Abstract
BackgroundMandatory 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.MethodsWe 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.ResultsThe 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).ConclusionsThe 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.
Highlights
Mandatory trial registration, and later results reporting, were proposed to mitigate selective clinical trial publication and outcome reporting
The enactment of FDA Amendments Act (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 Food and Drug Administration (FDA) approval of drugs for neuropsychiatric indications
Pre-FDAAA, 64% (65 of 101) of clinical trials were registered on ClinicalTrials.gov, while 100% (41 of 41) of post-FDAAA trials were registered (p < 0.001; Fig. 2)
Summary
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 FDAregulated medical interventions and results reporting for approved drugs. Clinical studies supporting approved drugs for neuropsychiatric indications, such as paroxetine (Paxil) [17], reboxetine (Edronax) [18], gabapentin (Neurontin) [19], and lamotrigine (Lamictal) [20], have been identified as being subject to underreporting Data demonstrating these drugs to be potentially ineffective for approved indications or suggesting harm were not publicly disclosed until the pharmaceutical companies’ internal documents were reviewed during legal proceedings [16, 21, 22]. The FDAMA only required registration of a small number of trials, while the ICMJE recommendation was only followed on a voluntary basis and still permitted publication of unregistered trials [32, 33]
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