Leveraging EX-US Data for US Development

Introduction

When a drug is initially developed outside the US, with clinical studies conducted overseas and US marketing approval as a goal, expanding the clinical development program to the US requires careful planning.  Beyond meeting US approval requirements, it is essential to ensure that the data are applicable to US patients and medical practice. This includes establishing a robust plan to address population differences and to ensure that clinical findings are applicable to US patient populations and medical practice.

Transitioning from an ex-US program to a US program or including the US as part of global development demands a tailored, risk-based approach rather than a one-size-fits-all solution. Several key aspects must be considered:

• Development Stage and Existing Data: The current development phase and the data collected so far, along with the integration strategy for foreign data.
• Nature and Cass of the Product: The product characteristics, including whether it is a small molecule, monoclonal antibody (mAb), or cell & gene therapy and others, its metabolic pathway, and the known intrinsic and extrinsic factors—such as ethnic, racial, and genetic differences, as well as treatment/environment variations—that may influence drug response across populations (e.g., Asian vs. non-Asian groups) for the class of drug.
• Indications Related: the target indication, unmet medical need, treatment landscape, patient population, prognosis, access to care, and standard-of-care practices differences between the US and other countries.
• Available Information: The known safety, efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and therapeutic window data of the study drug and class of drugs.
• Purpose of the US Study: The objective of the US study and the identification of foreign data (e.g., safety, efficacy, PK/PD data) to support the study and inform the development program.
• Regulatory Approval Pathway: The regulatory pathway for approval, such as NDA, BLA, 505(b)(2), ANDA, or biosimilar, each with its own requirements and regulatory considerations.

To effectively plan the strategy, it’s essential to understand the drug development process and the types of data collected at each stage. Although clinical development plans vary for each drug and indication, a general framework for a drug development process may include Phase 1, Phase 2, and Phase 3 studies.

In Phase 1, the common focus is understanding the preliminary safety profile of the drug relative to the doses administered.  At the same time, these studies—including clinical pharmacology components— can also make important contributions to the company’s preliminary understanding of efficacy, PK, PD and early dose-response relationships.  Phase 2 continues to explore these areas more extensively, often incorporating proof-of-concept and dose-finding/ranging studies. The primary objective is to further evaluate safety and efficacy, continue exploring PK, PD, and dose/exposure–response relationships, and identify the optimal dose or dosing range for use in pivotal trials. These studies also generate critical data to inform the design of pivotal studies. Pivotal trials (e.g., Phase 3, and some phase 2) aim to confirm the safety and efficacy of the drug at established doses in a larger population to support a marketing application. Pivotal trials are known to be the most time-consuming and costly stage of drug development, emphasizing their critical role in the overall process.

Pivotal trials are conducted to demonstrate that a study drug is safe and effective when used as directed across the intended patient population. In the US, this presents unique challenges due to the country’s exceptional genetic diversity, stemming from successive waves of immigration and the intermingling of different ancestral populations. This has resulted in a wide range of genetic profiles that must be taken into account when evaluating drug response.  The FDA recognizes that drug safety and efficacy cannot be fully characterized within a single genetic or geographic population. Differences across regions—such as underlying risk factors, treatment landscapes, healthcare access, socio-cultural factors, and other intrinsic (e.g., age, race, body weight, disease stage) and extrinsic (e.g., smoking status, diet) factors—can also significantly influence drug response. As such, pivotal trials conducted exclusively in a non-US region are generally insufficient to support US marketing approval unless the sponsor can demonstrate that the data are applicable to the US patient population and US medical practice.

Sponsors who initiate a US regulatory strategy late in development – especially during or after pivotal – often face significant challenges. By that stage, the study design, enrolled population, and data may no longer be aligned with FDA expectations, making it difficult to demonstrate relevance to US patients and medical practice. If a company plans to seek US regulatory approval, it’s imperative to plan for a representative population early on. While foreign data are not automatically excluded, reliance on such data alone for approval is likely to be problematic. However, the FDA does offer some flexibility. If multiple pivotal studies are planned, data from one region can be bridged with results from other trials to support their applicability to the US patient population.

