Achieving Sufficient Accrual to Address the Primary Endpoint in Phase III Clinical Trials from U.S. Cooperative Oncology Groups

Abstract

Purpose Assessing impact of poor accrual on premature trial closure requires a relevant metric. We propose defining accrual sufficiency on apparent ability to address primary endpoints (PE) rather than attaining accrual targets. Experimental Design All phase III trials open January 1, 1993, to December 31, 2002, by five U.S. oncology Clinical Trials Cooperative Groups (CTCG) were evaluated for accrual sufficiency and scientific results. Sufficient accrual included meeting accrual target, CTCGs documentation attesting adequate accrual, or conclusive results at interim analysis; insufficient accrual included poor accrual as cited closure reason or other reasons rendering a trial unable to address its primary endpoints. Closure rates based on our accrual sufficiency definition are compared with rates of meeting accrual targets and addressing the primary endpoints. A percentage of target accrual above which trials commonly answer the intended scientific question was identified to serve as an alternative to meeting full target accrual in designating accrual success. Results Of 238 eligible trials, 158 (66%) closed with sufficient accrual. Among 80 trials with insufficient accrual, 70 (29%) closed specifically because of poor accrual. Inadequate accrual rates are overemphasized when defining accrual success solely by meeting accrual targets. Nearly 75% of trials conclusively addressed the primary endpoints with positive results in 39% of trials. Exceeding 80% of target accrual serves as a reliable proxy for answering the intended scientific question. Conclusions Approximately one third of phase III trials closed with insufficient accrual to address the primary endpoints, primarily due to poor accrual. Defining accrual sufficiency broader than meeting accrual targets represents a fairer account of trial closures.

Characteristics of Oncology Clinical Trials

“…6,7 Concerns about clinical research in the United States already exist, prompting the reorganization of the cancer cooperative groups, 4,8 the creation of the Patient-Centered Outcomes Research Institute, 9 and the development of research metrics such as success in accrual of intended study sample size. 10,11 However, to our knowledge, the data needed to truly understand the characteristics of oncology trials being conducted and their ability to advance clinical care do not yet exist.…”

Predicting Low Accrual in the National Cancer Institute’s Cooperative Group Clinical Trials

“…Although many studies have investigated the perceived barriers to accrual from the patient or provider perspective (7,8), the extent to which differences between trials could predict low accrual has not been comprehensively evaluated. The few prior studies that have explored trial characteristics associated with accrual were importantly limited in the breadth of candidate predictors and number of trials studied (3,9). The purpose of this study was to evaluate the association and predictive properties of a broad set of putative trial-level factors and low accrual within the portfolio of adult cooperative group-sponsored cancer clinical trials.…”

Identifying Barriers to Accrual in Radiation Oncology Randomized Trials

“…In oncology specifically, estimates suggest that 30%-40% of oncology trials are unsuccessful 1,2 . From a health care perspective, several negative consequences ensue from failed clinical trials, including waste of money, institutional resources, and time.…”