Use Of Larger Versus Smaller Drug-Safety Databases Before Regulatory Approval: The Trade-Offs

Abstract

Although efforts to revamp the drug-safety system have been directed at strengthening postmarketing surveillance, strategies for the preapproval stage may be useful. One strategy would be to require larger sample sizes in preapproval safety databases. To evaluate the potential benefits and costs of this approach, we developed a hypothetical model to estimate the expected incremental number of adverse drug events that could be avoided in a postapproval population. We found that the potential to limit adverse events can be an important consideration in sample-size determinations for preapproval trials. Requiring larger preapproval databases could be a cost-effective means of reducing adverse events in postapproval populations. M o s t i n d u s t ry-s p o n s o r e d c l i n i c a l t r i a l s of new drugs are powered to detect differences on the primary efficacy endpoint that will drive regulatory approval. Detection of adverse drug events (ADEs) is rarely considered when sample-size calculations are undertaken for clinical trials. Thus, the statistical power to detect ADEs is inherently a by-product of considerations of efficacy. w 3 6 0 5 A u g u s t 2 0 0 8 D r u g S a f e t y

End Points for Comparative Effectiveness Research in Heart Failure

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“…52 In order to be valid, a surrogate endpoint should meet clearly defined criteria: 1) the surrogate must be in the causal pathway from the intervention to the clinically relevant outcome, as reflected by a strong association between the surrogate and the target; and 2) there must be no important effects of the intervention on the outcome which are not mediated through or captured by the surrogate. 51 Because it is challenging to establish that these criteria are met, regulatory agencies have generally required that new therapies address clinically relevant outcomes before approval, and major policy decisions that favor one therapy over another should also be based on CER data that relates to clinically meaningful findings.…”

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