Timely Completion of Scientifically Rigorous Cancer Clinical Trials: An Unfulfilled Priority

Clinical trials that seek biologic vulnerabilities in human tumors are essential components of the current translational paradigm for cancer prevention and treatment. However, lack of timely patient accrual to oncologic clinical investigations, based on patient performance status requirements, inadequate insurance coverage, protocol complexity, or distance to the clinical trial site, has been decried for decades. The broad range of causes that contribute to slow or inadequate accrual of patients to cancer clinical trials has been welldocumented. These causes include lack of availability of studies appropriate for the clinical population; inadequate understanding of the role of clinical trials within the spectrum of oncologic care; attitudes of primary care or specialty physicians that are not conducive to referral for clinical trial consideration; constrained economic resources available to conduct or participate in clinical trials; availability of multiple alternate on-label or off-label treatments that can supplant clinical trial referral; perceived lack of time, education, staff, or expertise, as well as the enhanced regulatory burden required to conduct clinical trials in the community practice setting; and, finally, limited patient awareness of the benefits of participation in clinical trials, as well as the impact of health disparities in making the decision to enroll. Recognizing the critical importance of the rate of accrual to clinical studies (which is central to answering the scientific questions posed by such investigations in a realistic time frame) rather than simply the total number of patients accrued has focused the attempts of clinical trialists, clinical trial consortia, patient advocacy groups, industry sponsors, and the National Cancer Institute (NCI) to understand and overcome barriers to timely clinical trial completion. Cancer clinical trial accrual is predictably robust when therapeutically active investigational drugs are integral components of a study. Accrual of 746 patients with advanced gastrointestinal stromal tumors in 9 months across the NCI’s clinical cooperative group network for a study testing two dose levels of imatinib mesylate before approval of the agent by the US Food and Drug Administration is a powerful example of the importance of both drug availability and desired access to an effective treatment to overcome barriers to rapid clinical trial completion. Other factors that favor an enhanced accrual rate include the clinical relevance of the study and how closely it parallels standard practice in the community, as well as the absence of competing trials, and the clinical trial experience level of the health professional charged with obtaining informed consent. In contrast, adding personnel to screen patients for trial eligibility or using eligibility screening software before an initial patient encounter has met with mixed success. State-mandated insurance coverage for cancer clinical trials, though important in a variety of other contexts, has not been demonstrated conclusively to improve accrual. The ability of even the most experienced clinical trialists or statisticians to predict that a specific randomized clinical study will be completed in a timely fashion is limited at best. Finally, the utility of widely accessible Web sites supported by the NCI that contain up-to-date information about active clinical trials in the United States or detailed educational materials and information about clinical trial accrual best practices (AccrualNet) is currently being evaluated. Although these efforts have broadened the availability of important tools to improve the accrual rate of cancer clinical trials, the direct effects of these efforts on patient accrual have not yet been demonstrated. It is appropriate to emphasize, furthermore, that current and future requirements to conduct scientifically rigorous trials studying targeted therapeutic agents will add to, not diminish, the complexity of molecularly focused investigations. Such studies, whether driven by the need to demonstrate target engagement as a pharmacodynamic end point early in drug development or by a requirement for assessment of predictive molecular markers to enrich specific patient populations under study, necessitate acquiring tumor tissue for molecular evaluation. Although formalin fixed, paraffin-embedded tissues may be suitable for these investigations, the value of the biomarker will, for the most part, be optimized through the use of tumor tissue obtained immediately before study entry. Thus, eligibility requirements that include frequent, broader, and more sophisticated molecular analyses of tumor or normal tissues could be viewed as insurmountable hurdles that may slow cancer clinical trial accrual further. However, the extraordinary power to understand the mechanism of action and resistance of targeted therapeutic agents provided by recent advances in mutational profiling and molecular characterization of tumors is spawning a new era of biologically driven cancer treatment choice, occurring one patient at a time. It seems reasonable to suggest, therefore, that in the near future access to novel diagnostics, not just drugs, could become a dominant force driving more rapid clinical trial accrual. In this scenario, the extraordinary utility of molecular assays may foster the dramatic improvements in tissue access that are needed to markedly change our current system of cancer clinical trials. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 27 SEPTEMBER 2