Analysis of Impact of Post-Treatment Biopsies in Phase I Clinical Trials.

Abstract

The use of biopsy-derived pharmacodynamic biomarkers is increasing in early-phase clinical trials. It remains unknown whether drug development is accelerated or enhanced by their use. We examined the impact of biopsy-derived pharmacodynamic biomarkers on subsequent drug development through a comprehensive analysis of phase I oncology studies from 2003 to 2010 and subsequent publications citing the original trials. We conducted a search to identify and examine publications of phase I oncology studies including the use of biopsy-derived pharmacodynamic biomarkers between 2003 and 2010. Characteristics of those studies were extracted and analyzed, along with outcomes from the biomarker data. We then compiled and reviewed publications of subsequent phase II and III trials citing the original phase I biomarker studies to determine the impact on drug development. We identified 4,840 phase I oncology publications between 2003 and 2010. Seventy-two studies included a biopsy-derived pharmacodynamic biomarker. The proportion of biomarker studies including nondiagnostic biopsies increased over time (P = .002). A minimum of 1,873 tumor biopsies were documented in the 72 studies, 12 of which reported a statistically significant biomarker result. Thirty-three percent of studies (n = 24) were referenced by subsequent publications specifically with regard to the biomarkers. Only five positive biomarker studies were cited subsequently, and maximum tolerated dose was used for subsequent drug development in all cases. Despite their increased use, the impact of biopsy-derived pharmacodynamic biomarkers in phase I oncology studies on subsequent drug development remains uncertain. No impact on subsequent dose or schedule was demonstrated. This issue requires further evaluation, given the risk and cost of such studies.