Patient Enrollment per Month (Accrual) in Clinical Trials Leading to the FDA Approval of New Cancer Drugs.

Abstract

Background: Insufficient patient enrollment per month (=accrual) is the leading cause of cancer trial termination.

Objective: To identify and quantify factors associated with patient accrual in trials leading to the US Food and Drug Administration (FDA) approval of new cancer drugs.

Data: All anti-cancer drugs with FDA approval were identified in the Drugs@FDA database (2000-2022). Data on drug indication's background-, treatment-, disease-, and trial-related factors were collected from FDA labels, clinicaltrials.gov, and the Global Burden of Disease study. The association between patient accrual and collected variables was assessed in Poisson regression models reporting adjusted rate ratios (aRR).

Results: We identified 170 drugs with approval in 455 cancer indications on the basis of 292 randomized and 163 single-arm trials. Among randomized trials, median enrollment per month was 38 patients (interquartile range [IQR]: 26-54) for non-orphan, 21 (IQR: 15-38, aRR 0.88, p = 0.361) for common orphan, 20 (IQR: 10-35, aRR 0.73, p <0.001) for rare orphan, and 8 (IQR 6-12, aRR 0.30, p < 0.001) for ultra-rare orphan indications. Patient enrollment was positively associated with disease burden [aRR: 1.0003 per disability-adjusted life year (DALY), p < 0.001), trial sites (aRR: 1.001 per site, p < 0.001), participating countries (aRR: 1.02 per country, p < 0.001), and phase 3 vs. 1/2 trials (aRR: 1.64, p = 0.037). Enrollment was negatively associated with advanced-line vs. first-line treatments (aRR: 0.81, p = 0.010) and monotherapy vs. combination treatments (aRR: 0.80, p = 0.007). Patient enrollment per month was similar between indications with and without a biomarker (median: 27 vs. 32, aRR 0.80, p = 0.117). Patient enrollment per month was substantially lower in government-sponsored than industry-sponsored trials (median: 14 vs. 32, aRR 0.80, p = 0.209). Enrollment was not associated with randomization ratios, crossover, and study blinding.

Conclusions: Disease incidence and disease burden alongside the number of study sites and participating countries are the main drivers of patient enrollment in clinical trials. For rare disease trials, greater financial incentives could help expedite patient enrollment. Novel trial design features, including skewed randomization, crossover, or open-label masking, did not entice patient enrollment.