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

 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.

survival (OS) remains the gold standard for demonstrating clinical benefit in oncology clinical trials.

 However, OS is also the clinical end point that takes the longest time to mature and can extend drug development timelines significantly.

 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.

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.

 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.

 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.

 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.

 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.

 SAF-189s had already demonstrated robust efficacy in the randomized phase 3 REMARK trial (NCT06569420) conducted in China, significantly prolonging PFS (HR, 0.23, 

 < .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.

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,

 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.

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Articles

Bridging studies are crucial for translating Chinese drug development data to meet US regulatory standards, particularly in oncology. The selection of clinical endpoints, such as overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), plays a pivotal role in these studies. While OS is the gold standard, it can delay timelines. ORR offers a quicker assessment and can be pivotal in bridging studies when robust foreign data exists. The SAF-189s case exemplifies how strategic endpoint selection can expedite US market entry, highlighting the FDA's openness to endpoint innovation.

Evan S. Wu, MD, PhD, delves into the one of the most pivotal aspects of designing a successful bridging study: the selection of clinical end points.

Choosing Clinical End Points in China for US Bridging Studies

Translational researchers in drug development focus on advancing new therapeutics based on preclinical laboratory findings using animal models. This lengthy and costly process often spans several years before a drug candidate progresses from preclinical to first-in-human studies. Enter China. The recent tsunami of drug candidates successfully trialed in humans in China at a blistering pace is creating a new definition of translational research in the United States, one where clinician-scientists are translating early-phase data from China to a US population.

In this 3-part monthly series, I will explore key (and controversial) issues surrounding the translatability of Chinese drug development data to a US population, including the novel concept of bridging studies, the selection of end points in China-to-US translational studies, and racial/ethnic differences in drug metabolism.

In 2024, China accounted for an astonishing 23% of global drug candidates, second only to the United States.

 The number of oncology drugs developed in China has steadily risen since the launch of the “Made in China 2025” strategic plan in May 2015, with record levels being reported in 2024 and even higher numbers forecasted for 2025.

 This initiative aimed to position China as a global manufacturing leader, targeting the industrialization of 20 to 30 innovative drugs by 2025. As of March 2025, the Chinese initiative has well superseded its goal. The success of Chinese drug developers can be attributed to their ability to move rapidly and at a lower cost compared with US counterparts due to competitive advantages in staffing and supply chains.

 Biotech start-ups in China can go from launch to first-in-human data reporting in 18 months or less, compared with a few years in the US.

However, nothing in life is without controversy, and the question of transcontinental applicability looms large. The FDA has historically rejected China-developed cancer drugs when they have been trialed exclusively in China. Geopolitical considerations aside, previous research has shown that racial and ethnic differences can affect the maximum tolerated dose (MTD) in phase 1 clinical trials. For example, studies conducted in Japan have shown differences in MTD for cytotoxic and targeted anticancer drugs between Japanese and Western populations, attributed to both intrinsic and extrinsic ethnic factors.

How do we bridge the gap? The innovative concept of bridging studies plays a crucial role in demonstrating the translatability of China-only early-phase clinical trials to a Western population.

 With an increasing share of new drugs originating in China, bridging studies are becoming an integral part of US drug development. Although the goal of oncology drug development is to improve the quantity and quality of life for patients with cancer, the reality is that biotech firms face immense pressure to bring drugs to market as swiftly and efficiently as possible. Bridging studies accelerate global drug approval by supplementing existing data with region-specific findings. Successful bridging studies that prove translatability from China to the US must enroll a diverse US population including Black and Hispanic patients, show pharmacokinetic (PK) and pharmacodynamic similarities across racial/ethnic groups, and confirm that efficacy and safety align with those observed in the original study. These elements are crucial for a bridging study to achieve the ultimate goal of a successful biologics license application with the FDA.

As coprincipal investigator of the Henlius-sponsored, phase 3 ASTRIDE clinical trial (NCT05468489) for small cell lung cancer (SCLC), I have had firsthand experience with the complexities of bridging studies. The ASTRIDE trial seeks to demonstrate the applicability of data from the global but China-majority phase 3 registrational ASTRUM studies to a US-only population. ASTRUM-004 (NCT04033354) and ASTRUM-005 (NCT04063163) successfully established that the PD-1 inhibitor serplulimab, in combination with chemotherapy, improved overall survival (OS) and progression-free survival in patients with advanced squamous non–small cell lung cancer and extensive-stage SCLC, respectively, compared with chemotherapy alone.

 Despite the inclusion of 31% White patients from Europe in ASTRUM-005,

 the FDA raised concerns due to the absence of US participants and the lack of representation from Black and Hispanic populations in the registrational study. In response, the FDA recommended that Henlius collect additional data to demonstrate the relevance of ASTRUM’s findings to US patients. After careful deliberation and design consideration, the ASTRIDE bridging study was conceived. This 2-arm descriptive study would enroll 100 patients per arm, with one group receiving serplulimab plus chemotherapy and the other receiving atezolizumab (Tecentriq) plus chemotherapy.

The success of bridging studies such as ASTRIDE depends on leveraging previously reported clinical trial data. The FDA approved the descriptive study design for ASTRIDE, rather than a superiority study, because the global ASTRUM trials had already validated the efficacy and safety of serplulimab plus chemotherapy in a large, non-US cohort. The primary objective of ASTRIDE is to confirm the applicability of ASTRUM’s findings to the US patient population by demonstrating similar safety, efficacy, and PK data, without the aim of proving statistical superiority or noninferiority. Although the concept of a descriptive bridging study may seem unconventional to clinical trial purists, the rapid pace of Chinese drug development and the FDA’s commitment to providing the US population with the most effective therapies available globally serve as motivating drivers for this flexible study design.

In the next article, I will examine the challenges associated with clinical end point selection and trial design in bridging studies, particularly in cases where preexisting data are limited to Chinese patients or when OS is not a logistically feasible end point for cancers with a favorable prognosis. I will explore the most efficient strategies for translating data from China to the US in these more complex scenarios.

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

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China's rapid drug development, particularly in oncology, is reshaping translational research by providing early-phase data for US populations. Bridging studies are crucial for translating Chinese clinical trial data to the US, addressing racial and ethnic differences in drug metabolism. The ASTRIDE trial exemplifies this approach, aiming to validate the applicability of Chinese data to US patients. Despite challenges, such as FDA concerns over diverse representation, bridging studies offer a pathway to accelerate global drug approval, ensuring effective therapies reach diverse populations efficiently.

In a 3-part series, Evan S. Wu, MD, PhD, will explore key issues surrounding the translatability of Chinese drug development data to a US population.

Evan S. Wu, MD, PhD

Articles

Choosing Clinical End Points in China for US Bridging Studies

Redefining Translational Research and China’s Impact on US Drug Development