In today's era where global drug R&D has entered a phase of clinical globalization and diversified approval pathways, how drug regulatory authorities evaluate and accept data from diverse sources is no longer merely a technical judgment-it also involves institutional mutual trust, geopolitics, and even the reshaping of industrial structures.
According to the FDA's "2024 Drug Trials Snapshots" report, in 2024, the FDA approved four drugs with no participation from U.S. subjects. This rare move is widely interpreted as a sign that the FDA's stance on global data sources has begun to loosen under specific conditions.
Zero U.S. Subjects: Observing Trend Shifts Through Individual Cases
In 2024, the FDA approved a total of 50 new drugs, 4 of which included no U.S. subjects at all.
These four drugs are: EXBLIFEP (for complicated urinary tract infections), PIASKY (a rare disease therapy for paroxysmal nocturnal hemoglobinuria), TEVIMBRA (a PD-1 drug for esophageal cancer), and UNLOXCYT (for advanced cutaneous squamous cell carcinoma untreatable by surgery or radiotherapy).
EXBLIFEP (cefepime/enmetazobactam combination)
Developer: Allecra Therapeutics (Germany)
Indication: Complicated urinary tract infections (cUTI) in adults
Approval Date: February 2024 12. Modality: Small molecule
Clinical Trial Distribution: Phase III studies primarily conducted in Europe
Why zero U.S. subjects was feasible: The project received FDA QIDP (Qualified Infectious Disease Product) designation. Its Phase III study was a rigorous double-blind, randomized controlled trial with piperacillin + tazobactam as the control, showing significantly superior efficacy. Due to the widespread distribution of cUTI patients in Europe and the similarity of their microbiota profiles to the U.S. population, the FDA recognized its statistical and medical extrapolation value.
PIASKY (crovalimab)
Developers: Co-developed by Roche (Switzerland) and Chugai (Japan)
Indication: Long-term maintenance treatment for PNH (paroxysmal nocturnal hemoglobinuria) patients aged 12 and above
Approval Date: June 2024
Modality: Monoclonal antibody
Clinical Trial Distribution: Multiple Asian countries (including Japan, China, Singapore) and select EU countries
Why zero U.S. subjects was feasible: It is the first subcutaneous complement inhibitor with significant compliance advantages. Roche submitted a comprehensive global dataset from the COMMODORE 2 study to the FDA, comparing it with existing eculizumab therapy. Given the extremely low incidence of PNH in the U.S., the FDA accepted historical controls and external validation models as reasonable alternatives.
TEVIMBRA (tislelizumab)
Developer: BeiGene (China)
Indication: Locally advanced or metastatic esophageal squamous cell carcinoma previously treated with chemotherapy
Approval Date: March 2024
Modality: Monoclonal antibody
Clinical Trial Distribution: Key Phase III studies (RATIONALE 302, 305) conducted in China, Japan, and South Korea
Why zero U.S. subjects was feasible: Esophageal squamous cell carcinoma is rare in the U.S. but prevalent in East Asia. The RATIONALE 302 study, an open-label trial with placebo control, showed tislelizumab significantly prolonged median OS. BeiGene supplemented with meta-analyses of globally approved PD-1 drugs, pharmacokinetic bridging data, and immunomic comparisons between Asian and Caucasian populations, leading the FDA to accept the "population adaptability" inference.
UNLOXCYT (cosibelimab)
Developer: Checkpoint Therapeutics (U.S.)
Indication: Advanced cutaneous squamous cell carcinoma (cSCC) untreatable by surgery or radiotherapy
Approval Date: December 2024
Modality: Monoclonal antibody
Trial Distribution: Primary recruitment in Australia, Thailand, South Africa, and European countries
Why zero U.S. subjects was feasible: cSCC is one of the most common invasive subtypes of skin cancer. The trial was single-arm, but the FDA allowed approval via the "historical control" pathway due to the absence of standard treatments. Additionally, cosibelimab is a fully humanized PD-L1 antibody with a mechanism highly consistent with durvalumab and atezolizumab. These four projects share common traits. First, most target areas with highly unmet medical needs, such as rare diseases, high-risk cancers, or anti-infectives.
