Healthy Skepticism Library item: 14094

Warning: This library includes all items relevant to health product marketing that we are aware of regardless of quality. Often we do not agree with all or part of the contents.

Publication type: Journal Article

Reed SD, Anstrom KJ, Seils DM, .
Use Of Larger Versus Smaller Drug-Safety Databases Before Regulatory Approval: The Trade-Offs
Health Affairs 2008 Aug 5;
http://content.healthaffairs.org/cgi/content/full/hlthaff.27.5.w360/DC1

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. [Health Affairs 27, no. 5 (2008): w360-w370 (published online 5 August 2008; 10.1377/hlthaff.27.5.w360)]

Most industry-sponsored clinical trials 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.

For medications intended to treat chronic, non-life-threatening conditions, the International Conference on Harmonization recommends that premarket clinical safety databases include data on 1,500 patients, of whom 300-600 have been treated for at least six months and 100 have been treated for one year.1 Although the guidelines recommend higher numbers when safety concerns have been expressed about similar compounds, the recommended sample size implies that preapproval safety evaluations will not characterize rare ADEs. Yet these databases might not even have adequate power to detect adverse events that occur in as many as one in 100 patients.

In the aftermath of several highly publicized withdrawals of drugs from the market in the United States, concern has been raised about the adequacy of clinical development programs to inform regulatory authorities and the public about drug safety.2 Proponents of reforming the current system have focused on revamping postmarketing efforts.3However, others have called for larger clinical trials to identify ADEs before regulatory approval.4 For extremely rare ADEs, only postmarketing strategies are practicable (or reasonable). However, for less rare ADEs, the methodological benefits of randomization combined with additional statistical power make a policy that requires larger preapproval safety databases appealing. Of course, a prominent concern about such a policy is its cost.5

To frame this debate, we developed a model to determine the magnitude of the expected benefit—measured by the avoidance of ADEs—of requiring larger versus smaller clinical-safety databases for regulatory approval of a hypothetical new drug, and we evaluated the potential cost-effectiveness of this. To increase the real-world applicability of the model, we consulted the literature on cardiovascular and cerebrovascular events among patients enrolled in clinical trials of cyclooxygenase-2 (COX-2) inhibitors to guide estimates of model parameters.6