted, the best approach may be a combination strategy in which a range of different observational study types are initiated, with a postmarketing trial required only if the required observational research does not adequately clarify the concern. Third and fourth are the issues of the magnitude of effect that is being sought, either with respect to benefit or harm, and how this magnitude compares to the expected or plausible degree of confounding. Very large relative increases in the background rate, such as the almost 1,000-fold increase in progressive multifo - cal leukoencephalopathy with natalizumab treatment in patients with multiple sclerosis or Crohn’s Disease (Drazen, 2005; Kleinschmidt-DeMasters and Tyler, 2005; Langer-Gould et al., 2005; Van Assche et al., 2005), or the greater than ten-fold increase in intussusception seen with rotavirus vaccine, are likely beyond the bounds of anything that can be explained through imbalances on other risk factors for those outcomes, that is confounders. In the setting of large relative risks for an adverse event, designs with quite weak control of confounding, like those that compare the number of cases arising from an exposed population to an expected number based on background population rates, might be sufficient for public policy purposes. On the other hand, relative risks of 1.20 to 2.0, within the reach of plausible confounding (depending on case-specific considerations), might require designs with substantial confounding control, such as an RCT or an observational study with a very strong instrumental variable, mimicking ran - domization. The degree of plausible confounding due to known factors can be modeled, as can be the strength of confounding due to unknown or unmeasured confounders that would be sufficient to create (or obscure) a relationship of a given magnitude (Greenland, 2005). Another issue when considering the magnitude of effect that must be detect - able by a given design is what degree of increase would be relevant to the policy decision. An increase of a rare effect, or one not designated as a “serious adverse event”, might not be sufficient to outweigh a drug’s benefit. A design is needed

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176 STUDYING THE SAFETY OF APPROVED DRUGS that is sufficient to detect a policy-relevant increase in that outcome, which again might justify an observational design with weak confounding control if the policy-relevant effect is large, or a stronger design if the effect is small rela - tive to the potential for confounding. If the event, like myocardial infarction, or serious asthma exacerbations, has a high background rate in the population, then relatively small relative increases (for example, 20 percent to 30 percent) in that rate could raise the absolute risk in the population sufficiently to offset the drug’s benefit. In choosing designs for the postmarketing assessment of either benefit or risk, the key considerations then become how large an effect in either benefit or risk is necessary to be of policy relevance. Fifth is the quality of available data, discussed in Chapter 3. If existing data are of sufficient completeness and quality, it may be possible to provide the evi - dence that regulators need through an observational design based on that data. With the advance of sophisticated electronic medical records in integrated health care systems that capture patient data accurately and efficiently, and analytic techniques that allow greater approximation of inferences generally reserved for randomized designs, the likelihood that observational studies based on existing data will on occasion be able to provide high-quality evidence about postmarket - ing risks and, in some cases, postmarketing benefit increases. Indeed, with those developments and the advent of the Sentinel initiative and the Observational Medical Outcomes Partnership (OMOP), observational research is likely to play a larger role in postmarketing risk research, whether conducted by manufacturers as required by FDA or conducted by FDA directly or through FDA contractors (Reskin, 2007; Stang et al., 2010). Even as data sources continue to improve, however, Evans (2012) points out that drug companies and the academic research- ers and research firms with which they contract may face challenges accessing data needed for large-scale observational studies held by health care systems, insurance companies, and the like. Such entities are subject to the Privacy Rule and the Administrative Simplification Rule5 developed in response to the Health Insurance Portability and Accountability Act of 1996 (HIPAA; PL 104-191) which sets strict limits on their ability to release the information in their databases to others (see below for further discussion). Sixth is the likely transportability of results from a given study. The target population at risk must be defined, and the achievable design measured against its relevance for that population. For example, the public health question may be whether the drug has an acceptable benefit–risk profile in high-risk patients, but the RCT that is deemed feasible may need to exclude some people at high risk for either ethical or practical reasons (for example, patients who have severe disease that may be difficult to enroll and keep under observation). Another factor that often differs between controlled trials and observational studies of community practice is the degree of monitoring or expertise involved in care. If proper use 5 45 CFR Parts 160 and 164, Subparts A and E.

