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Original Investigation
December 2016

Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results

Author Affiliations
  • 1Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 2Radcliffe Institute for Advanced Study and Faculty of Arts and Sciences, Harvard University, Cambridge, Massachusetts
JAMA Intern Med. 2016;176(12):1826-1833. doi:10.1001/jamainternmed.2016.6008
Key Points

Question  Why and how often do experimental drugs fail in phase 3 clinical trials, and how often are trial results published?

Findings  Using public sources and commercial databases covering drugs and biologics that started trials between 1998 and 2008, 54% of agents carried into pivotal trials failed, primarily owing to inadequate efficacy or safety concerns. Trial results were published for 40% of these failed agents.

Meaning  Although many drugs fail in late-stage trials, the rate of publication of trial results is poor.

Abstract

Importance  Many investigational drugs fail in late-stage clinical development. A better understanding of why investigational drugs fail can inform clinical practice, regulatory decisions, and future research.

Objective  To assess factors associated with regulatory approval or reasons for failure of investigational therapeutics in phase 3 or pivotal trials and rates of publication of trial results.

Design, Setting, and Participants  Using public sources and commercial databases, we identified investigational therapeutics that entered pivotal trials between 1998 and 2008, with follow-up through 2015. Agents were classified by therapeutic area, orphan designation status, fast track designation, novelty of biological pathway, company size, and as a pharmacologic or biologic product.

Main Outcomes and Measures  For each product, we identified reasons for failure (efficacy, safety, commercial) and assessed the rates of publication of trial results. We used multivariable logistic regression models to evaluate factors associated with regulatory approval.

Results  Among 640 novel therapeutics, 344 (54%) failed in clinical development, 230 (36%) were approved by the US Food and Drug Administration (FDA), and 66 (10%) were approved in other countries but not by the FDA. Most products failed due to inadequate efficacy (n = 195; 57%), while 59 (17%) failed because of safety concerns and 74 (22%) failed due to commercial reasons. The pivotal trial results were published in peer-reviewed journals for 138 of the 344 (40%) failed agents. Of 74 trials for agents that failed for commercial reasons, only 6 (8.1%) were published. In analyses adjusted for therapeutic area, agent type, firm size, orphan designation, fast-track status, trial year, and novelty of biological pathway, orphan-designated drugs were significantly more likely than nonorphan drugs to be approved (46% vs 34%; adjusted odds ratio [aOR], 2.3; 95% CI, 1.4-3.7). Cancer drugs (27% vs 39%; aOR, 0.5; 95% CI, 0.3-0.9) and agents sponsored by small and medium-size companies (28% vs 42%; aOR, 0.4; 95% CI, 0.3-0.7) were significantly less likely to be approved.

Conclusions and Relevance  Roughly half of investigational drugs entering late-stage clinical development fail during or after pivotal clinical trials, primarily because of concerns about safety, efficacy, or both. Results for the majority of studies of investigational drugs that fail are not published in peer-reviewed journals.

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