Executive Summary

Yes—U.S. representation in oncology MRCTs is becoming a stronger expectation that can influence approvability, particularly for accelerated approvals and when trial results must be generalized to U.S. practice. While FDA still accepts predominantly ex‑U.S. data when applicability to the U.S. is well justified, the agency’s 2024 oncology MRCT guidance and 2025 accelerated approval draft guidance elevate expectations for a “sufficient number” of U.S. participants and early, substantial U.S. enrollment. Recent decisions increasingly pair approvals with Postmarketing Requirements/Commitments (PMR/PMCs) that explicitly require study populations reflecting the racial and ethnic diversity of U.S. patients, and reviewers are flagging limited U.S. representation as a review or potential approvability issue in some cases ^{98101119121801823624019617537333124112}.

What FDA Guidance and Policy Now Signal

2024 Oncology MRCT Guidance: “Sufficient U.S. participants”

FDA’s oncology MRCT guidance emphasizes enrolling a “sufficient number of U.S. participants” so evidence supports robust assessment of safety and effectiveness in U.S. patients and practice. It warns that low U.S. enrollment can limit assessment of treatment-effect consistency and weaken applicability of foreign data to U.S. decisions. FDA strongly recommends early consultation to align on U.S. representation to avoid additional studies or delays ^{9899101102100}. FDA also urges:

• Conducting MRCTs across major regions and justifying region/sample-size distribution, including rationale for U.S. representation ¹⁰⁴.
• Ensuring control arms reflect evolving U.S. standards of care to maintain U.S. applicability ¹⁰⁰¹⁰³.
• Selecting U.S. sites capable of enrolling demographically representative patients (including community settings) and planning prespecified U.S./regional subgroup analyses for efficacy and safety ^103100102.

FDA notes a “decreasing proportion of U.S. participants” in oncology MRCTs, underscoring that this trend can limit generalizability and regulatory acceptability if not addressed ⁹⁸¹⁰¹.

2025 Accelerated Approval Draft Guidance: Early and substantial U.S. enrollment

For confirmatory trials, FDA advises sponsors to prioritize early U.S. recruitment and have U.S. recruitment “closer to completion” at the time of accelerated approval to mitigate accrual/retention challenges—making U.S. enrollment an explicit planning benchmark when determining whether a trial is truly “underway” ¹¹⁹¹²¹. FDA may consider requiring enrollment completion at approval if accrual is especially challenging ¹¹⁹.

Diversity/Representativeness Framework: PMRs/PMCs and Diversity Plans

FDA’s broader policy framework is also tightening expectations:

• FDA can require PMRs/PMCs to obtain data in underrepresented populations when pivotal trials lack adequate representation; confirmatory trials should reflect the diversity of U.S. patients expected to use the drug ^{128129130131132}.
• A new statutory requirement under FD&C Act section 505(z) will require diversity action plans for phase 3/pivotal studies, formalizing upfront planning for representativeness (including U.S. subpopulations) ^129127132.

Collectively, these policies reinforce a stronger ex ante expectation for meaningful U.S. representation and a stronger ex post safety net (PMRs/PMCs) if gaps remain.

What Recent Decisions and Case Reviews Show

Explicit scrutiny and “applicability to U.S.” expectations

• Nivolumab (esophageal SCC): Trial enrolled only one U.S. patient; FDA reviewers highlighted the limited U.S. representation as a review issue affecting applicability to U.S. patients ³⁷³. FDA also expects sponsors of ex‑U.S. trials to address how safety/efficacy in U.S. minorities will be examined and the applicability of comparators and disease characteristics to the U.S. ⁵³.
• Tislelizumab (Tevimbra): FDA requested a standalone justification that results from a predominantly Asian population (2.6% U.S.) are applicable to the U.S., referencing ICH E5 and acceptability of foreign data; planned a post‑marketing commitment to assess safety/efficacy in underrepresented U.S. racial groups ^424344331.
• Axatilimab (NIKTIMVO): FDA flagged very low Black (2%) and Hispanic (8%) representation as a potential filing/approvability issue to be addressed pre‑submission, asking the sponsor to speak to applicability to the U.S. population ¹⁷⁵¹⁷⁶.

Approvals paired with representativeness requirements

• Zanubrutinib (BRUKINSA): FDA PMRs require future randomized trials to enroll populations sufficiently representative of U.S. racial/ethnic diversity; FDA cited low U.S. enrollment in a prior study (only 19 U.S. subjects) and required post‑marketing efforts to ensure interpretable results for U.S. patients ^181614374.
• Tucatinib (TUKYSA): FDA required a randomized trial “sufficiently representative” of U.S. racial/ethnic diversity to allow interpretation in the U.S. population ⁸⁰.
• Pirtobrutinib (JAYPIRCA): Confirmatory/PMR trials must enroll populations reflecting U.S. racial/ethnic diversity to allow interpretation in U.S. subpopulations ^236240238.
• Futibatinib (LYTGOBI): FDA’s PMR requires adequate representation of racial/ethnic minorities in the randomized trial and asks for U.S. demographic justification of applicability at NDA ⁸⁶²⁹⁶.
• Lurbinectedin (ZEPZELCA): 2025 commitment requires an integrated analysis that includes sufficient racial/ethnic representation to reflect the U.S. population, enabling interpretation in these groups ¹⁹⁶.

Trials planning around U.S. enrollment feasibility

• AVMAPKI (avutometinib + defactinib): RAMP‑301 projected 80–100 U.S. patients with scenarios modeling a 50% reduction or cessation in U.S. accrual post‑regulatory action; FDA interactions emphasized rapid U.S. site activation and feasibility given risk of loss of equipoise—reflecting the importance FDA places on sustaining meaningful U.S. enrollment within MRCTs ^155154156.

