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Ethical and Scientific Issues in Studying the Safety of Approved Drugs (2012)

Chapter: 4 Selection and Oversight of Required Postmarketing Studies

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Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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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.

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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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 randomized 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 considerations 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,

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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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 investigators, 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 premarketing 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 setting 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 investigational drug by patients is possible only through participation in research conducted to satisfy FDA premarketing requirements or through a few other selected avenues that are also controlled by FDA, such as expanded access through “compassionate 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 methodologically 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 unacceptable 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

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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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 decisions 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 greatest 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 participants 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 reasonable 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 additional 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) processes 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.

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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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 observational 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 question 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, nontransportability, and random error.

In practice, however, a number of constraints can make the ideal trial infeasible. 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 difficult 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 collection of studies that comes as close as possible to emulating the ideal hypothetical 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

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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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, outcomes, confounders and effect modifiers.

•  how study design, conduct or context are likely to affect the transportability 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 pharmacological 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 benefits 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

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4FDAAA (PL 110-8521) § 355-1(b)(1)(E), (b)(4), and (b)(5) (2010).

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
×

assessing such risks, whereas small, short-term RCTs can be used to 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 multifocal 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 randomization. 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 detectable 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

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
×

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 relative 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 evidence 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 postmarketing 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 researchers 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

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545 CFR Parts 160 and 164, Subparts A and E.

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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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 taking 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 sufficient 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, confidentiality, 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 postmarketing 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 subsection (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 responsible 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

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621 USC § 355(o)(3)(D)(i), (ii).

7The 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.

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
×

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 necessarily less risky to patients than randomized designs. Some observational studies 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 experience 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, treatment 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 randomly. Although maximizing benefits and minimizing risks to the particular patients participating in a trial remain goals, these considerations do not determine 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

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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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 promising 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 observational 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 particularly 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 decision 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 sufficiently to inform a responsible regulatory decision.

•  FDA will use the results of the observational study in making the regulatory decision in a timely fashion.

•  the observational study can be carried out in a manner that provides sufficient protection of and respect for research participants.

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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It should be emphasized that it would be unethical for FDA not to require an RCT in a context in which only an RCT can provide the kind of evidence needed to inform the regulatory decision on a public health question. FDAAA permits FDA to require an RCT in such cases. When the primary public health concern is about a drug’s risks, observational designs can often provide evidence of sufficient quality for regulatory decision-making. However, if the adverse event of concern can be pre-specified, is expected to occur frequently and soon after initiation of drug treatment, and the relative risk is moderate, RCTs may be more appropriate (Golder et al., 2011). In such cases, the quality of evidence produced by RCTs may be superior to that obtainable with observational studies,8 and, depending on the public health question and relevant ethical and practical considerations, the additional quality may be of sufficient regulatory importance to justify FDA’s requiring an RCT.

In addition, if evidence emerges that a marketed drug is not producing the intended effect—that is, it is not producing the clinical benefit that it was approved to produce—FDAAA allows FDA to require a study to re-evaluate the drug’s benefit–risk profile. Because the focus would be on the drug’s benefits, it is less likely that observational studies would provide evidence of sufficient quality to answer the public health question, given concerns about confounding and potential limitations in the ability to control for these concerns. RCTs are likely to be needed to aid decision-making when the primary concern in the postmarketing context is a drug’s intended effects or its effectiveness.

Thus, FDA is sometimes ethically justified in requiring a postmarketing RCT using its authorities in FDAAA.9 The circumstances under which FDA is justified in requiring a manufacturer to conduct a postmarketing RCT are those in which

•  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 or evidence that could be obtained from new observational studies.

•  it is expected that an RCT can be properly designed and implemented to reduce uncertainty about the benefit–risk balance sufficiently to inform a responsible regulatory decision.

•  FDA will use trial results in the making of the regulatory decision in a timely fashion.

•  the RCT can be carried out in a manner that provides sufficient protection of and respect for research participants.

Whether this last, independent condition is satisfied hinges on such issues as the ability to obtain meaningful informed consent, whether the risks to research

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8Basic design variations of RCTs are described in Strom (2005).

921 USC § 355(o) (2010).

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
×

participants in the trial can be justified, the presence of a robust safety-monitoring plan and other mechanisms for minimizing risk and harm to participants, and the equitable selection of participants.

Determining whether the other conditions are satisfied entails a thorough assessment of the evidence available and potentially available from observational studies. That assessment would be expected to address a number of questions, such as the following:

•  What are the limitations of the available evidence and the studies that provided it, and how important are these limitations?

•  Have possible uses of all existing data pertaining to the public health question been adequately explored?

•  What new information could FDA reasonably expect to obtain from new observational studies?

•  Would unacceptably large knowledge gaps or levels of uncertainty remain if FDA relied on observational studies or required additional observational studies to be conducted?

That determination also requires assessment of the likelihood that an RCT can provide the missing information with such questions as these:

•  Is it likely that a sufficient number of the eligible research participants could be recruited?

•  Is the expected timeframe of such a study to return information sufficient to inform FDA’s policy decision?

•  Would an appropriately designed RCT entail serious practicability issues?

DESIGN, ANALYTIC, AND ETHICAL CONSIDERATIONS IN SELECTING SPECIFIC OBSERVATIONAL AND RCT DESIGNS TO REQUIRE

Observational Studies

The determination by FDA that the additional evidence it needs to resolve a public health question can be obtained with observational studies presupposes that FDA has already identified a specific type of observational design that is both capable of generating the needed data and can be feasibly and ethically implemented. The success of an observational study in generating valid and reliable evidence requires access to sufficient high-quality data on the interventions compared, the outcomes of interest, and potential confounders to allow researchers to use analytic techniques that can approximate randomization to intervention assignment and preserve the study’s implications for causal inference.

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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As a general rule, observational studies should be designed so that the start of the clinical interventions to be compared coincides with the start of followup. Studies with followup observation that begins after the initiation of drug treatment may be affected by selection bias. If the drug affects the early risk of developing the outcome, then cases that occurred between the initiation of the drug and the initiation of followup will be disproportionately excluded from the treated group (Danaei et al., 2012; Hernán et al., 2008; Robins et al., 2007). Also, including people who are already taking the drug is problematic if the drug alters risk factors for the outcome of interest and thus makes controlling for potential confounders difficult. Controlling for potential confounders may result in adjusting for variables on the causal pathway and result in a false conclusion that there is no association between the drug and the outcome of interest (that is, a false-negative conclusion), but not adjusting for them may lead to confounding and biased estimates of the drug’s effect (Fisher, 1996).

