The Imperative of US Site Selection in a Changing Regulatory Landscape
Introduction
For many years, the expectation that clinical trials—especially those supporting drug approvals in the United States—should enroll a representative number of US participants has lingered as a quiet but persistent undertone in regulatory guidance that may have been overlooked in the name of rapid trial completion. Despite the United States leading participation in clinical trials, based on the World Health Organization’s Data, multi-regional trials, particularly in oncology do not often see a large bolus of their participants come from the United States. In fact, in a study evaluating drug approvals in oncology from 2013-2017, of the 42 approved drugs, 14 of these were based on pivotal clinical data with less than 20% of patients from the U.S. Among these 14 trials, the average percent of U.S. patients was just 8%.
Yet, recent actions by the U.S. Food and Drug Administration (FDA) have transformed this expectation into a clear mandate, compelling sponsors to re-examine not only their site selection strategies but also how they define critical-to-quality factors in trial operations. Nowhere is this shift more evident than in the FDA’s decision to publicize complete response letters (CRLs), highlighting deficiencies in U.S. enrollment and reinforcing the message that global trials must yield data directly relevant to U.S. patients.
In this article, we will explore the growing pressure from U.S. regulatory agencies to ensure robust U.S. enrollment in pivotal clinical trials, dissect the implications of recent FDA actions and guidelines, and outline why U.S. site selection has become an imperative—one that must be tracked with the same vigilance as any other critical quality metric. By analyzing recent examples and regulatory commentaries, we will clarify how sponsors can adapt to this new reality, safeguarding their development programs and, ultimately, patient access to novel therapies.
The Regulatory Foundation: A History of Expectation
The expectation that drugs approved for US patients be studied in populations reflective of the U.S. demographic has long been articulated in regulatory guidance. Both the FDA and the International Council for Harmonisation (ICH) have emphasized the importance of generalizability of clinical trial results. The FDA’s 2016 guidance, “E17 General Principles for Planning and Design of Multi-Regional Clinical Trials,” states that “data that are intended to support approval in a specific region should include a sufficient number of subjects from that region to enable assessment of the drug’s effects in the population.” In addition, the FDA released in September 2024 a draft guidance focusing specifically on Multiregional oncology clinical trials. At the time of release the director of the FDA’s Oncology Center of Excellence stated that, “It is important that data from multiregional clinical trials are applicable to patients in the United States who may use the drug and our current standards of oncological care.” He went on to say that, “The new draft guidance, when finalized, will not only support the agency’s review of data generated from multiregional clinical trials, but also help sponsors improve the generalizability and applicability of results from these trials to the U.S. population and to U.S. medical practice.”
Despite these clear references, enforcement often lagged rhetoric. Sponsors frequently utilized global trials enrolling patients from a mix of countries, with U.S. participation sometimes peripheral or nominal. Based on WCG benchmarking data, over the past three years, of 85 oncology trials with 10 or more countries involved, only 8% of participants come from the United States. In many instances, sponsors could counter concerns by providing statistical justifications, subgroup analyses, or bridging studies. However, this tolerance seems to have waned as the FDA seeks to close the gap between regulatory approval and real-world effectiveness among the U.S. population.
Recent FDA Actions: Complete Response Letters and Public Accountability
The regulatory landscape has shifted decisively with the FDA’s recent move to publish complete response letters (CRLs) in greater detail. These letters—issued when an application cannot be approved in its current form—now shed light on the FDA’s rationale for its decisions, making enrollment shortfalls and other deficiencies visible not only to sponsors but also to the public, investors, and patients. Of the 202 CRLs released by the FDA on July 10, 2015, seven cited inadequate representation of U.S. patients in clinical studies as a reason for non-approval.
A striking example, outside of the counts above, involves a Phase III oncology trial conducted across 13 countries. Of the 364 patients enrolled, only 9%—approximately 33 individuals—were recruited from the United States. The FDA cited this lack of U.S. representation as a fundamental reason for withholding approval, asserting that such a small proportion was insufficient to demonstrate the drug’s safety and efficacy for U.S. citizens. The message was unmistakable: global participation is welcome, even necessary, but U.S. representation is not optional.
This public airing of enrollment shortfalls has raised the stakes for sponsors. No longer can enrollment patterns be discussed solely in closed-door meetings or confidential submissions. Instead, they are now subject to scrutiny by a wider audience, further amplifying the reputational and financial risks of inadequate U.S. engagement.
Why US Enrollment Matters: Scientific, Regulatory, and Societal Dimensions
The FDA’s insistence on robust U.S. enrollment is not bureaucratic red tape—it is grounded in scientific, regulatory, and ethical considerations.
- Population Diversity: The U.S. population is remarkably diverse in terms of genetics, lifestyle, comorbidities, and access to healthcare. Results from trials dominated by non-U.S. participants may not extrapolate cleanly to U.S. patients, particularly if underlying risk factors, standard-of-care treatments, or sociodemographic profiles differ.
- Medical Practice Variability: Practices, diagnostic criteria, and background therapies often vary significantly from one country to another. A drug that performs well against the standard of care in Europe or Asia may face different comparators, reimbursement systems, or clinical guidelines in the United States.
- Regulatory Consistency: The FDA must ensure that any drug it approves will deliver benefits and manage risks appropriately in the U.S. healthcare context. The agency’s mandate is first and foremost to the U.S. public; data from non-U.S. sites, while valuable, cannot substitute for evidence gathered from Americans.
