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.

The future of psychopharmacology: a critical appraisal of ongoing phase 2/3 trials, and of some current trends aiming to de‐risk trial programmes of novel agents

“…While a large number of trials adopted the single‐blind placebo lead‐in period as a form of full enrichment of the trial in placebo non‐responders, this enrichment has failed to show benefits, as suggested by a meta‐analysis of 101 antidepressant trials 164 and recently replicated in a meta‐analysis of 347 antidepressant trials, of which 174 used a single‐blind placebo run‐in period 165 . Single‐blind placebo and open‐label medication lead‐in phases are inferior to other enrichment study designs, such as sequential parallel design 166 , and have longer duration and higher costs. Accounting for costs, sample size, and duration of trials, the sequential parallel design may to be more effective for phase 3 trials aiming to regulatory approval 166 .…”

“…Single‐blind placebo and open‐label medication lead‐in phases are inferior to other enrichment study designs, such as sequential parallel design 166 , and have longer duration and higher costs. Accounting for costs, sample size, and duration of trials, the sequential parallel design may to be more effective for phase 3 trials aiming to regulatory approval 166 .…”

Statins and antidepressants induce similar in vitro gene expression responses

“…Despite the continuous efforts in developing new treatments, many drug candidates fail to advance in clinical trials due to efficacy or safety-related reasons [2, 3]. Drug repurposing refers to the process of identifying novel therapeutic effects of existing drugs, and represents a more efficient and cost-effective approach for identifying new therapeutic treatments [4].…”

Placebo response mitigation with a participant-focused psychoeducational procedure: a randomized, single-blind, all placebo study in major depressive and psychotic disorders

“…For example, psychiatric medications are among the least successful, with a 6.3% ultimate likelihood of approval, success rates of 23.7% in Phase II and 55.7% in Phase III, and with substantially longer (about 2 years) Phase II and III development timelines than non-CNS indications [1,2]. In most cases, these failures are due to a lack of efficacy in demonstrating that active treatment signal separates from placebo and is a crucial reason several pharmaceutical companies have reduced or even closed their psychiatric research and development programs [3][4][5].…”