1 Department of Clinical Pharmacy, University of California San Francisco, San Francisco, California, United States of America, 2 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America, 3 Division of General Internal Medicine, University of California San Francisco, San Francisco, California, United States of America
The United States (US) Food and Drug Administration (FDA) approves new drugs based on sponsor-submitted clinical trials. The publication status of these trials in the medical literature and factors associated with publication have not been evaluated. We sought to determine the proportion of trials submitted to the FDA in support of newly approved drugs that are published in biomedical journals that a typical clinician, consumer, or policy maker living in the US would reasonably search.
We conducted a cohort study of trials supporting new drugs approved between 1998 and 2000, as described in FDA medical and statistical review documents and the FDA approved drug label. We determined publication status and time from approval to full publication in the medical literature at 2 and 5 y by searching PubMed and other databases through 01 August 2006. We then evaluated trial characteristics associated with publication. We identified 909 trials supporting 90 approved drugs in the FDA reviews, of which 43% (394/909) were published. Among the subset of trials described in the FDA-approved drug label and classified as "pivotal trials" for our analysis, 76% (257/340) were published. In multivariable logistic regression for all trials 5 y postapproval, likelihood of publication correlated with statistically significant results (odds ratio [OR] 3.03, 95% confidence interval [CI] 1.78-5.17); larger sample sizes (OR 1.33 per 2-fold increase in sample size, 95% CI 1.17-1.52); and pivotal status (OR 5.31, 95% CI 3.30-8.55). In multivariable logistic regression for only the pivotal trials 5 y postapproval, likelihood of publication correlated with statistically significant results (OR 2.96, 95% CI 1.24-7.06) and larger sample sizes (OR 1.47 per 2-fold increase in sample size, 95% CI 1.15-1.88). Statistically significant results and larger sample sizes were also predictive of publication at 2 y postapproval and in multivariable Cox proportional models for all trials and the subset of pivotal trials.
Over half of all supporting trials for FDA-approved drugs remained unpublished = 5 y after approval. Pivotal trials and trials with statistically significant results and larger sample sizes are more likely to be published. Selective reporting of trial results exists for commonly marketed drugs. Our data provide a baseline for evaluating publication bias as the new FDA Amendments Act comes into force mandating basic results reporting of clinical trials.
Citation: Lee K, Bacchetti P, Sim I (2008) Publication of Clinical Trials Supporting Successful New Drug Applications: A Literature Analysis. PLoS Med 5(9): e191. doi:10.1371/journal.pmed.0050191
Academic Editor: Mike Clarke, UK Cochrane Centre, United Kingdom
Received: February 19, 2008; Accepted: August 8, 2008; Published: September 23, 2008
Copyright: © 2008 Lee et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The project described was supported in part by funds from the United States Presidential Early Career Award for Scientists and Engineers awarded to IS and administered under grant LM-06780, and by National Institutes of Health/National Center for Research Resources (NIH/NCRR) University of California San Francisco–Clinical and Translational Science Institute (UCSF-CTSI). Grant number UL1 RR024131 and grant number KL2RR024130 to KL. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The granting agencies had no role in the design, conduct, review, or publication approval of this study.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: CI, confidence interval; CINAHL, Cumulative Index for Nursing and Allied Health Literature; FDA, Food and Drug Administration; NDA, new drug application; OR, odds ratio; US, United States
* To whom correspondence should be addressed. E-mail: email@example.com