New MHLW Guidance Aims to Facilitate Inclusion of Japanese Participants in Global Clinical Trials
Mayumi Hasegawa, PhD Senior Director, Drug Development Solutions, Certara
Previously, sponsors had to conduct additional phase 1 studies with Japanese participants before Japan could be included in global clinical trials. This approach delayed approval of new medicines in Japan. With its new guidance, MHLW is endeavoring to expedite drug development by removing this step for drugs where early clinical development is preceding outside Japan.
On September 13, 2023, the Ministry of Health, Labour and Welfare’s (MHLW’s) "Study Group on the Drug Regulation System to Enhance Drug Discovery and Ensure Stable Supply" agreed that "there is no need to conduct additional phase 1 studies on Japanese [participants] before the start of global clinical trials" for products whose development has already been advanced overseas. However, the committee also notes that "it is desirable to collect information on pharmacokinetics (PK) in Japanese [participants] as much as possible.” There had been cases where Japan alone was required to conduct additional phase 1 trials, which proved disadvantageous because it prevented the country’s participation in some global joint clinical trials. To minimize these disadvantages, while also ensuring the safety of Japanese participants in international joint clinical trials, the Ministry issued a new notification on December 25, 2023, entitled “Basic principles for conducting phase 1 studies in Japanese prior to initiating multi-regional clinical trials [MRCTs] including Japan for drugs in which early clinical development is preceding outside Japan.”1 This announcement also repealed the 2014 notification entitled “Basic Policy on Conducting Phase 1 Clinical Trials in Japanese Patients Prior to the Start of Global Clinical Trials.”2 In addition, it removed the requirement to obtain both PK and safety data in Japanese participants to compare with non-Japanese before global clinical trials, which was described in the #Notification No.0928010 issued by MHLW in 2007.3 Furthermore, the notification "Basic Approach to International Clinical Trials (Reference Examples)" (MHLW, Pharmaceutical and Food Safety Bureau, September 5, 2012)4 was updated as follows:
1) What are the general points to consider in comparing PK data between different ethnicities?
In general, it is recommended that interethnic PK comparison is based on data collected according to the same protocol including measurement methods etc. (also applies to studies conducted separately) to minimize variations caused by non-intrinsic ethnic factors. If genetic variation in metabolic enzymes or transporters is expected to affect the PK of the investigational drug, genetic tests should be performed in the clinical trial to examine the incidence of genetic variation in different ethnicities and the PK-genotype relationship. If no PK data are available from Japanese and non-Japanese participants included in studies conducted under the same protocol, collection of PK data is recommended in consideration of the characteristics of the drug at several time points in the major ethnic groups to be included in a confirmatory trial, at least before submission of [a new drug application] an NDA (previously “initiating a global confirmatory trial”).
2) When only a monotherapy study of an investigational drug was conducted in Japan, is it possible for the drug to be used in an exploratory global clinical trial including Japan investigating its combined treatment with Drug A?
Previously, data on the investigational drug in Japanese participants who had received the combination therapy with Drug A was needed before their participation in a global clinical trial. In addition, only when the dose of Drug A had been used in patients in Japan and its safety had been established, could a global clinical trial for the combination therapy be initiated. This description has been replaced by the statement that “In principle, if it is considered that there is no risk of increased safety risks associated with the concomitant administration of Drug A based on the results of non-Japanese clinical trials, it is possible for Japan to participate in global clinical trials investigating its combined treatment with Drug A without conducting a study for the combination therapy in Japan prior to Japan’s participation.”
It should be noted that the new notification1 is intended for drugs in which early clinical development is preceding outside Japan. In recent years, there has been an increase in the number of innovative drugs, mainly those developed by emerging biopharmaceutical companies, which are in advanced clinical development overseas. To keep Japan up to speed with these developments, Japan's participation in MRCTs has been considered in an increasing number of cases. The participation of Japanese patients in a global clinical trial has a significant impact on the drug’s potential approval in Japan.
The new guidance1 says: “In general, it is not mandatory to conduct a phase 1 study in each race/ethnicity or country/region before initiating MRCTs. In principle, an additional phase 1 study in Japanese is not needed unless it is deemed necessary after assessing whether the safety/tolerability of the dosage to be evaluated in the MRCTs in Japanese participants can be explained and the safety is clinically acceptable/manageable based on the data available prior to Japan’s participation.”
However, the Pharmaceuticals and Medical Devices Agency (PMDA) recommends conducting a phase 1 study in Japanese participants when the number of target patients in Japan is large and there is sufficient time to conduct a phase 1 study in Japanese prior to the MRCTs.
