Ethical and Scientific Issues in Studying the Safety of Approved Drugs (2012) / Chapter Skim
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5 Synthesis
5 Synthesis
Pages 213-226
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From page 213... ...
In support of the equal public health importance of regulatory oversight of drugs before and after approval, the authorities granted to FDA by the Food and Drug Administration Amendments Act (FDAAA) of 20071 provide FDA with the tools it needs to adopt a comprehensive lifecycle approach to the assessment of the benefits and risks associated with marketed drugs.
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From page 214... ...
and gathers its broad findings and recommendations.2 RESPONSES TO THE CHARGE QUESTIONS How should FDA factor in different kinds of safety evidence in consider ing different kinds of regulatory actions? In response to this question, the committee notes that no single algorithm can determine how to factor different kinds of safety evidence into regulatory decision-making, but does specify processes and principles to guide how this should occur.
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From page 215... ...
FDA should review and finalize the BRAMP document. In the postmarketing setting, FDA staff who did not play a primary role in the drug's approval process and who have expertise in surveillance, epidemiology, and the evaluation of safety data collected from different observational and clinical trial designs, would review and modify the BRAMP document at pre-specified intervals throughout the lifecycle of the drug and when new information warrants re-evaluation of the drug's benefit–risk profile.
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From page 216... ...
For example, the value of an observational study of a harm based on existing data depends on whether the harm was reliably recorded in the dataset being used. A clinical trial too short to find a delayed effect is going to provide less relevant safety evidence than a design based on patient registry data with long follow-up.
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From page 217... ...
Although the committee agrees that a well-conducted, high-quality RCT has many theoretical advantages over other study designs, it also recognizes that what can be achieved in practice in assessing safety endpoints can fall short of the ideal. Noncompliance, cross-over and dropout, limitations in study size or duration, failure of the study population or procedures to adequately represent circumstances in the general population of users, and the realization that safety endpoints are sometimes unforeseeable and cannot always be specified in advance can decrease the advantages of RCTs over observational studies for evaluating the risks posed by approved drugs.
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From page 218... ...
As previously noted, modest relative risks, particularly those less than 1.5, can require substantial control of confounding that might only be achievable in a clinical trial. One way to ameliorate this problem is to conduct multiple observational studies with a variety of designs and data sources unlikely to share similar biases.
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From page 219... ...
Superiority studies evaluate whether a new treatment performs better than a previous, accepted treatment or, in the case of safety studies, poses less risk of adverse effects than the accepted treatment. One concern with noninferiority studies is the consequence of poor study conduct.
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From page 220... ...
Those characteristics might appear in the case of drugs that were approved on the basis of surrogate endpoints when different surrogate endpoints yield conflicting evidence about clinical effect or safety; drugs that are first-in-class and were validated on the basis of surrogate endpoints with drugs in a different class; drugs about which safety signals appear in premarketing data or postmarketing surveillance when there is a substantial public health concern, drugs where a severe adverse event is seen, or there is a strong biologic rationale for a particular adverse effect; drugs that are expected to have a different benefit–risk profile in a particular group or under real-world conditions; drugs in a class about which a substantial safety signal has previously been identified; and drugs of which evidence of a lack of benefit emerges in the postmarketing setting. The earliest and easiest step that FDA can take is to ensure that it is making maximum use, perhaps through meta-analysis, of the data already in its posses sion, which often would have been submitted as part of a New Drug Application, or may pre-exist because of studies performed for a different indication.
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From page 221... ...
One key determinant of the kinds of designs that might be considered is whether the safety signal is a harm to be offset by a known benefit or the harm is a failure to provide expected benefit, either overall or in specific populations. FDAAA defines the latter as a safety concern, or more specifically "any failure of expected pharmacological action of the drug".4 A failure to provide expected clinical benefit is most likely to be observed if that benefit was not directly tested in the approval process, for example, if surrogate endpoints were used, or if non-responsive subpopulations were not well represented in premarketing trials.
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From page 222... ...
What are the ethical and informed consent issues that must be considered when designing randomized clinical trials to evaluate potential safety risks? An assessment of the ethics of FDA's requiring a postmarketing RCT is inextricably intertwined with an assessment of the science related to the underlying public health question and regulatory decision.
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From page 223... ...
The ethics of selecting an appropriate comparator for an FDA-required RCT are discussed under Question 4, below. 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 about which a safety signal has prompted concerns about risk, and potentially about the acceptability of the drug's benefit–risk profile.
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From page 224... ...
In making the determination that an RCT that FDA is considering requiring can be carried out in a manner that provides sufficient protection of and respect for research participants, FDA must always balance its ethical obligations to protect the public from unsafe drugs with its ethical obligations to safeguard the rights and interests of people who participate in research supporting the agency's deci sions about drug benefits and risks. Difficult choices must be confronted when the 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.
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From page 225... ...
and DMCs with sufficient information to permit appropriate continuing oversight of the RCT in accordance with their roles. That should include information about the public health question at issue, the specifics of the study design that it has deemed suitable to address the question -- including any design features that it 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 RCT that might affect the benefit–risk profile of the drug and influence a person's decision about whether to continue to participate.
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From page 226... ...
2004. Interventions to improve research participants' understanding in informed consent for research.
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