Selective publication of antidepressant trials and its influence on apparent efficacy: Updated comparisons and meta-analyses of newer versus older trials.

Background: Valid assessment of drug efficacy and safety requires an evidence base free of reporting bias. Using trial reports in Food and Drug Administration (FDA) drug approval packages as a gold standard, we previously found that the published literature inflated the apparent efficacy of antidepressant drugs. The objective of the current study was to determine whether this has improved with recently approved drugs.
Methods and Findings: Using medical and statistical reviews in FDA drug approval packages, we identified 30 Phase II/III double-blind placebo-controlled acute monotherapy trials, involving 13,747 patients, of desvenlafaxine, vilazodone, levomilnacipran, and vortioxetine; we then identified corresponding published reports. We compared the data from this newer cohort of antidepressants (approved February 2008 to September 2013) with the previously published dataset on 74 trials of 12 older antidepressants (approved December 1987 to August 2002). Using logistic regression, we examined the effects of trial outcome and trial cohort (newer versus older) on transparent reporting (whether published and FDA conclusions agreed). Among newer antidepressants, transparent publication occurred more with positive (15/15 = 100%) than negative (7/15 = 47%) trials (OR 35.1, CI95% 1.8 to 693). Controlling for trial outcome, transparent publication occurred more with newer than older trials (OR 6.6, CI95% 1.6 to 26.4). Within negative trials, transparent reporting increased from 11% to 47%. We also conducted and contrasted FDA- and journal-based meta-analyses. For newer antidepressants, FDA-based effect size (ESFDA) was 0.24 (CI95% 0.18 to 0.30), while journal-based effect size (ESJournals) was 0.29 (CI95% 0.23 to 0.36). Thus, effect size inflation, presumably due to reporting bias, was 0.05, less than for older antidepressants (0.10). Limitations of this study include a small number of trials and drugs-belonging to a single class-and a focus on efficacy (versus safety).
Conclusions: Reporting bias persists but appears to have diminished for newer, compared to older, antidepressants. Continued efforts are needed to further improve transparency in the scientific literature.
Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: ET previously worked as a Medical Officer for the US Food and Drug Administration (FDA) and reviewed applications submitted by pharmaceutical companies to determine they should be approved for US marketing. He has no financial interest in any pharmaceutical products, approved or otherwise. AC is supported by the National Institute for Health Research (NIHR) Oxford Cognitive Health Clinical Research Facility, by an NIHR Research Professorship (grant RP-2017-08-ST2-006), by the NIHR Oxford and Thames Valley Applied Research Collaboration and by the NIHR Oxford Health Biomedical Research Centre (grant BRC-1215-20005). He has received research and consultancy fees from INCiPiT (Italian Network for Paediatric Trials), CARIPLO Foundation and Angelini Pharma, outside the submitted work. TAF reports grants and personal fees from Mitsubishi-Tanabe, personal fees from MSD, grants and personal fees from Shionogi, outside the submitted work; in addition, he has a patent 2020-548587 concerning smartphone CBT apps pending, and intellectual properties for Kokoro-app licensed to Mitsubishi-Tanabe. GS has received fees paid to the University of Bern for participating in a meeting as real-world evidence and metaanalysis expert from Biogen and Merck. YV has no competing interests.