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177 SELECTION AND OVERSIGHT OF REQUIRED POSTMARKETING STUDIES of a drug, like warfarin, involves close monitoring of drug levels or drug effects (for example, coagulation measures), then the hazards posed by the drug from non-optimal monitoring in non-investigational settings may not be replicable in designs in which the patient is prospectively followed. Seventh is whether a given design is feasible, with the key factors being patient availability, data availability, cost, and other logistical factors. Some observational studies require only a review of existing data and thus do not require the direct participation of patients or clinicians, but do require this data to be adequate to address the question. With respect to patient availability, there needs to be a sufficient sample of comparable patients both taking and not tak- ing the drug to detect a safety signal of a given magnitude. To the extent that an RCT excludes patients with particular conditions from participation, the pool of people eligible for the study decreases, and it may be challenging to enroll suf - ficient numbers of participants. Observational studies, either prospective or based on existing data, can typically involve more patients, but this must be assessed against the potential for confounding, selection bias, and measurement error. The act of consent or extensive pre-screening can reduce the pool of patients for both observational studies and RCTs, but the need to agree to randomization in the latter case often reduces that enrollment yet further. Finally, are ethical dimensions in study design, including consent, confiden - tiality, and study oversight. Discussions of these elements follow in subsequent sections. The Presumption in Favor of Observational Designs FDAAA provides FDA with a starting point for decisions about which type of postmarketing studies to require. FDAAA specifies that in the postmarket - ing setting FDA may require an RCT only when sufficient information cannot be obtained from an observational study. Specifically, the law states that “[t]he Secretary may not require the responsible person to conduct a study under this paragraph, unless the Secretary makes a determination that the reports under sub- section (k)(1) and the active postmarket risk identification and analysis system as available under subsection (k)(3) will not be sufficient to meet the purposes set forth in subparagraph (B)”, and that “[t]he Secretary may not require the respon - sible person to conduct a clinical trial under this paragraph, unless the Secretary makes a determination that a postapproval study or studies will not be sufficient to meet the purposes set forth in subparagraph (B)”.6,7 Thus, the statute explicitly specifies a priority for observational study designs. The committee notes that 6 21 USC § 355(o)(3)(D)(i), (ii). 7 The reports referred to in subsection (k)(1) are from the drug sponsor’s records of “data relating to clinical experience and other data or information”. FDA’s Sentinel system is the “active postmarket risk identification and analysis system as available under subsection (k)(3)” of FDAAA.

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178 STUDYING THE SAFETY OF APPROVED DRUGS FDAAA does not provide an explanation for the particular design hierarchy that it imposes on FDA’s authority to require manufacturers to conduct postmarketing studies. Clinical trials are generally more expensive and complicated to conduct than observational studies and so are more burdensome for manufacturers. A common view in the ethics of research is that observational studies are also less burdensome for research participants (FDA, 2010a). All observational studies of a drug’s benefits and risks, however, are not equal in their ethical implications. Some observational studies ask patients to respond to surveys or to use special devices that monitor adherence to drug regimens; others impose no burdens on patients and rely only on information available in health records. It is not the case that observational studies are neces - sarily less risky to patients than randomized designs. Some observational stud - ies impose no clinical risks on patients beyond what they would experience in ordinary clinical care, but that is also true of some RCTs. However, studies that alter the clinical experience of participants with regard to how their medical condition will be diagnosed or treated generally require more justification and greater protections and oversight than studies that do not. That is so not because they necessarily impose more risks on research participants or because they necessarily offer participants less in the way of offsetting clinical benefits, but because research that alters the clinical experi - ence of patients in such ways also is likely to alter the norms and expectations of the clinical encounter. Most notably, in the traditional clinical context, treat - ment choices are made with the intent of bringing about the best outcome for the patient that is commensurate with the patient’s values and priorities. That is, they are driven by the patient’s and the physician’s assessment of that patient’s interests. In contrast, treatment assignment in clinical RCTs is determined ran - domly. Although maximizing benefits and minimizing risks to the particular patients participating in a trial remain goals, these considerations do not deter- mine treatment assignment. Rather, in many trials, both the array of available therapeutic options and the method by which research participants are assigned to them are driven by scientific objectives—that is, the need to obtain a valid answer to a scientific question. Patients are sometimes better off if they receive their medical care through participation in research that modifies their clinical experience than if they receive it through standard medical practice, even if the modification includes randomization of treatment, that is, there are collateral benefits to participating in a study (King, 2000). In some studies, research-related alterations in clinical management may redound to participants’ clinical benefit. In the premarketing context, research participation in a clinical trial may be the only way patients can secure access to a promising new intervention. Although the outcome is uncertain, randomization to the experimental arm of a clinical trial may—if the investigational therapy proves efficacious, safe, and well-tolerated—result in improved health compared with what is likely under standard care. Participation

