Patient Enrollment Per Month (accrual) in Clinical Trials Leading to the FDA Approval of New Cancer Drugs

OBJECTIVES: Insufficient patient enrollment per month (=accrual) is the leading cause of cancer trial termination. This study identifies and quantifies factors associated with patient accrual in trials leading to the US Food and Drug Administration (FDA) approval of new cancer drugs.

METHODS: 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 based on 292 randomized and 163 single-arm trials. Among randomized trials, accrual rates were 0.30-times (p<0.001), 0.73-times (p<0.001), and 0.88-times (p=0.361) lower for ultra-rare, rare, and common than non-orphan indications. Accrual was positively associated with disease burden (aRR: 1.0003 per 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). Accrual was 0.80-times lower (p=0.209) in government-sponsored vs. industry-sponsored trials.

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