In recent years, the FDA has promoted flexible review policies in these fields, prioritizing the strength and clinical significance of efficacy signals over strict geographical representativeness when treatment options are scarce. Second, these trials generally feature scientifically sound designs, clear endpoints, high-quality data, and smooth regulatory communication. Regardless of whether subjects were U.S.-based, their protocols already aligned with FDA pre-review comments or Special Protocol Assessment (SPA) requirements. Furthermore, some products-like PIASKY or TEVIMBRA-have mechanisms highly comparable to approved peers, reducing their classification as "risk assets" in statistical inference and safety assessments, thereby minimizing the impact of "geographical bias" on review decisions.
Nonetheless, this phenomenon raises broader institutional questions: Do such FDA approvals signal that requirements for local subjects are being subordinated to global clinical logic? The answer is more complex than simple "inclusivity." In practice, the FDA is moving toward accepting data "based on scientific quality rather than geographical origin," but this shift remains selective, cautious, and marked by regional biases.
For example, data from the EU, Japan, or Australia is often trusted due to equivalent regulatory systems and established cooperation in areas like data auditability, clinical ethics, patient management, and adverse event reporting. In contrast, data from countries with divergent regulatory systems-such as China, India, Russia, or Latin America-may face heightened technical thresholds, stricter statistical extrapolation demands, or requirements for supplementary bridging trials, even as the FDA maintains review flexibility.
In recent years, the FDA has promoted flexible review policies in these fields, prioritizing the strength and clinical significance of efficacy signals over strict geographical representativeness when treatment options are scarce. Second, these trials generally feature scientifically sound designs, clear endpoints, high-quality data, and smooth regulatory communication. Regardless of whether subjects were U.S.-based, their protocols already aligned with FDA pre-review comments or Special Protocol Assessment (SPA) requirements. Furthermore, some products-like PIASKY or TEVIMBRA-have mechanisms highly comparable to approved peers, reducing their classification as "risk assets" in statistical inference and safety assessments, thereby minimizing the impact of "geographical bias" on review decisions.
Nonetheless, this phenomenon raises broader institutional questions: Do such FDA approvals signal that requirements for local subjects are being subordinated to global clinical logic? The answer is more complex than simple "inclusivity." In practice, the FDA is moving toward accepting data "based on scientific quality rather than geographical origin," but this shift remains selective, cautious, and marked by regional biases.
For example, data from the EU, Japan, or Australia is often trusted due to equivalent regulatory systems and established cooperation in areas like data auditability, clinical ethics, patient management, and adverse event reporting. In contrast, data from countries with divergent regulatory systems-such as China, India, Russia, or Latin America-may face heightened technical thresholds, stricter statistical extrapolation demands, or requirements for supplementary bridging trials, even as the FDA maintains review flexibility.
The FDA's Pragmatic Choices Under Multiple Pressures Why has the FDA gradually accepted non-U.S. data? Three key factors drive this shift:
Institutional impetus for accelerated review
Since" the 21st Century Cures Act"was passed, the FDA has increasingly relied on single studies and surrogate endpoints to expedite approvals. In 2022, 24 of 37 approved new drugs were based on single-trial results. In rare diseases, oncology, and severe infections-where traditional multi-center, phased trials are slow-the FDA has adopted flexible tools to accelerate pathways. The COVID-19 pandemic further spurred reevaluation of trial sources and data collection. Amid pressures for efficiency and transparency, the FDA developed a "compliance flexibility" strategy, moderately accepting non-U.S. studies while safeguarding scientific rigor and ethics.