One design to emulate the ideal hypothetical trial is the prospective cohort study in which a sample of persons (a cohort) is followed to see whether they develop the outcomes of interest. Like a clinical trial, these studies should have pre-specified protocols, endpoints, analytic plans, and procedures in place to ensure timely recruitment, adequate and uniform follow-up, ascertainment and adjudication of endpoints, and other steps to ensure data quality. Data on exposure (that is, drug treatment) and other covariates of interest are collected at baseline before the initiation of treatment and, depending on the specific design, may continue to be collected throughout the study. Patients are monitored throughout the defined risk period to determine whether and when they experience the event of interest. The data are analyzed to estimate the effect of the exposure on the outcome of interest among groups defined by exposure status.

Case–control and case–cohort designs may also be used to generate data on the endpoint of interest to the regulatory decision but use only a sample of persons in the cohort. Rather than selecting patients on the basis of the exposure of interest and observing whether they develop the outcome of interest, case–control designs select persons on the basis of whether they have experienced the outcome of interest and then select controls—persons who have not experienced the outcome of interest—to compare their past exposures (such as use of a particular drug). One potential weakness of such designs, if drug exposure is obtained, for example, by patient self report, is that the knowledge of the outcome is potentially known, and, therefore, can bias the ascertainment of the exposure. Steps must be taken to assure this does not occur.

Case–control and case–cohort designs are especially helpful when the measurement of a key variable is difficult or expensive, when health outcomes in an administrative claims database need to be validated against actual medical records, when the outcome is too rare to study prospectively, or when additional data collection is required to measure confounders. In those settings, case–control designs may be more efficient for emulating the hypothetical RCT by reduc-

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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ing the logistical burden of sampling and generating data. Box 4-1 provides an example of an observational case–control study that uses electronic health care records that detected an increased risk of an adverse outcome associated with the use of a drug.

Selecting the appropriate comparison group is key in the design of observational studies. In an RCT, randomization is used to ensure an equal distribution of measured and unmeasured risk factors in large samples, and this reduces the

BOX 4-1
Rofecoxib and Coronary Heart Disease:

An Observational Study

A nested case–control study was conducted with computer records from the database of an integrated managed-care organization to evaluate the risk of acute myocardial infarction (MI) and sudden cardiac death among users of rofecoxib and users of celecoxib and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) (Graham et al., 2005).a The study population comprised people who filled at least one prescription for rofecoxib, celecoxib, or a nonselective NSAID between January 1, 1999, and December 31, 2001; who met medical eligibility criteria; and who had at least 12 months of health-plan coverage before their entry into the cohort, which allowed the researchers to obtain data on potential risk factors for serious coronary arterial disease. The exposure status of cases and controls was classified on the basis of the number of pills dispensed, and ascertainment of outcomes was validated through studies of computerized hospital and laboratory data. A telephone survey of a “random sample of controls currently exposed to celecoxib, ibuprofen, naproxen, or rofecoxib, or controls with remote exposure to a NSAID” was used to assess potential confounding by variables that were not included in the computer database (such as use of over-the-counter NSAIDs, smoking, and family history of MI). The results of this observational study provided strong high-quality evidence that supported the hypothesis that the use of rofecoxib increases the risk of serious coronary heart disease compared with celecoxib and other NSAIDS. In fact, at a March 2007 Food and Drug Administration–organized, public meeting on the Sentinel system, Dr. Richard Platt discussed the potential of a system such as Sentinel, if it has enough sets of records, detecting a signal for myocardial infarctions within months of rofecoxib entering the market (FDA, 2007). Well-designed observational studies can provide evidence of sufficient quality for regulatory decision-making and may be completed in much less time than a randomized controlled trial.

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aClinical trials of rofecoxib are discussed in Chapter 2.

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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possibility of confounding. Through the selection of an appropriate comparison group, observational studies can emulate the hypothetical RCT and limit confounding by attempting to achieve a similar distribution of known risk factors between groups.

Observational cohort designs that come the closest to emulating an RCT are those that can build into their design a feature or “instrument” that mimics randomization. This instrument must be highly correlated with the receipt of treatment, but not by itself related to the outcome. In this way, treatment assignment can mathematically resemble the flip of a coin, determining treatment assignment but with no relation to the outcome. The most common “instrument” is practice location, when there is variation in the use of a particular drug that is a function of local practice patterns but that has little to do with the kinds of patients seen. When such an instrument exists, “instrumental variable” methods of analysis can produce results quite similar to randomized controlled trials (Hernán and Robins, 2006; Mcclellan et al., 1994). The validity of the assumptions underlying the claim for a given instrument, however, must be closely scrutinized; those assumptions typically cannot be tested empirically.

The choice of a comparison group can also affect measurement error. Some new drugs, especially ones that are first in their class (that is, the first drug in a given class to be used), may make the selection of a comparator difficult. For example, patients who are first to use a newly approved drug are likely to differ in many ways from patients who are using traditional and previously approved therapies. For example, they may have better insurance coverage or the ability otherwise to afford expensive new medications. Or they may not be doing well on previously approved therapies or may have physicians who are early adopters of new interventions. Such differences may influence the identification or ascertainment of health outcomes of interest.

Case reports or series are usually ranked near the bottom in traditional evidence hierarchies and are useful for generating hypotheses about features such as latency period, drug-drug interactions and susceptible populations, (Concato et al., 2000; Stolberg et al., 2004), but, for the most part, do not emulate the hypothetical RCT in relevant respects. However, they may in some cases be able to provide critical information about especially risky endpoints. As noted previously, an adverse effect may be so unusual and so rare in the untreated population that there is little need for a well-defined comparison group. Many drug-safety problems, such as drug-induced liver injury, are identified and confirmed by using little more than reported occurrence rates in exposed patients and general information about population rates of the adverse effect.

High-quality observational research can provide sufficient evidence to ground a well-reasoned regulatory decision; in some cases, such research can provide more relevant and timely evidence than any feasible RCT.

Observational studies of harm outcomes have some advantages over RCTs. In the case of some safety signals, additional analysis of the adverse-event report-

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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ing data with relative reporting rates (comparing observed to expected numbers of adverse event reports) may be the quickest method of obtaining additional information. For other signals, simple analyses of administrative data may be the best step; for still others, analytic epidemiologic efforts or designs that involve direct contact with patients may be required.

