Only 42% of 96,944 CETP-inhibitor trial subjects ever appeared in a published report, a case study in biomarker-driven drug development finds (Circ Cardiovasc Qual Outcomes 2017)

Original title: Success, Failure, and Transparency in Biomarker-Based Drug Development: A Case Study of Cholesteryl Ester Transfer Protein Inhibitors

Circ Cardiovasc Qual Outcomes · 1 June 2017 · 6

Hey SP, Franklin JM, Avorn J, Kesselheim AS

A systematic portfolio analysis of clinical research on five CETP inhibitors (anacetrapib, dalcetrapib, evacetrapib, TA-8995, torcetrapib), used as a case study of biomarker-based drug development, since none had yet reached approval despite years of work. Searching PubMed and ClinicalTrials.gov, the authors identified 100 studies involving 96 944 human subjects, of whom only 41 201 (42%) had their data presented in a published report. For the three discontinued CETP inhibitors, they found a consistent pattern: positive results on lipid-modification endpoints followed by negative results on clinical endpoints. The authors argue that relying on an inadequately validated biomarker, HDL-C, across successive trial failures caused avoidable harm to subjects and research waste, and call for regulators and funders to play a greater coordinating role.

Original abstract

Background: Although biomarkers are used as surrogate measures for drug targeting and approval and are generally based on plausible biological hypotheses, some are found to not correlate well with clinical outcomes. Over-reliance on inadequately validated biomarkers in drug development can lead to harm to trial subjects and patients and to research waste. To shed greater light on the process and ethics of biomarker-based drug development, we conducted a systematic portfolio analysis of cholesterol ester transfer protein inhibitors, a drug class designed to improve lipid profiles and prevent cardiovascular events. Despite years of development, no cholesterol ester transfer protein inhibitor has yet been approved for clinical use.

Methods And Results: We searched PubMed and Clinicaltrials.gov for clinical studies of 5 known cholesterol ester transfer protein inhibitors: anacetrapib, dalcetrapib, evacetrapib, TA-8995, and torcetrapib. Published reports and registration records were extracted for patient demographic characteristics and study authors' recommendations of clinical usage or further testing. We used Accumulating Evidence and Research Organization graphing to depict the portfolio of research activities and a Poisson model to examine trends. We identified 100 studies for analysis that involved 96 944 human subjects. The data from only 41 201 (42%) of the human subjects had been presented in a published report. For the 3 discontinued cholesterol ester transfer protein inhibitors, we found a pattern of consistently positive results on lipid-modification end points followed by negative results using clinical end points.

Conclusions: Inefficiencies and harms can arise if a biomarker hypothesis continues to drive trials despite successive failures. Regulators, research funding bodies, and public policy makers may need to play a greater role in evaluating and coordinating biomarker-driven research programs.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.