Choosing Clinical End Points in China for US Bridging Studies

Evan S. Wu, MD, PhD

In the first installment of this 3-part series on the translatability of Chinese drug development data to US regulatory standards, we discussed bridging studies, which are clinical trials designed to assess whether data generated outside the US can be considered applicable to a US population. These studies typically feature a condensed trial design incorporating patients in the US to confirm the efficacy and safety of an investigational therapy within the US health care and demographic context.

This second article delves into one of the most pivotal aspects of designing a successful bridging study: the selection of clinical end points. Specifically, we explore end point selection as it relates to regulatory acceptability in oncology drug development. As drug developers strive to bring promising therapies to market, the choice of end point can accelerate or, in some cases, delay approval.

Overall survival (OS) remains the gold standard for demonstrating clinical benefit in oncology clinical trials.1,2 However, OS is also the clinical end point that takes the longest time to mature and can extend drug development timelines significantly.1 In scenarios where a robust phase 3 trial has already demonstrated an OS advantage, such as in a China-only study, the question becomes whether those data can be leveraged to develop an expedited US bridging study. If so, what additional data are needed from a US cohort to satisfy the FDA’s evidentiary standards?

From a regulatory perspective, bridging studies are not meant to repeat the large registrational study, but instead, investigators use them to confirm consistency of efficacy and safety in a representative US population. This opens the door to consideration of alternative end points apart from OS, such as progression-free survival (PFS)and objective response rate (ORR). Although PFS is widely accepted as a surrogate end point in oncology trials, its use in bridging studies presents unique challenges, particularly due to the constancy assumption.3 This assumption assumes that the treatment effect remains stable over time. In other words, PFS HRs assume that the treatment effect between the intervention and control groups are the same at 3 months, 6 months, 12 months, and the end of the study.3 This assumption can be problematic in many oncology trials involving immunotherapy or targeted therapies, where PFS curves often exhibit delayed separation or varying slopes over time. Additionally, PFS can be confounded by differences in imaging schedules, assessment frequency, and clinical practice patterns.4 These limitations make interim PFS analyses potentially unreliable and challenge the interpretability of short-term data from small US bridging cohorts.

In contrast, ORR provides a more immediate, binary assessment of tumor response, typically based on RECIST criteria.5 ORR is not dependent on time-to-event analyses and can be evaluated early, making it well-suited for use in abbreviated bridging studies, especially when prior larger registrational trials have already demonstrated durable PFS and OS benefits.5 Although ORR alone is generally insufficient for regulatory approval, in the context of bridging studies where comprehensive efficacy data already exist, it may provide additional safety and efficacy data in a US population to show global consistency leading to FDA approval.

A recent example of this approach involves SAF-189s, a next-generation ALK/ROS1 inhibitor developed by Fosun Pharma/Henlius Biotech.6,7 SAF-189s had already demonstrated robust efficacy in the randomized phase 3 REMARK trial (NCT06569420) conducted in China, significantly prolonging PFS (HR, 0.23, P < .0001) and reducing the risk of central nervous system progression by 96% compared with crizotinib (Xalkori) in treatment-naive patients with ALK-positive NSCLC. The trial also showed a compelling OS signal.6

I was approached by Fosun/Henlius to assist in developing a US bridging study. The sponsor initially proposed PFS as the primary end point. However, in discussions with the FDA, concerns were raised about the validity of early interim PFS data, given the statistical challenges related to the constancy assumption. The FDA allowed ORR to serve as the primary end point for the bridging study based on the robust data from the REMARK trial (ORR, PFS, OS, safety) and recognition that interim PFS analyses could be misleading due to time-dependent variability. The ORR data from a proposed US cohort in a future study, in combination with OS and PFS results from the REMARK trial,6 were deemed sufficient to demonstrate consistency of efficacy and safety. By allowing ORR to serve as the pivotal end point, the FDA demonstrated flexibility and scientific pragmatism in its regulatory decision-making, underscoring different strategies for global oncology drug development.

The SAF-189s case highlights the ever-changing landscape in global drug development. In bridging studies, especially those involving highly active anticancer therapeutics with clear OS signals outside the US, using a short-term end point such as ORR can: (1) reduce the time needed to generate confirmatory data in the US by leveraging clinical data from outside the US, and (2) avoid statistical pitfalls associated with early PFS readouts.

In conclusion, bridging studies are an increasingly common strategy for global oncology drug development, especially for Chinese sponsors seeking US market entry. End point selection in these studies is not merely a technical decision: It is a clinical and regulatory strategy that can influence timelines, approval pathways, and patient access. As demonstrated in the SAF-189s experience, a thoughtful approach that pairs robust foreign data with a clinically meaningful, efficient US end point can satisfy regulatory requirements while expediting development. The FDA is open to end point innovation, particularly when paired with data from large clinical trials outside the US.

In the third and final installment of this series, we’ll explore operational execution in China-to-US bridging studies, including site selection, cultural barriers, and timelines to ensure successful trial delivery.

Evan S. Wu, MD PhD, is an assistant professor at the University of Hawai’i Cancer Center in Honolulu.

References

1. Delgado A, Guddati AK. Clinical endpoints in oncology - a primer. Am J Cancer Res. 2021;11(4):1121-1131.
2. Kilickap S, Demirci U, Karadurmus N, Dogan M, Akinci B, Sendur MAN. Endpoints in oncology clinical trials. J BUON. 2018;23(7):1-6.
3. Clinical trial endpoints for the approval of cancer drugs and biologics guidance for industry. FDA. December 2018. Accessed June 13, 2025. https://www.fda.gov/media/71195/download
4. Pasalic D, McGinnis GJ, Fuller CD, et al. Progression-free survival is a suboptimal predictor for overall survival among metastatic solid tumour clinical trials. Eur J Cancer. 2020;136:176-185. doi:10.1016/j.ejca.2020.06.015
5. Mushti SL, Mulkey F, Sridhara R. Evaluation of overall response rate and progression-free survival as potential surrogate endpoints for overall survival in immunotherapy trials. Clin Cancer Res. 2018;24(10):2268-2275. doi:10.1158/1078-0432.CCR-17-1902
6. Xiong A, Yang N, Dong X, et al. Randomized, open-label, phase III study of SAF-189s versus crizotinib in first-line ALK-positive advanced non-small cell lung cancer (NSCLC). Presented at: IASLC 2024 World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract OA09.03
7. Yang JJ, Zhou J, Cheng Y, et al. SAF-189s in advanced, ALK-positive, non–small cell lung cancer: results from a first-in-human phase 1/2, multicenter study. J Clin Oncol. 2022;40(suppl 16):9076. doi:10.1200/JCO.2022.40.16_suppl.9076