Choosing among observational designs requires that risks to research participation be reasonable in relation to a study’s expected benefits and that the risks be kept to a minimum. In observational study designs that rely exclusively on existing data, the major risk to participants typically is breach of confidentiality. Ethical concerns about such studies are tractable as long as the study protocol includes adequate provisions for data security and confidentiality that are closely adhered to by the investigators and research staff. Observational studies that involve collection of new data directly from participants raise further ethical issues related to the burden on participants. Such burdens may range from inconvenience and loss of time associated with the completion of questionnaires and interviews to physical risks associated with medical tests that are done purely for research purposes. Selecting an observational design that involves an increased burden on research participants over designs that involve a smaller burden requires a determination that the additional benefit outweighs the increased burden.

While often methodologically superior to studies that use existing data, an FDA-required postmarketing observational study that requires the collection of new data—such as a study for which followup begins at the same time as the start of the clinical intervention—can raise ethical issues that are parallel in some respects to the issues raised by an RCT, assuming both are initiated at the same time in the drug’s lifecycle. In both cases, some patients are starting to take a drug about which FDA is sufficiently concerned to require research. In the case of the observational study, the decision to take the drug is made by the treating physician in consultation with the patient; FDA plays no direct role in that decision. In the case of the RCT, the patient is randomly assigned to take the drug in a trial that FDA has required be conducted. As a consequence, FDA arguably has different ethical obligations to patients in the RCT than it has to patients in the prospective observational study. That said, from the standpoint of the rights and interests of patient participants, it is not possible to determine in the abstract if it is preferable for FDA to require a prospective observational study or an RCT. The answer to that question will depend on the specifics of the situation, including the nature and severity of the concern that prompted FDA to require research, the state of the relevant evidence, and current clinical practice patterns with regard to the drug and any alternative treatments. It is important to emphasize, however, that if FDA already had decided that the available evidence was sufficient to warrant a regulatory action to restrict access to the drug, it would not be requiring research.

Nevertheless, in such circumstances, there may be ethical advantages to FDA’s requiring an observational design that is retrospective in the sense that

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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patients have already been exposed to the drug of interest or its comparator, with the outcome already having occurred. Although physicians may continue to prescribe the drug, the success of the research does not depend on their doing so. Moreover, assuming that the public health question of interest can be adequately addressed, a retrospective design may allow FDA to better honor its ethical obligations to the public by allowing it to make a more rapid determination as to whether any new regulatory action is needed to protect the public’s health. The ability of such designs to provide the information FDA requires for regulatory action rests, in turn, not only on the availability of high quality of data but also on access to that data. Access is itself a function of ethical considerations related to privacy and authorization, a tension that the committee recognizes is likely to occur increasingly and in different forms; a structure to provide guidance on ethical challenges as they emerge over time could help FDA resolve such tensions, particularly for activities that are not or may not be subject to Institutional Review Board (IRB) review.

Randomized Controlled Trials

If FDA determines that the evidence that it needs to resolve a public health question includes data obtainable only with an RCT, it must then determine which type of RCT to require. Just as in the selection of observational studies, FDA should consider which RCT would best approximate the ideal hypothetical trial, subject to ethical, legal, and practical constraints.

As with observational studies, the choice of a comparator for a drug is an important element in the design of an RCT. If in current clinical practice there is no alternative treatment to the drug whose performance is to be studied, placebo-controlled trials or trials that involve standard care (such as symptom management) are the main options.10 Placebo-controlled trials have routinely satisfied FDA’s criterion of “adequate and well-controlled studies” for the purpose of drug approval.

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; in the postmarketing setting, there may be additional scientific reasons for considering an active-controlled design. As noted previously, the public health question at issue in most postmarketing regulatory decisions is whether the health of the public would on balance be better if the drug in question were removed from the market or its use were limited. Under either scenario, medical practice would presumably shift to alternative interventions, perhaps nonpharmacologic, if no drug for the same indica-

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10One difference between placebo-controlled studies and studies that use standard care is that blinding is possible in the former but typically not in the latter.

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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tion existed. In that situation, at least one arm of any postmarketing study should include the most likely alternative treatment. That does not mean that FDA must act to restrict use of the drug of concern if it proves inferior to its active control on either effectiveness or safety; to do so could constitute too fine a regulation of medical practice. Many drugs remain on the market when they have been superseded by newer therapies that have superior benefit–risk profiles. Sometimes these drugs are preferred by a subset of patients who have different perspectives on which risks are most important to avoid or minimize. But such comparisons would provide the needed evidence for a regulatory decision, including whether the availability of the inferior therapy constitutes a true public health risk because its benefit–risk profile is judged to be unacceptable.

The primary rationale for the use of the active-controlled design in the regulatory setting is sometimes an ethical one. The ethics of placebo-controlled trials have been discussed at length in the literature (Castro, 2007; CHMP, 2011; Emanuel and Miller, 2001; Halpern et al., 2002; Lurie and Wolfe, 1998; Miller and Rosenstein, 2002; Temple and Ellenberg, 2000). There is a longstanding view that it is unethical to conduct a placebo-controlled trial if an effective treatment that prevents or treats a serious or life-threatening condition is available. It may be ethically acceptable for FDA to require a placebo-controlled postmarketing trial even if an alternative treatment is available under some specific circumstances—such as studies of interventions intended to provide symptomatic relief for minor, self-limiting conditions—if the trial can answer the public health question. In addition, placebos are often used in short-term trials to evaluate surrogate endpoints, such as blood pressure or lipid profiles.

One RCT design that can be implemented most easily early after the introduction of a drug is a cluster randomized design, when regions, practices, or hospitals are randomized to use that drug for specified indications. This is more difficult but still possible once the drug is in wide use (Hennessy et al., 2010; Mazor et al., 2007; Platt et al., 2010). Cluster randomized designs combine some of the features and advantages of observational and randomized designs in being easier to implement randomization and enroll large populations, capturing many of the characteristics of care in community settings, and retaining advantages of randomization, but being somewhat more susceptible to confounding and having lower precision than an individually randomized RCT of equal size.

