Preliminary evaluation of factors associated with premature trial closure and feasibility of accrual benchmarks in phase III oncology trials

Abstract

Background A major challenge for randomized phase III oncology trials is the frequent low rates of patient enrollment, resulting in high rates of premature closure due to insufficient accrual. Purpose We conducted a pilot study to determine the extent of trial closure due to poor accrual, feasibility of identifying trial factors associated with sufficient accrual, impact of redesign strategies on trial accrual, and accrual benchmarks designating high failure risk in the clinical trials cooperative group (CTCG) setting. Methods A subset of phase III trials opened by five CTCGs between August 1991 and March 2004 was evaluated. Design elements, experimental agents, redesign strategies, and pretrial accrual assessment supporting accrual predictions were abstracted from CTCG documents. Percent actual/predicted accrual rate averaged per month was calculated. Trials were categorized as having sufficient or insufficient accrual based on reason for trial termination. Analyses included univariate and bivariate summaries to identify potential trial factors associated with accrual sufficiency. Results Among 40 trials from one CTCG, 21 (52.5%) trials closed due to insufficient accrual. In 82 trials from five CTCGs, therapeutic trials accrued sufficiently more often than nontherapeutic trials (59% vs 27%, p = 0.05). Trials including pretrial accrual assessment more often achieved sufficient accrual than those without (67% vs 47%, p = 0.08). Fewer exclusion criteria, shorter consent forms, other CTCG participation, and trial design simplicity were not associated with achieving sufficient accrual. Trials accruing at a rate much lower than predicted (<35% actual/predicted accrual rate) were consistently closed due to insufficient accrual. Limitations This trial subset under-represents certain experimental modalities. Data sources do not allow accounting for all factors potentially related to accrual success. Conclusion Trial closure due to insufficient accrual is common. Certain trial design factors appear associated with attaining sufficient accrual. Defining accrual benchmarks for early trial termination or redesign is feasible, but better accrual prediction methods are critically needed. Future studies should focus on identifying trial factors that allow more accurate accrual predictions and strategies that can salvage open trials experiencing slow accrual.

Tamoxifen-Induced Venothromboembolic Events: Exploring Validation of Putative Genetic Association

“…The 21% observed enrollment rate among both cases and controls was somewhat lower than the 27% historical enrollment reported by Schroen et al 10 for NCI-supported non-therapeutic trials performed by the Clinical Trials Cooperative Group. Based on the most frequently cited reasons offered by the subjects who declined enrollment, institutional access was cited most frequently by those declining participation.…”

“…8 Several recent studies examining accrual to federally funded treatment trials reported that 50% to 80% of trials did not achieve the projected accrual goals within the proposed accrual timeframe, and over one-third failed to meet minimum accrual goals at the time of closure. 9,10 Notably, among 82 cancer trial cooperative group trials, therapeutic trials had superior accrual to non-therapeutic trials (59% vs. 27%, P=0.05). 10 Importantly, the group indicated that those studies that conducted pre-trial accrual assessment achieved higher rates of sufficient accrual compared to those studies that did not (67% vs 47%) and emphasized a need to identify approaches that more accurately identify accrual to clinical studies.…”

“…9,10 Notably, among 82 cancer trial cooperative group trials, therapeutic trials had superior accrual to non-therapeutic trials (59% vs. 27%, P=0.05). 10 Importantly, the group indicated that those studies that conducted pre-trial accrual assessment achieved higher rates of sufficient accrual compared to those studies that did not (67% vs 47%) and emphasized a need to identify approaches that more accurately identify accrual to clinical studies. 10 Studies seeking to validate genetic association generally require large sample sizes.…”

“…10 Importantly, the group indicated that those studies that conducted pre-trial accrual assessment achieved higher rates of sufficient accrual compared to those studies that did not (67% vs 47%) and emphasized a need to identify approaches that more accurately identify accrual to clinical studies. 10 Studies seeking to validate genetic association generally require large sample sizes. This becomes particularly challenging when proposing definition of biomarkers predictive of serious adverse response to pharmaceutical intervention where enrollment of a relatively large cohort of persons impacted by the target adverse event is required in the face of the low event rate among users of the medication.…”

Clinical Trial Development as a Predictor of Accrual Performance—Response

“…At a single institution, she observes that more than half of phase III trials closed to insufficient accrual (3). Similarly, Go and colleagues (4) reported that "over a quarter of the trials" of all Eastern Cooperative Oncology Group (ECOG) phase II and phase III trials from 1977 to 2006 failed to achieve accruals goals and complete.…”