Zou et al. Trials (2018) 19:581 https://doi.org/10.1186/s13063-018-2957-0 RESEARCH Open Access Registration, results reporting, and publication bias of clinical trials supporting FDA approval of neuropsychiatric drugs before and after FDAAA: a retrospective cohort study Constance X. Zou1, Jessica E. Becker2,3,4, Adam T. Phillips5, James M. Garritano1, Harlan M. Krumholz6,7,8, Jennifer E. Miller9 and Joseph S. Ross7,8,9* Abstract Background: Mandatory trial registration, and later results reporting, were proposed to mitigate selective clinical trial publication and outcome reporting. The Food and Drug Administration (FDA) Amendments Act (FDAAA) was enacted by Congress on September 27, 2007, requiring the registration of all non-phase I clinical trials involving FDA- regulated medical interventions and results reporting for approved drugs. The association between FDAAA enactment and the registration, results reporting, and publication bias of neuropsychiatric trials has not been studied. Methods: We conducted a retrospective cohort study of all efficacy trials supporting FDA new drug approvals between 2005 to 2014 for neuropsychiatric indications. Trials were categorized as pre- or post-FDAAA based on initiation and/or completion dates. The main outcomes were the proportions of trials registered and reporting results in ClinicalTrials.gov, and the degree of publication bias, estimated using the relative risks pre- and post-FDAAA of both the publication of positive vs non-positive trials, as well as of publication of positive vs non-positive trials without misleading interpretations. Registration and results reporting proportions were compared pre- and post-FDAAA using the two-tailed Fisher exact test, and the degrees of publication bias were compared by calculating the ratio of relative risks (RRR) for each period. Results: The FDA approved 37 new drugs for neuropsychiatric indications between 2005 and 2014 on the basis of 142 efficacy trials, of which 101 were pre-FDAAA and 41 post-FDAAA. Post-FDAAA trials were significantly more likely to be registered (100% vs 64%; p < 0.001) and report results (100% vs 10%; p < 0.001) than pre-FDAAA trials. Pre-FDAAA, positive trials were more likely to be published (relative risk [RR] = 1.52; 95% confidence interval [CI] = 1.17–1.99; p = 0.002) and published without misleading interpretations (RR = 2.47; CI = 1.57–3.73; p < 0.001) than those with non-positive results. In contrast, post-FDAAA positive trials were equally likely to have been published (RR = 1; CI = 1–1, p = NA) and published without misleading interpretations (RR = 1.20; CI = 0.84–1.72; p = 0.30). The likelihood of publication bias pre-FDAAA vs post-FDAAA was greater for positive vs non-positive trials (RRR = 1.52; CI = 1.16–1.99; p = 0.002) and for publication without misleading interpretations (RRR = 2.06, CI = 1.17–3.61, p =0.01). (Continued on next page) * Correspondence: [email protected] 7Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA 8Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zou et al. Trials (2018) 19:581 Page 2 of 11 (Continued from previous page) Conclusions: The enactment of FDAAA was followed by significantly higher proportions of trials that were registered and reporting results on ClinicalTrials.gov and significantly lower degrees of publication bias among trials supporting recent FDA approval of drugs for neuropsychiatric indications. Keywords: FDAAA, ClinicalTrials.gov, Clinical trial registration, Clinical trial results, Selective publication, Publication bias Background biological products, or devices. The FDAAA mandated Research suggests that as many as 15–50% of completed that sponsors and investigators register all such trials in clinical studies are never published [1–10] and that pub- ClinicalTrials.gov prior to subject enrollment and report lication bias persists: trials with non-positive results are results to ClinicalTrials.gov within 30 days post approval significantly more likely to remain unpublished than tri- of the indication being studied. The FDAAA is applic- als with positive results [3, 11–15]. Although under- or able to trials that began after September 27, 2007 and to non-publication of clinical trials is a problem ubiquitous earlier trials that were still ongoing as of December 26, in medicine and science, many considered the problems 2007. Inappropriately delayed registration and results to be particularly severe among clinical studies in neur- reporting, as well as reporting of false results, are pun- ology and psychiatry [16]. Clinical studies supporting ap- ishable by fines of up to $10,000 per day and can lead to proved drugs for neuropsychiatric indications, such as withholding of funding from studies receiving federal paroxetine (Paxil) [17], reboxetine (Edronax) [18], gaba- support. pentin (Neurontin) [19], and lamotrigine (Lamictal) [20], It has now been ten years since the FDAAA was have been identified as being subject to underreporting. enacted. Its impact on clinical trial registration, results Data demonstrating these drugs to be potentially inef- reporting, and publication bias has largely remained un- fective for approved indications or suggesting harm were determined. One recent study demonstrated that the not publicly disclosed until the pharmaceutical compan- FDAAA was associated with increased registration and ies’ internal documents were reviewed during legal pro- publication of clinical studies of new drugs approved to ceedings [16, 21, 22]. Similarly, among trials evaluating treat cardiovascular disease and diabetes [35]. However, drugs indicated for depression [7], anxiety [23], and no study has focused on trials involving drugs treating psychotic disorders [24] that were first approved by the neurological and psychiatric conditions, an area in which US Food and Drug Administration (FDA) in recent de- concern for selective publication and outcome reporting cades, 80–90% of trials with negative or equivocal results remains. were either not published or were published in a mis- The objective of our study was to compare the propor- leading manner to suggest a positive result, while nearly tions of trials that were registered and reporting results 100% of trials with positive results were published. on ClinicalTrials.gov, as well as the degree of publication A publicly accessible, centralized trial registry can pre- bias, before and after the FDAAA, among clinical trials vent clinical trials from remaining hidden by allowing in- supporting FDA approval of drugs for neuropsychiatric terested individuals, including patients, clinicians, and indications. We designed a retrospective cohort study regulators, to identify all trials relevant to a specific using a cohort of clinical trials that were submitted to medical condition or to a specific medical product. In and reviewed by the FDA for the approval of New Drug 1997, Congress passed the FDA Modernization Act Applications (NDAs) between 2005 and 2014 for the (FDAMA), which mandated the first USA-based public treatment of neurologic and psychiatric conditions. For registry ClinicalTrials.gov [25] in 2000, maintained by each trial, we determined their FDAAA eligibility based the National Institutes of Health (NIH) [26]. In 2005, on trial initiation and/or completion dates [34], as well the International Committee of Medical Journal Editors as their registration, results reporting, and publication (ICMJE) issued a policy requiring trial registration as a status. condition of publication in member journals [27], which was followed by an increase in registered trials [28–31]. Methods Nonetheless, the FDAMA only required registration of a Data sources small number of trials, while the ICMJE recommenda- Data were obtained from three sources: Drugs@FDA tion was only followed on a voluntary basis and still per- [36], ClinicalTrials.gov, and PubMed’s listing of mitted publication of unregistered trials [32, 33]. MEDLINE-indexed journals. Drugs@FDA is a public In 2007, Congress passed the FDA Amendments Act database maintained by the FDA, providing access to (FDAAA) [34], applicable to essentially all non-phase I regulatory actions and documents issued for each drug interventional studies involving FDA-regulated drugs, approved by the agency. ClinicalTrials.gov is a public Zou et al. Trials (2018) 19:581 Page 3 of 11 clinical trial registry database maintained by the National FDA, or at times not assigned by the FDA and thus de- Library of Medicine at the NIH [25]. PubMed’s list of termined using a previously described method [38]. MEDLINE-indexed journals includes more than 5500 biomedical journals. Determination of FDAAA status The FDAAA, as enacted in 2007, clarified that new re- quirements would apply to trials that were initiated after Novel therapeutics approved