US oncology trials are at an inflection point. Structural and regulatory forces are converging in ways that fundamentally challenge long-standing models of trial design and execution. These pressures are not incremental; they represent a drastic change that requires sponsors to rethink the foundations of their enrollment strategies.
Regulatory reckoning and the changing economic reality
Three forces are putting pressure on the traditional way of conducting trials.
First, regulators are setting a higher bar for US patient representation. In 2025, the Food and Drug Administration denied label expansion and full approval for Columvi, which treats diffuse large B-cell lymphoma, mainly due to a lack of US patient participation in the pivotal global trial, and Blenrep, a monoclonal antibody for multiple myeloma, was denied approval for market reintroduction partly for the same reason.
Second, disruptions in funding from the National Institutes of Health and the National Cancer Institute (NCI) are causing financial and operational shortfalls at clinical sites. Sponsors are becoming an increasingly vital economic lifeline as they step up to cover fixed research costs and support staff, which is altering their relationship with research sites.
Third, recent policy changes—including Medicaid coverage adjustments and Affordable Care Act subsidy reductions—are putting financial strain on cancer treatment providers, making it more difficult for them to enroll patients in clinical trials and complicating patient recruitment.
Taken together, these three forces create conflicting pressures: Regulators are demanding more inclusive enrollment, and site and patient economics are reducing sponsors’ ability to provide it.
Structural barriers to patient enrollment
The US healthcare landscape presents unique complexities that greatly complicate recruiting for clinical trials. These are not minor operational problems but deeply rooted, structural challenges built into the system.
The core challenge in improving oncology-patient recruitment is the severe institutional and geographic disparity in access and accrual. A large portion of US oncology trial enrollment is concentrated in a small number of elite academic and NCI-designated centers, which enroll five times more patients than community sites.1 Concurrently, a significant percentage of activated clinical-trial sites enroll zero patients or one patient for a given study, a failure compounded by the fact that 70 percent of US counties lack a single active cancer trial.2
In addition, because access to advanced standards of care and next-line therapies is widespread in the United States, eligible patients often have less incentive to enroll in Phase II and Phase III trials than they do in other countries. While the representation of US patients in Phase I trials is high, later trials consistently under-enroll by about 15 percent.3
Second, the practical reality of clinical work complicates trial alignment. In the United States, how care is delivered in clinical settings often diverges from the standard care for clinical trials. This is exacerbated by a diverse healthcare infrastructure; while academic centers are staffed to manage these protocol demands, community-based and specialty centers often are not. This operational complexity can make both patients and providers reluctant to participate.
No pharmaceutical company has successfully addressed these issues or achieved a clear advantage in US patient recruitment, because sponsors continue to use global trial designs that do not accommodate the fragmented US environment.
Untapped opportunities in diversity and data depth
While the US oncology environment presents significant barriers, it also offers opportunities that are difficult to replicate elsewhere, which could allow sponsors to turn structural challenges into a source of differentiation.
This capability is supported by the depth of the US data infrastructure, which includes extensive electronic health record (EHR) systems, claims databases, and genomic repositories that can enable advanced analytics—from AI-enabled patient identification to predictive modeling of trial outcomes—at scale. Furthermore, since the United States is often where new drugs launch, sponsors can more seamlessly link trial design with commercial strategy. Trials can be structured with adoption in mind, enabling a smoother transition from R&D onward.
The robust US innovation ecosystem, with its many biotech companies, digital health startups, and technology players, enables rapid testing of novel trial models. For example, the structural disparities in the US healthcare system—many patients reside far from academic hubs and have poor access to advanced care—present an opportunity for sponsors to expand trial access by activating community and satellite sites to help recruit patients, designing lower-burden protocols and tailoring outreach to populations currently underserved by traditional research hotspots.
The United States should be viewed not as a problem geography for trial enrollment but as a market where sponsors can pilot innovative approaches that set global precedents.
Building the next-generation operating model
Sponsors can overcome the complexities of the US environment and take advantage of its unique opportunities by designing recruitment strategies that will enlarge the patient pool while accounting for differences—both within the United States and as it compares with other countries—in trial economics, site engagement, patient access and expectations, and clinical practices.
In the near term, sponsors can begin with a comprehensive risk assessment of regulatory, economic, and policy shifts in ongoing trials. Leading organizations are already going further, and smaller sponsors can incorporate immediate actions such as:
- Performing blinded interim data reviews: Implementing reviews of blinded data stratified by subpopulation can identify early signals of safety and efficacy responses and allow for proactive regulatory or protocol adjustments.
- Analyzing site performance more deeply: Companies can identify low-quality sites early and proactively reallocate operational resources to high-performing partners by analyzing metrics such as patient-to-screen ratio, cycle time for contract and activation, and demographic capture rates.
- Examining real-world evidence (RWE): For mature or established indications, RWE sources such as EHRs and claims data can be leveraged to generate baseline demographic and outcome comparisons. This allows sponsors to rigorously understand whether their actual trial enrollment dynamics align with the characteristics and practice patterns of the true target-patient population.
Beyond these immediate actions, sponsors could raise their game in clinical operations. The US environment offers unique levers that aspiring leaders can deploy to differentiate their approach:
- Activate and support community sites: Extend clinical research beyond traditional academic hubs into the community-based oncology practices where most US cancer patients receive care. This will require creating formal programs to support the onboarding of new-to-research sites by covering training for existing staff, providing specialized staff infrastructure such as remote coordinators, and automating trial-management processes.
- Understand referral patterns: Strengthen clinical and digital links between major academic centers and their affiliated community sites to expand patient access, and establish connections and processes to simplify and streamline enrollment at the community sites for trials at the hub.
- Use technology to target eligible patients: Capitalize on the depth of US oncology data—including EHRs, claims, and genomics—with advanced analytics tools, including artificial intelligence and machine learning. These tools can precisely identify eligible patients who might otherwise be overlooked and direct efforts to areas with the highest patient density and unmet need.
- Enhance enrollment through trial design: Design protocols that are practical and patient-centric by aligning with real-world standards of care and patient expectations, minimizing unnecessary burden and simplifying eligibility criteria to reflect typical comorbidity levels.
- Get continuous feedback from sentinel programs: Establish specialized monitoring loops for the first enrolled patients to track early patient responses and operational challenges. This feedback will help sponsors make tactical adjustments to trial design, site selection, and regulatory strategy.
The challenges in US oncology clinical trial enrollment are substantial, but they also offer opportunities for innovation. By embracing them, pharmaceutical companies can transform the United States from a problem geography into a proving ground for pioneering approaches. Those that strategically adapt their clinical-development models now can position themselves as leaders in a new era of patient-centric research and development.
The authors wish to thank Gaurav Agrawal and Kevin Webster for their contributions to this blog post.
1 Joseph M. Unger et al., “National estimates of the participation of patients with cancer in clinical research studies based on Commission on Cancer accreditation data,” JCO Oncology Practice, 2024; M. Kelsey Kirkwood et al., “State of geographic access to cancer treatment trials in the United States: Are studies located where patients live?” JCO Oncology Practice, 2024.
2 Assessing single patient investigator sites in cancer clinical trials, Phesi, January 2023; David M. Dilts et al., “Accrual to clinical trials at selected comprehensive cancer centers,” Journal of Clinical Oncology, September 2010.
3 Kenneth A. Getz, “Enrollment performance: Weighing the ‘facts,’” Applied Clinical Trials, May 1, 2012.