In early November 2025, a session at the Friends of Cancer Research’s annual meeting and a new report from the Reagan-Udall Foundation for the FDA both focused on challenges and considerations for conducting multiregional clinical trials in oncology. As the FDA continues to stress the importance of applicability of trials to the U.S. population, while simultaneously rolling back policies based on diversity and equity considerations, AgencyIQ walks through how we got here and where policy could move next. Hint: Possibly moving toward a single institutional review board in multicenter trials.

Background: Global clinical trials and the FDA

• The FDA’s approval of a new drug or biologic requires data from clinical trials, but not exclusively from patients or trials in the U.S., and many clinical trials rely on data obtained from sites outside the U.S. As of Nov. 5, 2025, the ClinicalTrials.gov database maintained by the National Institutes of Health lists 557,067 studies with locations in all 50 states plus 224 countries and territories.The FDA can face heightened challenges in assessing the applicability of this evidence because the U.S. is more racially and ethnically heterogeneous than many other countries, which can make obtaining representative foreign data challenging. Moreover, foreign countries can have different standards of clinical care that can affect the conduct and results of a clinical trial.
• Traditional regulatory strategies for interpreting foreign data have involved “bridging” study data from one population to another. As its name implies, this technique refers to quantitatively connecting data across populations. The International Council for Harmonisation E5 guideline – which was expanded upon in a 2006 Q&A document – addresses ethnic factors in foreign clinical data. As the Q&A document explains: “If the data developed in one region satisfy the requirements for evidence in a new region, but there is a concern about possible intrinsic or extrinsic ethnic differences between the two regions, then it should be possible to extrapolate the data to the new region with a single bridging study.” Depending on the context, this could range from pharmacodynamic or dose-response studies to an additional clinical trial.
• The multiregional clinical trial, or MRCT, approach provides an alternative to bridging by providing more “robust evidence,” according to the ICH E17 standard. MRCTs are generally defined as a clinical trial conducted in multiple countries or regions under the same protocol and intended to support a future submission for approval to a regulator.

Regulatory context: Addressing applicability challenges with MRCTs

• In recent years, there has been growing concern that oncology trials rely too much on unrepresentative foreign data. The FDA’s criticism reached a flash point during the 2021-2022 review of Lilly and Innovent Biologics’ sintilimab, an anti-PD-1 antibody proposed for first-line treatment of certain non-small cell lung cancer patients. The clinical trial supporting the application was conducted in 48 hospitals, all in China.
• The FDA’s top oncology regulators outlined issues with the application and its data in a February 2022 commentary in The Lancet Oncology. Oncology Center of Excellence Director RICHARD PAZDUR and then-Division Director HARPREET SINGH wrote, “The degree of regulatory flexibility in establishing the acceptability of data from a single country and its generalizability to a new population should be balanced against the drug’s innovation,” indicating that bridging studies may be insufficient in some cases. Further, the paper stressed the need to ensure data reliability and accuracy, citing a 2016 study that concluded that “80% of China’s clinical trial data are fraudulent.” [Read AgencyIQ’s full analysis of the paper here.] Also in February 2022, the FDA’s Oncologic Drugs Advisory Committee reviewed sintilimab’s data package and reached a similar conclusion, voting 14-1 that additional trials showing applicability to U.S. patients and care should precede a regulatory decision. [Read AgencyIQ’s full analysis of the meeting here.]
• Ultimately, Lilly reported in March 2022 that the application resulted in a Complete Response Letter that recommended the firms conduct “an additional clinical study, specifically a multiregional clinical trial comparing standard of care therapy for first line metastatic [non-small cell lung cancer] NSCLC to sintilimab with chemotherapy utilizing a non-inferiority design.”
• To set expectations, OCE released new draft guidance on conducting MRCTs for cancer in September 2024. “The paramount consideration for FDA when evaluating such oncology trials is whether the results are applicable to the intended use population in the U.S., and to U.S. standard oncological care,” the document states. MRCTs are “encouraged in the appropriate context,” and sponsors should at a minimum consider patient-related factors, disease-related factors, health care system factors, and socio-cultural factors. The FDA, in turn, will weigh “the impact of both intrinsic and extrinsic factors on study outcomes” when determining applicability. [Read AgencyIQ’s analyses of the guidance content and additional implications.]