THE FOOD AND DRUG ADMINISTRATION’S ETHICAL OBLIGATIONS REGARDING THE CONDUCT AND OVERSIGHT OF REQUIRED POSTMARKETING STUDIES

As noted by the National Bioethics Advisory Commission, two principal mechanisms of protecting research participants are independent peer review, such as that provided by IRBs, and voluntary informed consent (National Bioethics Advisory Commission, 2001 #3514; National Bioethics Advisory Commission,

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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2001 #3514). To those can be added safety monitoring during the course of the research, which can be particularly important in the postmarketing context if concerns about risk have already been raised. This section addresses FDA’s duties to ensure that the postmarketing research it requires is conducted ethically; it explores FDA’s responsibilities with respect to each of the mechanisms of protection, including FDA’s role in the ethical oversight of such research.

Informed Consent Issues in the Postmarketing Setting

One component of FDA’s obligation to ensure that required postmarketing research is conducted ethically focuses on securing the voluntary informed consent of research participants. An important goal of the general requirement that research participants provide voluntary informed consent is to verify that they have freely agreed to participate on the basis of an accurate understanding of the research purpose and procedures, its potential benefits and risks, and the alternatives to participation. It is a basic principle of research ethics that participants who would be placed at risk in human research should receive an understandable, unbiased, accurate, and appropriate disclosure of the potential benefits and risks attached to study participation (DHEW, 1979; ICH, 1996). The general requirements for disclosure have been codified and described in federal regulations11 and are now well-understood by IRBs and investigators, particularly for premarketing studies. However, a few issues are worth noting when considering the application of informed consent requirements to studies of already marketed drugs.

Observational Designs

One key issue is that the ethical obligation to obtain prior informed consent is not applicable to all required postmarketing research; some observational designs are in many relevant respects similar to activities that are not considered to be research, or research with human participants. Surveillance and other activities undertaken by FDA to monitor for and pursue the benefits and risks of marketed drugs, including the activities of Sentinel (McGraw et al., 2012; Rosati et al., 2010), have been determined by relevant federal offices to be public health practice, and not research. A number of human-subjects research regulations, including those requiring informed consent, do not apply if an activity is considered public health practice. It is often impossible, however, to draw a clear or ethically relevant distinction between some kinds of observational research that FDA could require manufacturers to conduct and FDA activities that are classified as public health practice. For example, if FDA were to require a postmarketing

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11See, for example, the eight basic elements and six additional disclosures that FDA requires be presented to research subjects, at 21 CFR 50.25(a)(b). The same categories are found at 45 CFR 46.116(a)(b).

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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observational study that entailed only secondary use of de-identified data, as is the current practice in the Sentinel Initiative, requiring the consent of participants for that study but not for a Sentinel activity would be difficult to defend.

Nowhere is it clearly stated whether FDA’s human subjects regulations (21 CFR 50 and 56), rather than the Common Rule (45 CFR 46 Subpart A), are the operative regulations for FDA-required, postmarketing observational studies. FDA’s 2011 guidance to industry-related postmarketing requirements states that “[a]pplicants conducting postmarketing studies and clinical trials must continue to comply with … Health and Human Services (HHS) and FDA human subject protection regulations at 45 CFR part 46 and 21 CFR parts 50 and 56 when applicable”, but it is not clear whether FDA’s definition of “clinical investigations” includes any types of observational studies. It is also not clear whether in 21 CFR 50—which appears to have been designed with clinical trials in mind—observational studies are subjected to more, less or different requirements for review and consent than would be applicable under the Common Rule. For example, unlike the Common Rule, FDA’s human subjects regulation does not appear to permit exceptions to the informed consent requirement. Thus, even if HIPAA is not a significant obstacle to drug companies securing access to health information without prior consent for required postmarketing observational research, which Evans (2012) maintains is unlikely, FDA’s human subjects regulations might still impose informed consent requirements, making the conduct of at least some kinds of observational studies infeasible. Whether the barrier is HIPAA, FDA human subjects regulations, or both, as Evans (2012) argues, the end result might be restriction, if not elimination, of the role of at least some required observational studies from the arsenal of FDA’s responses to safety signals. That outcome would likely be ethically and scientifically unacceptable, and counter to the interests of the public’s health.

Going forward, it is important that FDA clarify whether its human subjects regulations govern required postmarketing observational studies, and, if so, how FDA will address and will expect IRBs to address any differences in oversight and research participant protections, including consent requirements, for different observational designs between 21 CFR 50 and 45 CFR 46 so that its regulations are not a bar to what would otherwise be ethically acceptable observational designs. FDA also will need to determine how best to ensure that required postmarketing observational studies can be feasibly conducted, in view of HIPAA and other potential constraints, while still protecting the privacy of the people whose data are used.

Moreover, it is likely that the use of large data sets to pursue concerns about the benefits and risks of marketed drugs will only increase, whether conducted under the auspices of FDA-supported surveillance systems like Sentinel and deemed public health practice, or, assuming the aforementioned issues can be addressed, conducted by manufacturers as required by FDA and interpreted by at least some to be research. It is also likely that the desirability of linking data

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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sets and of obtaining additional information from patients or otherwise needing access to some identifying information about patients will increase over time, raising additional ethical questions about the adequacy of data security practices, authorization for access to different data sets and different research and public health purposes, and beyond. In order to assure the public that surveillance and required observational studies are conducted with appropriate controls and protections, an independent advisory body should be formed by FDA. In the near term, this body should advise FDA on how to resolve the challenges of human subjects regulatory oversight and access to health data for required postmarketing observational studies. Going forward, this body will be needed to advise FDA on the ethics of the postmarketing research and surveillance activities involving large data sets that it conducts or requires, including, for example, activities that raise questions about re-identification of data or of linking to new or existing identifiable information.

Randomized Controlled Trials

Although there is commentary defending the conduct of some clinical trials without prior express consent (Faden et al., 2011; Largent et al., 2011; Truog et al., 1999), the dominant view in research ethics is that clinical trials are paradigmatic of the sorts of study designs that must involve informed consent. Informed consent obligations may be especially salient in the context of required postmarketing trials because patients may be asked to submit to a drug regimen where a safety signal has prompted concerns about risk, and possibly about the acceptability of the drug’s benefit–risk profile.

