Benefit, Risk, and Outcomes in Drug Development: A Systematic Review of XXXX .

@entity1 @entity137 @entity2240 @entity5 @entity204
BACKGROUND: Little is known about the total @entity1 burden associated with clinical development and where burdens fall most heavily during a drug development program. Our goal was to quantify the total @entity1 burden/benefit in developing a new drug. METHODS: We measured risk using drug-related adverse events that were grade 3 or higher, benefit by objective response rate, and trial outcomes by whether studies met their primary endpoint with acceptable safety. The differences in risk ( @entity204 rate) and benefit (overall response rate) between industry and nonindustry trials were analyzed with an inverse-variance weighted fixed effects meta-analysis implemented as a weighted regression analysis. All statistical tests were two-sided. RESULTS: We identified 103 primary publications of @entity2240 monotherapy, representing 9092 @entity1 and 3991 @entity1 -years of involvement over 10 years and 32 different @entity5 . In total, 1052 @entity1 receiving @entity2240 monotherapy experienced objective @entity5 response (15.7% of intent-to-treat population, 95% confidence interval [CI] = 15.3% to 16.0%), 98 died from drug-related @entity137 (1.08%, 95% CI = 1.02% to 1.14%), and at least 1245 experienced grade 3-4 drug-related @entity137 (13.7%, 95% CI = 13.3% to 14.1%). Risk/benefit worsened as the development program matured, with several instances of replicated negative studies and almost no positive trials after the first responding @entity5 were discovered. CONCLUSIONS: Even for a successful drug, the risk/benefit balance of trials was similar to phase I cancer trials in general. @entity2240 monotherapy development showed worsening risk/benefit, and the testing of new indications responded slowly to evidence that @entity2240 monotherapy would not extend to new @entity5 . Research decision-making should draw on evidence from whole research programs rather than a narrow band of studies in the same indication.