The justification for the recommended dose regimen in Japanese participants for MRCTs should be established based upon pooled data from non-clinical studies, non-Japanese clinical studies, and ethnic sensitivity consideration.
Japan can participate in MRCTs without conducting a phase 1 study in Japanese provided appropriate informed consent is obtained for drugs with high unmet medical needs, such as drugs for rare diseases, diseases that are refractory and serious, or pediatric regardless of whether the drug is developed in adults, where participation in planned or ongoing MRCTs are considered desirable to develop the drug in Japan.
Regulatory Approvals
In FY2022, 32 drugs containing new active ingredients (excluding vaccines) were approved in Japan. Of these, 21 products were approved based on an MRCT as a pivotal study, and there were two products (vosoritide and cabotegravir/rilpivirine for chondrodysplasia and HIV-1 infection, respectively) where no Japanese phase 1 studies were conducted.5 In addition, there were three approved medicines in FY2022 whose pivotal studies were domestic studies and for which Japanese phase 1 studies were not conducted: pegvaliase for phenylketonuria, cholic acid for inborn errors of bile acid metabolism, and immunosuppressant anti-human thymocyte immunoglobulin for aplastic anemia.
The reasons why Japanese patients were recruited to the registrational clinical trials without first conducting Japanese phase 1 studies included the fact that the disease had a high medical need, there was a limited number of patients, and the phase 3 trials were planned to give sufficient consideration to the safety of the Japanese population. All five products had been designated as orphan drugs. For the 32 approved medicines, no clinically meaningful differences in PK between Japanese and non-Japanese participants have been reported based on phase 3 clinical data.
However, this does not mean that all orphan drugs and pediatric drugs do not need to have Japanese phase 1 studies. That will ultimately be determined based on the characteristics of each drug and the available scientific data. For example, with anticancer drugs, which are expected to cause a high frequency of serious adverse events, have a narrow safety margin, and where there is limited safety information, (e.g., there is no experience of administration in Japanese patients of any age or indication), whether a Japanese phase 1 study is necessary should be judged more carefully.
What points should be considered to determine whether the safety of Japanese participants is clinically acceptable and manageable in MRCTs?
The MHLW Q&A6 says the risks of the study drug should be comprehensively examined (see points 1 and 2 below), to confirm whether there is a possibility that the risk for Japanese participants is greater than that for non-Japanese participants. If so, it must be determined whether the safety considerations for Japanese participants in the MRCT are clinically acceptable and manageable in the proposed dosing regimen.
1) Safety of study drug
• The results of non-clinical studies suggest no significant risk with an unclear mechanism of onset at the dose used in the MRCT.
• The maximum dose used in the MRCT has a sufficient safety margin, and no clinically significant risks have been identified in the preceding foreign clinical trials.
• There are clear approaches and monitoring methods for mitigating potential risks and the potential risks are manageable by defining appropriate measures/monitoring in the MRCT.
• No clinically significant risks that increased in incidence or severity dose-dependently have been identified in the preceding foreign clinical trials.
• When there are similar drugs which can be used as a reference in the safety evaluation, no clinically significant risk of the study drug is anticipated from the safety data of those drugs.
2) Effect of ethnic factors on study drug
• Ethnic differences in PK are unlikely based on comprehensive considerations
• The drug has characteristics that make the safety and PK unlikely to be affected by ethnic factors.
• There is no significant impact of ethnic factors such as race, region, body weight on the safety or PK based on previous clinical trial(s) in which the drug has been administered in multiple races/regions, or participants covering a wide range of body weight.
• When there are similar drugs which can be used as a reference in a safety evaluation, no clinically significant ethnic differences in the safety are observed with those drugs, and the same is anticipated for the study drug.
Recruiting Japanese Patients
When sponsors are starting to recruit Japanese patients into a registrational MRCT without conducting a local phase 1 study in Japanese participants, what additional measures can be taken to ensure their safety? Q&A guidance5 says safety measures differ depending on the characteristics of each study drug. The appropriate safety measures should be selected based on prior information about the drug, the study design, and how those additional measures could affect the safety evaluation.
In many registrational MRCTs in oncology, a safety-lead-in cohort has been set up to evaluate the safety and intensive PK of a small number of Japanese patients (usually three or six participants) prior to the main part of the study. In these cases, this safety-lead-in cohort serves as a “mini-phase-1-study in Japanese [participants] embedded into a MRCT” to compare both safety and PK data with non-Japanese participants before the main part of the MRCTs.