Investigators, IRBs, and FDA should ensure that several kinds of disclosure are made in the informed consent process. First, it is important to provide information about why a new study is required. This may be particularly true for persons already taking the drug who may undergo a change in regimen as a result of study participation. Prospective research participants need to understand why additional research is important even though the drug that they are taking was found by FDA to have a favorable benefit–risk profile on the basis of existing evidence. They also need to understand why, since the study is prompted by concerns about risk or the drug’s benefit–risk profile, it is still considered to be ethically acceptable to ask them to consider participating in the study. To convey that information, the informed consent process may involve providing general information about how experts view the relative benefits and risks associated with the different medications to be administered in the study, as well as the important public health question driving the need to conduct the study, and the societal benefit that is expected to result from the study. In addition, provisions may need to be made to ensure adequate discussion of how well patients’ existing treatment is working for them.

Second, special care may be needed to ensure that prospective participants

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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understand the risks posed by study participation in the postmarketing context. When a substantial amount of information indicating that a drug to be studied may involve serious risks has already accumulated, there are heightened obligations to ensure that potential research participants understand the risks posed by study enrollment. Those obligations may include special efforts to communicate complex risk information clearly and to establish that research participants understand what the risks mean to them. The emphasis given to risk information in the consent process should increase with the severity of risk and the level of confidence about the causal association between the drug and the adverse outcome. At a minimum, risks that should be disclosed should include any boxed warnings, the “major statement” currently listed in direct-to-consumer advertisements, any adverse-event findings of an FDA advisory committee, and a summary of evidence from published peer-reviewed studies.

Communicating complicated risk information and research findings to potential research participants poses challenges to investigators, IRB, and participants. To fulfill the ethical obligation to obtain informed consent, research participants should understand what is being asked of them, including the benefits (if any) and risks, and not merely be given information (Faden and Beauchamp, 1986). It can be difficult for potential participants to understand the nature, purpose and risks of clinical research. For example, it is well established that some research participants in clinical trials have difficulty understanding the role that randomization plays in their care and believe that treatment decisions are being determined solely based on what is in their medical best interests even when they are not (Appelbaum et al., 1987; Joffe et al., 2001; Kodish et al., 2004; Wendler, 2009). At the very least, a “kitchen sink” approach to consent-form drafting, in which voluminous information is included with little attempt to distill it into a short format that is useful to potential participants, should be avoided. Research participants are likely to be overwhelmed by a long and complex form and unable to weigh conflicting study findings or findings about different types of risk. That is particularly true of people who have low levels of health literacy or educational attainment. Special efforts should be made to ensure that they understand the study information. For example, there is a growing set of additional resources (such as decision aids, videos, and interactive electronic presentations) to supplement written materials that may enhance potential research participants’ understanding of complex clinical information. Although evidence about the effectiveness of techniques designed to improve and document understanding by potential research participants is mixed (Kass and Taylor, 2008), such interventions as engaging in additional personal conversations with potential participants (Flory and Emanuel, 2004; Kass and Taylor, 2008; Lindegger et al., 2006) and asking them to explain the study to a friend (Lindegger et al., 2006) have been shown to be helpful.

Whatever efforts are used to communicate with potential research participants, it is important that they include information that is useful to participants about where the weight of the evidence falls with regard to serious risks and the

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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level of confidence that experts have in drawing conclusions about the risks. A statement that “some studies have found that the drug causes X, whereas other studies have not” may be true but misleading if nearly all well-designed studies have reached the same conclusion and there is little or no reliable evidence on the other side.

Third, in addition to considerations of benefits and risks, people who are considering participation in research need to know how the care that they will receive in a protocol may differ from the care that they would ordinarily receive. Thus, information about “Alternatives to Participation” should convey the current standard of care for the health condition that the study drug targets. That is particularly crucial in cases in which medical practice has shifted away from prescribing the study drug because accumulating evidence from passive surveillance, observational studies, and small trials or meta-analyses suggests that another therapy is as effective and has a more favorable risk profile. A statement that if a potential participant does not enroll in the trial, he or she is more likely to have a different drug prescribed should be communicated in this situation. If clinical practice continues to shift during the trial period, the statement should be strengthened; researchers have an ethical obligation to disclose all new developments that may affect a person’s willingness to continue to participate in a research study.

The Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study provides an example of a consent form that did not satisfy those disclosure requirements.12 Graham and Gelperin (2010) outlined a number of concerns with that form at the July 13, 2010, Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, including a misleading study title and the absence of a clear statement of purpose. The committee agrees that the TIDE consent form is inadequate in several key respects—most notably, in not providing information about the issues discussed above—and should not have been approved by an IRB or ethics review board: it is too long, too complex, too confusing, poorly organized, lacks clear explanations of the purpose and procedures to be followed, and excludes or renders opaque important information that a reasonable person might need to have prior to deciding whether to participate. The committee outlines its concerns, in addition to those of Graham and Gelperin (2010), in Box 4-2.

Comprehensive informed consent processes can help to ensure that trial participants understand the potential consequences of study participation in addition to what they are contributing to the advancement of public health in the regulatory arena. They cannot, however, serve as an exclusive or sufficient ethi-

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12The Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study informed consent form is available at http://www.circare.org/consents/Avandia-TIDE-trial_consentform.pdf (accessed March 3, 2012).

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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BOX 4-2
The Committee’s Concerns with Informed
Consent in the Thiazolidinedione Intervention
with Vitamin D Evaluation (TIDE) Trial
a,b

1. Study Title

•  The study title does not provide an accurate description of the study. It describes the study as a cardiovascular endpoint trial without referring to cardiovascular disease, and it does not mention that rosiglitazone is the primary source of cardiovascular concern in the study.

2. Discussion of the Purpose of the Study

•  There is no clear statement of the purpose of the study, and the emphasis in the consent form is shifted away from the cardiovascular risks by the extent of discussion of other aspects of the study. For example, acute myocardial infarction is mentioned only 5 times, whereas cancer and Vitamin D are mentioned 4 and 18 times, respectively.

•  Multiple unrelated potential side effects are lumped together (for example, it refers to heart attack, stroke, death, broken bone, and cancers as “diseases”).

•  Rosiglitazone and pioglitazone are discussed together, which could be interpreted to mean that current evidence suggests that they pose the same risks. There is no clear statement indicating that Food and Drug Administration (FDA) is not concerned about cardiovascular effects with pioglitazone.

•  The form does not highlight that the association between vitamin D and cancer was weak.

•  It is not made clear that the inclusion of a Vitamin D arm in the study is not relevant to the reason study was required (that is, concerns about the adverse cardiovascular effects of rosiglitazone), and the discussion about Vitamin D and cancer introduces confusion and could be distracting.

