Who's Eligible Anyway? Risk Modeling for Clinical Trial Accrual

In this issue of Clinical Cancer Research, Massett and colleagues (1) describe the many challenges facing accrual to early-phase clinical trials sponsored by the NCI (Bethesda, MD), analyze proposed ways to increase accrual, and assess the utility of corrective action plans (CAP) to improve accrual.

Clinical trials offer opportunities for cancer patients, as standard therapies are often not enough to successfully suppress cancer and lengthen life. For investigators and sponsors, trials also provide an important avenue for testing drug safety and efficacy, spawning data to report and publish in the peer-reviewed environment. This is paramount for the drug's regulatory approval. All stakeholders are thus excited about protocol finalization and activation but equally disappointed with patient ineligibility or premature trial closure. How can we best approach this ongoing problem of poor trial accrual and clinical trial eligibility?

With cancer clinical trial participation at staggeringly low levels with about 3% of patients enrolled in trials (2), efforts to streamline processes have occurred. The NCI has implemented initiatives to reevaluate and improve the lifecycle of trials. Cancer Therapy Evaluation Program (CTEP) Investigational New Drug (IND) trials are subject to regular accrual review, with those falling below 50% of their projected accrual rate receiving a letter. The letter includes an accrual summary and a request for a CAP, providing explanation for slow accrual and proposing means of improvement to achieve enrollment goals. Massett and colleagues (1) reported that CAP requests were made for 46% of CTEP IND-holding studies active from August 2011 through February 2013, indicating that a significant number of trials did not accrue as planned. Safety and toxicity were primary concerns cited for slow accrual to phase I trials. Safety and toxicity issues are often a concern with phase I trials; if this reason for slow accrual is omitted, then for both phase I and II trials, eligibility criteria and design/protocol concerns were the two most commonly investigator-cited reasons for slow accrual. Other reasons cited included delays due to institutional or administrative problems, extended institutional review board (IRB), or site activation delays.

Oncology trials that are slow to accrue early in their lifecycle are more likely to fail (3). In fact, in 2011, 19% of trials registered as “newly closed” were terminated due to unsuccessful accrual or completed with less than 85% of anticipated enrollment (4). Thus, it is important to identify trials that are in danger of not meeting their accrual goals early on. Even more importantly, it is imperative that we ensure the trial has the potential to accrue successfully prior to study activation.

The approach to optimizing trial accrual requires a different perspective. The accrual challenges facing all trials, regardless of phase and/or sponsorship, come from an array of sources (sponsors, enrolling sites, regulatory organizations, investigators, and even patients). Generally, across all sources, there is an overestimation of willing, eligible patients and an underestimation in the variety of accrual challenges (1). There are additional misinterpretations of operational feasibility and limited measures in place to enforce accountability for trials slow to accrue.

Achieving successful trial accrual begins with the study sponsor and/or investigator at the concept development stage. Often, a protocol evolves from a template or prior protocol, which replicates language, regardless of study phase or patient population. Although this may be aligned with goals to reduce error, improve safety, and speed approval, these generic templates may deter editing of eligibility criteria. This has already been witnessed in some molecularly driven protocols that contain template language from cytotoxic protocols.

Streamlining eligibility criteria is a worldwide priority (5). The American Society of Clinical Oncology's (ASCO) Cancer Research Committee evaluated issues regarding eligibility criteria in molecularly driven trials (6) and reported recommendations for establishing eligibility criteria based on the scientific objective, the broader nonstudy population, patient safety and drug toxicity, and active study review. Following the report, ASCO, the FDA, and Friends of Cancer Research have collaboratively identified eligibility criteria that hamper accrual (7). Potential changes to restrictions on brain metastasis, HIV status, hepatitis C status, organ dysfunction, and minimal age requirements may result in expanding patient opportunities. Their goal is to expand eligibility and consequently increase accrual without compromising safety or research outcome.

Investigators are ultimately responsible for the trial success. Although one applauds optimism and creating opportunities for patients, there is sufficient precedent that investigators need help with estimating accrual for a study.

Many enrolling institutions work to improve accrual through preactivation and postactivation interventions. Expedited protocol approval and trial activation may improve accrual depending on potential competing trials or interested patient populations. Utilization of a common IRB allows for trials to open efficiently and at multiple sites. Promoting clinical trial awareness (internally and externally) was frequently cited in CAPs as a means to increase accrual (1). At Carolinas HealthCare Systems' Levine Cancer Institute (Charlotte, NC), trials are placed on tumor-specific pathways accessible to physicians across 25 locations. Interactive trial icons allow physicians to assess trial status, obtain documents (summary, protocol, and consent), and contact study coordinators.

Last, and most importantly, patients are required for accrual success. Patient enrollment to clinical trials has been problematic for decades. A disconnect clearly remains. Engagement in clinical trials is one of the hallmarks of high-quality cancer care. Those invested in providing high-quality care must bridge this gap through education about clinical trials in general or reassurance of participation impact.

Completing trial enrollment and reporting results support all key stakeholders. When trials close due to poor accrual, stakeholders are affected and need to consider an alternate approach. Similarly, when oncologists recognize that curative therapy may not be achievable, a preventative strategy in confronting cancer may be more productive. Clinical trial accrual may benefit from a comparable tactic (Fig. 1). Primary, secondary, and tertiary chemoprevention aim at preventing or slowing the process of “multi-step carcinogenesis,” a series of events during which normal cells become precancerous and ultimately an invasive malignancy (8). Strategies targeting each transition point include smoking prevention/cessation (primary prevention), identifying premalignant lesions (secondary prevention), and preventing recurrence or second primary tumors with chemopreventive agents (tertiary prevention). Clinical trial development may be likened to multistep carcinogenesis as it starts with a concept, transitions into a protocol, and concludes with activation, accrual, and completion. As risk modeling is important for cancer prevention and treatment, a parallel approach could be considered for clinical trial accrual. By assessing the “risk” of a trial not completing accrual prior to activation, preventive measures can be inserted proactively. Likewise, if accrual is slow, then measures, such as those discussed above, can be implemented. Finally, if there is precedent in a particular disease or trial setting, then the information should guide a different method of evaluation or management (tertiary prevention).

To ensure timely, successful trials, a cultural shift in trial accrual planning and monitoring is paramount. CAPs alone are not sufficient to create significant improvement in trial accrual. Future trials would benefit from an accrual strategy plan early in trial development with the goal to limit the need for some intervention, such as a CAP. By establishing a preventative rather than reactive approach, we may be more successful in achieving our goals, not just in patient accrual and trial completion, but in the greater paradigm of cancer cure.

No potential conflicts of interest were disclosed.

Conception and design: K.F. Mileham, E.S. Kim

Development of methodology: K.F. Mileham, E.S. Kim

Writing, review, and/or revision of the manuscript: K.F. Mileham, E.S. Kim

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): K.F. Mileham, E.S. Kim