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

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.

Ethics review in compassionate use

“…Some authors suggest that the percentage of investigational drugs abandoned at different clinical trial stages because of safety concerns might be even higher [31]. Another study of 640 investigational drugs in late-stage clinical development revealed that 54% failed during or after pivotal clinical trials; most of these failed because of inadequate efficacy (57%) or safety concerns (17%) [32]. …”

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“…For instance, trials have compared new agents with placebos rather than the best existing therapies, underdosed comparator drugs, or relied on surrogate endpoints65 that may not predict outcomes. Some commercially funded researchers have also selectively published (and republished) positive results 866 or concealed negative findings,67 while firms have ended trials prematurely for purely commercial reasons 68…”

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