Regulatory approval of cancer risk-reducing (chemopreventive) drugs: moving what we have learned into the clinic.

This article endeavors to clarify the current requirements and status of regulatory approval for chemoprevention (risk reduction) drugs and discusses possible improvements to the regulatory pathway for chemoprevention. Covering a wide range of topics in as much depth as space allows, this report is written in a style to facilitate the understanding of nonscientists and to serve as a framework for informing the directions of experts engaged more deeply with this issue. Key topics we cover here are as follows: a history of definitive cancer chemoprevention trials and their influence on the evolution of regulatory assessments; a brief review of the long-standing success of pharmacologic risk reduction of cardiovascular diseases and its relevance to approval for cancer risk reduction drugs; the use and limitations of biomarkers for developing and the approval of cancer risk reduction drugs; the identification of individuals at a high(er) risk for cancer and who are appropriate candidates for risk reduction drugs; business models that should incentivize pharmaceutical industry investment in cancer risk reduction; a summary of scientific and institutional barriers to development of cancer risk reduction drugs; and a summary of major recommendations that should help facilitate the pathway to regulatory approval for pharmacologic cancer risk reduction drugs.

Clinical trial design for target-based therapy.

Anticancer drug discovery has shifted from an empiric random screening directed approach to a more rational and mechanistic, target-based approach, which reflects our rapidly expanding knowledge of the pathogenesis of a variety of forms of cancer at the molecular level, providing new targets for drug discovery and development. The clinical development of target-based anticancer drugs will require fundamental changes to the traditional clinical trial design and end points that have been used for conventional cytotoxic drugs. In the phase I and II settings, traditional end points (toxicity and response) may not be suitable for more selective, cytostatic target-based agents, and these end points may be replaced by biological or pharmacokinetic end points to define the optimal doses and the therapeutic effects of these drugs on their targets. For phase III trials, measurable clinical benefit will continue to be the primary end point. As our understanding of the complex pathways and networks controlling cell signaling, proliferation, and cell death expands, we must learn how and when to use agents to target specific steps in malignant transformation and proliferation, and we must adapt clinical trial design to test the clinical utility of this promising new class of anticancer drugs.