Interim Analyses: An Update of an FDA Reviewer's Experience and Perspective *

Abstract

Food and Drug Administration (FDA) clinical and statistical guidelines request that sponsors document considerations which will govern the conduct of interim analyses in clinical trials. These considerations include clearly stating the reasons for such interim analyses, the planned number of or the (information/calendar) times when the interim analyses will be carried out, adequate stopping rules, and measures taken to minimize bias.

Statistical reviewers at the FDA often encounter clinical trials whose conduct and analyses present interim analysis issues that require serious considerations. These issues include: conducting one or more unplanned (posthoc) interim analyses without any stated purpose or reason, leaving the final p-values unadjusted for interim analyses, resizing the trial without p-value adjustment after interim analyses on treatment differences, changing the design and conduct of the trial after interim looks without addressing their impact on the final results, and so forth. These questionable practices of interim analysis observed in clinical trial submissions raise concern among (statistical) reviewers at the FDA. This paper addresses some of these practices and their impact on the review and approval process of clinical trial submissions.