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Incorporating Benefit and Risk Assessment and Benefit–Risk Management into Food and Drug Administration Decision-Making

As part of its charge the committee was asked how the US Food and Drug Administration (FDA) should “factor in different kinds of safety evidence in considering different kinds of regulatory action”. To respond to that question, the committee considered the relevance of different evidence to decisions about different potential regulatory actions, and how FDA should apply that evidence across the lifecycle of a drug. The committee concluded that there is no one answer to that question, because the evidence and circumstances surrounding each regulatory decision are different. Although decisions as to how to weigh evidence will always have to be made case by case, the committee provides a broad overall approach to guide the assessment of safety evidence and FDA decision-making. In this chapter, the committee highlights the importance of a lifecycle approach to FDA’s regulatory decisions and proposes two mechanisms to facilitate adopting such an approach: a framework for decision-making and a document, referred to as a Benefit and Risk Assessment and Management Plan (BRAMP), to formalize the implementation of the lifecycle approach discussed in Chapter 1, and make FDA’s decisions about each drug transparent. The framework is not intended as a one-time activity, but rather an activity that recurs when questions about the benefits or risks associated with a drug arise. The document is a record that tracks the experience of a drug across its lifecycle, to be updated whenever the framework is used to evaluate the benefits and risks associated with a drug.

EVALUATING BENEFIT AND RISK OVER A DRUG’S LIFECYCLE

FDA’s decision to approve a drug for sale in the United States is based on a judgment that in view of the evidence from premarketing studies and clinical



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2 Incorporating Benefit and Risk Assessment and Benefit–Risk Management into Food and Drug Administration Decision-Making As part of its charge the committee was asked how the US Food and Drug Administration (FDA) should “factor in different kinds of safety evidence in considering different kinds of regulatory action”. To respond to that question, the committee considered the relevance of different evidence to decisions about differ- ent potential regulatory actions, and how FDA should apply that evidence across the lifecycle of a drug. The committee concluded that there is no one answer to that question, because the evidence and circumstances surrounding each regula- tory decision are different. Although decisions as to how to weigh evidence will always have to be made case by case, the committee provides a broad overall approach to guide the assessment of safety evidence and FDA decision-making. In this chapter, the committee highlights the importance of a lifecycle approach to FDA’s regulatory decisions and proposes two mechanisms to facilitate adopting such an approach: a framework for decision-making and a document, referred to as a Benefit and Risk Assessment and Management Plan (BRAMP), to formalize the implementation of the lifecycle approach discussed in Chapter 1, and make FDA’s decisions about each drug transparent. The framework is not intended as a one- time activity, but rather an activity that recurs when questions about the benefits or risks associated with a drug arise. The document is a record that tracks the experience of a drug across its lifecycle, to be updated whenever the framework is used to evaluate the benefits and risks associated with a drug. EVALUATING BENEFIT AND RISK OVER A DRUG’S LIFECYCLE FDA’s decision to approve a drug for sale in the United States is based on a judgment that in view of the evidence from premarketing studies and clinical 61

