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Executive Summary

Tumor response rate should be an acceptable efficacy endpoint for the approval of new cancer drugs, the National Cancer Institute (NCI) concluded in a draft of recommendations it plans to submit to FDA for consideration in developing approval criteria for cancer agents. The draft document, approved by NCI's Board of Scientific Counselors at it Feb. 18 meeting, states: "Response rates above a certain level might constitute a basis for approval provided that the responses are of meaningful duration and the toxicity of the agent is not substantial enough to outweigh the beneficial effects." Demonstration of response rates was one of five efficacy endpoints that the NCI endorsed in its recommendations to FDA. Other efficacy endpoints that FDA should consider as acceptable for NDA or product license application studies, according to NCI, are: survival benefit, time to treatment failure (or disease progression), complete response rate, and beneficial effects on disease-related symptoms and/or quality of life. FDA's criteria for approval of cancer agents has been an ongoing issue between FDA and NCI. The letter of recommendations follows an Oct. 2 meeting of NCI's Board of Scientific Directors at which NCI officials criticized the FDA for requiring survival data for the approval of cancer drugs ("The Pink Sheet" Oct. 5, T&G-9). At the October meeting, FDA Office of Drug Evaluation I Director Robert Temple, MD, reported that the agency considers a number of efficacy endpoints besides survival in reviewing a marketing application, including tumor response rates, duration of response, time to tumor progression, and palliation. Despite Temple's explanation of approval requirements, NCI officials at the Feb. 18 meeting reiterated their concern. For example, NCI Division of Cancer Treatment Cancer Therapy Evaluation Program Associate Director Robert Wittes, MD, stated: "There's absolutely no doubt that the way the regulations are commonly interpreted and the whole tone of the way the agency tends to deal with sponsors . . . is couched in terms of survival. So sponsors feel that that is the surest route to FDA approval." NCI's recommendations emphasize that "the approval process should be based on evidence that net benefit results from treatment for defined poplations (or subpopulations) of patients." The institute cites four specific examples of evaluation based on net benefits: "Agents showing significant benefit in patients with refractory cancer might be approved even in the face of very substantial toxicity." "Agents that confer modest but reproducible levels of benefit in patients with refractory cancer should be approved if the level of toxicity is minimal." "For agents with intermediate degrees of benefit and toxicity, the weighing of this balance is more difficult, but the decision rests ultimately on whether demonstrated benefits to the treated population outweigh adverse effects." "Agents that avoid signficant and specific organ toxicity may be approvable if they demonstrate benefit equivalent to a standard agent in a particular cancer." NCI said it plans to submit the recommendations to FDA "as soon as possible" for use in their review of the approval process for cancer agents. Through its Oncologic Drugs Advisory Committee, FDA began a review of approval criteria for cancer drugs, on a tumor-by-tumor basis, in March when the committee looked at efficacy endpoints for the approval of drugs for ovarian cancer.

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