Ethical and Scientific Issues in Studying the Safety of Approved Drugs (2012) / Chapter Skim
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2 Incorporating Benefit and Risk Assessment and BenefitRisk Management into Food and Drug Administration Decision-Making
2 Incorporating Benefit and Risk Assessment and BenefitRisk Management into Food and Drug Administration Decision-Making
Pages 61-120
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From page 61... ...
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)
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From page 62... ...
In the remainder of this chapter, the committee outlines a three-stage framework 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.)
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From page 63... ...
. THREE-STAGE FRAMEWORK FOR REGULATORY DECISION-MAKING Overview and Rationale Responding in a timely and appropriate way to safety signals from alreadyapproved drugs is among the most important and challenging public health jobs that FDA must accomplish.
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From page 64... ...
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.
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From page 65... ...
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)
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From page 66... ...
. 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.
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From page 67... ...
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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From page 68... ...
2. In contrast, when deciding about postmarketing regulatory decisions about aprotinin (Trasylol®)
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From page 69... ...
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.
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From page 70... ...
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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From page 71... ...
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.
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From page 72... ...
All FDA regulatory decisions involve complex relationships between scientific evidence, regulatory authority, ethical values, and practical considerations. The public health question and the context within which it is being asked need to be clearly defined to ensure that all those relationships and the potential public health consequences of alternative actions, are properly considered from the onset of the decision-making process.
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From page 73... ...
The major considerations that should be taken into account when specify ing the public health question that underlies a regulatory decision are discussed below. The goal of the "public health question" is to ascertain what the public health impact would be of different regulatory responses triggered by new data pertaining to a drug's benefit–risk profile, not simply whether the use of the drug incurs unacceptable risk.
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From page 74... ...
The public health question cannot be properly specified without careful characterization of the population that is taking the drug and could take it in the future. Key considerations include the size of the population; whether it includes people who are in need of special protections, such as children and those with serious cognitive disabilities; whether it is made up largely of communities where there are substantial health disparities; and whether it is a population of mainly well or ill people.
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From page 75... ...
Additional characteristics related to safety include the severity, duration and reversibility of potential adverse events associated with the drug, whether it would be easy to mitigate or improve outcomes resulting from adverse events with close monitoring or other treatments, and whether estimates of efficacy are based on clinical endpoints or surrogate markers. Availability of Alternative Treatments for the Disease or Condition When deciding how to specify the public health question raised by new information about an approved drug, FDA should consider whether the drug is "first-in-class", and the benefits and risks of any alternative treatments, includ ing whether there is a subgroup of patients in whom the other treatments do not appear to be effective.
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From page 76... ...
PMCs are not required. Requirement that the Drug Sponsor Conduct a Postmarketing Study FDA may require a manufacturer to conduct postmarketing studies (postmarketing requirements, PMRs)
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From page 77... ...
. If a drug was granted accelerated approval for a serious or life-threatening disease, FDA has the authority to use an expedited procedure to remove it from the market if later clinical trials fail to confirm its expected clinical benefit or if the manufacturer did not satisfy its obligations for additional postmarketing studies.g a 21 USC § 355(o)
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From page 78... ...
At the end of Stage I, FDA should have a clearly stated and carefully specified public health question that identifies the relevant regulatory actions under consideration. For example, as noted previously, when the decision-making process is initiated because of new evidence of harms associated with a drug, the general public health question is whether any regulatory action is needed to ensure that the approved drug or class of drug still has a favorable benefit–risk profile, and, if so, what those actions should be.
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From page 79... ...
disease that has a characterized public health impact for which alternative interventions are or are not available. The specification of the public health question should have engaged patients and other stakeholders including clinicians, indus try, and family members, and incorporate their perspectives when planning the benefit and risk assessments, and to identify their concerns, including practical considerations related to different regulatory actions.
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From page 80... ...
The assessments therefore should be designed with the public health question that needs to be answered and the array of regulatory actions in mind. The available evidence relevant to the public health question at issue, the expertise required to assess that evidence, and the additional evidentiary needs should be identified at the onset of the assessments.
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From page 81... ...
Characterization of the Strength of Evidence The estimates of the benefits and risks associated with a drug need to be characterized for regulatory decision-makers and stakeholders. The characterization should include a discussion of the nature of the evidence, including the types of studies that have been conducted (for example, observational studies and clinical trials)
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From page 82... ...
