Staged Risk Management of Candidate Drug Efficacy

Abstract

There is a broad need within the drug development industry for a new approach to understanding the ‘levels-of-proof’ that operate within a drug development programme. This article outlines a proposed system to address this need. We suggest a hierarchy, which could be used as a general communication tool and riskassessment device when managing stages of clinical development and discussing the proofs, and possible profits, of ‘effect’. This structure starts with low levels of proof such as basic pharmacokinetics being proof of systemic exposure; higher levels of proof then include proof of compartmental exposure where appropriate. The hierarchy then graduates on to proof of pharmacological activity ascending from simple receptor activities through to more downstream pathway-related effects. The final tiers in the hierarchy represent proof of activity in diseaserelated pathways, disease-related surrogates, registrable endpoints and finally the highest level of proof is in health economic-related outcomes such as quality-adjusted life-years.

The proposed ‘structure’ is intended to improve the confused terms of ‘proof of concept’ and ‘proof of principle’ and more adequately address the outmoded terms that relate to ‘phased drug development’. We do not envisage that these terms will be replaced but note that this new structure has the advantage of being based on scientific and medical rationale. Furthermore, we use this tool to aid thinking about risk/portfolio management.