The Food and Drug Administration Safety Innovations Act (FDASIA) of 2012 authorized the FDA accelerated approval program, permitting marketing authorization for drugs for serious conditions that fill an unmet medical need, based on a surrogate or intermediate clinical endpoint. Confirmation based on a clinical endpoint is required. A risk of accelerated-approval development is potential for crossover. Once accelerated approval is achieved, patients receiving the study treatment as subsequent therapy can confound subsequent assessment and render confirmatory trial results inconclusive. In addition, even in the absence of accelerated approval, crossover can be required by ethics committees or DMCs in ongoing trials based on preliminary evidence of efficacy, confounding OS analyses in ongoing trials. Susan Ellenberg [1] has described crossover is one of the critical sponsor risks of the accelerated approval process not addressed by the Johnson et al [2]'s characterization of the FDA experience or addressed at the FDA's 2011 ODAC on accelerated approval in oncology. [3]

The purpose of this discussion is to examine the scope of the problem and evaluate strategies for addressing or avoiding it, including: a. Performing the confirmatory trial in a different population from the accelerated-approval trial

b. Greater alignment between the evidence needed to ethically require crossover within a trial and the evidence needed to support approval in the general population

c. Statistical adjustment for crossover

d. Changes to the accelerated approval program

A successful surrogate-endpoint trial followed by a confounded confirmatory trial represents a waste to all parties. What strategies can sponsors, regulatory agencies, and ethics committees use to avoid this waste?

[1] Ellenberg, S. Accelerated approval of oncology drugs: Can we do better? JNCI 1-3:616=617 (2011) [2] Johnson JR, et al. Accelerated approval of oncology products: the Food and Drug Administration experience. JNCI103:636–44 (2011) [3] FDA. February 8, 2011: Oncologic Drugs Advisory Committee Meeting Announcement. 2011 Available from: http://www.fda.gov/AdvisoryCommittees/Calendar/ucm239360.htm.