; deciding on the appropriate regulatory actions, including whether further study should be required; implementing the regulatory actions; and evaluating the effects of the regulatory actions. Integrating the Assessment of the Evidence with Other Considerations When making a regulatory decision, FDA should take into account not only the best available scientific evidence on a drug's benefits and risks but also a variety of legal, ethical, and practical considerations.
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From page 83... ...
, but FDA can order a postmarketing requirement based on an indication of a potential seri ous health risk.7 Most of the listed postmarketing regulatory actions also have procedural requirements -- such as notice to the manufacturer and an adminis trative hearing with the right of judicial appeal8 -- that generally increase with the consequences of the regulatory action for stakeholders (Evans, 2010; FDA, 2012a)
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From page 84... ...
, people's values affect their preferences for health states, their perceptions of the benefit–risk balance of a drug, and their views regarding appropriate drug regulatory decisions. That is as true for policy makers, scientists, regulators, and industry executives as it is for patients, physicians, and health care managers.
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From page 85... ...
Those views will drive stakeholders' perceptions of what postmarketing regulatory actions are appropriate in response to new information that emerges about a marketed drug. An additional value concerns the overall purposes or objectives of regulatory decisions.
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From page 86... ...
The drug sponsor, with FDA's support, suspended the marketing of natalizumab, and FDA placed ongoing clinical trials on hold and issued a public health advisory informing patients and health-care providers to suspend its use (FDA, 2010b)
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From page 87... ...
The committee is not commenting on, or drawing any conclusions about, the timing or nature of the regulatory decisions.
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From page 88... ...
However, when the reasons differ because various stakeholders and technical experts use different values to attach meaning to the findings, such as how important it is to secure or avoid a particular benefit or risk, disagreements may be more difficult to bridge. Practical Considerations FDA should take into account a number of practical considerations when making its regulatory decisions.
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From page 89... ...
Decisions are most difficult when there is large uncertainty in the scientific evidence, there is a potential for severe public health consequences if a wrong regulatory action is taken, and there is considerable disagreement among stake holders and technical experts about what the right action should be. Difficult regulatory decisions should be identified and resolved in a more formal process.
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From page 90... ...
For any particular drug, it remains difficult to find a clear, concise document that outlines the public health questions that have arisen over the drug's lifecycle that have prompted regulatory decisions; summarizes the benefit–risk assessment, including the evidence on which it was based; outlines the scientific, ethical, and practical considerations that influenced the decision; and describes plans to manage any potential or known risks associated with a 9 21 USC § 360bbb–6 (2010)
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From page 91... ...
Communication of its regulatory decisions on rosiglitazone (Avandia®) is a good example.
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From page 92... ...
. The drug sponsor argued that dabigatran should be approved at both doses and that the 100-mg twice-daily dose should be available to people who were at risk for bleeding.
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Evaluations should be conducted on a periodic basis to identify key facilitators of and barriers to timely regulatory action and potential improvements in the decision-making process. Such evaluations should also assess whether regulatory decisions are having the intended effects on drug use and health outcomes and whether unintended consequences are occurring.
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From page 94... ...
The evaluations should be used to help to determine whether regulatory decisions should be revisited. All evaluations should consider whether and when it is appropriate to solicit stakeholder input.
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From page 95... ...
Although FDA is responsible for making regulatory decisions about approved drugs, responsibility for ensuring that the benefits of a drug outweigh its risks is shared by FDA and the drug sponsor. For each new drug, therefore, responsibility for the initial development of some of the content that would go into the BRAMP document should rest with the drug sponsor; much of that material is already submitted as part of the documentation for approval, such as a summary and benefit and risk assessment, and any proposed postmarketing-study designs or REMS.
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From page 96... ...
For example, data from surveillance and observational studies are much more likely to be available. In the postmarketing setting, therefore, expertise is needed in surveillance, epide miology, and the evaluation of safety data collected from different observational studies, as well as clinical trial designs, biostatistics, medicine, pharmacology, risk communication, and ethics.
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From page 97... ...
b. The public health question and the uncertainties that need to be decreased to enable a regulatory decision.
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From page 98... ...
Having a single, living, publicly available summary document that contains the history of all regulatory actions related to a drug and a description of the rationale and support for the decisions is critical for improving FDA's ability to manage drugs in the postmarketing setting and to increase the transparency of FDA's regula tory decisions. SPECIAL CONSIDERATIONS IN THE DECISION OF WHETHER TO REQUIRE A POSTMARKETING STUDY Balancing the desire for more certainty about drug safety against the need for timely decisions is a key challenge in drug regulation.