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62 STUDYING THE SAFETY OF APPROVED DRUGS needs, it is, all things considered, in the interest of the public’s health for the drug to enter the marketplace. In other words, the benefits of the drug outweigh its risks for the intended use and population. Although at the time of approval knowledge about efficacy from small, short-term clinical-trial populations is limited, far less is known about the drug’s risks. Some adverse effects may be too rare to be identified in the small numbers of people who participate in pre - marketing studies. For example, although the premarketing clinical trials for a second-generation rotavirus vaccine involved relatively large numbers of research participants, the small, increased risk of intussusceptions with rotavirus vaccines was only identified in post-licensure safety monitoring (approximately 1 of every 51,000 to 68,000 vaccinated infants) (Greenberg, 2011; Patel et al., 2011). Other adverse events may have a latent period longer than the duration of premarketing trials or may occur in people who are unlike those who participated in the pre - marketing trials in relevant respects. For example, they may be less healthy, take other medications, or have comorbidities. Such patients are often excluded from or enrolled in small numbers in premarketing trials (Fung, 2001). For several reasons, questions about the effectiveness of a drug in actual clinical practice may also remain at the time of approval (Borer et al., 2007; Hiatt, 2006; IOM, 2007a; Ray and Stein, 2006). Long drug exposure during the postmarketing period could lead to a loss of effectiveness as tolerance or resis- tance to the drug develops. The population taking an approved drug is likely to be more heterogeneous than the people who participated in premarketing clinical trials. The drug may not be as effective in the postmarketing general population as it was in the premarketing test population. Many factors can account for those differences, including differences in environmental factors, genetics, age, race, ethnicity, or sex; interactions with other drugs; comorbidities; and problems with drug adherence. For example, a person who has liver disease might not fully metabolize and activate a drug, leading to decreased clinical effectiveness. A drug approved on the basis of a surrogate endpoint might not be as effective in improv - ing a clinical endpoint, for example tumor shrinkage may not correlate strongly with survival. Once a drug is allowed to enter the market, physicians are free to use it, on-label or off-label, for any indication, including those of which there may be little or no scientific evidence of effectiveness from premarketing trials. In the remainder of this chapter, the committee outlines a three-stage frame- work for making regulatory decisions and how FDA could apply the framework as part of the lifecycle approach to drug safety discussed in Chapter 1. (See Box 2-1 for definitions of key terms used in this chapter.) The committee then proposes a BRAMP document as a mechanism for implementing a lifecycle approach to drug regulation and for making FDA’s decisions transparent. Figure 2-1 shows how FDA can incorporate the framework and the BRAMP into a lifecycle approach to drug oversight. The chapter concludes by addressing the circumstance under which regulatory decisions should include requiring manu - facturers to conduct postmarketing studies, a focus of the committee’s charge (see

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63 BENEFIT–RISK AND FDA DECISIONS BOX 2-1 Key Definitions Benefit assessment and risk assessment: The gathering and analyzing of information on the nature and magnitude of potential benefits and potential harms (risks) associated with a drug and the determination of the likelihood that those benefits and harms will occur. Benefit–risk profile: An overall evaluation of the benefits and risks associated with a drug. Benefit–risk management: The process of identifying, evaluating, selecting, and implementing actions to increase benefits and reduce risk to human health. The goal of benefit–risk management is scientifically sound, integrated actions that increase or maintain benefits and reduce or prevent risks while taking into account social, cultural, ethical, political, and legal considerations. “A good risk management decision emerges from a decision-making process that elicits the views of those affected by the decision, so that differing technical assessments, public values, knowledge, and perceptions are considered” (Presidential/Congressional Commission on Risk Assessment and Risk Management, 1997). The process of benefit–risk management should include not only information about current regulatory actions but plans for future evaluations and regulatory actions as part of the lifecycle process. Uncertainty: Lack or incompleteness of information. Quantitative uncertainty analysis attempts to analyze and describe the degree to which a calculated value may differ from the true value; it sometimes uses probability distributions. Uncertainty depends on the quality, quan- tity, and relevance of data and on the reliability and relevance of models and assumptions. Box 1-1; the question of which study designs FDA should require is addressed in Chapter 4). THREE-STAGE FRAMEWORK FOR REGULATORY DECISION-MAKING Overview and Rationale Responding in a timely and appropriate way to safety signals from already- approved drugs is among the most important and challenging public health jobs that FDA must accomplish. Permitting a drug to stay on the market that is on

