Minimizing Non-Enrolling Clinical Trial Sites

In clinical trials, every site that is activated begins in a non-enrolling state until it successfully enrolls its first participant. This period often includes screening activities, where patients consent and undergo evaluation but may fail to meet eligibility requirements. Some sites ultimately never attract eligible participants or face withdrawal of screened patients and remain non-enrolling throughout the study.

Because of these dynamics, non-enrollment is both a transitory status and, in some cases, a persistent problem. The true measure is the proportion of sites that fail to enroll any participants by the end of a study. Industry benchmarks suggest that up to a third of clinical trial sites never enroll a single patient, with some particularly challenging studies seeing considerably higher rates. These non-enrolling sites represent a significant loss of time and resources and can jeopardize the overall success of a trial.

Reducing the percentage of non-enrolling sites is therefore a critical objective. The PPD™ clinical research business of Thermo Fisher Scientific devotes considerable effort to converting activated sites into active contributors of patient data. By closely monitoring recruitment progress and supporting sites through targeted interventions, the company consistently achieves a higher-than-average proportion of enrolling sites across its portfolio, ensuring that even complex studies progress with greater efficiency.

Minimizing the proportion of non-enrolling sites is not simply a matter of efficiency; it is central to maximizing the value of clinical trial data while controlling costs. Each inactive site represents sunk investment in activation, monitoring, and oversight without yielding patient outcomes in return.

The growing complexity of study designs is a major contributor to this problem. Trials increasingly involve restrictive inclusion and exclusion criteria, which can result in high screen failure rates. As inclusion and exclusion criteria become increasingly restrictive, even highly motivated sites may see many potential participants disqualified after screening, extending timelines, and straining staff resources.

The environment in which sites operate has also become more challenging. With an unprecedented volume of clinical research underway, sites often juggle multiple studies at once, competing not only for eligible patients but also for scarce staff and infrastructure. Even when patient populations do not directly overlap, limited site capacity creates competition across protocols. At the same time, efforts to reduce patient burden and embrace decentralized approaches rely on rapidly evolving technologies that can strain resources. Inadequate staffing, insufficient training, and high turnover rates at the site level are frequent consequences, undermining enrollment efforts.

High-performing contract research organizations (CROs) can play a decisive role in mitigating these pressures. By maintaining strong, trust-based relationships with sites, ensuring staff are well-trained and adequately supported, and facilitating clear, consistent communication, effective CROs help sites navigate operational challenges and remain engaged. Equally important, CROs serve as advocates for sites, representing their needs, constraints and feedback to sponsors, to ensure that study expectations and resources are aligned for successful enrollment. This proactive support also directly improves the likelihood that sites move from activation to enrollment and continue contributing meaningfully throughout the study.

The foundation for avoiding non-enrolling sites is laid long before recruitment begins. Site selection is one of the most decisive factors in determining enrollment success, yet it is also one of the most challenging steps in study planning. Competitive market pressures demand rapid movement from protocol concept to site activation, leaving limited time to conduct thorough feasibility assessments. These compressed timelines increase the risk of selecting sites that look strong on paper but ultimately fail to enroll. This challenge has become more pronounced in Europe under the EU Clinical Trials Regulation (EU CTR), where fixed timelines for assessment and approval can limit flexibility in adding or substituting sites, raising the likelihood that those identified late may struggle to recruit as expected.

Sponsors and CROs often rely heavily on historical performance data — past enrollment levels by country, region or indication — to estimate a site’s potential. While useful, this approach is inherently limited. Patients are not an infinite resource, and without the specific inclusion and exclusion criteria of the new protocol, predictions can be misleading. A site might commit to enrolling 10 patients in a year, but once faced with the final study design, evolving standards of care or competing trials, those commitments may prove unrealistic. Compounding the issue, many sites count patients who have consented or been screened rather than those who successfully meet criteria and enroll, further inflating projections.

Country selection adds another layer of complexity. Ideally, studies should be placed in geographies with strong patient populations and proven site capacity. In practice, regulatory realities often override clinical potential: the country with the most suitable patients may be excluded if approval timelines do not align with study schedules. Even after sites are activated, mid-study changes, such as new competing therapies or evolving regulatory requirements, can erode the feasibility of previously promising locations.

Ultimately, clinical trials are conducted by people, with patients and site staff at the center. Human and socioeconomic factors, including staffing shortages, investigator motivation, and site resources, strongly influence whether a site can operationalize a study successfully. Predictive tools powered by artificial intelligence and machine learning are increasingly used to identify high-performing sites, and they continue to evolve, developing the capability to account for these human and operational nuances through learned patterns and expanding data sets.

To mitigate these risks, we provide sponsors with our Non-Enrolling Site Tool, which integrates historical performance and predictive performance indicators to flag sites at higher risk of non-enrollment. This tool helps us and our customers make more informed decisions and take precise, data-driven actions to reduce the likelihood of non-enrollment while strengthening the evidence base for future site selection.

Among the clearest predictors of whether a site will succeed in enrolling patients is its level of engagement. Principal investigators, in particular, weigh whether a study offers meaningful benefits or new options for their patients. Trials with restrictive eligibility criteria, complex designs or procedures outside of standard practice are far less appealing, reducing investigator motivation to prioritize enrollment.