•  There is no mention that the purpose of the trial was to establish whether or not there is harm definitively, and the wording does not make clear that there is conflicting evidence about whether thiazolidinedione or Vitamin D helps or harms.

•  The fact that the previous data suggest opposing results is not made clear.

•  There is no mention that GlaxoSmithKline was ordered by FDA to do the study.

contiued

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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BOX 4-2 continued

•  Some of the language is confusing. For example, in the following sentence on page 1 of the form, what the agents are being added to is not clear: “This study will compare adding a [thiazolidinedione] (either rosiglitazone or pioglitazone) to adding a placebo (a pill with no active ingredients)”.

•  The outcomes being studied are combined together in a run-on sentence, and will likely make little sense to someone reading it. A clear statement, perhaps in bullet form, of what the outcomes are would be preferable.

•  The paragraph about ethics review is misplaced. It should be in a separate place, such as on Page 4 in the section titled “Monitoring”.

3. Discussion of the Study Procedures

•  Eligibility criteria should be clearly stated in a distinct section of the informed consent form to avoid patients automatically think that they will be enrolled in the study if they sign the consent form. Eligibility in the TIDE study is not clear. For example, the first sentence in the study procedures section mentions that “if you agree to be considered”, whereas the first two sentences of the “Introduction” assert that, “You are invited to take part in a research project, You have been considered because [explain reason]”.

•  The second page of the “Procedures, Visits, Randomization Strategy” section contains lengthy paragraphs that are very difficult to understand. It would help to have better formatting or organization (for example, providing a timetable of visits and describing what would happen at each visit), and to include introductory sentences (such as “This study is scheduled to last 2 years, with a longer-term follow-up study planned as well. If you agree to participate you will be expected to participate for at least 2 years, with XX visits over that time”).

4. Discussion of Long-Term Follow-Up

•  The duration of follow-up is not clear. This section states that long-term follow-up is a maximum of 5 years, whereas elsewhere in the document it states that it is up to 10 years.

•  This section contains the description of long-term follow-up, reminders that patients can withdraw from the study, and encouragements

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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   to participate in the study. Those multiple messages dilute the key, simple message that this section is supposed to convey.

5. Discussion of Possible Side Effects, Risks, Discomforts

•  No explanation of the likelihood of the risks manifesting as harms is included in this section.

•  The lengths of some of the descriptions of risks are not commen-surate with the severity of the adverse events. For example, there is a paragraph about low-risk blood draws and electrocardiograms, but only a brief description of other risks.

•  The organization of the discussion of risks is confusing. For example, discussing the risks from all thiazolidinedione first, and then discussing the risks specific to rosiglitazone and pioglitazone is confusing.

•  Although there is a paragraph devoted to the company’s prior safety data about rosiglitazone, the importance of that information is not clear because of its wording and location. The paragraph reads more as a type of liability statement rather than a statement about risk of heart attack to those participating. Its location after the discussion of additional risks from rosiglitazone make it less likely that potential research participants will take not of it.

•  The consent form’s disclosure about “important new information” is worded such that it is not clear if this information is about adverse events.

6. Other Issues

•  There is no mention of the 2007 FDA advisory committee vote, labeling differences between rosiglitazone and pioglitazone, or the American Diabetes Association recommendation against using rosiglitazone.

•  The trade names for Avandia and Actos should be mentioned by name earlier in the document.

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aA number of these concerns were previously outlined by Graham and Gleperin (2010).

bThe Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study informed consent form is available at http://www.circare.org/consents/Avandia-TIDE-trial_consentform.pdf (accessed March 3, 2012).

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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cal justification for conducting a postmarketing trial. The other justifications for initiating a trial should be independently satisfied. People should not be asked to assume risks that are not justified in light of the benefits of the trial to participants or society. Particularly in research settings in which participants have low literacy, low income, and poor access to modern health care and medicines, even a robust consent process may do little to countervail the pressures that lead people to participate in research. Regulators, IRBs, and data-monitoring committees (DMCs) should serve as particularly strong bulwarks against unethical research in such settings.

Safety Monitoring in the Postmarketing Research

Among the ethical requirements for conducting postmarketing clinical trials (or other studies that alter the experience of participants in ways that pose risks of harm)—whether they are required by FDA or not—is a comprehensive and robust risk-monitoring plan. This is necessary to address a key criterion for continuing approval of the study by IRBs, that there is “adequate provision for monitoring the data collected to ensure the safety of subjects”.13 In the case of studies that FDA has required, it is also necessary to fulfill FDA’s ethical responsibility to the research participants whose clinical experience its decision has affected. For example, despite significant concerns about risk, there was no DMC for the Vioxx trials of older adults, which was a surprise to FDA when it inquired about the trials’ mortality findings (Psaty and Kronmal, 2008).

For all FDA-required postmarketing clinical trials, a properly qualified DMC should be appointed and given a written charter and pre-specified data-monitoring plan. The data-monitoring plan should include statistical guidelines for stopping the trial early (Ellenberg et al., 2003; Grant et al., 2005). The DMC should meet before trial initiation to review and approve the charter, protocol, and monitoring procedures and then at regular intervals to review not just outcomes and adverse events, but also indicators of whether the research team is adhering strictly to the protocol and of the quality of data being collected. The frequency and intensity of ongoing DMC review should be determined on the basis of the seriousness, incidence, and timing of known or possible harms of the study drug to research participants.

As discussed in the letter report (IOM, 2010), a critical issue for risk monitoring is the standard of evidence required to halt a study on the basis of harm. Typically, differences that cross pre-specified boundaries of statistical significance are required to halt trials for efficacy. However, depending on the type and degree of benefit, boundaries for harm may vary. The criteria for stopping a trial if the efficacy endpoint veers in the direction of harm are typically less stringent than the criteria for stopping for efficacy differences in the direction of benefit.

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1321 CRF 56.111(a)(6).

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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Modest evidence of an adverse effect on an efficacy endpoint may be sufficient to rule out a clinically meaningful benefit even if the point estimate does not exclude a null effect. On the other hand, if benefit on one endpoint is established (for example, cardiovascular health), but the trial is being done to assess a suspected harm on a different endpoint (for example, gastrointestinal bleeding), a higher standard of proof of the harm signal might be required. The Women’s Health Initiative trial, for example, stopped its estrogen–progestin arm because the breast-cancer outcome crossed the pre-specified safety boundary and because the global index outcome just trended in the direction of harm, effectively ruling out a substantive net benefit (Rossouw et al., 2002; Wittes et al., 2007).

