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

Abstract

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.

Fig. 1

Death rates from cancer and heart disease for ages younger than 85 and 85 and older. Rates are age-adjusted to the 2000 U.S. standard population (U.S. Mortality Public Use Data Tapes 1060 to 2001, National Center for Health Statistics, Center for Disease Control and Prevention, 2004).

Fig. 2

A nosology of biomarkers. A, the hierarchy of validity highlights the critical lack of validated surrogate endpoint biomarkers (SEBs) available for chemoprevention research. B, determining when a biomarker is on the path of and becomes a true surrogate for the cancer endpoint is a challenging task. As indicated by the dotted lines following them, only genetic, molecular, biochemical, and histologic and clinical biomarkers that ultimately transverse pathways 4 and 5 would be SEBs. Cancer biomarkers may not be present at earlier stages of the pathway to cancer and thus may not serve as SEBs. Modified from ref. and reprinted with permission of Springer.

Fig. 3

Qualitative ranking of cancer risk reduction interventions based on drug toxicity. The level of toxicity that would be acceptable to the patient increases with conditions that lead to a higher risk of cancer.