Success and efficiency of phase 2/3 adjunctive trials for MDD funded by industry: a systematic review

• Published in: Molecular psychiatry Vol. 25; no. 9; pp. 1967 - 1974
• Main Authors: Salloum, Naji C., Fava, Maurizio, Ball, Sophia, Papakostas, George I.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2020; Nature Publishing Group
• Subjects: 631/378; 692/699/476/1414; Analysis; Antidepressants; Antidepressive Agents - therapeutic use; Aripiprazole; Behavioral Sciences; Biological Psychology; Clinical trials; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Depression, Mental; Depressive Disorder, Major - drug therapy; Double-Blind Method; Drug approval; Drug therapy; Efficiency; Evidence-based medicine; Humans; Medical research; Medicine; Medicine & Public Health; Medicine, Experimental; Mental depression; Neurosciences; Patients; Pharmacotherapy; Placebos; Product development; Psychiatry; Randomized Controlled Trials as Topic; Review; Review Article; Sample Size; Single-Blind Method; Success; Systematic review; Treatment Outcome
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-020-0646-3

To review the success rate and efficiency of industry-sponsored phase 2/3 clinical trials for adjunctive therapies for antidepressant partial- and non-responders with major depressive disorder (MDD), a systematic search of Pubmed/Medline was conducted, in addition to abstracts of major psychiatric meeting held since 2010, of randomized, placebo-controlled adjunct oral pharmacotherapy trials in this patient population. Forty-six ( n  = 33,900; 70 drug compactor arms) trials were pooled, yielding only three approved drugs. Twenty-two (31.4%) drug-placebo comparisons were successful. Numerically, success rates for treatment arms from studies with one versus more than one drug-placebo comparison were higher (39.3% versus 26.2%). The antidepressant lead-in employing single-blind placebo and the sequential-parallel comparison design (SPCD) were successful in 50% and 40% of cases, respectively. The direct randomization (no lead-in) design yielded positive results in one third of cases. The success rate of open-label antidepressant lead-ins without placebo or using double-blind placebo was very poor (<15%). There was also a pronounced discrepancy in terms of efficiency across study designs. Accounting for sample size requirements, a phase 3 program using SPCD would have a higher cumulative chance of yielding two positive trials (50%) than a phase 3 program using a single-blind placebo lead-in (40%). Future programs should carefully weigh the need for a lead-in, which is time-consuming, expensive and, in some cases (i.e., open-label antidepressant without placebo or with double-blind placebo) nearly futile. Instead, more effort should involve the use of studies where patients are directly randomized, such as the SPCD, with more investment shifted towards the accurate and independent vetting of subject eligibility.