By Erin Stanley, Halloran Consulting Group, Inc.
If 2020 has amplified anything for us, it’s that running a clinical trial is complicated. And for what feels like the first time in a long time, the entire world has eyes on our industry. We’ve been presented with the opportunity and demand to change the status quo across protocol design, patient experience, and clinical monitoring, just to name a few. And another important topic that must be revisited is the site selection process.
The numbers behind clinical trial performance are not favorable, with 70% of trials experiencing start-up delays, nearly 80% of trials failing to meet on-time enrollment, and 45% of trials completing beyond original projected timelines.1,2 Trial success is often jeopardized by factors foreseeable during the site selection process, specifically across start-up, patient recruitment, and site staffing.3,4,5 However, our current approaches for assessing potential sites is not keeping pace with the increase in trial complexity observed across the industry.6 By adjusting our strategy during this critical state of a trial, we take a step toward improving overall clinical trial performance and ultimately advancing treatments more quickly and efficiently.
Leverage Cross-Functional Expertise And Revisit Input
It’s important that cross-functional planning occur at a level appropriate for the phase and complexity of the trial. Depending on how well-established a sponsor company and its processes are, it’s possible to see site selection driven exclusively by a single department. While seemingly efficient, this process may not be optimized to gather the key cross-functional information that could dramatically reshape a study’s ideal site profile. Early in study planning, request the following input from key stakeholders:
- Clinical operations to provide recent predictive analyses on similar trials’ start-up timelines, successful patient recruitment techniques, and individual site performance in terms of start-up, average time to first patient in, enrollment rate, and protocol adherence.
- Quality departments to provide data on similar trials’ most common areas of quality issues as seen through monitoring, audits, and inspections.
- Data management and any internal or external systems vendors to provide input on the required site infrastructure for the support of any digital solutions. For example, if you plan to implement an eSource platform, what are the technical specifications for integration with a site’s electronic medical records (EMR) system? Or, will it be possible for sites with exclusively paper source documents to adequately participate in the trial?
- Sponsors, medical affairs, and outside therapeutic area experts (i.e., key opinion leaders) can provide insight into the successes and failures of past similar trials and give a deeper understanding of the target patient population.
- Patient advocacy groups’ expertise should be solicited, particularly for the more complex therapeutic areas and trials. We know from experience that identifying sites capable of supporting a rare disease population is more nuanced than identifying sites capable of supporting patients with diseases of higher prevalence. Therefore, patients and their caregivers from these smaller populations are well-positioned to provide feedback on what type of physicians they go to for current treatments, their experiences with other trials, and their priorities for participation.7
Collectively, cross-functional input will conceptualize the target patient population, the types of sites that will have access to these patients, and the site capabilities required for timely start-up, enrollment, and production of high-quality data. Using these criteria to develop a site scorecard can help sponsors objectively assess potential sites as they move through the selection process. Depending on the therapeutic area, it will be important to give certain stakeholders more decision weight than others. For example, if you’ve identified from your early risk management process that enrolling patients will be the main barrier to trial success, then contributions from experts around patient accrual information (e.g., key opinion leaders and patient advocacy groups) should be weighted more heavily. Plan, discuss, and document this process and revisit it throughout the trial if site-level factors begin to impact trial deliverables. The “set it and forget it” mindset is nearly a guarantee to fall victim to start-up delays, enrollment delays, and additional costs as the trial inevitably stalls.
Target The Feasibility Questionnaire
One approach is to provide a lengthy questionnaire inquiring about every site capability and study procedure, but this will cause fatigue (and probably annoyance) among the site staff members stuck filling it out. The feasibility questionnaire is only one step in the site selection process and is far from your only opportunity to collect information from sites. Leverage either internal or centralized site information databases like the Shared Investigator Platform to review basic site capabilities, then direct site energy to providing answers to study-specific questions. Also consider creating an electronic platform (Google Sheet or Microsoft Form) for the feasibility questionnaire, as this will be quicker for sites to complete and easier for you to centrally analyze site responses.
