Date of Award

January 2019

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Joseph S. Ross

Abstract

Evidence-based medicine (EBM) promotes the use of randomized controlled trials (RCTs) published in peer reviewed medical journals as the “gold standard”. However, up to 50% of the completed clinical trials are never published and trials with results in favor of studied interventions are 2-4 times more likely to have been published then those with non favorable results. Publication bias seems to be a particularly severe problem for RCTs evaluating newly approved brand-name neuropsychiatric drugs. Mandatory trial registration, and later results reporting, were proposed to mitigate selective clinical trial publication and outcome reporting. Congress enacted the FDA Amendments Act (FDAAA) on September 27, 2007 requiring the registration of all non-phase I clinical trials involving FDA-regulated medical interventions and results reporting for FDA approved drugs. It’s been 10 years since FDAAA enactment, the impact of FDAAA on the selective publication of clinical trials has not been studied. Our objective is to determine whether FDAAA enactment is associated with improvements in trial registration and results reporting, as well as with decreased publication bias of clinical trials evaluating new neuropsychiatric drugs. We conducted a retrospective cohort study of all efficacy trials supporting FDA new drug approval between 2005 to 2014 for neuropsychiatric indications. Trials were categorized as pre- or post-FDAAA based on initiation and/or completion dates as outlined by the statue. The main outcomes were the proportions of trials registered, proportions reported results in ClinicalTrials.gov, and the degree of publication bias. Publication bias was estimated using the relative risks pre- and post-FDAAA of both the publication of positive vs non-positive trials, as well as of publishing positive vs. non-positive trials without misleading interpretations. Registration and results reporting proportions were compared pre- and post-FDAAA using two-tailed Fisher Exact Test and the degrees of publication bias were compared by calculating the ratio of relative risks (RRR) for each period. Our study sample included 101 Pre-FDAAA and 41 Post-FDAAA efficacy trials supporting the FDA approval of 37 new drugs for neuropsychiatric indications between 2005 and 2014. 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 (RR=1.52; 95% Confidence Interval [CI]=1.17-1.99; P=0.002) and published without misleading interpretations (RR=2.47; Cl=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; Cl=1-1, p=NA), and published without misleading interpretations (RR=1.20; Cl=0.84-1.72; p=0.30). The likelihood of publication bias pre-FDAAA vs. post-FDAAA was greater for publication of positive vs. non-positive trials (RRR=1.52; Cl=1.16-1.99; p=0.002) and for publication without misleading interpretations (RRR=2.06, Cl=1.17-3.61, p=0.01). The enactment of FDAAA was followed by significantly higher proportions of trials that were registered and reported results on ClinicalTrials.gov, and with significantly lower degrees of publication bias among trials supporting recent FDA approval of drugs for neuropsychiatric indications.

Comments

This is an Open Access Thesis.

Download
Open Access

This Article is Open Access

Share

COinS