Patient enrollment is a common subject of discussion among both sponsors and research sites. Challenges to enrollment can be myriad, and the root causes are hard to pin down. But effective enrollment is critical to the ultimate success of any clinical trial, and there are steps that research sites and sponsors alike can take to ensure that each site is capable of enrolling sufficient patients before they sign on for a particular clinical trial.
In theory, sponsors should be picking sites that have known patients that fit a protocol’s inclusion/exclusion criteria. But that does not always happen for a variety of reasons. For instance, a site may have access to many patients with a specified condition, but when it comes to enrolling in accordance with the protocol requirements, sites seem to struggle.
According to some estimates, fewer than 7% of sites enroll the patient numbers they promise, even though sponsors tend to cut site estimates of available patients by one-third to one-half to account for overestimation.
More sophisticated sites do this evaluation. Sites have to be more discriminatory due to tighter resources (personnel). Can’t take studies that are going to sit in contracts approval for a year and don’t know we have patients. Won’t move forward without validation. Some wait for sponsors to say they’ll pay you. Some just don’t. IT’s their obligation for ICH. Changing slowly.
Conduct enrollment feasibility validation
Savvy sites will validate enrollment feasibility by conducting their own data mining against the inclusion/exclusion criteria established in a protocol. This should include an evaluation of how many patients meet the trial criteria out of the total number with the target condition seen during a particular period, such as a month. This can include a review of outreach partners like affiliated healthcare systems and patient advocacy groups, if needed.
It is noteworthy that these activities are included in ICH requirements, which state that research sites must provide evidence of their ability to meet the requirements, including enrollment goals, of a clinical trial.
Information gleaned in this way can be used strictly internally to determine if a particular trial is viable or it may be shared back to the sponsor, possibly with suggestions on modifications to the inclusion/exclusion criteria that might boost the number of potential patients that site could provide while still meeting the demands of the protocol.
If sites take that approach, they must be sure to have data to back up their recommendations. Regardless, however, those suggestions may not be accepted. Safety or regulatory considerations may require that certain exclusions be included in a protocol, for instance, and the sponsor can’t do anything about that.
And despite the ICH requirement and the intrinsic value in these activities, some sites may opt to take on a clinical trial even if a feasibility validation shows scant numbers of viable patients; sites can be concerned that they wouldn’t be selected for future trials if they pass on one.
Another consideration is how—and whether—sites are compensated for these efforts by trial sponsors. Some sponsors and CROs do require an enrollment feasibility validation step and include compensation for the time and effort required to complete that evaluation. However, this is not universal, leading some sites to skip this step simply because they cannot afford to have their key staff spend time on uncompensated work.
Develop an enrollment strategy
If a site determines that it can indeed meet the enrollment needs of a protocol, it should develop an enrollment strategy that maximizes the resources it has, including automating some steps or having clerical staff conduct simple yes/no reviews of criteria.
In a nutshell, sites must filter through potential patients to see which do and do not meet the protocol inclusion/exclusion criteria; however, inefficiencies in this process are rampant. some of these decisions are simple—such as whether a patient does or does not have this specific disease state—and can potentially be handled by an algorithmic review of health records and/or clerical staff using simple keywords.
It’s not common for sites to think about segmenting the enrollment criteria in their workflow. Many sites just cut-and-paste the enrollment criteria into a list or spreadsheet without considering the order in which they review each criterion. For larger sites with expansive IT capabilities, AI could be applied to electronic records to screen patients out based on simple, clear-cut criteria like age or stage of disease. Similarly, a medical assistant could pre-screen for some inclusions.
At some point, higher-level staff such as PIs or coordinators will need to be involved, but if other resources can be brought to bear to reduce the number of patients those employees must review, they can focus on the tougher decisions and more detailed screening, initial testing and informed consent procedures, which often occur concurrently.
But just as they struggle with the human resources side of feasibility validation, sites can struggle to have key staff devote too many FTE hours to patient screening. If only one patient out of 100 screens, for instance, that can add up to a lot of hours spent for very little return.
Batching criteria into items that can be prescreened by AI, medical assistants or clerical staff and then more nuanced decisions—such as concomitant conditions or risk combinations—would be made by an investigator or coordinator. By spreading the workload in this way, sites can increase the efficiency of their process for identifying and enrolling prime candidates.
Technology can play a role here, as well. Challenges like inability to log into the CRF system because it’s not yet finalized, having to log into multiple systems to complete screening and enrollment tasks can lead to an amount of work that is disproportionate to the payment the sponsor provides. A carefully considered strategy that plans patient screening and enrollment activities around availability of all necessary technical systems can ease this burden.
Provide protocol-specific enrollment training
And sponsors can help with workflow by considering this when developing protocol-specific training for their sites. That training could suggest ways in which sites could batch patient reviews to improve the efficiency of ruling potential patients in or out.
Carefully targeted training is especially important in the current environment of frequent staff turnover at research sites. A WCG survey of 50 site leaders conducted in 2021 indicated that nearly one in five sites has staff turnover rates greater than 30%.
And sponsors need to think hard about how they provide training to sites, Jenna Rouse, chief experience officer at Pro-ficiency, said, because one size does not fit all.
“You have to inform sites the right way, using something that helps visualize and absorb complex enrollment standards, as well as what your expectations are for enrollment,” she cautioned. “Enrollment strategies are more effective than enrollment criteria lists. Helping sites with that will help them enroll more effectively.”
In other words, rather than simple lists of inclusion and exclusion criteria presented to a site, sponsors should strive to provide clear illustrations of those criteria, how they relate to each other and how they relate to trial schedules and visit timelines.
An important consideration is that sites are expected to implement enrollment criteria over a substantial period of time, often with a degree of lag between when they receive training and when they begin enrolling patients in a trial. Providing aids to help remind site staff of how they should conduct enrollment activities and what the sponsors expectations are can be a helpful part of any enrollment strategy. Useful job aids could include checklists aligned with the workflow, as well as reminders about what criteria do and do not need to be reviewed by a physician or research nurse.
And while it may take more effort up front to provide this sort of training, it can also help sponsors avoid having to retrain sites or deal with enrollment shortfalls after a study has begun.
In fact, the notion of pay now or pay later applies to the approach both sites and sponsors should take to patient enrollment planning and implementation. Carefully analyzing a site’s true capacity to provide patients from existing pools, providing detailed and strategically organized training and developing a strategy to efficiently use resources to identify carefully targeted patients more likely to opt into—and stay in—a clinical trial are ultimately necessary to ensure that both enrollment targets and study timelines are properly met.
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Beth Harper, Chief Learning Officer at Pro-ficiency, is on a mission to eliminate protocol deviations. Beth brings 35-plus years of experience in clinical research operations to Pro-ficiency, utilizing this knowledge along with her years of creating live protocol simulation training to create cutting-edge simulation training programs at Pro-ficiency. Beth has published and presented extensively in the areas of study feasibility, site selection, patient recruitment, protocol optimization, sponsor/site relationship management and clinical research professional competencies. Beth received her B. S. in Occupational Therapy from the University of Wisconsin and an M.B.A. from the University of Texas.