Meta-Analysis of Clinical Dose–Response in a Large Drug Development Portfolio

TLDR

The meta‑analysis aimed to identify consistent quantitative dose–response patterns across multiple compounds and diseases. The authors collected efficacy data from all clinically effective compounds (1998–2009), summarized study designs, and fitted an Emax model to each compound’s dose–response data. Most compounds followed Emax models with Hill parameters near 1.0, and potency predictions were within a ten‑fold range of final estimates for 90% of cases, except one compound with a nonmonotone response. The findings provide an empirical basis for designing and analyzing new dose‑finding studies using parametric Emax models and Bayesian estimation with empirically derived priors.

Abstract

AbstractThis article reports the results of a meta-analysis based on dose–response studies conducted by a large pharmaceutical company between 1998–2009. Data collection targeted efficacy endpoints from all compounds with evidence of clinical efficacy during the time period. Safety data were not extracted. The goal of the meta-analysis was to identify consistent quantitative patterns in dose–response across different compounds and diseases. The article presents summaries of the study designs, including the number of studies conducted for each compound, dosing range, the number of doses evaluated, and the number of patients per dose. The Emax model, ubiquitous in pharmacology research, was fit for each compound. It described the data well, except for a single compound, which had nonmonotone dose–response. Compound-specific estimates and Bayesian hierarchical modeling showed that dose–response curves for most compounds can be approximated by Emax models with "Hill" parameters close to 1.0. Summaries of the potency estimates show pharmacometric predictions of potency made before the first dose ranging study within a (1/10, 10) multiple of the final estimates for 90% of compounds. The results of the meta-analysis, when combined with compound-specific information, provide an empirical basis for designing and analyzing new dose finding studies using parametric Emax models and Bayesian estimation with empirically derived prior distributions.Key Words: Bayesian pharmacometric modelsDosing designEmax