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64 STUDYING THE SAFETY OF APPROVED DRUGS Premarketing Setting Postmarketing Safety Monitoring Postmarketing Setting Product Discovery Product Pre-Clinical Studies Remains on and NDA Market Clinical Trials Review BRAMP Developed Drug Approved Drug’s Benefit–Risk FDA Oversight Product Update and Enters the Profile is Questioned or Begins Removed from BRAMP Market There is a Periodic Market Evaluation of the Drug Make and Define Public Assess Implement Health Drug Benefits Regulatory Question and Risks Decision Framework for Decision-Making FIGURE 2-1 The lifecycle of a drug for a new molecular entity. After a product is discov- ered and the sponsor approaches FDA with the product as an investigational new drug, FDA oversight begins. During approval, the company submits information about the benefits, risks, and benefit–risk profile of the drug, and FDA develops a BRAMP. After approved, FDA and the drug sponsor conduct postmarketing safety monitoring of the drug, which could include passive surveillance, active surveillance, observational studies, and random - ized controlled studies. If evidence arises that calls into question the benefit–risk profile of the drug, FDA uses the decision-making framework to review the new evidence in the context of existing evidence and the public health context of the drug, to make a regulatory decision about the drug. Depending on the decision, the drug will remain on the market, either with the same or different restrictions and conditions, or will be removed from the market. FDA updates the BRAMP document when it considers a regulatory decision for the drug, and when periodic evaluations occur over the drug’s lifecycle. FDA oversight of the drug continues for as long as the drug is on the market. balance harmful threatens public well-being,1 but so too does limiting access to a drug whose benefits outweigh its harms. As discussed in Chapter 1, the Food and Drug Administration Amendments Act (FDAAA) of 20072 provides FDA with new tools and authorities to adopt a lifecycle approach to regulatory decision- making—an approach that FDA has endorsed (FDA, 2004). However, FDA has not yet taken full advantage of its new tools and authorities to implement a life - cycle approach in a systematic or comprehensive manner. 1 There are instances where a drug is, on balance, harmful to the overall population but nevertheless provides a net benefit to a specific subgroup within the population. In those instances, the drug could remain on the market with restrictions to limit its use to those subgroups for whom the drug has a favorable benefit–risk profile. 2 Food and Drug Administration Amendments Act of 2007, PL No. 110-85, 121 Stat. 823 (2007).

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65 BENEFIT–RISK AND FDA DECISIONS The assessment of benefits and risks and making management decisions in response to the assessment are not new challenges for FDA. The agency has a process in place for reviewing premarketing data on efficacy and risks, and making regulatory decisions about approving a drug on the basis of those data and other considerations. Similarly mature processes do not exist for evaluating a drug’s benefits and risks in the postmarketing setting using FDA’s authority in FDAAA, although in April, 2011 FDA issued guidance providing information for industry on how it would implement the section of FDAAA3 that authorizes FDA to require postmarketing research. The link between benefit assessment, risk assessment, and FDA’s regulatory decision-making has been criticized for failing to be explicit and transparent to external stakeholders (Asamoah and Sharfstein, 2010; Transparency Task Force et al., 2010). Other US government agencies and organizations have a history of making decisions on the basis of formal assessments of risks. The US Environmental Protection Agency (EPA), for example, conducts formal chemical risk assess - ments to guide its decisions on allowable concentrations of chemicals in the environment (see for example EPA, 2005, 2009). The process used by EPA has evolved after publication of a number of reports outlining best practices for risk assessment and regulatory decision-making (NRC, 1983, 1989, 1996, 2009; Presidential/Congressional Commission on Risk Assessment and Risk Manage - ment, 1997). Characteristics of those best practices include the use of the best available scientific evidence, the involvement of parties that would be affected by the decision in the decision-making process, especially to incorporate the per- spectives of patients and consumers in the process, and transparency in the pro- cess (NRC, 1989, 1996, 2009; Presidential/Congressional Commission on Risk Assessment and Risk Management, 1997). The 2009 National Research Council report Science and Decisions: Advancing Risk Assessment proposed that EPA use a formal three-phase framework when making its regulatory decisions (NRC, 2009, 2011). The framework includes a problem-formulation phase, a phase for the planning and conduct of the risk assessment, and a risk-management phase. A recent National Research Council report, A Risk-Characterization Framework for Decision-Making at the Food and Drug Administration, highlighted the 2009 framework and its general usefulness for FDA in its regulatory purview (NRC, 2011). It proposed a similar, three-step process for decision-making that involved identifying and defining the decision context, estimating or characterizing the public health consequences of each decision option, and using the completed characterization to compare decision options and to communicate their public health consequences within the agency, to decision-makers, and to the public. The report highlighted factors that are considered in FDA’s decision-making, including scientific, social, and political factors, as well as the importance of the context of the decision to all steps of the decision-making process. 3 21 USC § 355(o) (2010).

