• Marc R Theoret, Lee H Pai-Scherf, Meredith K Chuk, Tatiana M Prowell, Sanjeeve Balasubramaniam, Tamy Kim, Geoffrey Kim, Paul G Kluetz, Patricia Keegan, and Richard Pazdur.
• Office of Hematology and Oncology Products (OHOP), Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. Marc.Theoret@fda.hhs.gov.
• Clin Cancer Res. 2015 Oct 15; 21 (20): 4545-51.

AbstractIn 1962, the passage of the Kefauver-Harris Amendment to the 1938 Food, Drug, and Cosmetic Act required that sponsors seeking approval of new drugs demonstrate the drug's efficacy, in addition to its safety, through a formal process that includes "adequate and well-controlled" clinical trials as the basis to support claims of effectiveness. As a result of this amendment, FDA formalized in regulation the definitions of various phases of clinical investigations (i.e., phase I, phase II, and phase III). The clinical drug development paradigm for anticancer drugs intended to support marketing approval has historically followed this "phased" approach with sequential, stand-alone trials, with an increasing number of patients exposed to an investigational drug with each trial in order to fulfill the objectives of that particular stage in development. Increasingly, it is the Office of Hematology and Oncology Products' experience that commercial sponsors of solid tumor oncology drug development programs are amending ongoing phase I trials to add expansion cohorts designed to evaluate study objectives typical of later-phase trials. For investigational anticancer drugs that demonstrate preliminary clinical evidence of substantial antitumor activity early in clinical testing, use of expansion cohorts as a component of the solid tumor oncology drug development pathway, with appropriate measures to mitigate the risks of this approach, may fit in well with the goals and concepts described by FDA's expedited programs for serious conditions.©2015 American Association for Cancer Research.

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