Increasing challenges to trial recruitment and conduct over time

Abstract

Objective: This study was undertaken to evaluate how the challenges in the recruitment and retention of participants in clinical trials for focal onset epilepsy have changed over time.

Methods: In this systematic analysis of randomized clinical trials of adjunct antiseizure medications for medication-resistant focal onset epilepsy, we evaluated how the numbers of participants, sites, and countries have changed since the first such trial in 1990. We also evaluated the proportion of participants who completed each trial phase and their reasons for early trial exit. We analyzed these trends using mixed effects generalized linear models accounting for the influence of the number of trial sites and trial-specific variability.

Results: The number of participants per site has steadily decreased over decades, with recent trials recruiting fewer than five participants per site (reduction by .16 participants/site/year, p < .0001). Fewer participants also progressed from recruitment to randomization over time (odds ratio = .94/year, p = .014). Concurrently, there has been an increase in the placebo response over time (increase in median percent reduction of .4%/year, p = .02; odds ratio of increase in 50% responder rate of 1.03/year, p = .02), which was not directly associated with the number of sites per trial (p > .20).

Significance: This historical analysis highlights the increasing challenges with participant recruitment and retention, as well as increasing placebo response. It serves as a call to action to change clinical trial design to address these challenges.

Keywords: antiepileptic drugs; clinical trials; epilepsy; time to event.

Figure 1:

Number of participants randomized per clinical trial site over time. Each dot reflects an individual trial. The red line and grey shading reflect a weighted average and standard deviation with Gaussian smoothing (width 3 years).

Figure 2:

Placebo response over time as measured by [A] median percent reduction in seizure frequency (MPR) and [B] 50% responder rate (50RR). The red line reflects a weighted average. The grey shading reflects the [A] standard deviation (MPR) or [B] binomial exact 95% confidence interval (50RR) with Gaussian smoothing (width 3 years).

Figure 3:

Meta-analytic percent of participants screened who received at least one dose of randomized treatment over time. The red line and grey shading reflect a weighted average and binomial exact 95% confidence interval of the average percent of participants with Gaussian smoothing (width 3 years). The width of the binomial exact confidence intervals was based on the total number of participants across trials (total n participants=20,570) with random effects terms to account for between-trial variability (n trials = 65). See Supplemental Figure 4.