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66 STUDYING THE SAFETY OF APPROVED DRUGS The need for a systematic process for drug-regulatory decisions has been discussed previously. The Pharmaceutical Research and Manufacturers of Amer- ica’s Benefit–Risk Action Team (BRAT)4 discussed the need for a consistent framework for “transparent, rational and defensible decision-making that benefits patients, drug developers, and decision makers” (Coplan et al., 2011). The BRAT proposed a six-step framework for decision-making (Coplan et al., 2011). Health Canada and the European Medicines Agency have also discussed the need for a benefit–risk framework (CHMP, 2008; Health Canada, 2000). In the present report, the committee adapts the framework from Science and Decisions: Advancing Risk Assessment specifically to FDA’s postmarketing drug-regulatory setting to facilitate managing the benefits and risks associated with a drug throughout its lifecycle (see Figure 2-2). The framework should be used whenever FDA needs to make a regulatory decision about a drug; given its charge, the committee focuses on the use of the framework in the postmarketing setting where it could be used, for example, in choosing regulatory actions when the presence of a serious safety signal may precipitate or require consideration of a regulatory action. The adapted framework has three stages: define the public health question, assess the drug’s benefits and risks, and make and implement the regulatory decision. Central to the framework is the need to elicit and incorporate the perspective of the patient.5 The three-stage framework is designed to be broadly applicable and assist the decision-maker in the exercise of sound judgment. It is intended to place rea- sonable demands on the limited resources of FDA given the volume of approved drugs, but to ensure that comprehensive evaluations of benefit and risk can be conducted when disagreements arise or when the public health effects may be substantial. FDA’s decisions vary in their complexity (see Box 2-2). A recent NRC report noted that FDA’s decision-making framework should be flexible enough to be applicable to the broad array of decisions FDA faces for its different regulatory purviews (NRC, 2011). That need for flexibility is equally true within the drug-regulatory setting. Although all three stages are necessary regardless of the complexity of the regulatory decision under consideration, the scope of each stage required to support sound policy decision-making will depend on the circumstances and available evidence. Many regulatory decisions will not require comprehensive evaluations at every stage, and efforts should be scaled accordingly. A number of methods have been proposed for assessing benefits and risks, and for making regulatory decisions in response to these assessments. Some 4 The Pharmaceutical Research and Manufacturers of America has transferred its Benefit–Risk Action Team (BRAT) framework to the Centre for Innovation in Regulatory Science “to further the program’s technical development and broaden input from the scientific community” (PhRMA, 2012). 5 FDA also recognizes the importance of the participation of patients, patient advocates, and health professional organizations in its regulatory decisions, and has established an office to facilitate such interactions (FDA, 2011a).

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(from Stage 2) Do the benefits of a drug continue to outweigh its risks? If not, are there actions (such as labeling changes, box warnings, or REMS) that FDA could require that would adequately mitigate the risks? 67 FIGURE 2-2 Three-stage framework for regulatory decision-making. SOURCE: Modified from Science and Decisions: Advancing Risk Assessment (NRC, 2009).

