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

Abstract

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.

Conflict of interest statement

GIP has served as a consultant for Abbott Laboratories, Acadia Pharmaceuticals, Inc*, Alkermes, Inc, AstraZeneca PLC, Avanir Pharmaceuticals, Axsome Therapeutics*, Boston Pharmaceuticals, Inc., Brainsway Ltd, Bristol-Myers Squibb Company, Cala Health, Cephalon Inc., Dey Pharma, L.P., Eli Lilly Co., Genentech, Inc*, Genomind, Inc*, GlaxoSmithKline, Evotec AG, H. Lundbeck A/S, Inflabloc Pharmaceuticals, Janssen Global Services LLC*, Jazz Pharmaceuticals, Johnson & Johnson Companies*, Methylation Sciences Inc, Mylan Inc*, Novartis Pharma AG, One Carbon Therapeutics, Inc*, Osmotica Pharmaceutical Corp.*, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer Inc., Pierre Fabre Laboratories, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Sage Therapeutics, Shire Pharmaceuticals, Sunovion Pharmaceuticals, Taisho Pharmaceutical Co, Ltd, Takeda Pharmaceutical Company LTD, Theracos, Inc., and Wyeth, Inc. GIP has received honoraria (for lectures or consultancy) from Abbott Laboratories, Acadia Pharmaceuticals Inc, Alkermes Inc, Asopharma America Cntral Y Caribe, Astra Zeneca PLC, Avanir Pharmaceuticals, Bristol-Myers Squibb Company, Brainsway Ltd, Cephalon Inc., Dey Pharma, L.P., Eli Lilly Co., Evotec AG, Forest Pharmaceuticals, GlaxoSmithKline, Inflabloc Pharmaceuticals, Grunbiotics Pty LTD, Jazz Pharmaceuticals, H. Lundbeck A/S, Medichem Pharmaceuticals, Inc, Meiji Seika Pharma Co. Ltd, Novartis Pharma AG, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer, Pharma Trade SAS, Pierre Fabre Laboratories, Ridge Diagnostics, Shire Pharmaceuticals, Sunovion Pharmaceuticals, Takeda Pharmaceutical Company LTD, Theracos, Inc., Titan Pharmaceuticals, and Wyeth Inc. GIP has received research support (paid to hospital) from AstraZeneca PLC, Bristol-Myers Squibb Company, Forest Pharmaceuticals, the National Institute of Mental Health, Neuralstem, Inc, PAMLAB LLC, Pfizer Inc., Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Sunovion Pharmaceuticals, Tal Medical, and Theracos, Inc. GIP has served (not currently) on the speaker’s bureau for BristolMyersSquibb Co and Pfizer, Inc. MF reports 3-year disclosures below, and all lifetime disclosures can be viewed online at: http://mghcme.org/faculty/facultydetail/maurizio_fava; research support: Alkermes, Inc., Johnson & Johnson, Axsome, Acadia Pharmaceuticals, Cerecor, Lundbeck Inc., Neuralstem, Otsuka, Taisho, Marinus Pharmaceuticals, BioHaven, Takeda, Vistagen, Relmada Therapeutics Inc., Stanley Medical Research Institute (SMRI), National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH), and PCORI. MF has not done any personal consulting. Any consulting he has done has been on behalf of Massachusetts General Hospital. Stock/Other Financial Options: Equity Holdings: Compellis; PsyBrain, Inc. Royalty/patent, other income: patents for Sequential Parallel Comparison Design (SPCD) (US_7840419, US_7647235, US_7983936, US_8145504, US_8145505); and patent application for a combination of Ketamine plus Scopolamine in MDD, licensed by MGH to Biohaven. Patents for pharmacogenomics of Depression Treatment with Folate (US_9546401, US_9540691). Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs and Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte. Ltd. * Asterisk denotes activity undertaken on behalf of Massachusetts General Hospital. NCS worked in the Pfizer digital medicine group, as part of his clinical translational fellowship at MGH. His work at Pfizer presents no financial or non-financial conflict of interest with the current manuscript.

Figures

Fig. 1. Study arm distribution by design.

AD antidepressant; SPCD sequential parallel comparison design.

Fig. 2. Percent study arm success across designs.

AD antidepressant, SPCD sequential parallel comparison design.

Fig. 3. Reduction in depression severity scores MADRS or HAMD17) on placebo at week 4.

AD antidepressant, SPCD sequential parallel comparison design.

Fig. 4. Average number of subjects enrolled per drug arm across study designs.

AD antidepressant, SPCD sequential parallel comparison design.