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179 SELECTION AND OVERSIGHT OF REQUIRED POSTMARKETING STUDIES in premarketing clinical trials can be especially attractive for patients who have few if any clinical options. In the postmarketing context, the potential advantage of access to a prom- ising experimental intervention is less relevant; unless distribution of the drug is restricted—for example, by a risk evaluation and mitigation strategy—or patients have financial barriers to access, the drug is available for physicians to prescribe in standard practice and thus for patients to use. Recruitment of research participants can be more problematic when the intervention or drug is available outside the trial (Campbell et al., 2004). One possible explanation is that patients are not interested in the uncertainty that randomization introduces when they already have unimpeded access to the treatment option that they prefer. The principal health advantage of research participation to patients in the postmarketing context, when FDA has required research in response to a safety signal, is the prospect that research participation may offer them regular or extra clinical monitoring. However, clinical monitoring may in the end involve more burden than benefit. The relative merits of RCTs and observational studies in the postmarketing context are thus more nuanced than the statutory conditions prioritizing obser- vational designs stipulated in FDAAA, which, for example, does not distinguish between observational studies that impose burdens or additional risks on patients and observational studies that do not. Nonetheless, because RCTs alter a particu - larly salient feature of a patient’s clinical experience in the postmarketing context, the committee believes that the general requirement established by FDAAA in favor of observational research is ethically justifiable and consonant with FDA’s ethical obligations to research participants in the postmarketing context. Circumstances Justifying the Requirement of Observational Studies and RCTs The circumstances under which FDA is justified in requiring a manufacturer to conduct a postmarketing observational study are those in which • uncertainty about the benefit–risk balance is such that a responsible deci- sion about the future regulatory status of the drug cannot be made on the basis of existing evidence or evidence that can be obtained by existing surveillance activities. • it is expected that an observational study can be properly designed and implemented to reduce uncertainty about the benefit–risk balance suf - ficiently to inform a responsible regulatory decision. • FDA will use the results of the observational study in making the regula- tory decision in a timely fashion. • the observational study can be carried out in a manner that provides suf- ficient protection of and respect for research participants.

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202 STUDYING THE SAFETY OF APPROVED DRUGS recommendations and constitute a forum where logistics of data-sharing could be explored. That information should be included in the drug’s BRAMP. FDA has an obligation to ensure that the postmarketing studies that it requires are conducted ethically. The main mechanisms through which FDA can honor that obligation are requiring studies whose designs can provide the evidence needed to help to resolve a public health question, assessing the ethics of candidate designs as it makes its determination about what kinds of studies to require, and accepting specific responsibilities to work closely with IRBs and, when it is appropriate, DMCs to protect the rights and interests of research par- ticipants. It is the committee’s view that FDA has expertise and information that are critical for research participants protection and that these must be routinely shared with IRBs and DMCs. Finally, in required postmarketing research, people are being asked to participate in research or to have information about them used to advance the public’s health. An FDA decision to require postmarketing research is ethical only if the findings of the research are put to that common goal. FDA must take steps to ensure that postmarketing research that it requires is completed in a timely fashion and should use the findings of the research in making its regulatory response to the public health question. FINDINGS AND RECOMMENDATIONS Finding 4.1 A decision by FDA to require postmarketing research can put research partici - pants at risk. It can also put patients and the public at risk by delaying a regulatory decision 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.

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203 SELECTION AND OVERSIGHT OF REQUIRED POSTMARKETING STUDIES Finding 4.2 For postmarketing investigations authorized under Section 901 of FDAAA,19 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 - 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 therapy 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 con - dition. 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. 19 21 USC § 355(o) (2010).

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204 STUDYING THE SAFETY OF APPROVED DRUGS 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 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,

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205 SELECTION AND OVERSIGHT OF REQUIRED POSTMARKETING STUDIES 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, 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.

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206 STUDYING THE SAFETY OF APPROVED DRUGS 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. 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 professional standards that arise over the course of the study that might affect the risk– benefit 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 FDAAA20 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 20 2 1 USC § 355(o) (2010).

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207 SELECTION AND OVERSIGHT OF REQUIRED POSTMARKETING STUDIES 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. 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. REFERENCES Appelbaum, P. S., L. H. Roth, C. W. Lidz, P. Benson, and W. Winslade. 1987. False hopes and best data: Consent to research and the therapeutic misconception. Hastings Center Report 17(2):20-24. Campbell, M. K., C. Snowdon, D. Francis, D. Elbourne, A. M. McDonald, R. Knight, V. Entwistle, J. Gracia, I. Roberts, and A. Grant. 2004. Recruitment to randomised trials: Strategies for trial enrollment and participation study. The STEPS study. Vol. 11. London, England: Health Technology Assessments. Castro, W. M. 2007. Selenium in critically ill patients with systemic inflammatory response. Nutricion Hospitalaria 22(3):295-306. CHMP (Committee for Medicinal Products for Human Use). 2011. Reflection paper on the need for active control in therapeutic areas where use of placebo is deemed ethical and one or more established medicines are available. London, UK: European Medicines Agency. Concato, J., N. Shah, and R. I. Horwitz. 2000. Randomized, controlled trials, observational stud - ies, and the hierarchy of research designs. New England Journal of Medicine 342(25):1887- 1892.

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