22 CASE STUDIES WHERE PHASE 2 AND PHASE 3 TRIALS HAD DIVERGENT RESULTS

FDA
January 2017 :: 44 pages
Overview
Pre-market clinical testing usually progresses in phases, with increasingly rigorous methods at each phase. Product candidates that appear insufficiently safe or effective at one phase may not proceed to the next phase. Roughly 9 in 10 drugs/biologics that are tested in humans are never submitted to FDA for approval.[1] Typically, a candidate drug is submitted to the FDA for marketing approval after phase 3 testing. In recent years, there has been growing interest in exploring alternatives to requiring phase 3 testing before product approval, such as relying on different types of data and unvalidated surrogate endpoints.

To better understand the nature of the evidence obtained from many phase 2 trials and the contributions of phase 3 trials, we identified, based on publicly available information, 22 case studies of drugs, vaccines and medical devices since 1999 in which promising phase 2 clinical trial results were not confirmed in phase 3 clinical testing.* Phase 3 studies did not confirm phase 2 findings of effectiveness in 14 cases, safety in 1 case, and both safety and effectiveness in 7 cases. These unexpected results could occur even when the phase 2 study was relatively large and even when the phase 2 trials assessed clinical outcomes. In two cases, the phase 3 studies showed that the experimental product increased the frequency of the problem it was intended to prevent.

This paper is not intended to assess why each of these unexpected results occurred or why further product development was not pursued. Rather, these cases, chosen from a large pool of similar examples, illustrate the ways in which controlled trials of appropriate size and duration contribute to the scientific understanding of medical products.