Research designs for proof-of-concept chronic pain clinical trials: IMMPACT recommendations

Abstract

Proof-of-concept (POC) clinical trials play an important role in developing novel treatments and determining whether existing treatments may be efficacious in broader populations of patients. The goal of most POC trials is to determine whether a treatment is likely to be efficacious for a given indication and thus whether it is worth investing the financial resources and participant exposure necessary for a confirmatory trial of that intervention. A challenge in designing POC trials is obtaining sufficient information to make this important go/no-go decision in a cost-effective manner. An IMMPACT consensus meeting was convened to discuss design considerations for POC trials in analgesia, with a focus on maximizing power with limited resources and participants. We present general design aspects to consider including patient population, active comparators and placebos, study power, pharmacokinetic-pharmacodynamic relationships, and minimization of missing data. Efficiency of single-dose studies for treatments with rapid onset is discussed. The trade-off between parallel-group and crossover designs with respect to overall sample sizes, trial duration, and applicability is summarized. The advantages and disadvantages of more recent trial designs, including N-of-1 designs, enriched designs, adaptive designs, and sequential parallel comparison designs, are summarized, and recommendations for consideration are provided. More attention to identifying efficient yet powerful designs for POC clinical trials of chronic pain treatments may increase the percentage of truly efficacious pain treatments that are advanced to confirmatory trials while decreasing the percentage of ineffective treatments that continue to be evaluated rather than abandoned.

Keywords: Clinical trials; IMMPACT; Methodology; Proof of concept.

Figure 1

Examples of early stage proof-of-concept designs: Drop-the-loser dose finding and single dose studies. (A) In drop-the-loser dose finding trials, the “best” dosage from Stage 1 is selected based on efficacy, or a combination of safety and efficacy. That dosage is then tested in a new set of subjects. Data from Stages 1 and 2 are combined for both the placebo group and the “best” dosage group for final efficacy analysis [71]. (B) In single dose trials, treatment groups can be compared with respect to frequent assessments in a single session using area under the curve (AUC) as an outcome variable.

Figure 2

Example later stage POC designs: Sequential parallel comparison design (SPCD) and enriched cross-over design. (A) SPCD incorporates Stage 2 data from Stage 1 placebo non-responders only, potentially decreasing the impact of the placebo response [32]. *Indicates groups that are included in the final analysis. (B) In an enriched crossover design, two single-blind run-in phases (drug with known efficacy followed by placebo) used to identify subjects who appear to respond to the currently indicated drug. The experimental drug is tested only in these “responders” [46].

Figure 3