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Trials. 2018 Oct 23;19(1):581. doi: 10.1186/s13063-018-2957-0.

Registration, results reporting, and publication bias of clinical trials supporting FDA approval of neuropsychiatric drugs before and after FDAAA: a retrospective cohort study.

Author information

1
Yale School of Medicine, New Haven, CT, USA.
2
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
3
McLean Hospital, Boston, MA, USA.
4
Harvard Medical School, Boston, MA, USA.
5
Division of Cardiovascular Medicine, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
6
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
7
Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA.
8
Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, USA.
9
Section of General Medicine, Department of Internal Medicine, Yale School of Medicine, PO Box 208093, New Haven, CT, 06520, USA.
10
Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA. joseph.ross@yale.edu.
11
Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, USA. joseph.ross@yale.edu.
12
Section of General Medicine, Department of Internal Medicine, Yale School of Medicine, PO Box 208093, New Haven, CT, 06520, USA. joseph.ross@yale.edu.

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).

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:

Clinical trial registration; Clinical trial results; ClinicalTrials.gov; FDAAA; Publication bias; Selective publication

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