Publication of Pivotal Efficacy Trials for Novel Therapeutic Agents Approved Between 2005 and 2011: A Cross-sectional Study

Pivotal efficacy trials, which are trials that form the basis of the US Food and Drug Administration’s (FDA) decision to approve a novel therapeutic agent,¹ have great relevance to clinical practice because when these therapies are first approved for use, few clinical trials have been conducted. However, studies focused on pharmacotherapies approved prior to 2005 found that more than one-quarter of these trials were not published,^2,3 although efforts to promote clinical trial transparency and dissemination have since intensified.⁴ We determined publication status and timeliness among pivotal trials supporting the approval of novel therapeutics by FDA from 2005 through 2011.

As described previously,¹ we assembled a cohort of pivotal trials for all novel pharmacologic drugs and biologic agents approved by FDA between 2005 and 2011. Trials were categorized by therapeutic and trial characteristics, including randomization, allocation strategy, duration, and number of patients (Table).

To determine trial publication status, 2 of us (J.W.S., N.S.D.) independently searched the biomedical literature during the period from April through October 2013 using a systematic strategy. Publications were identified in 1 of 2 ways: we searched the Scopus database (Elsevier Inc) using the terms “[generic drug name]” AND “clinical trial.” Alternatively, manufacturer-designated trial identification numbers of 6 or more characters were entered into the advanced search feature of ClinicalTrials.gov.⁵ We used 4 criteria to identify matching publications: study design, indication, intervention, and intention-to-treat enrollment; publication enrollment was allowed to exceed that reported by FDA because enrollment often extends beyond regulatory submission. Publications that pooled results from multiple trials were credited to all relevant trials if trial design was discussed in detail. For all unpublished trials, a third reviewer (J.S.R.) independently confirmed publication status.

To determine trial publication timeliness, we calculated time from approval to publication in months for all trials that were published. We examined associations between publication and both therapeutic and trial characteristics using Pearson χ² analysis, performed with JMP software (version 10.0.0; SAS Institute Inc).

There were 380 pivotal efficacy trials associated with 149 novel therapeutic agents approved for 164 indications by the FDA; the median number of trials per indication was 2. Overall, 86% of pivotal trials (326 of 380) were published in peer-reviewed biomedical journals. Among 164 indications, at least 1 pivotal trial was published for 96% (157 of 164), whereas all pivotal trials were published for 82% (134 of 164). Among all published trials, 48% (157 of 326) were published before or during the month of FDA approval; among trials published after approval, the median time from approval to publication was 7.0 months (range, 1.0-73.0). Finally, there were significant differences in publication rates by therapeutic area (P = .003) and by total number of patients (P = .02), but not by other characteristics (Table).

Among the pivotal trials supporting the approval of all novel therapeutic agents by the FDA from 2005 through 2011, 86% were published in the peer-reviewed biomedical literature, although timeliness varied. This rate is slightly more than the 76% published for drugs approved from 1998 through 2000 and the 69% for antidepressants approved from 1987 through 2004, although the former used a slightly different search strategy and the latter included both pivotal and supporting trials.^2,3 Nevertheless, our findings suggest there is opportunity for to improve and ensure that all pivotal trials are published. These trials are critical both to FDA approval decisions and to clinical practice, as there is otherwise limited clinical research available to inform physician and patient decision-making when therapies are first approved for use.

Our study was limited to pivotal trials; we did not examine whether the many supporting trials submitted as part of novel therapeutic applications were published, although we expect their publication rates to be lower. In addition, we did not contact manufacturers to confirm that trials were unpublished, nor did we determine whether unpublished trials reported results on ClinicalTrials.gov.

Corresponding Author: Joseph S. Ross, MD, MHS, Section of General Internal Medicine, Yale University School of Medicine, PO Box 208093, New Haven, CT 06520 (joseph.ross@yale.edu).

Published Online: July 28, 2014. doi:10.1001/jamainternmed.2014.3438.

Author Contributions: Mr Smithy had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Downing, Ross.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Smithy.

Study supervision: Downing, Ross.

Conflict of Interest Disclosures: Mr Smithy reports that he owns a small number of shares of the following pharmaceutical companies: Bristol-Myers Squibb, Gilead, Johnson & Johnson, and Roche. Dr Ross receives support from Medtronic Inc and Johnson & Johnson to develop methods of clinical trial data sharing, from the Centers for Medicare and Medicaid Services (CMS) to develop and maintain performance measures that are used for public reporting, and from the Food and Drug Administration (FDA) to develop methods for postmarket surveillance of medical devices. Dr Ross reports that he is a member of a scientific advisory board for FAIR Health Inc. No other disclosures are reported.

Additional Information: Dr Ross is supported by the National Institute on Aging (K08 AG032886) and by the American Federation for Aging Research through the Paul B. Beeson Career Development Award Program.