In December 2023, Japan introduced important regulatory changes that significantly reshape global drug development strategies. Under new guidance issued by Japan’s Ministry of Health, Labour and Welfare (MHLW), drug developers will now be allowed to include Japanese subjects in their multi-regional clinical trials (MRCT) without first conducting a stand-alone Japanese Phase I study, provided that they obtain an agreement from the Pharmaceuticals and Medical Devices Agency (PMDA) and adhere to additional restrictions. The revised framework is intended to tackle the drug lag in Japan while maintaining appropriate protection for patient safety.

Requirement for Japanese Phase I Studies

In the past, it was mandatory for drug sponsors to conduct a separate Phase I study in Japanese subjects before including them in an MRCT. This was to ensure that no significant differences in safety or pharmacokinetics (PK) existed between Japanese and non-Japanese populations. The Japanese regulatory authorities were concerned that ethnic factors, such as genetic polymorphisms, metabolic pathways, or differences in body weight, could influence drug exposure and safety. Therefore, early confirmation in Japanese patients was generally required before joining global trials.

However, over time, this requirement became challenging for sponsors. They often needed to allocate additional time and resources to conduct a Japanese Phase I study, which could significantly delay Japan’s inclusion in global programs. Ultimately, this resulted in the issues of drug lag and drug loss – delaying Japanese patients’ access to new drugs approved overseas (usually by the US FDA or EMA).

Overview of the December 2023 Notification and Guidance

In late December 2023, new guidance from the MHLW clarified when a Japanese Phase I study might be waived for drugs with early clinical development outside of Japan. The updated framework clarifies that a standalone Japanese Phase I study is not always required before inclusion in an MRCT. Instead, PK comparisons between Japanese and non-Japanese populations will need to be adequately addressed before submission of the Japanese New Drug Application (J-NDA), instead of before Japanese participation in global trials.

The PMDA’s Notification explains that the decision to waive a Japanese Phase I study should primarily depend on two considerations: 1. the safety profile of the study drug and 2. the potential impact of ethnic factors. If safety can be adequately demonstrated and deemed clinically acceptable for Japanese participants based on available nonclinical and foreign clinical data, and if ethnic differences are unlikely, a Phase 1 waiver may be possible.

The necessity for a Japanese Phase I study must be carefully evaluated on a case-by-case basis. Key issues that will be considered include the drug’s risk profile, sensitivity to ethnic factors, medical demand, and the potential disadvantage of excluding Japanese patients from MRCT participation.

Safety Considerations Supporting a Waiver

Regarding the safety issue, the PMDA indicates that a waiver may be appropriate when nonclinical results do not suggest significant risks with unclear mechanisms at the MRCT dose. Specifically, the maximum dose planned for the MRCT should have a sufficient safety margin. Additionally, earlier foreign clinical studies should not have identified clinically significant risks at relevant exposure levels.

In addition, sponsors should establish clear monitoring strategies to mitigate potential risks within the MRCT. If similar drugs, such as those with the same active pharmaceutical ingredient (API), the same mechanism of action (MOA), or biosimilars, have not demonstrated clinically significant safety concerns, their data may be utilized to further support the safety evaluation.

Evaluation of Ethnic Factors

Another important consideration is the potential impact of ethnic factors on pharmacokinetics and safety. Ethnic differences are less likely to be clinically significant when the drug exhibits linear PK (direct proportionality between the dose administered and drug exposure) and when it is either poorly metabolized or processed through multiple metabolic pathways. Drugs that are minimally absorbed systemically and act locally may also be less likely to show ethnic sensitivity. Furthermore, prior multinational clinical trials that show no meaningful impact of race, region, or body weight on PK or safety can provide supportive evidence that ethnic factors are unlikely to alter the drug’s clinical profile.

When a Japanese Phase I Study Should Be Considered

Despite this December 2023 guidance, a Japanese Phase I study should still be carefully considered in certain circumstances. For drugs with frequent serious adverse events or a narrow therapeutic window (such as certain oncology drugs), greater caution is warranted. If there is a large potential patient population for the drug in Japan, a Phase I study may be feasible and also provide important information for further studies. If there is insufficient data to conclude that there is acceptable safety for Japanese subjects, then sponsors are strongly encouraged to speak with the PMDA to identify the appropriate next steps.

Additional Safety Measures in MRCTs

If a Japanese Phase I study is waived, the PMDA expects additional participant safety measures to be implemented. Examples include establishing a small Japanese cohort to evaluate safety before enrolling larger numbers of participants in the MRCT. In some cases, dosing may be staggered. For example, administering the investigational product to one Japanese participant at a time with appropriate intervals before proceeding with more participants.

Sponsors may also increase the frequency of visits and safety monitoring during the early stages of administration. In certain cases, Japanese participants may be hospitalized or observed at the study site for a certain period after initial dosing to allow close monitoring. These measures are particularly relevant when there are limited data.

Regulatory Process for Waiver

If a Phase 1 waiver appears justified, a formal consultation with the PMDA is required to obtain formal agreement on waiving a Japanese Phase 1 study. The consultation should discuss the scientific rationale, safety assessment, consideration of ethnic factors, and any proposed additional safety measures. Once agreement is obtained, a Clinical Trial Notification can be submitted, and Japanese participants may be enrolled in the MRCT.

Please note that in some cases, the PMDA may still request a Japanese Phase 1 study or require additional safeguards despite a strong justification for the Phase 1 waiver.

Conclusion

The December 2023 guidance represents a meaningful shift toward a less stringent regulatory approach. A standalone Japanese Phase I study is no longer automatically required prior to inclusion in global MRCTs. As a result, this change offers an opportunity to integrate Japan into global development programs earlier and more efficiently. At the same time, Japan maintains its strong emphasis on protecting patient safety through careful case-by-case assessment and close regulatory oversight by the PMDA.