When investigators are not genuinely interested from the outset, the likelihood of patient recruitment drops sharply. Even if they believe the investigational therapy has clinical value, skepticism about a site’s resources — staffing, infrastructure, or administrative capacity — can discourage active participation. In many cases, these concerns are not voiced during feasibility, as sites may hesitate to raise potential challenges in hopes of being selected for new opportunities. As a result, past performance often takes precedence, and issues surface only after selection.

Engagement must also be understood in a broader context. A site that is initially enthusiastic may lose momentum if competing studies with greater perceived benefit for patients become available, or if new therapies alter the standard of care. Without adequate support, even committed investigators can struggle to sustain motivation. Recognizing and addressing these early warning signs is essential to minimizing the risk of non-enrollment.

Clear, consistent communication is one of the most powerful levers for reducing non-enrolling sites. CROs play a central role in aligning expectations among sponsors, investigators, and site staff, ensuring that every party understands the importance of the study and feels supported in carrying it forward.

At the site level, clinical research associates (CRAs) are the face of the study. They act as both recruitment representatives and advocates, maintaining the relationship that ultimately influences whether a site invests energy in enrollment. When CRAs are well-prepared and supported, they can provide the guidance and encouragement sites need to translate patient identification and screening activity into actual enrollment.

Breakdowns occur when communication becomes fragmented: when sponsors bypass CROs, when information fails to cascade effectively or when sites perceive a lack of contact. In such cases, investigators may deprioritize a study, seeing little reason to commit resources if they do not feel the sponsor or CRO is equally committed. Streamlined communication, coupled with strong working relationships across functional leads, CRAs, sites, and sponsor teams, ensures that sites remain engaged and motivated to recruit participants.

When sites struggle to enroll patients, proactive intervention is essential. Continuous monitoring provides the first line of defense. We employ a dedicated patient recruitment team to track site performance in real time, working closely with CRAs to identify obstacles and activate mitigation measures defined in the study’s recruitment plan. These plans typically include early actions, such as recruitment calls within weeks of activation, ensuring that investigators and site staff are aligned on expectations.

If enrollment remains stalled, more direct steps may be required. Onsite visits and sponsor collaboration to review study risks, eligibility criteria, and workflow can uncover the root causes of perceived poor performance. While such visits are resource-dependent, they often reinvigorate site teams by clarifying procedures, resolving barriers and boosting motivation.

Analyzing broader enrollment patterns is equally important. By distinguishing between site-level issues (such as staffing shortages), country-specific factors (such as competing therapies), or study-wide challenges (such as high screen failure rates), CROs can tailor their response. In some cases, additional budget or support (e.g., for additional site resources or increased travel reimbursements) can salvage a site; in others, it may be more effective to redirect resources toward higher-performing locations. Decisions to close sites are always weighed carefully: eliminating a site can reduce costs but may also shrink access to scarce patient populations, a particular concern in rare disease trials.

Throughout this process, transparent communication with sponsors and sites is critical. We emphasize partnership, working closely with sponsors to pursue strategies that not only address operational hurdles but also boost site morale and engagement. This collaborative approach strengthens site capabilities and increases the likelihood of sustained enrollment.

Sponsors partnering with us benefit from extensive experience across therapeutic areas, with thousands of sites engaged worldwide. This breadth of knowledge provides insight into how competing studies, site history, and regional dynamics affect patient recruitment and how best to mitigate the risks of non-enrollment.

Central to this effort is our dedicated patient recruitment and engagement lead (PREL) function. Established in 2022, the PREL role was created to ensure that recruitment strategy is not simply an added responsibility for clinical or project managers, but a dedicated area of expertise. From study initiation, PRELs focus exclusively on identifying enrollment risks, designing tailored strategies, and using data-driven insights to avoid reliance on assumptions. This separation allows clinical teams to concentrate on operational delivery while benefiting from specialized recruitment leadership.

The value of this approach has been clear. What began with just two PRELs has expanded to a team of more than 20 in only a few years, reflecting strong sponsor demand. The team works collaboratively, sharing lessons learned across projects to continuously refine strategies. Their role goes well beyond vendor management or traditional recruitment interventions. PRELs drive site engagement, enhance CRA training and analyze both quantitative and qualitative data across studies to ensure that recruitment strategies are comprehensive, adaptable and effective at the study, country and site levels.

By embedding dedicated recruitment leadership within project teams, we deliver a proactive, data-informed model that strengthens site performance and reduces the likelihood of non-enrolling sites across studies.

As clinical trials grow more complex and competition for patients intensifies, recruitment and enrollment strategies must continually evolve. We have built a specialized team dedicated to meeting this challenge, combining deep experience across therapeutic areas with a focus on both patient needs and site realities. By aligning careful strategy development with proactive support and training, the team helps reduce the risk of non-enrollment and ensures resources are used effectively.

This approach goes beyond immediate trial delivery. Our organization continually invests in improving communication with sites and sponsors, integrating new technologies, and refining data-driven tools to anticipate recruitment challenges earlier and respond more effectively. The result is a model that benefits all stakeholders: patients gain access to new therapies through thoughtfully supported trials, sites are empowered with the resources and engagement needed to succeed and sponsors realize more efficient, reliable study outcomes.