Bridging the Gap Between Preclinical and Clinical Evaluation of Therapeutic Candidates

Session 2

Evaluating Efficacy in Phase 0: Improving Phase 2 Survival

Bruce H. Littman, M.D.
Vice President, Translational Medicine, Pfizer Global Research and Development

The greatest challenge to the economic viability of the pharmaceutical and biotech industry is the high cost of discovering new medicines that meet important medical needs and differentiate from currently available drugs. This is driven primarily by very low survival rates of novel targets and compounds with unprecedented mechanisms of action. Expensive phase 2 attrition (about 80%), primarily due to inadequate efficacy, is the key issue. In this presentation the strategy of extending the concept of phase zero to include very early human efficacy screening is explained. This strategy depends on selection of subjects, usually patients, that represent the “molecularly correct” subpopulation that is the best test of the drug target-efficacy connection. It also involves selection of subjects that will reduce the variability of the primary clinical endpoint or biomarker with high linkage to clinical outcome (efficacy). The study is designed to be a “proof of non-viability” for the drug target and requires evidence of the compound’s pharmacological activity at a dose that is also used to probe its connection to efficacy. An in-depth example of how to develop such a protocol for rheumatoid arthritis and other examples are provided.

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