Worsening U.S. clinical cost and speed disadvantages
The U.S. no longer dominates trial resource allocation. As Craig Koch, Executive Vice President of Velocity (a clinical operations firm), noted in 2025, U.S. trial costs, recruitment expenses, and administrative burdens are globally high. Coupled with reduced NIH funding and shrinking academic research resources due to healthcare reforms, domestic trials have declining cost-effectiveness. For rare diseases or targeted therapies, scarce U.S. patient pools make multinational trials or data from high-prevalence Asian regions practical alternatives. Rigid adherence to traditional pathways would delay patient access.
Evolving technology and patient applicability
Technologically, more drugs target specific populations or genotypes. For example, PIASKY showed strong safety and hemolysis control in Asian PNH patients, while TEVIMBRA demonstrated survival benefits in East Asian esophageal squamous cell carcinoma-both rare in the U.S. The FDA now accepts data from "foreign target populations" for such drugs, often with labeling restrictions. This trend aligns with advancing integration of statistical extrapolation and real-world evidence (RWE). For low-incidence indications, the FDA may lower statistical thresholds using comparable historical controls instead of mandating U.S. control groups-reflecting a dynamic balance between scientific tolerance and regulatory pragmatism.
Not Applicable to All Countries While the FDA relaxes non-U.S. data rules, China remains an exception. Unlike data from Eastern Europe, Latin America, Japan, South Korea, or Australia- which may be accepted under specific conditions-Chinese data faces persistent institutional distrust and review barriers.
''Regulatory trust disparities'' The FDA's caution toward Chinese data stems from institutional asymmetric trust, manifesting in:
''Regulatory trust disparities'' The FDA's caution toward Chinese data stems from institutional asymmetric trust, manifesting in:
Ethical and review gaps: Doubts about GCP compliance, informed consent adequacy, and traceable on-site audits.
Insufficient data auditability: Concerns over source data transparency, especially in Chinese trial centers lacking repeated FDA/ICH inspections, limiting "post-hoc reconstruction" capabilities.
Lack of regulatory mutual recognition: Despite China's ICH membership, high-intensity, regular engagement with the FDA on communication, cross-border visits, or post-marketing safety frameworks remains underdeveloped.
Intertwined commercial-political signals: U.S.-China trade and tech tensions have made drug registration-a high-value, technology-intensive field-increasingly susceptible to broader policy dynamics.
Biosafety policies exacerbating institutional rifts
In January 2025, the U.S. imposed new national security restrictions on access to U.S. citizens' sensitive biological data by "countries of special concern," with China as a core target. Focused on genomic/cellular data and platform collaboration, these rules were followed by the FDA's June 2025 suspension of approvals for trials involving "sending U.S. cells to China for gene editing and reinfusion," impacting CAR-T and gene-editing collaborations. Though targeted at specific technologies, these policies have destabilized U.S.-China biopharmaceutical cooperation. The FDA now applies stricter standards to purely Chinese data, defaulting to "insufficient extrapolation" even for well-designed studies. In today's geopolitical climate, Chinese firms are seen as competitors for technological sovereignty rather than R&D partners, leading to heightened scrutiny of their data.
In January 2025, the U.S. imposed new national security restrictions on access to U.S. citizens' sensitive biological data by "countries of special concern," with China as a core target. Focused on genomic/cellular data and platform collaboration, these rules were followed by the FDA's June 2025 suspension of approvals for trials involving "sending U.S. cells to China for gene editing and reinfusion," impacting CAR-T and gene-editing collaborations. Though targeted at specific technologies, these policies have destabilized U.S.-China biopharmaceutical cooperation. The FDA now applies stricter standards to purely Chinese data, defaulting to "insufficient extrapolation" even for well-designed studies. In today's geopolitical climate, Chinese firms are seen as competitors for technological sovereignty rather than R&D partners, leading to heightened scrutiny of their data.