- Equity and Access: The move aligns with broader government initiatives to improve access and representation in clinical research. There is growing recognition that certain groups within the United States have been underrepresented in trials, with resulting disparities in drug efficacy and safety.
The Role of Site Selection: More Than a Logistical Choice
Against this backdrop, the process of site selection—often viewed as a logistical decision driven by historic experience, feasibility, investigator interest, or speed—has become mission-critical. The choice of which U.S. sites to activate, their capacity to enroll representative patients, and the ability to provide high-quality data are now under the regulatory microscope.
Why is U.S. site selection so imperative?
- Regulatory Risk Mitigation: Sponsors who fail to adequately enroll U.S. participants risk delayed approvals, additional study requirements, or, in the worst case, inability to bring a product to market.
- Data Relevance: Sites in the U.S. are essential for collecting data on safety, efficacy, and real-world outcomes that are directly relevant to the U.S. patient population and U.S. clinical practice.
- Stakeholder Confidence: Robust U.S. enrollment assures regulators, payers, clinicians, and patients that a new therapy has been tested in settings and populations that match those for whom the therapy is intended.
- Accelerated Adoption: Drugs with strong U.S. data are more likely to be adopted quickly by health systems, reimbursed by insurers, and trusted by prescribers.1,2
Tracking US Enrollment: A Critical-to-Quality Factor
Given the heightened scrutiny, sponsors must elevate U.S. enrollment and site performance to the status of a critical-to-quality (CTQ) factor—a core determinant of trial success. This means tracking site activation, enrollment rates, participant demographics, and overall participant geographies with the same rigor applied to safety reporting, data integrity, and protocol compliance. In essence, the focus for trials seeking approval in the United States needs to be less on completing the trial as fast as possible regardless and more on ensuring that participants are coming from the geographies in which the sponsor is looking to receive regulatory approval and align with the U.S. patient population. The United States’ diverse patient population and healthcare model make it difficult to run transferrable trials ex-U.S. and ensure an appropriate risk-benefit profile for the U.S. population.
Key strategies include:
- Early Planning and Feasibility: Incorporate U.S. site selection and enrollment targets into protocol development, feasibility assessments, and country allocation plans from the outset. Engage U.S. investigators and patient groups early to identify barriers and opportunities.
- Real-Time Monitoring: Implement dashboards and performance metrics to track U.S. enrollment in real time. Course-correct promptly if lagging, rather than relying on end-of-study reconciliations.
- Incentivizing Participation: Structure compensation, recruitment and retention support, and recognition programs that encourage U.S. sites to prioritize recruitment and retention of diverse, representative patients.
- Transparent Communication: Keep regulatory authorities informed of enrollment patterns, corrective actions, and contingency plans. Proactivity is viewed favorably and can mitigate potential regulatory concerns before they become non-approvals.
- Continuous Quality Improvement: Use root cause analysis to investigate enrollment shortfalls at U.S. sites. Iterate on site selection, training, and support to optimize performance over the life of the trial.
Implications for the Pharmaceutical Industry
The consequences of failing to prioritize U.S. site selection and enrollment are profound:
- Financial Impact: Delays in approval can cost millions, erode investor confidence, and threaten the commercial viability of promising therapies.
- Operational Complexity: Remediation efforts, such as conducting additional U.S. focused studies, are costly, time-consuming, and may strain relationships with investigators and patients.
- Reputational Risk: Public disclosure of enrollment deficiencies in CRLs exposes sponsors to scrutiny from investors, advocacy groups, and the media.
- Patient Harm: Most importantly, delays in approval or access may deprive U.S. patients—especially those with limited options—of life-saving therapies.
Recommendations for Sponsors
To thrive in this evolving regulatory environment, sponsors should:
- Make U.S. Enrollment a Board-Level Issue: Elevate oversight of U.S. enrollment to executive leadership, ensuring resources and accountability.
- Integrate Regulatory Insights: Engage early and often with the FDA to align enrollment expectations and proactively address concerns.
- Incorporate Diversity Goals: Go beyond U.S. enrollment numbers to ensure representation of key demographic groups, improving both regulatory acceptance and real-world impact.
- Leverage Technology and Data: Use advanced analytics, electronic health records, and patient registries to identify and engage prospective U.S. trial participants efficiently.
- Promote Transparency: Share enrollment plans, challenges, and successes openly with investigators, participants, and the public.
Conclusion: Embracing the New Normal
The FDA’s recent actions—amplified by the publication of complete response letters—underscore a new era of regulatory enforcement, where adequate U.S. patient enrollment in clinical trials is not merely preferred but required. For sponsors, the message is clear: thoughtfully selected, well-supported, and closely monitored U.S. sites are no longer a “nice-to-have,” but a central pillar of regulatory, operational, and commercial success.
Site selection in the United States must now be treated as critical to quality—planned with intention, tracked with precision, and continuously optimized to ensure that trial results are truly relevant to U.S. patients. Those who adapt swiftly will not only expedite approvals and maximize return on investment, but, more importantly, deliver on the promise of innovation for the patients who need it most. In this new normal, local representation is not a box to check, but the foundation on which trust, efficacy, and patient impact are built.
For more information on WCG Benchmarking Services to understand geographical patient distributions across trials, please visit https://www.wcgclinical.com/solutions/benchmarking-performance-management/
For more information on WCG Site Identification and Feasibility Services, please visit: https://www.wcgclinical.com/technologies/total-feasibility/
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