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68 STUDYING THE SAFETY OF APPROVED DRUGS BOX 2-2 Two Examples of the Diversity and Complexity of Food and Drug Administration (FDA) Decisions FDA’s decisions on drugs range from relatively easy decisions for which the science and the appropriate regulatory action are clear to ones for which the scientific evidence can be complex or contradictory and determining the appropriate regulatory action would benefit from input from many experts. 1. As an example of the former, the scientific evidence on the risk of liver problems associated with trovafloxacin (Trovan®), an antibiotic used for treatment for various infections, was clear soon after it was approved. Trovafloxacin was approved by FDA in December 1997 and became available to patients two months later (FDA, 1999). None of the 7,000 patients in the premarketing clinical trials experienced serious liver problems (hepatic failure, sometimes requiring liver transplantation, or death), but soon after entered the market, FDA began to receive reports of adverse events as early as two days after treatment; more serious adverse events (acute liver failure) occurred in patients after more than two weeks of treatment. Within seven months of approval, FDA had received more than 100 reports of patients’ experiencing symptomatic and asymptomatic hepatic toxicity; some who sustained hepatic damage had to have transplants or died (FDA, 1999). In July of 1998, FDA worked with the drug sponsor to add further toxicity informa- tion on the medication label and package insert, informing physicians of the potential for hepatic toxicity. In addition, distribution of trovafloxacin was limited to inpatient facilities, patients receiving trovafloxacin had to have life-threatening or limb-threatening disease, and a physician must believe that the drug’s benefits outweighed the risks it posed for a patient (FDA, 1999). In this example, once the drug was marketed, there was evidence of an association between trovafloxacin and se- vere, sometimes fatal adverse events. Other drugs that could be used effectively to treat for most infections were on the market. Given that evidence, FDA placed severe restrictions on the use of Trovan. 2. In contrast, when deciding about postmarketing regulatory decisions about aprotinin (Trasylol®), FDA was faced with conflicting scien- tific evidence about the risks associated with the drug. Aprotinin is a bovine-derived natural protease inhibitor that was approved by FDA in 1993 for use during coronary arterial bypass surgery to reduce blood loss and diminish the need for blood transfusions in surgical patients. From the time of its FDA approval through 2005, several studies and meta-analysis of results of randomized controlled trials supported

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69 BENEFIT–RISK AND FDA DECISIONS the efficacy of aprotinin for reducing the inflammatory response, the need for transfusions, and the risk of stroke, and it showed either no effect or a reduction in mortality, myocardial infarction, or renal failure risk (Henry et al., 2001; Levi et al., 1999; Sedrakyan et al., 2004). In early 2006, however, two observational studies further raised concerns about aprotinin’s safety. Mangano et al. (2006) compared health outcomes related to the use of aprotinin (1,295 patients) with outcomes related to the use of two other hemostatic agents—amino- caproic acid (883 patients) and tranexamic acid (822 patients)—and results in 1,374 patients who did not receive a hemostatic agent. The study found that use of aprotinin doubled the risk of renal failure and was associated with higher rates of heart attacks and stroke than the use of other medications or no treatment. The study by Karkouti et al. (2006) used propensity scores and compared 449 of 586 patients who had received aprotinin during high–transfusion-risk surgery with 449 patents who received tranexamic acid; it determined that aprotinin may be associated with renal dysfunction. On the basis of the results of those two studies, FDA released a public health advisory for apro- tinin in February 2006, detailing the results of the two observational studies and cautioning physicians to “consider limiting [aprotinin] use to those situations in which the clinical benefit of reduced blood loss is essential to medical management of the patient and outweighs the potential risks”. In late September 2006, after FDA held a public meeting of the Cardiovascular and Renal Drugs Advisory Committee, the drug spon- sor disclosed preliminary findings from a new observational study that confirmed the findings of the previous observational studies. The new study, which was commissioned by the drug sponsor, reviewed hospital records of 67,000 patients who had undergone coronary bypass graft surgery. Preliminary study results found that the 30,000 patients who received aprotinin during surgery had an increased risk of death, renal failure, congestive heart failure, and stroke. Final study results, pub - lished in 2008, concluded that patients who received aprotinin had an estimated mortality 64% higher than patients who received aminocaproic acid (relative risk [RR], 1.64; 95% confidence interval [CI], 1.56–2.02) (Schneeweiss et al., 2008). Another advisory committee meeting was held, but the committee did not find the evidence compelling enough to recommend withdrawal of the product from the market, but did find it compelling enough to recommend a label change and that an RCT be Continued