When a sponsor has obtained clinical data from outside the US, a key question becomes how to effectively leverage those data to advance US clinical development. In practice, the approach will depend on the quantity and quality of the available information, as well as the clinical stage of development. While strategies may vary case by case, a core principle is to prioritize patient safety while maximizing the utility of existing data – including PK, PD, safety, efficacy, and dosing information – and to assess these data in the context of whether differences in factors (e.g., intrinsic, extrinsic, or risk factors) may impact their relevance or interpretation. When uncertainties exist regarding the extrapolation of foreign data to the US population, a PK/PD bridging study may be warranted; however, the need for such a study is determined on a case-by-case basis. Ultimately, the goal is to ensure that the data is applicable to US patients and consistent with US medical practice.

A few examples are presented that showcase different strategies for drugs at various stages of development, demonstrating how to effectively leverage that data.

Case Studies

1. Case 1. Ongoing Phase 1

The first case involved a client whose Phase 1 dose escalation study in China was currently underway. We proposed a US IND study that integrates the US study into the ongoing dose escalation trial in China. The dose escalation study in China had reached a dose level which had already been confirmed as safe. We proposed that the US study begin at one dose level below the level confirmed in the China trial. This approach ensured that, even if differences existed between the US and Chinese populations, participant safety in the US would be assured by starting at a lower dose level (of course, it’s important to assess whether reducing the dose level further is needed based on specific circumstances). In this case, we did not propose a PK bridging study.  As long as the trial continues, we can collect safety, efficacy, and PK/PD data from both populations. We will then compare the results to determine whether the two populations show consistent outcomes and, if not, the extent of any discrepancies.  This plan was acceptable to the US FDA.

1. Case 2. End of Phase 1

The second case involved a client who had completed a Phase 1 dose escalation study outside of US. They did not wish to repeat the dose escalation study in the US, and we also believed it was not necessary to start the dose escalation process from scratch.  Therefore, we proposed a simplified US dose escalation study. This study included only two dose levels, starting with a dose that was one step below the previously confirmed safe dose level. This approach ensured the safety of US participants. As in the previous case, we did not propose a PK bridging study. Following this trial, we can subsequently compare the PK/PD and safety/efficacy data between the two populations.  

Based on our experience, if the dose selected for the US trial is significantly lower than the maximum tolerated dose (MTD) established or a well confirmed dose in the outside of US study, such a small dose escalation study may not be necessary. 

1. Case Study 3 – End of Phase 2

In the third case, the client’s clinical progress was more advanced compared to the first two. They had completed Phase 2 studies outside of US and were prepared to move on to Phase 3. As we discussed earlier, an important aspect at Phase 2 stage is identifying one or more doses for the final Phase 3 trials. It is essential to ensure that the doses derived from the ex-US studies are also applicable to the US population. To address this, we proposed a small PK bridging study to confirm the consistency of the dosing.  Following this, the company planned to proceed with an international multi-center Phase 3 clinical trial.  This plan was also acceptable to the US FDA.

1. Case Study 4 – End of Phase 2

In another case, although the client’s program was also at the end of Phase 2, the dose was well-defined during the Phase 2 study. Unlike the previous example, this drug belongs to a well-known class, and there were minimal concerns about differences in safety, efficacy, and PK/PD across populations. Therefore, the company proposed beginning their Phase 3 study directly in the US, relying solely on prior data obtained from outside the US. Early monitoring of a safety PD biomarker was incorporated into the study design to protect patients in case the biomarker levels exceeded a safe threshold.

1. Case Study 5 – Ongoing Phase 3

A recent successful case involves a client currently in the middle of a phase 3 study outside of the US. The client plans to expand their study to include US sites as part of the phase 3 study and has obtained a successful IND. The success of this IND was achieved through the client’s study plan, which included enrolling an adequate number of US patients to ensure the study reflects the US population. Additionally, the control arms used in both the US and outside of the US were selected consistently or justified to be consistent to ensure uniform comparisons.  The sponsor previously conducted a phase 1 study in the US, which helped justify that there are no significant differences in PK and PD among different populations.