In 2025, U.S. applicability of oncology trials has remained a high-profile issue

• During a May meeting, the agency’s Oncologic Drugs Advisory Committee considered Genentech’s supplemental application for glofitamab as a second-line treatment for a subset of diffuse large B-cell lymphoma patients. While the study met its primary endpoint of overall survival, the meeting’s briefing packet explained, “FDA is concerned by the lack of internal consistency observed in the STARGLO trial and how the results of the Asian region appear to be driving the overall trial results.” The agency flagged challenges in interpreting the control arm because data showed low utilization rates in the U.S., and Pazdur engaged directly with Genentech regarding the firm’s decision-making around targeted Chinese enrollment. The committee voted 8-1 against the application, and Genentech announced that FDA issued a Complete Response Letter on July 18.
• A few months later, similar themes arose during the advisory committee’s July 17 consideration of GSK’s belantamab mafodotin as a second-line multiple myeloma treatment. With less than 5% of patients in both pivotal trials enrolled in the U.S., the FDA questioned the relevance of findings from the study populations to the U.S. population. The agency flagged that older adults and Black or African American patients were underrepresented compared to the demographics of the disease population in the U.S. While the advisory committee voted against the product’s risk-benefit profile, the FDA ultimately approved the product on Oct. 23.
• Also in July, OCE published a new “From a Global Perspective” article regarding international oncology trials. In an interview format, Pazdur discussed some of the underlying reasons for low U.S. enrollment in MRCTs. He noted that cost is not the only issue, saying, “For example, there are structural reasons involving contract negotiations with individual clinical sites that tend to take longer in the United States. If you have multiple institutional review boards [IRBs], multiple IRBs will review the protocol, and that may result in delays. Also, since newer drugs come on the market earlier in the United States, investigators may have less interest in putting patients on a trial if the control arm does not represent the current standard, in the investigator’s opinion.”
• Pazdur also described OCE’s Project Site Selector, a pilot program the center started in 2022 that has focused mostly on hosting workshops. He wrote in the perspective piece, “Drug regulators have traditionally not thoroughly queried companies prior to the trial initiation on methods to select sites and the generalizability of the data collected from these sites to the U.S. population and medical practice. We traditionally spend a lot of time discussing the trial design, but then frequently not enough time is spent on clinical trial site locations.” Based on these statements, and similar remarks he made at the Drug Information Association’s annual meeting, the oncology industry should be prepared to see more discussion of clinical trial sites during conversations with the agency.
• Meanwhile, the conversation surrounding onshoring drug development activities has ramped up. While many new initiatives aim to incentivize domestic manufacturing, such as the “PreCheck” program for facilities, leadership has spoken about encouraging clinical trials in the U.S. as well. In May 2025, at the Food and Drug Law Institute’s annual meeting, GRACE GRAHAM, the FDA’s deputy commissioner for policy, legislation, and international affairs, said during a keynote address that “the studies that innovators may hope to rely on for FDA review aren’t as representative of the U.S. population as they need to be, which can lead to further delay and duplication.” In addition, Congress has acknowledged competitive threats from China, and clinical trial speed was a focal point of a recent Senate Committee on Health, Education, Labor and Pensions hearing. [Read full AgencyIQ analysis here.]

On Nov. 4, 2025, stakeholders discussed MRCT comparator selection at the Friends of Cancer Research’s annual meeting