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70 STUDYING THE SAFETY OF APPROVED DRUGS BOX 2-2 Continued conducted (FDA, 2007a). Taking the preliminary data into account, FDA issued a new statement in September 2006, reiterating the cautions from the earlier health advisory and asking physicians to monitor patients for the occurrence of toxicity. In December 2006, FDA strengthened the safety warnings regarding aprotinin and added a warning that the drug increases the possible risk of renal damage. The advisory also included guidance for minimizing the risk. In the meantime, the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART)—a multicenter, blinded, randomized, con- trolled study comparing aprotinin with two other antifibrinolytic agents (aminocaproic acid and tranexamic acid)—had begun to enroll patients in 2002. In October 2007, the study was halted early when preliminary results indicated a higher death rate seen in aprotinin-treated patients (RR, 1.53; 95% CI, 1.06–2.22) (Fergusson et al., 2008). In November, 2007, FDA announced that the sponsor agreed to an FDA-requested marketing suspension of aprotinin in February 2007, after preliminary results from the BART were released. In May 2008, FDA announced that the drug sponsor would remove remaining stock of aprotinin from the market and limit access to aprotinin to investigational use. The special protocol allows the use of aprotinin for “certain patients who are at increased risk of blood loss or transfusions during coronary artery bypass surgery and who have no acceptable alternative therapy” (FDA, 2008a). The differences in the complexity of these two examples illustrate FDA’s need for a scalable framework for decision-making. Where the evidence is somewhat more clear-cut, such as the case of trovafloxacin, FDA could use the three stages of the framework, but the decision might not require as extensive weighing of the evidence, or engagement of stakeholders and external experts. Where the evidence is not as clear, where scientists might disagree about the value of different sources of evidence, or where requiring a randomized controlled trial is likely to be ethically controversial, such as in the case of aprotinin, each of the three stages might be more involved, with FDA eliciting external scientific advice, the perspectives of patients, and the concerns of other stakeholders. a Thecommittee uses these drugs as examples of the variability in FDA’s decisions and its ap- proach to safety signals, evidence, and regulatory decision-making. The committee is not com- menting on, or drawing any conclusions about, the timing or nature of the regulatory decisions.

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71 BENEFIT–RISK AND FDA DECISIONS researchers and decision scientists have proposed the use of either decision- conferencing or multicriteria decision analysis for benefit-and-risk–based regulatory decision-making (see Appendix D for discussion) (NRC, 2011). The process of decision-conferencing or multicriteria decision analysis can increase transparency in regulatory decision-making, provide formal opportunities for input from stakeholders, and delineate the sources of disagreements among par- ticipants. Some of the methods, however, rely heavily on using a common met - ric, such as dollars saved, lives saved or quality-adjusted life-years, to quantify benefits and risks related to different endpoints and assigning numerical values to a number of subjective considerations, such as the importance of a given adverse event or a specific improvement in quality of life. Appendix C discusses the use of those processes as tools to elicit input into the decision-making pro - cess. They can be useful, and, in some cases, can provide informative results, but the committee emphasizes, as have others, that reducing benefits and risks to a common metric as the only output considered in a decision can sometimes lead to oversimplifying complex decisions, misunderstanding, and a lack of trust (NRC, 1989, 2011). Consistent use by FDA of the proposed framework for decision-making would be valuable for several reasons. First, it would allow stakeholders to understand and anticipate key components of the process by which decisions are made. Second, it would emphasize the dynamic nature of benefit and risk assessments, particularly in the postmarketing setting, and the need for continual re-evaluation of decisions by an organization dedicated to protecting and pro- moting the public health. Third, it would provide an opportunity to consider the value of additional postmarketing studies (for example, through postmarketing requirements), to explore scientific and ethical issues with regard to the type of postmarketing studies under consideration, and to evaluate the potential effects of future regulatory decision-making. Fourth, use of a systematic approach for the routine re-evaluation of benefits, risks, and regulatory decisions could minimize long delays in decision-making or lack of transparency in the rationale for regu - latory decisions may be minimized. It is important to note that while the need to change or modify a regulatory decision about a drug in the postmarketing context can sometimes be traced to errors in premarketing regulatory decision-making, often that is not the case. Rather, the ability to respond to the changing knowledge base regarding the benefit–risk balance is a valued characteristic of the agency that seeks to secure population benefits while mitigating harms, and modifications of regulatory decisions should be expected in the postmarketing phase and not regarded as reflecting a failure. The following sections describe the three stages and the key elements for consideration in each stage. The three stages should not be interpreted as iso - lated activities, but as interconnected activities that inform each other and help to ensure that the characterization of risks or, in this case benefits and risks, is decision-driven, recognizes all significant concerns, includes both analysis and