Other issues that affect the evidence threshold for stopping for harm are whether and how external information is used. If an emerging signal of harm is similar to that seen in external studies, it is ethically justified and may be ethically required to halt a study earlier than if such evidence did not exist (Pocock, 1996).

International Challenges

The ability of FDA to discharge its ethical obligations to ensure adequate oversight of the postmarketing studies it requires is complicated when studies are conducted outside of the United States (Office of Inspector General, 2010). During the past two decades, the volume of premarketing clinical trials conducted outside the United States has increased dramatically, with many of these studies occurring in economically developing countries (Thiers et al., 2008; Wadman, 2007). Particularly when studies are conducted in resource poor countries, concerns have been raised about the quality, reliability and transportability of research results, and about the adequacy of research participant protections (HHS, 2001; Kimmelman et al., 2009; Lavery, 2004; NBAC, 2001). The committee recognizes that these concerns may apply as well to FDA required postmarketing research.

As the TIDE experience suggests, FDA required postmarketing trials are also being conducted at sites outside the United States. For example, the TIDE trial was conducted at 190 sites in more than 20 countries. Some of the countries in which the TIDE trial was conducted had research and oversight infrastructures equivalent or superior to those in the United States, but others did not have equivalent systems. Concerns about research quality and participant protections in some non-US sites pose challenges for FDA’s obligations to ensure adequate protection of the rights and interests of research participants in premarketing and postmarketing research that it requires and to ensure that such research can provide the evidence needed to identify the appropriate regulatory response to a public health question. The International Research Panel of the Presidential Commission for the Study of Bioethical Issues found that “ongoing international dialogue between U.S. and international bodies is critical to protecting human subjects in research” (PCSBI, 2011). FDA’s Office of International Programs,

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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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 (FDA, 2011c). It is critical that this office work to resolve the challenges with other federal offices and international counterparts and that it have sufficient resources and authority to do so.

Meeting Ethical Obligations: The Architecture of Ethical Review

To discharge its ethical obligations to ensure adequate oversight of the postmarketing studies that it requires, FDA can draw on both its internal resources for ethical review and relationships with external IRBs and DMCs. Potential roles for each type of organization are described below.

FDA has substantial statutory authority to regulate in the arena of human-subjects protection for studies that are related to its drug-approval process.14 Parts 50 and 56 of Title 21 of the Code of Federal Regulations extend the authority to “all clinical investigations regulated by the Food and Drug Administration under sections 505(i) and 520(g) of the Federal Food, Drug, and Cosmetic Act, as well as clinical investigations that support applications for research or marketing permits for products regulated by the Food and Drug Administration”.15 The regulations include requirements for informed consent16 and standards for the “composition, operation, and responsibility of an Institutional Review Board (IRB)”.17 FDA has created several structures to support its ethics-oversight function. The Office of Good Clinical Practice, in the Office of Special Medical Programs of the Office of the Commissioner, addresses issues related to human research trials regulated by FDA. Its activities include drawing up policies and long-range goals, leading FDA’s Human Subject Protection (HSP)/Bioresearch Monitoring (BIMO) council, acting as a liaison with other federal agencies, and contributing to international Good Clinical Practice harmonization activities.

The HSP/BIMO initiative was launched in 2006 as part of FDA’s Critical Path Initiative. The initiative (FDA, 2010a)

is aimed at modernizing and strengthening the agency’s oversight and protection of subjects in clinical trials and the integrity of resulting data. … [The] overarching goals of the agency’s BIMO program are to protect the rights, safety, and welfare of subjects involved in FDA-regulated clinical trials; to determine the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications; and to assess compliance with FDA’s

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14Pursuant to Sections 403, 406, 409, 412, 413, 502, 503, 505, 510, 513–516, 518–520, 721, and 801 of the Federal Food, Drug, and Cosmetic Act (PL 75-717, 52 Stat 1040 [1938]).

1521 CFR 50.1(a).

1621 CFR Part 50.

1721 CFR 56.107(a).

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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regulations governing the conduct of clinical trials, including those for informed consent and ethical review.

A September 2010 report on the HSP/BIMO initiative (FDA, 2010a) highlights as progress the publication of a number of rules and guidance documents related to IRBs, safety reporting, and protection of study participants (FDA, 2009, 2010b) and work on the joint European Medicines Agency–FDA Good Clinical Practice (GCP) Initiative (EMA and FDA, 2011).

Finally, all “human subject research conducted, supported, or funded in whole or in part by FDA except for those categories of research specifically exempted or waived under HHS regulations and not otherwise included by FDA policy” must be reviewed and approved by an internal FDA IRB, the Research Involving Human Subjects Committee (RIHSC) (Human Subjects Research [45 CFR 46]). As previously noted, although Sentinel is funded by FDA, its activities have been determined to be public health activities and not research and thus do not require review by the RIHSC, because the federal Office for Human Research Protections “determined that the regulations that [the Office for Human Research Protections] administers (45 CFR 46) do not apply to the activities that are included in the Food and Drug Administration’s Sentinel Initiative” (Rosati et al., 2010) (see Exhibit 1, letter from Dr. Jerry Menikoff); they are public health activities, not human research (McGraw et al., 2012; Rosati et al., 2010). In the future, FDA may choose to conduct or support more complex surveillance systems that include, for example, the capacity to contact patients, draw blood samples, and conduct genome-wide association analyses to identify generic variants associated with a serious adverse event. An independent review body to advise FDA on the ethics of postmarketing activities involving large datasets could play an important role in helping to ensure that more complex surveillance systems are designed appropriately. Some of these activities may well be determined to constitute research that requires oversight by the RIHSC or other IRBs.

Although the BIMO program and other internal resources provide FDA with considerable capacity in the ethical oversight of postmarketing studies, the agency must partner with external IRBs and DMCs to carry out oversight activities on studies it requires others to conduct. FDA should, however, retain several specific roles rather than delegating the entire oversight process to IRBs. Those roles are outlined below.