• Conversations about global trials permeated during the daylong event, with some discussion during a “Future Policy Perspectives” panel preceding the session focused on MRCT comparators. There, Friends President and CEO JEFF ALLEN pointed out stalled clinical trial participation rates in the U.S. and asked how to balance representativeness and timeliness in the context of global trials. AstraZeneca’s AMY McKEE agreed that the tension is there, saying, “You want to get promising new therapy to patients as quickly as possible. And so, you would love to be able to enroll in the fastest enrolling places, but you have to have a patient population that’s representative for all countries. Because, let’s be honest, I don’t want to steal the thunder from the last panel, but all of the pharma representatives on that panel are like, ‘Yeah, I’m going to do one global trial in this particular indication. I’m not going to do two or three.’ And so, you have to try to get the representation you need for all the health authorities represented.” She asserted that the FDA is the “gold standard” health authority and explained that she sees technical and data sharing enhancement as a way to mitigate the health care delivery complexity that challenges U.S. clinical trials.
• The event’s third and final session centered around a new white paper released ahead of the meeting. The goal of the document is “to identify key considerations and potential strategies for selecting and justifying comparators in oncology MRCTs.” The authors laid out challenges with defining standard-of-care and comparator options and the tension between feasibility and applicability. The paper provides approaches to maintain applicability in a table, grouping them into three buckets: (1) design strategies for prospective flexibility, (2) contextual evidence additions during or post-trial and (3) alternative or complementary evidence generation. Both advantages and limitations are described for each approach. Finally, the paper concludes by proposing a step-by-step approach to comparator selection based on the target setting.
• Singh – currently with Precision for Medicine, formerly with OCE, and co-author of the sintilimab paper – opened with a summary presentation. “In today’s environment, clinical trials must be run across multiple regions in order to enroll enough patients and to ensure a broad understanding of an asset’s safety and efficacy,” she emphasized. She posed two foundational questions: “How do we design a clinical trial and select a control arm that regulatory agencies will accept when the standard of care may vary from region to region, and further, how do we plan for the fact that standards of care may be at risk of changing over the course of an ongoing trial?” According to Singh, challenges in comparator selection occur when multiple standard-of-care options are available, and sponsors must “decide which to prioritize without appearing outdated or nonrepresentative.” She acknowledged that trials can build in investigator choice or regionally determined comparators, which “does increase feasibility, and it adds statistical and interpretive complexity.”
• Singh moderated the subsequent panel, which featured additional white-paper authors JUDD ENGLERT from Amgen; SUMITHRA MANDREKAR from Mayo Clinic; KRISTIN McJUNKINS, a Friends of Cancer Research advisory advocate; RAYMOND OSAROGIAGBON from the Baptist Hospital Group; and KATHLEEN WINSON from Genentech. Osarogiagbon spoke to the unknowns that come with navigating an evolving oncology treatment landscape, saying, “That’s a great question, and it’s a increasingly germane question because of the fundamental excitement we all have to remind ourselves of. It’s a good thing, right? Rapid cycle development, discovery – we have so many more options. With that has come this complexity. OK, let’s embrace it, right?”
• The speakers drilled down on the pros and cons of incorporating multiple control arms into one study protocol. Genentech’s Winson described a case in which the company designed a Phase 2/3 adaptive trial that incorporated expectations for the treatment landscape. When two other treatments received accelerated approval, the study switched to an investigator’s choice comparator. While this pivot succeeded – the trial has enrolled patients – the panelists acknowledged that prospective planning can be challenging based on the timing of approvals and trial status.
• The panelists highlighted the importance of considering feasibility of comparators. Amgen’s Englert said, “There’s a number of agents that are out there now that have gotten approval and are considered standard of care – radioligand therapies, CAR T, other cell therapies, gene therapies – that can be very difficult for a sponsor to deliver as part of the control arm for a trial. And so, we also have to look at the practical standpoint of, can we actually even include this, and be able to supply it as part of our trial?” From a practical standpoint, Singh emphasized the importance of information sharing with regulators. “I was moved, as a former regulator, by data that was brought to me on patterns of practice, what was happening in the U.S., and in light of approvals, what was actually happening in clinics, in community settings. And I do think that that’s really critical data to gather,” she said.
• The speakers agreed that stakeholder engagement and discussion are crucial to MRCT design decisions. Multiple panelists explained that when input is not accounted for, patients often “vote with their feet.” Englert concluded, “I think it comes back to being patient- and customer-centric, right? At the end of the day, if you pick your control arm because you believe patients will enroll on it and want to be on that just as much as the investigational therapy, that, to me, is the No. 1.”

The same week as the Friends’ annual meeting, the Reagan-Udall Foundation for the FDA issued a new report on improving oncology MRCTs