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110 STUDYING THE SAFETY OF APPROVED DRUGS required, by integrating the evaluation of the evidence of benefits and risks from Stage II with legal and ethical considerations and input from stakehold- ers; communicate to the public the reasoning behind the decision; imple - ment the regulatory response; and, particularly for difficult or controversial decisions (see Recommendation 2.5), evaluate the impact of the regulatory response. Finding 2.2 No single, clear, comprehensive, and public document currently captures FDA’s assessments of a drug’s benefits and risks over the course of its lifecycle, nor does any documentation help to standardize FDA’s decision-making processes or describe FDA’s rationale for its regulatory actions. Capturing such information in a living document would formalize the lifecycle approach to drug regulation, improve regulatory oversight, and improve the transparency of FDA’s decisions. Recommendation 2.2 FDA should require and maintain, for each new drug and for already approved drugs for which questions about the benefit–risk profile are raised, a publicly available and understandable Benefit and Risk Assessment and Management Plan (BRAMP). For new drugs, the BRAMP document should be initiated during the drug-approval phase and updated over the lifecycle of the drug at pre-specified times in the postmarketing setting and when - ever questions about the drug’s benefit–risk profile arise. The document should include a description of: any public health questions raised during the drug’s lifecycle; the benefit and risk assessment specific to each public health question; key stakeholder input specific to each question; any regu - latory decisions or actions and the rationale for each decision, including requirements for postmarketing research or a risk evaluation and mitigation strategy (REMS); a schedule for future assessments of benefits and risks; and plans for and results of evaluating the effectiveness of any regulatory decisions or actions. • n the premarketing phase, the drug sponsor should provide a summary of I the drug’s benefits and risks, any uncertainties in the evidence, and plans for decreasing those uncertainties. FDA should use that information as a starting point to develop the BRAMP document. FDA staff involved with the drug’s premarketing application and staff with expertise and knowl - edge in postmarketing safety assessment should finalize the initial entry to the BRAMP document. • n composing teams to monitor the safety of a drug and maintain its I BRAMP in the postmarketing phase of the drug’s lifecycle, FDA should

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111 BENEFIT–RISK AND FDA DECISIONS consider the real or perceived confirmation bias of staff that played a sig - nificant role in approving the drug. This should be managed by ensuring that the leader of the postmarketing safety monitoring team is without the potential for such bias. The monitoring team should have expertise in surveillance, epidemiology, and the evaluation of safety data collected from different observational and clinical trial designs. The team should review and modify the BRAMP document at specified intervals through- out the lifecycle of the drug, including when new information warrants re-evaluation of the drug’s benefit–risk profile. Finding 2.3 In the premarketing setting, evidence is derived primarily from randomized con - trolled trials. In the postmarketing setting, however, evidence may be derived from surveillance, observational studies, patient registries, published and unpub - lished clinical trials, meta-analyses, and relevant case reports or series. Data sources, study designs, and analytic approaches for the postmarketing context are evolving rapidly. Given those differences, the expertise needed to evaluate and characterize the quality of evidence in the postmarketing setting is different from and broader than that needed in the premarketing setting. Recommendation 2.3 In making determinations about appropriate regulatory decisions to be imple- mented in the postmarketing context, FDA should ensure that the full range of methodologic expertise is used to evaluate the strength of evidence of a drug’s benefits and risks from a wide range of designs. For complex regula- tory decisions, including decisions about requiring additional postmarketing research, such expertise should include, but not be limited to • Clinical medicine and clinical practice, such as pharmacy. • Biostatistics: Bayesian, frequentist, and causal inference methods. • Epidemiology and pharmacoepidemiology. • Clinical trials. • Benefit–risk analysis. • Research and public health ethics. • Risk communication. Finding 2.4 Section 901 of FDAAA14 stipulates the purposes for which FDA has the authority to require postmarketing observational studies and RCTs, and 2011 FDA guid - 14 21 USC § 355(o) (2010).