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From page 99... ...
Much of the committee's charge focuses on the scientific and ethical issues associated with postmarketing requirements, so the committee discusses requiring postmarketing research in more detail in this section. This section begins with a discussion of two specific circumstances under which FDA should give serious consideration to requiring a postmarketing requirement and should provide a public rationale if it decides not to do so.
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From page 100... ...
When FDA requires a postmarketing study, at a minimum, it should specify to drug sponsors and the public what information is needed to help reach an appropriate answer to the public health question that prompted the research. The type of study design needed to answer the question also should be specified, as should study endpoints and inclusion and exclusion criteria (see Chapter 4)
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From page 101... ...
. In addition to its obligation to ensure that a study will provide the requisite information, FDA has an obligation to ensure timely use of study findings in its regulatory decisions.
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From page 102... ...
. In other words, VOI analysis describes the relationship between the knowledge that might come from the considered source of information and its potential for improving decision outcomes, and it can help to establish a threshold for specific regulatory decisions.
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From page 103... ...
Drugs that qualify for the accelerated approval mechanism require confirma tory postmarketing studies as a condition of approval, but about one-third of drugs that go through the traditional approval process are approved solely on the basis of evidence on surrogate endpoints (GAO, 2009b) , which have been discussed extensively by scientists in and outside FDA (Fleming and DeMets, 1996; Prentice, 1989; Psaty et al., 1999; Temple, 1999)
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From page 104... ...
Drugs approved on the basis of surrogate endpoints have on occasion been the subjects of postmarketing drug-safety problems. For instance, the premarketing studies of rosiglitazone demonstrated a reduction in fasting glucose and glycated hemoglobin (see Table 2-1)
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From page 105... ...
The findings from these studies provide critical information about the reliability and the validity of surrogate endpoints that are likely to be used for the approval of future medications. As an essential element of the lifecycle approach to improving regulatory science at FDA, the ability to refine, enhance and improve the surrogate endpoints used for future drug approvals represents an effort to protect the health of the public and prevent the adverse events occasioned by faulty or flawed inferences on the basis of trial results from surrogate endpoints that turn
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From page 106... ...
Since FDAAA specifies "failure of expected pharmacological action" as a safety issue, improving methods to predict drug effectiveness in the postmarketing context can be regarded as part of FDA's drug safety responsibility.
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From page 107... ...
Postmarketing experience and research helped to shape and improve the methods by which future medications in the same class will be evaluated. Like the guidance on anti-diabetic therapies, the guidance on drug-induced liver injury incorporates experience from postmarketing studies to improve the use of surrogate endpoints for safety in future drug evaluations (FDA, 2009c)
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From page 108... ...
Had the VIGOR trial been designed to evaluate both the gastrointestinal benefits and the thromboembolic adverse events because of the safety signal in premarketing studies and the biologic rationale for such effects, more complete informa tion about the benefit–risk profile of rofecoxib might have been available much sooner. (Interestingly, VIGOR was conducted at twice the daily recommended chronic dose, which underscores the importance of being attentive to dose levels both for benefits and risk contrasts [Bombardier et al., 2000]
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From page 109... ...
FINDINGS AND RECOMMENDATIONS Finding 2.1 FDA's current approach to drug oversight in the postmarketing setting is not sufficiently systematic and does not ensure consistent assessment of benefits and risks associated with a drug over its lifecycle. Use of a standardized regulatory decision-making framework that is flexible enough to adapt to decisions of dif ferent complexity could make FDA's decision-making process more predictable, transparent, and active, allowing FDA to better anticipate postmarketing research needs and to plan for such research early when more design options with fewer ethical tensions might be possible.
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From page 110... ...
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.
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From page 111... ...
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.
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From page 112... ...
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.
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From page 113... ...
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.
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From page 114... ...
2004. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol.
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From page 115... ...
Paper read at Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee, Hilton Gaithersburg.
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From page 116... ...
2011f. Guidance for industry postmarketing studies and clinical trials -- implementation of section 505(o)
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2009b. New drug approval: FDA needs to enhance its oversight of drugs approved on the basis of surrogate endpoints.
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2007. Drug safety reform at the FDA -- Pendulum swing or systematic improvement?
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From page 119... ...
1989. Surrogate endpoints in clinical trials: Definition and operational criteria.
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From page 120... ...
2010. Regulatory action on rosiglitazone by the U.S.
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