Cheng et al3
report 49.2% (30 of 61) of CTEP-approved nonpediatric phase III trials failed to achieve at least 25% of accrual goals. Recently, the Institute of Medicine reported that 40% of CTEP-approved phase III trials failed to achieve minimum accrual goals,4
a figure that has been repeated elsewhere.5–7
We report here that we estimate that 28.3% of such nonpediatric trials will fail to achieve at least 90% of their accrual goals because of inadequate accrual, based on data from 149 trials (). The difference between the results can be attributed to exclusion of actively accruing trials by Cheng et al3
(leading to sampling bias) and their inclusion, as failures to achieve accrual goals, of trials that ended for other reasons besides inadequate accrual.4
We have chosen not to consider trials that failed to achieve at least 90% of their accrual goals because of formal interim monitoring, unacceptable toxicity, or drug supply issues as failures. This is an obvious decision for trials that closed because of interim monitoring, and one could argue for the other categories that failure to fully accrue was beyond the control of the investigators.
Overall, we estimate that 22.0% of all trials (adult and pediatric) will end with insufficient accrual because of inadequate accrual rates, and 1.7% of the total number of patients accrued on all trials will be on these trials. It is possible that a trial that ends with accrual < 90% of projected because of an inadequate accrual rate can still provide useful clinical information. For example, the Eastern Cooperative Oncology Group (ECOG) E4201 trial,8
which closed to accrual with 74 of 332 patients accrued, demonstrated the major advance of treating locally inoperable pancreatic cancer with radiation therapy in addition to gemcitabine.9
Another example is given by the Radiation Therapy Oncology Group (RTOG) 9813 trial, which closed to accrual with 201 of 454 patients accrued and is in follow-up. This trial, which compares temozolomide plus radiation versus nitrosourea plus radiation for treating anaplastic astrocytomas or mixed gliomas, may still provide relevant clinical information. Much more likely, trials that end early because of inadequate accrual will provide little useful clinical data. Although the number of patients involved in these trials is small (compared with the number of patients on all trials), there are still considerable resources involved in opening a trial, whether or not it accrues.
Should one aim for a clinical trials program to open only trials in which one is positive that they will accrue successfully? We would argue no, because this would preclude starting trials that address important questions but in which it is known at the start that accrual will be challenging. For example, the Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIRIT; American College of Surgeons Oncology Group [ACOSOG] Z0070), comparing radical prostatectomy versus brachytherapy in early-stage prostate cancer, accrued only 56 of a required 1,980 patients. Another example is given by the Southwest Oncology Group S0521 trial, which compared maintenance chemotherapy versus observation in patients with previously untreated low- and intermediate-risk acute promyelocytic leukemia. It accrued only 95 of a required 500 patients. Yet experts often cite the strong need for clinical trials for both these questions.
Although we believe it is important to attempt to perform important trials that may be a challenge for enrollment, it is also important to minimize the time and number of patients involved in trials that turn out to have insufficient accrual. One strategy is to examine characteristics of inadequately accrued trials to help inform trial prioritization.10
A second strategy is to open a trial first in a limited number of institutions to assess accrual feasibility. This strategy was used in the Surveillance Therapy Against Radical Treatment (START) trial (National Cancer Institute of Canada Clinical Trials Group [NCIC CTG] PR.11), testing radical prostatectomy or radiotherapy versus active surveillance for favorable-risk prostate cancer.
A third strategy is to stop trials early when it is apparent they will never reach their accrual goals because of inadequate accrual rates. To this end, we developed CTEP early-stopping guidelines11
that apply to slow-accruing phase III Cooperative Group trials activated after April 1, 2004 (trials that have < 20% of their projected accrual rates in quarters 5 and 6 after their activation are closed). (Twenty-six of the 41 trials that had inadequate accrual rates in were activated before April 1, 2004.) These guidelines were based on historical data that demonstrated that trials with poor accrual in this time interval would be extremely unlikely to ever reach their accrual goals.12
Our experience with the CTEP early-stopping guidelines will be reported when we have further follow-up of the trials activated after April 1, 2004.
A fourth strategy is to simplify the enrollment process and expand patient entry onto trials. To this end, CTEP has developed the Cancer Trials Support Unit (CTSU),13
which allows for a larger number of institutions to enter patients into different Cooperative Group trials in an efficient manner. This strategy appears to be successful, because CTEP data (not shown) indicate that cross-Group accrual (enrollments from Groups other than the lead Group) has increased from an average of 20% in the pre-CTSU 1990s to 40% in the post-CTSU 2000s.
A fifth strategy is to simplify the data collection required for patients on trials, which may encourage physicians to participate. CTEP is working with the US Food and Drug Administration to reduce certain types of adverse event reporting, which may help in this regard.14
Finally, because slow development of a trial concept to a protocol ready for enrollment is associated with its ability to achieve its accrual goal,3
CTEP, working in concert with the Cooperative Groups, developed the Central Institutional Review Board for faster protocol review15
and has recently instituted new timelines for all phases of trial development.16
The target timelines to move from a trial concept to a protocol ready for accrual for phase II and III Cooperative Group trials have been reduced to 7 and 10 months, respectively, a > 50% reduction from current timelines. If these target timelines are achieved, then we will be able to determine whether this promising approach is indeed successful in reducing the number of trials that fail to meet their accrual goal.