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112 STUDYING THE SAFETY OF APPROVED DRUGS ance for industry provides information on FDA’s implementation of that section of FDAAA. Although FDA’s decisions to require postmarketing research need to be made case by case, there are some identifiable conditions that are concordant with but more specific and detailed than those outlined in FDAAA and FDA guid- ance, which make information from additional postmarketing research important. Recommendation 2.4 FDA should prospectively determine and publicly identify specific condi - tions, including drug characteristics and other features, that are associated with greater uncertainty about a drug’s benefit–risk profile in the postmar- keting setting. Under those identified conditions, FDA should require post- marketing research in a timely fashion unless there is a compelling reason not to, and should make public the rationale for requiring or not requiring postmarketing research in each case. Those premarketing and postmarketing conditions should include the following • drug is approved when several surrogate endpoints provide conflicting A evidence about the likely health outcomes associated with the drug. • first-in-class drug is approved on the basis of surrogate endpoints used A in drugs of a different class. • drug is associated with safety signals from premarketing data or post- A marketing surveillance when there is a substantial public health concern, a severe adverse event is seen, or there is a strong biologic rationale for a particular adverse effect. • drug is expected to have a different benefit–risk profile in a subgroup A or under real-world conditions. • drug is in a class for which a substantial safety signal has previously A been identified. • vidence of a lack of benefit of a drug in the whole population or in E identifiable subgroups emerges in the postmarketing setting. Finding 2.5 Some FDA decisions in response to postmarketing public health questions are controversial or difficult. Complex instances tend to occur when FDA must make a decision despite scientific disagreement about the relevant evidence or when the likely effects of a given regulatory action are uncertain. These cases serve as important opportunities for FDA, external scientists, and the public to learn about the complexities of the decision-making process and the consequences of a regulatory decision, and for FDA to improve its processes and practices.

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113 BENEFIT–RISK AND FDA DECISIONS Recommendation 2.5 FDA should conduct after-action reviews of postmarketing drug-related deci- sions that are particularly controversial or difficult or when a major regulatory decision is made after marketing. Such a review should include an assessment of the decision-making process itself and the effects of the final decision on the public’s health. Finding 2.6 Surrogate endpoints are often relied on in the drug-approval process, and their use has been related to a number of high-profile drug-safety problems. The findings of postmarketing studies can be used to revise the approval process and improve the endpoints and methods used in it. Recommendation 2.6 As part of a continuing effort to improve regulatory science, FDA should maintain and annually update a list of surrogate endpoints allowed for use in the approval of drugs, the rationale for their use, the postmarketing expe - rience regarding their correlation with health outcomes of interest, and any revisions of approval requirements that may have been suggested by the results of the postmarketing studies. The list should accumulate the post - marketing experience of the successes and failures of various surrogates so that for each major drug class, the regulatory science related to approval methods can be modified and improved. FDA should also revise or develop guidance documents for the use of selected surrogate endpoints that, on the basis of postmarketing studies, appear to be inconsistently predictive of clinical outcomes. REFERENCES Abraham, J. 2010. Pharmaceuticalization of Society in context: Theoretical, empirical and health dimensions. Sociology 44(4):603-622. AHRQ (Agency for Healthcare Research and Quality). 2002. Systems to rate the strength of scientific evidence. Washington, DC: Department of Health and Human Services. Armitage, J., R. Souhami, L. Friedman, L. Hilbrich, J. Holland, L. H. Muhlbaier, J. Shannon, and A. Van Nie. 2008. The impact of privacy and confidentiality laws on the conduct of clinical trials. Clinical Trials 5(1):70-74. Asamoah, A. M., and J. M. Sharfstein. 2010. Transparency at the Food and Drug Administration. New England Journal of Medicine 362(25):2341-2343. Atkinson, A. J., W. A. Colburn, V. G. DeGruttola, D. L. DeMets, G. J. Downing, D. F. Hoth, J. A. Oates, C. C. Peck, R. T. Schooley, B. A. Spilker, J. Woodcock, and S. L. Zeger. 2001. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clinical Pharmacology & Therapeutics 69(3):89-95. Back, E. A., P. Esaiasson, M. Gilljam, O. Svenson, and T. Lindholm. 2011. Post-decision consolidation in large group decision-making. Scandinavian Journal of Psychology 52(4):320-328.

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