Factors Associated with Failure of Oncology Drugs in Late-Stage Clinical Development: a Systematic Review
A partir d'une revue systématique des données de la base "PharmaProject" portant sur 42 médicaments anticancéreux dont le développement a été abandonné entre 2009 et 2014, cette étude analyse les facteurs associés au taux d'échecs survenus lors des essais de phase III
Highlights :
•Drug development in oncology is characterized by a high rate of failure at the stage of phase III trials.
•Achieving proof of concept based on drug activity after a phase II trial increases the likelihood of later approval.
•Drugs developed under a biomarker-based selection strategy are less likely to fail at late stages of development.
Abstract :
Background : We aimed to describe the reasons for failure of experimental anticancer drugs in late-stage clinical development.
Material and Methods : We searched the PharmaProjects database (https://citeline.com/products/pharmaprojects/) for anticancer drugs discontinued between 01/01/2009 and 06/30/2014. Drug programs that reached phase III trials, but never gained Food and Drug Administration (FDA) approval were compared to 37 anti-cancer drugs achieving FDA approval in this time period.
Results : Forty-two drugs fit our criteria for development failures. These failed drugs (49% targeted, 23% cytotoxics, and 28% other) were tested in 43 cancer indications (drug programs). Only 16% (7/43) of failed drug programs adopted a biomarker-driven rationale for patient selection versus 57% (21/37) of successful drug programs (P < .001). Phase II trial information was available in 32 of 43 failed drug programs and in 32 of 37 successful programs. Nine of the 32 trials (28%) of failed drugs versus 28 of 32 trials (87%) of successful drugs (P < .001) achieved proof of concept (single agent response rate (RR) ⩾20% or combination therapy showing a ⩾20% RR increase above the median historical RR without the experimental agent (with a minimal absolute increase of 5%) or a randomized phase II trial showing significance (P ⩽ .05) for its primary outcome). No pattern of study sites, trial design or funding characteristics emerged from the failed drug analysis.
Conclusion : For drugs that reached Phase III, lack of a biomarker-driven strategy and failure to attain proof of concept in phase II are potential risk factors for later discontinuation, especially for targeted agents.
Cancer Treatment Reviews , résumé, 2015