Contrasting flexibility when justified

• Entrectinib (ROZLYTREK): FDA accepted predominantly ex‑U.S. data where extrapolation to U.S. patients was supported, and overall representativeness and totality of evidence were persuasive in an ultra‑rare setting ²⁴.
• Foreign data policy (e.g., quizartinib): Applications based largely on foreign data may be approved if applicable to U.S. population and practice, conducted by competent investigators, and verifiable via inspection; sponsors are expected to address applicability (including racial/ethnic minorities and U.S. standards of care), often by comparing U.S. subgroups with other regions ¹¹².

Reported U.S. representation snapshots (illustrative)

• Nivolumab esophageal SCC: 1 U.S. patient (very low) ³⁷³.
• Tislelizumab: 2.6% U.S.; 75% in Asia (50% China) ³³¹.
• Ponatinib: 41% U.S. (186/449) ²⁵⁷.
• AVMAPKI RAMP‑301: ~16% U.S. as of Sept 2024 (27 of 43 enrolled), with projections to increase U.S. accrual ¹⁵⁵¹⁵⁴.

These examples show both heightened scrutiny when U.S. participation is very low and the use of PMRs/PMCs to backfill representativeness, while retaining flexibility to accept ex‑U.S. evidence when appropriately justified.

What Is—and Isn’t—Required Today

• There is no fixed numeric threshold for U.S. enrollment in MRCTs. FDA’s position focuses on “sufficient” U.S. participation to assess consistency and applicability, with strong expectations to justify relevance if U.S. enrollment is limited ^101981122444.

• FDA increasingly expects:

  • Early engagement and explicit plans for U.S. representation and standards‑of‑care alignment ^102100103104.
  • Prespecified U.S./regional subgroup analyses and safety dose‑optimization considerations by subgroup ¹⁰⁰¹⁰².
  • For accelerated approvals, early and substantial U.S. accrual with U.S. enrollment near completion at approval to ensure confirmatory feasibility ¹¹⁹¹²¹.
  • Use of PMRs/PMCs when premarket enrollment is not sufficiently representative of U.S. racial/ethnic diversity ^{1281301318018236240196}.

• FDA remains open to approving applications with predominantly foreign data if robust scientific justification demonstrates applicability to the U.S. population and practice and if data can be validated (e.g., inspections), consistent with ICH E5 and FDA acceptability of foreign data ^1122444.

How the Trend Is Likely to Evolve (2025 and beyond)

Given the 2024 oncology MRCT guidance and 2025 accelerated approval draft guidance:

• Expect continued ratcheting of expectations for U.S. representation in MRCTs, with practical benchmarks and review questions focused on whether U.S. accrual is sufficient to support subgroup analyses and consistency assessments for U.S. practice ^98101119121.
• Anticipate more frequent use of PMRs/PMCs that explicitly require U.S.-representative racial/ethnic diversity if pivotal trials fall short, making representativeness a de facto condition of continued marketing in some settings ^{1880236240196129130131132}.
• For accelerated approvals, sponsors should plan for U.S. recruitment to be well advanced—potentially near completion—at the time of approval to avoid feasibility concerns that can impact approvability or trigger complete response letters unrelated to U.S. numbers but tied to overall trial “underway” expectations ^11912123211.
• FDA will likely maintain flexibility for rare diseases or where randomization is infeasible, provided that extrapolation to U.S. patients is rigorously justified and, when needed, complemented by targeted postmarketing studies ²⁴¹¹².

Overall, the direction of travel is clear: stronger, earlier, and more explicit expectations for meaningful U.S. patient and site representation or a robust, pre‑specified plan to justify applicability and bridge gaps.

Practical Implications for Sponsors

Plan for U.S. enrollment as a program‑critical deliverable

• Build MRCTs across major regions with a justified U.S. sample size and control arms aligned to evolving U.S. standards of care; pre‑specify U.S./regional analyses to assess intrinsic/extrinsic factors and consistency of effect ^{10410010198102}.
• Prioritize early U.S. site activation and accrual; for accelerated approval, bring U.S. enrollment close to completion by the time of approval to reduce feasibility risk ¹¹⁹¹²¹.

Design for representativeness and operational resilience

• Select a mix of academic and community U.S. sites to improve demographic representativeness; monitor accrual by key U.S. subgroups; employ adaptive mitigation if accrual lags ¹⁰³.
• Prepare Diversity Action Plans and align them to PMR/PMC contingencies; be ready to justify U.S. applicability with U.S. subgroup data or bridging analyses if overall U.S. accrual is limited ^{129127132100102}.

If U.S. enrollment is low or the trial is predominantly ex‑U.S.

• Provide a standalone justification of U.S. applicability (ICH E5; intrinsic/extrinsic factors, SoC, exposure–response, subgroup consistency, inspection plans) and propose targeted PMRs/PMCs to address U.S. representativeness gaps, as FDA requested in recent programs ^{441124243175176}.

Bottom Line

U.S. representation in oncology MRCTs is not a strict numeric requirement, but it is now a stronger, enforceable expectation that can affect approvability through feasibility assessments (especially for accelerated approvals), rigorous applicability justifications, and targeted PMRs/PMCs when U.S. representativeness is lacking. FDA guidance in 2024–2025 formalizes this trajectory, and sponsors should plan MRCTs to deliver sufficient U.S. enrollment and analyses—or robust justification and postmarketing strategies—to ensure timely, sustainable approvals for the U.S. patient population ^{98101119121801823624019637333124112}.