Chinese firms' efforts to communicate and compromise
Facing barriers, Chinese companies have sought solutions: integrating global bridging centers (e.g., in Australia, South Korea, Japan); adding external control groups, meta-analyses, and cross-population PK-PD models; and submitting additional audit and ethical evidence. Yet, for high-sensitivity areas like PD-1 drugs, anti-tumor monoclonals, and cell therapies, the FDA maintains a "high alert, high threshold, low approval" stance on Chinese-sourced data. This structural barrier means China's registration pathways depend on institutional alignment. Chinese clinical data will only be deemed equivalent once integrated into global regulatory trust networks. Notably, BeiGene's TEVIMBRA succeeded by including Japanese and South Korean sites, using third-party CROs for independent audits, and leveraging FDA-EMA joint rolling reviews-proving Chinese data can gain acceptance with pre-review trust-building.
Coalition-Building: Chinese Firms' Strategies To navigate the FDA's selective trust and high thresholds, Chinese firms must shift from "local data compliance" to "global clinical integration"-rebuilding capabilities, collaboration, and strategy.
Early multi-country parallel registration planning
The core breakthrough is integrating the FDA into registration design early, not retrofitting Chinese data. BeiGene and Zai Lab's experience shows that engaging the FDA and building foreign sites during key Phase II/early Phase III trials boosts efficiency and data credibility. For example, BeiGene's "U.S.-China dual initiation" for tislelizumab-with a U.S. R&D team, proactive pre-BLA communication, and overseas medical writing/statistics-enhanced FDA trust in data transparency.
Strengthening Sino-foreign data bridging
The FDA does not reject Chinese trials outright but requires bridging data to demonstrate U.S. applicability (*generalizability*). Chinese firms should focus on: - Multi-ethnic analyses in key PK and exposure-response models; - Bridging real-world data (RWD) with historical controls of approved peers; - Presetting "population qualifiers" in labels to reduce initial approval risks. Innovent's sintilimab rejection-due to lacking U.S. data, flawed statistics, and inadequate bridging-highlights these lessons.
Enhancing medical submission and communication
Many firms meet scientific standards but struggle with FDA engagement due to:
Poor English medical writing and CTD formatting;
Lack of familiarity with FDA divisions' (e.g., OPQ, OB) specific CMC, statistical, and labeling requirements;
Inability to present risk control and post-marketing plans in Pre-NDA/Type C meetings.
The solution is a "U.S.-led registration team" with FDA-experienced regulatory leads, collaborating with medical, statistical, and pharmacovigilance teams. Such "U.S.-China dual-headquarters hubs" are emerging among globalizing Chinese firms.
Partnering with multi-center PIs and international CROs
The FDA trusts familiar ecosystems. Collaborating with leading PIs (e.g., from MD Anderson, Mayo Clinic) and top CROs enhances data transparency, bias control, and regulatory engagement. Partnering with global patient groups, third-party IRBs, and real-time data platforms also boosts credibility.
Conclusion
The FDA's "global data window" is neither impenetrable nor easily opened. Approving "zero U.S. subject" drugs reflects responsiveness to global medical realities, not lowered standards. The FDA aims to shift from "geographical centrism" to "scientific credibility first" amid innovation, patient diversity, and resource mobility-a gradual, dynamic process balancing policy, data, ethics, and trust. For Chinese firms, opportunities exist but require more than technical compliance. Becoming co-creators of global rules demands aligning ethics with ICH, improving communication, exploring RWE mutual recognition, and participating in standard-setting. Future pharmaceutical regulation will be defined by data quality, ethics, transparency, and trust-not borders. Firms grounded locally but globally focused will lead. Through systemic upgrades, Chinese firms can establish stable "non-U.S. data + U.S. supplements" pathways, as BeiGene's tislelizumab and Junshi's toripalimab demonstrate-proving domestic innovatives can cross regulatory barriers into global markets.
References
Drug Trials Snapshots Summary Report*. FDA CDER. Retrieved July 18, 2025.
Baxter, A. FDA invites more data from abroad-with a wary eye on China. 'Pharma Voice'. July 16, 2025.