Some commentators challenge the capacity of IRBs to provide the independent peer-review function for which they are intended (Emanuel et al., 2004; IOM, 2002; Schluger, 2008), but IRBs, bolstered by DMCs as appropriate, remain the bulwark of our current system for the protection of research participants. The committee believes, however, that FDA cannot responsibly delegate the entire process of research ethics oversight to IRBs but retains some specific moral duties itself in that regard. The remit of IRBs is to protect research participants. Ensuring that the design of a proposed research study is scientifically acceptable

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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is a component of IRB determination, but in practice IRBs’ review of scientific aspects of study design is limited. Although federal regulations task IRBs with ensuring that “risks to subjects … are minimized by using study procedures that are consistent with sound research design”,18 IRBs tend to defer on scientific matters to investigators, study sponsors, and other reviewing bodies (such as study sections convened by the National Institutes of Health and foundations).

That deferral is generally appropriate, inasmuch as IRBs are not constituted with the aim of ensuring that their members have the full array of scientific expertise relevant to all the studies that they review. The perspective, responsibilities, and capabilities of FDA are quite different. Ensuring that studies are designed to return answers to scientific questions of regulatory and public health importance is central to the agency’s mission and concordant with the expertise of its staff.

IRBs do, however, have expertise and capability at least equal to those of FDA to review the research-participant protection issues that FDA-required studies may raise. FDA should not attempt to displace IRBs’ role in this realm, but it could do more to support IRB decision-making. Specifically, one role for FDA in the oversight process is to give each IRB (including any centralized IRBs and multiple IRBs) sufficient information to provide appropriate oversight. That should include 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 decision to join or remain in the study, which the IRB should consider for dissemination to potential and current study participants. FDA should also communicate to IRBs what it is (and is not) requiring the investigators to do with respect to study design. Such information should minimize IRBs’ attempts to alter study designs in ways that FDA would not approve and should ensure that investigators and pharmaceutical sponsors are not tempted to misrepresent FDA’s requirements.

One potential mechanism for that kind of communication between FDA and IRBs would be for FDA to send a letter to the pharmaceutical manufacturer (and the study’s principal investigator, if one has been identified) that sets forth the information that IRBs need to know about the study before initial IRB approval, as well as later letters as the study progresses if relevant information emerges and to require the manufacturer to submit such letters to each IRB involved with the study. FDA should also ensure that the relevant IRBs are provided with up-to-date Benefit and Risk Assessment Management Plans (BRAMPs) for the drugs under study.

With respect to clinical trials and other studies that alter the clinical experi-

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18CRF 56.111(a)(1).

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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ence of research participants in ways that pose a risk of harm, another role for FDA is to support the work of DMCs and data-monitoring committees. The latter can play a critical role in monitoring the safety of clinical-trial participants in both the postmarketing setting and the premarketing setting by providing DMCs with the same information that FDA provides to IRBs.

Thus, there is already an architecture in place for the ethical oversight of postmarketing studies required by FDA, but stronger relationships between the parts of the system are needed, including specific duties for FDA, to enhance its capacity to attend properly to the particular features of postmarketing research.

SUMMARY

Requiring drug manufacturers to conduct research is at the core of FDA’s regulatory responsibilities before drug approval. After a drug has entered the marketplace, it is only one of a variety of actions open to FDA in monitoring the drug’s benefit–risk profile. When FDA elects to pursue that action, the postmarketing setting poses a number of distinct challenges in considering which types of studies to require. One major challenge is created by the opportunity to require observational studies, an option that is generally not available in the premarketing setting. The statutory hierarchy in FDAAA that prioritizes observational designs is a starting point for the committee in providing guidance as to which kinds of study designs FDA should require. The committee finds that the presumption requiring that observational studies be ruled out before FDA can order an RCT is supported by ethical, practical, and scientific considerations. The committee concludes that there can be many circumstances when an observational design can provide evidence adequate to help to resolve the public health question at issue, but that there are also circumstances when only an RCT is able to provide the needed evidence. In theory RCTs provide the highest-quality evidence with respect to any outcome, but in practice observational studies may provide high quality evidence regarding a drug’s risks sufficient for policy decisions. In many cases, practical, scientific, and ethical considerations make it difficult or impossible to conduct an RCT that contains all the elements that give the ideal RCT its evidential superiority. To be consistent with ethical, legal, and practical considerations, the required study should be designed to provide evidence that is as close as possible to the evidence that would be obtained if the ideal trial specific to the public health question at issue could have been implemented.

Much of the information about a drug’s benefits and risks in the postmarketing context do not come from studies mandated by FDA. Therefore, FDA should endeavor to make the studies that it does require as informative as possible about both benefits and risks. FDA can do that by prospectively defining key endpoints, design aspects (such as details of drug administration), and covariates that postmarketing studies should use. FDA could develop such information internally or convene researchers for this purpose; the latter would maximize adherence to the

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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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 participants. 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 participants at risk. It can also put patients and the public at risk by delaying a regulatory decision that might be protective of public health. 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.

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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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 provide 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 potential 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 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.

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1921 USC § 355(o) (2010).

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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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 decision 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 participants 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 minimization 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) clinical management.

Finding 4.5

Although regulations governing human subjects research do not apply if an activity is considered public health practice, as is the case with the Sentinel system,

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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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 identifying 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 conduct 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 challenges, with particular focus on activities that are determined not to require IRB oversight.

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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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 postmarketing 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 following 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 postmarketing 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

image

2021 USC § 355(o) (2010).

Suggested Citation:"4 Selection and Oversight of Required Postmarketing Studies." Institute of Medicine. 2012. Ethical and Scientific Issues in Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press. doi: 10.17226/13219.
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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 governments 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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An estimated 48 percent of the population takes at least one prescription drug in a given month. Drugs provide great benefits to society by saving or improving lives. Many drugs are also associated with side effects or adverse events, some serious and some discovered only after the drug is on the market. The discovery of new adverse events in the postmarketing setting is part of the normal natural history of approved drugs, and timely identification and warning about drug risks are central to the mission of the Food and Drug Administration (FDA). Not all risks associated with a drug are known at the time of approval, because safety data are collected from studies that involve a relatively small number of human subjects during a relatively short period.

Written in response to a request by the FDA, Ethical and Scientific Issues in Studying the Safety of Approved Drugs discusses ethical and informed consent issues in conducting studies in the postmarketing setting. It evaluates the strengths and weaknesses of various approaches to generate evidence about safety questions, and makes recommendations for appropriate followup studies and randomized clinical trials. The book provides guidance to the FDA on how it should factor in different kinds of evidence in its regulatory decisions.

Ethical and Scientific Issues in Studying the Safety of Approved Drugs will be of interest to the pharmaceutical industry, patient advocates, researchers, and consumer groups.

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