• The foundation’s report draws from an invitation-only Sept. 4 roundtable discussion sponsored by BeOne Medicines, Jazz Pharmaceuticals, Lilly and Merck. Participants represented “the biopharmaceutical industry, oncology clinical trial sites, clinical research organizations, and cancer-focused non-profits.”
• The report has a generally broader scope than the Friends meeting, focusing on issues beyond the foundational study design. The paper is organized into two topical sections addressing (1) oncology site activation, enrollment and study startup timelines and (2) global harmonization of science-based approaches to clinical trial representativeness targets and generalizability analyses.
• The authors described regulatory policies to improve the speed of site activation, citing recent ICH good clinical practice guidelines and the FDA’s 2016 guidance that paved the way for electronic informed consent. One item in this section remains pending: single IRB regulations. The report states, “The FDA issued two Notices of Proposed Rulemaking, one on the single Institutional Review Board and one on the Protection of Human Subjects and IRBs (the Common Rule). These proposed regulations are intended to harmonize FDA regulations with the Common Rule and streamline informed consent processes. The final single IRB regulations are expected to be published in 2025.”
• The report emphasizes the need for baseline expectations around setting enrollment targets for generalizability, stating, “The Roundtable participants discussed the vital need for ICH, FDA, sponsors, clinical trial sites, and patients to collaborate and align on what scientific principles should drive representative targets and what statistical and data quality principles should drive analyses of the generalizability of safety and effectiveness in trials with patients from different regions.”
• Finally, the report broaches the topic of comparator selection from a different perspective, with a call for clarity from the FDA. The report reads, “Both sponsors and principal investigators at clinical trial sites have stated that there is not sufficient regulatory clarity about how best to manage evolving and varying standards of care across sites and regions. Additionally, changing control arms mid-trial is often not feasible in countries where proposed control-arm interventions are not yet approved in those countries. Continuously chasing an evolving standard of care can yield a sense of trials pursuing a moving target within, and between, regions.”

Analysis

• There are multiple policy lenses to consider who participates in clinical trials, and where. Before this year, conversations about MRCTs involved OCE’s work to implement Diversity Action Plan requirements. Reforms in the 2023 Consolidated Appropriations Act gave the FDA new statutory authority (Section 3601) to require DAPs for certain Phase 3 and pivotal premarket clinical studies. The law states that the product sponsor develops the DAP, which must include enrollment goals, the rationale by which these goals were developed, and “an explanation of how the sponsor intends to meet such goals.” The agency (belatedly) released draft guidance in June 2024 with compliance recommendations explaining how to set enrollment goals using data about the incidence or prevalence of a disease in the U.S. population. In the draft guidance, the FDA advised that study enrollment should ultimately reflect the U.S. intended-use population but that DAPs should account for participants outside the U.S. as well. [Read AgencyIQ’s extensive initial analysis and follow-up here.] In other words, this document addressed the question of how the FDA expects generalizability to be established.
• The future of the DAP guidance remains unclear. The document was pulled from the FDA’s website in late January 2025 after President DONALD TRUMP issued an executive order directing agencies to terminate their diversity-related “action plan” policies. It was reinstated following a Feb. 11 temporary restraining order but then removed from the agency’s website in May. In July, the guidance was put back on the FDA’s website, but with a note that reads, “Any information on this page promoting gender ideology is extremely inaccurate and disconnected from truth. The Trump Administration rejects gender ideology due to the harms and divisiveness it causes. This page does not reflect reality and therefore the Administration and this Department reject it.”
• Taken together, the Friends of Cancer Research and Reagan-Udall reports signal that external groups are looking to fill practical gaps and keep the conversation going about establishing U.S. generalizability of foreign clinical data.
• An area to watch: IRB requirements. In his July “Global Perspective” piece, Pazdur described onerous requirements that can result from multiple IRBs involved in multisite trials as one contributor to low U.S. enrollment numbers. This topic appears to be top-of-mind with the agency’s new leadership. In an episode of the “FDA Direct” podcast posted Nov. 5, FDA Commissioner MARTIN MAKARY summarized recent stakeholder engagements, saying, “We talked about health care costs and the struggles they have and how we can reform clinical trials by having more streamlined hospital contracting and central IRBs.” He explained that decentralized IRBs cause delays, giving an anecdote where the Johns Hopkins board rejected his survey proposal a year and a half after the request. With the FDA poised to finalize relevant rulemaking in January 2026 [See AgencyIQ’s Spring 2025 Unified Agenda explainer here], stakeholders can expect considerations related to boosting U.S. enrollment to be reflected in any regulatory changes.

Featuring previous research by Laura DiAngelo, Ned Pagliarulo and former AgencyIQ analyst Rachel Coe.

To contact the author of this item, please email Amanda Conti ( aconti@agencyiq.com).
To contact the editors of this item, please email Ashley C. Klein ( aklein@agencyiq.com) or Jason Wermers ( jwermers@agencyiq.com).

Key documents and dates

• Friends of Cancer Research Annual Meeting 2025 (Nov. 4, 2025, meeting materials and recording linked here)
• Reagan-Udall Foundation for the FDA Report: Improving Oncology Multi-Regional Clinical Trials

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