Preliminary evaluation of factors associated with premature trial closure and feasibility of accrual benchmarks in phase III oncology trials.
ABSTRACT 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.
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.
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.
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.
This trial subset under-represents certain experimental modalities. Data sources do not allow accounting for all factors potentially related to accrual success.
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.
- SourceAvailable from: ncbi.nlm.nih.gov[Show abstract] [Hide abstract]
ABSTRACT: Recent reports have suggested that 40% or more of National Cancer Institute (NCI) -sponsored Cooperative Group phase III trials failed to achieve their accrual goals. We examine in detail the accrual experience of the Cooperative Group phase III trials. All Cooperative Group phase III trials activated from 2000 to 2007 were examined for their accrual experience. For trials that stopped accrual with < 90% of their accrual goal, the reasons for having < 90% accrual were documented. We focus on trials that ended with < 90% accrual because of inadequate accrual rates rather than for other reasons, such as an interim monitoring analysis by an independent data monitoring committee that stops the trial early because one treatment is clearly superior. There were 191 trials activated from 2000 to 2007. We project that 22.0% of these trials will have < 90% accrual because of inadequate accrual rates. We project that there will be 176,627 patients eventually accrued on the 191 trials (current accrual, 154,579) and that 2,991 of these patients will be on trials that have < 90% accrual because of inadequate accrual rates (1.7%). For nonpediatric cancer trials, the corresponding percentages are 26.7% and 2.0%. We find that insufficient accrual rates are not as high as previously reported and that only a small proportion of patients were enrolled on trials that ended with insufficient accrual because of an inadequate accrual rate. NCI has implemented new procedures to reduce the number of trials that fail to reach their accrual goals and to minimize the number of patients accrued on these trials.Journal of Clinical Oncology 11/2010; 28(35):5197-201. DOI:10.1200/JCO.2010.31.5382 · 17.88 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The need to increase the number oncology clinical trials with sufficient enrollments is a well-known issue, particularly for trials targeting therapeutic applications. It is critical to identify early predictors of eventual study accrual achievement. All nonpediatric phase I, I/II, II, and III therapeutic studies supported by the National Cancer Institute Cancer Therapy Evaluation Program (NCI-CTEP) between 2000 and 2007 (n = 764) were analyzed for accrual performance. Accrual achievement is defined as those enrolling 100% or more of the stated minimum accrual goal at the time of trial closure. Two accrual milestones were analyzed per trial: time to first patient enrollment and expected time to accrual goal. Multivariate logistic regression analysis was used to calculate the OR with respect to the likelihood of clinical trial accrual achievement. A total of 81.5% (n = 623) of the trials did not achieve the projected accrual goals within the anticipated accruing period. Furthermore, 37.2% (n = 284) of trials failed to achieve the minimum projected accrual at study closure regardless of time the trial was open. Trials that accrue the first enrollment beyond 2 months (n = 379, 49.6%) are significantly less likely to achieve the accrual performance than those trials that enroll patients under 2 months (OR: 0.637, 95% CI: 0.464-0.875, P = 0.005). Of the studies that are open beyond the anticipated enrollment period (n = 603), those do not achieve at least 60.0% of the projected minimum accrual (n = 391, 64.8%) have a significantly less likelihood of achieving final accruals by study closure (OR: 0.190, 95% CI: 0.055-0.652, P = 0.008). The time to first patient enrollment and expected time to accrual goal are shown to be valid measures to evaluate the likelihood of achieving the minimum projected accrual.Clinical Cancer Research 03/2011; 17(7):1947-55. DOI:10.1158/1078-0432.CCR-10-1730 · 8.19 Impact Factor
- Clinical Cancer Research 06/2011; 17(13). DOI:10.1158/1078-0432.CCR-11-0673 · 8.19 Impact Factor