Allow the criteria developed during the cross-functional planning period to guide the development of key questions around start-up, patient recruitment, site staffing, and facilities. Examples could include anticipated intra-site contracting and budget complexities, the need for a specific patient recruitment method, the requirement for a certain medical specialist on-site, and capabilities around complex study procedures. Building this information into the feasibility questionnaire will allow early insight into the suitability of your sites, where to focus during the site feasibility visit, and what risks to plan for during study conduct. The worst (and best) case scenario is that the exercise indicates you’re looking at the wrong set of sites entirely, which allows you to reroute before investing further in time and resources.
Rethink The Site Feasibility Visit
It’s common for the site feasibility visit to be merely a formality and provide little to no new information about sites’ capabilities. Challenge yourself instead to invest more time and resources into remote, centralized site assessments through the cross-functional development of the ideal site profile and sites’ responses to the targeted feasibility questionnaire. You may want to establish a threshold for requiring site feasibility visits. For example, if your analyses indicate low protocol complexity and historically high performance from a specific group of sites, then skip their site feasibility visits and expedite them through start-up.
If forgoing site feasibility visits is not an option based on your company’s standard operating procedures (SOPs) and/or trial complexity, then ensure the visits are structured to thoroughly assess sites (and for sites to thoroughly assess the study). To start, depending on trial complexity, it may be appropriate for sponsor medical affairs to review the more advanced concepts with the investigator. The site monitor should anticipate this need and make the appropriate scheduling accommodations in advance. The site monitor should also be proactive in requesting to review site SOPs in advance of the visit, thus allowing more targeted discussions to occur when together with site staff.
Aside from confirming the basics of site setup and function, the site monitor should lead an exercise to operationalize the trial for the site. Following review of the protocol synopsis, the site monitor and site staff should perform a mock patient walk-through of the main study visits (e.g., screening). The walk-through should include stops across all relevant departments, procedure rooms, and applicable departmental delegates. This exercise produces a vast amount of insight covering the adequacy of facilities and equipment, operational and logistical sticking points, and the suitability of site staffing. While conducting this mock patient walk-through will add time to the site feasibility visits, it will pay dividends across the quality of trial planning and execution.
With more site feasibility visits being conducted remotely, the operationalizing of the trial will require some creativity. In lieu of an in-person exercise, the study team could develop a walk-through worksheet that allows site staff to conduct the exercise independently and report key information back to the sponsor (e.g., how many different departments, any observed gaps in equipment, etc.).
As trial complexity continues to increase,6 the site selection process must work in concert if we have any hope of changing the unfavorable statistics around clinical trial performance. Let’s take advantage of this point of inflection for the industry to bring site selection into focus and roll out an enhanced standard that is a clear win for all stakeholders.
- Johns Hopkins University. (2015). Successful Pharmaceutical Study Start-Up: Key Steps for Investigators.
- Bose, S. K., Sandu, A., & Strommenger, S. (2017). Clinical Trials: A data driven feasibility approach. Pharmaceutical Outsourcing.
- Farrell, B., Kenyon, S., & Shakur, H. (2010). Managing Clinical Trials. Trials, 11, 78-83. doi:10.1186/1745-6215-11-78
- The Michael J. Fox Foundation. (2011). Clinical trials recruitment best practices manual.
- Harper, B., & Zuckerman, D. (2006). Critical success factors for planning for site selection and patient recruitment planning. BioExecutive International, 2(6), 16-28.
- Getz, K. A., & Campo, R. A. Trial watch: Trends in clinical trial design complexity. Nature Reviews Drug Discovery, 16(5), 307. doi:10.1038/nrd.2017.65
- Johnston, J. & Ray, S. (2019, December 15). The case for including patients in protocol design. CenterWatch.
About The Author:
Erin Stanley has more than 14 years of experience in clinical operations, quality management, and project leadership. Her therapeutic experience primarily covers neurology, psychiatry, cardiology, rare disease, and oncology, and her product knowledge includes small molecules, gene therapy, monoclonal antibodies, and digital therapeutics. Prior to joining Halloran, she held positions of increasing responsibility at IQVIA, Inc. Stanley earned a Master of Science in health science in clinical research administration from the George Washington University and a Bachelor of Science in biology from Truman State University. She is also a Certified Clinical Research Associate (CCRA) and licensed Medical Laboratory Scientist (MLS(ASCP)CM).