Evolution of psychopharmacology trial design and analysis: six decades in the making

Abstract

Objective: The evolution of trial design and analysis during the lifespan of psychopharmacology is examined.

Background: The clinical trial methodology used to evaluate psychopharmacologic agents has evolved considerably over the past 6 decades. The first and most productive decade was characterized by case series, each with a small number of patients. These trials used nonstandardized clinical observation as outcomes and seldom had a comparison group. The crossover design became widely used to examine acute psychiatric treatments in the 1950s and 1960s. Although this strategy provided comparison data, it introduced problems in study implementation and interpretation. In 1962, the US Food and Drug Administration began to require "substantial evidence of effectiveness from adequate and well-controlled studies." Subsequent decades saw remarkable advances in clinical trial design, assessment, and statistical analyses. Standardized instruments were developed and parallel groups, double-blinding, and placebo controls became the benchmark. Sample sizes increased and data analytic procedures were developed that could accommodate the problems of attrition. Randomized withdrawal designs were introduced in the 1970s to examine maintenance therapies. Ethical principles for research became codified in the United States at that time. A wave of regulatory approvals of novel antipsychotics, antidepressants, and anticonvulsants came in the 1980s and 1990s, each based on data from randomized double-blind, parallel-group, placebo-controlled clinical trials. These trial designs often involved fixed-dose comparisons based, in part, on a greater appreciation that much of the benefit and harm in psychopharmacology was dose related.

Conclusions: Despite the progress in randomized controlled trial (RCT) design, the discovery of new mechanisms of action and blockbuster interventions has slowed during the past decade.

Figure 1

Confidence Intervals for Differences between Investigational Intervention and Active Comparator in Hypothetical Non-Inferiority Trials Notes: Non-inferiority of Investigational Intervention requires that the CI falls entirely to the left of +δ, the non-inferiority margin. (e.g., #'s 3, 4, 5 and 6). Superiority of the Investigational Intervention requires that the CI falls entirely to the left of 0 (e.g., #'s 4 and 6). If such a result is seen in a non-inferiority trial and a two-stage testing procedure was specified (first test non-inferiority, then test superiority), the evidence would support both non-inferiority and superiority. The Indeterminate result (#2) stems from the CI that overlaps both 0 and +δ, the non-inferiority margin. Assuming that the equivalence margin ranges from -δ to +δ, #s 3 and 4 not only provides evidence of non-inferiority, but also equivalence.