1. Recommendations

Begin with the End in Mind: The ultimate goal is to ensure that clinical data are applicable to US patients and medical practice. Therefore, it is critical that pivotal clinical trial data (e.g., Phase 3) are relevant to the US patient population and current medical practices. For products seeking US approval, in addition to conducting studies solely in the US, participation in global multicenter Phase 3 trials that include US sites can be an efficient and effective approach. In contrast, the FDA has declined approval for several drugs studied solely outside the US. For example, Eli Lilly and Innovent’s PD-1 inhibitor sintilimab was rejected in 2022 because its pivotal trial was conducted only in China. Similarly, Hutchmed’s application for surufatinib in pancreatic and extra-pancreatic neuroendocrine tumors (NETs) was also rejected due to reliance on pivotal data exclusively from ex-US studies. It’s also important to note that, to design effective global Phase 3 trials, early data collection prior to Phase 3 is crucial for assessing potential differences among populations.  Early-stage studies – such as pharmacokinetic, pharmacogenomic, dose-finding, and activity-estimating studies – should ideally be conducted in populations that reflect the intended regions to be represented in the trial. These studies can help identify early signals of differential drug effects across the population. When a sponsor already has ex-US clinical data, strategies for leveraging those data may vary. However, a consistent guiding principle is to prioritize patient safety while maximizing the utility of existing information – including PK, PD, safety, efficacy, and dosing data.

The FDA has recently halted new clinical trials involving the export of Americans’ living cells to foreign laboratories in “hostile” countries for genetic engineering and subsequent reinfusion into U.S. patients. This may affect the sponsor’s development plan if relevant, and we recommend that the sponsor take this into consideration and adjust their development strategies accordingly.

The FDA encourages sponsors to engage with the relevant review division as early as possible in development. Therefore, meeting with the FDA at the earliest feasible opportunity is strongly recommended. Depending on the development stage and therapy area/indication, the sponsor may also consider the feasibility of leveraging specific regulatory or development programs (e.g., expedited pathways, rare disease programs, Project Orbis) to facilitate the timely discussions with the Agency.

1. Other Important Considerations
   1. Study Conduct and Data Quality

Finally, it is important to ensure that clinical data obtained outside the US are of high quality and that the studies are well-designed and properly conducted. Sponsors should engage with FDA early to align with the agency on whether, and how, such data can be used to support the US development program.

1. Dose Optimization

In the context of international clinical studies, a common challenge faced by clients is the FDA’s increasing emphasis on dose optimization for the development of cancer therapies. The FDA may require sponsors to conduct a dose randomization study to optimize dosing following Phase 1 dose-escalation studies.

Due to differing requirements across regulatory authorities, many ex-US sponsors face challenges in meeting FDA expectations. Although their existing data may include hundreds of patients, it often comes from a single dose group—typically insufficient to demonstrate that the dose has been optimized. Without dose optimization, patients may be exposed to unnecessarily high doses with increased safety risks or to suboptimal doses that may fail to achieve sufficient efficacy.

1. Topic Summaries

The key points regarding the strategy for leveraging clinical data from outside of US are:

• Customized Approach: There is no universal strategy for leveraging clinical data; each plan should be tailored to the specific circumstances of the drug and its development.
• Understanding Development Strategies: A throughout understanding of the drug’s clinical development strategy and common practices for similar drugs and indications is essential.
• Safety First: Prioritize patient safety while maximizing the utility of the data you have already collected.
• Timing Matters: Engaging in a global Phase 3 study can be an efficient approach for streamlining the approval process
• Regulatory Compliance: Be mindful of the FDA’s specific requirements, particularly regarding dose optimization.

Ultimately, it is crucial to ensure that the data are applicable to US patients and medical practice.  Starting the global development program early and conducting preliminary studies in broad populations will greatly aid in designing effective global Phase 3 studies. This will not only meet regulatory expectations but also enhance the relevance of findings for various patient demographics, supporting the successful approval of products in the US, EU, and broader global markets.

The author would like to thank Brian Mayhew and Kathleen B. Retterson for their extensive review of this paper.