Sponsors should be aware that there is a possibility that the efficacy data from these safety-lead-in participants cannot be used in the primary endpoint analysis, while it could be used as supportive data because of the different setting from the main part of the MRCTs such as safety monitoring schedules and hospitalization conditions.
Other measures used to secure Japanese participants’ safety are 1) administer the drug to a small number of Japanese participants (e.g., one participant at a time) with appropriate intervals between each administration, 2) execute safety monitoring with special attention to Japanese participants in an organization composed of third parties, such as an independent data monitoring committee, 3) Japanese participants will either be hospitalized or observed at the study site for a certain period, 4) Increase the frequency of visits and monitoring during the early stage of administration.
Monoclonal Antibody Review
When a systematic review of monoclonal antibodies (mAbs) approved in Japan from 2007 through 2023 was conducted, the difference in PK parameters between Japanese and non-Japanese patients was less than two times. According to PMDA’s review reports, it was concluded that the PK difference was not clinically significant because there was no apparent difference in safety or efficacy profile in Japanese patients compared with non-Japanese. A 20-30% difference in PK was typically explained by the difference in body weight of participants included in the clinical trials.
The mAbs review7 revealed that the observed PK differences between Japanese and non-Japanese populations were either due to differences in body weight or differences in receptor expression between the populations. If the difference is covered by the safety margin, dose adjustment might not be necessary. Other literature reports no essential differences between Japanese and non-Japanese participants, particularly in healthy volunteers, in the exposure of mAbs that have been approved in Japan. The doses selected in subsequent Japanese patient phases were the same as those stated on the approved US labels, even if there were differences in PK in the healthy volunteer studies.8
It is recommended that the ethnic difference in PK is evaluated using Population PK modeling based upon pooled data from both non-Japanese and Japanese data, which would take other covariate effects into account. In addition, the impact of PK difference on the clinically recommended dose in patients should be evaluated through a thorough review of the clinical efficacy and safety profile, and the exposure-response analysis to evaluate the relationship between efficacy/safety and PK (estimated PK measures from the final Population PK model).
When it is difficult to determine PK differences due to small sample size, PMDA says that safety/efficacy should be monitored closely after approval and the label updated when needed.
Conclusion
Regardless of whether a Japanese phase 1 study is conducted, MHLW’s new announcement requests that the difference between Japanese and overseas patients be examined by collecting pharmacokinetic/pharmacodynamic data on Japanese patients prior to submission for marketing authorization approval. Considering that PMDA has been accepting modeling in NDAs9 and there are multiple cases where Japanese patients have been recruited into registrational MRCTs without conducting local Japanese phase 1 studies, this new guidance1,2 is not a surprise. But MHLW has made its opinion public to help diminish drug approval lag and encourage sponsors to include Japan in their global drug development programs as early as possible.
References
1. Basic principles for conducting phase 1 studies in Japanese prior to initiating multi-regional clinical trials including Japan for drugs in which early clinical development is preceding outside Japan. December 25, 2023, Notification No.1225-2. Ministry of Health, Labour and Welfare. Available from: https://www.mhlw.go.jp/hourei/doc/tsuchi/T231226I0020.pdf
2. Basic Principles for Conducting Phase 1 Trials in the Japanese Population Prior to Global Clinical Trials. Administrative Notice, October 27, 2014. Ministry of Health, Labour and Welfare. Available from: https://www.pmda.go.jp/files/000157777.pdf
3. Basic Principles on Global Clinical Trials. September 28, 2007, Notification No. 0928010. Ministry of Health, Labour and Welfare. Available from: https://www.pmda.go.jp/files/000157900.pdf
4. Basic Principles on Global Clinical Trials (Reference Cases). September 5, 2012, Administrative Notice. Ministry of Health, Labour and Welfare. Available from: https://www.pmda.go.jp/files/000208185.pdf
5. Material from Study Group on the Drug Regulation System to Enhance Drug Discovery and Ensure Stable Supply. September 13, 2023, Ministry of Health, Labour and Welfare. Available from: https://www.mhlw.go.jp/content/11121000/001146390.pdf
6. Q&A for basic principles for conducting phase 1 studies in Japanese prior to initiating multi-regional clinical trials including Japan for drugs in which early clinical development is preceding outside Japan. December 25, 2023, Ministry of Health, Labour and Welfare. Available from: https://www.mhlw.go.jp/hourei/doc/tsuchi/T231226I0030.pdf
7. Chiba et al. A comprehensive review of the pharmacokinetics of approved therapeutic monoclonal antibodies in Japan: Are Japanese Phase 1 studies still needed? J Clin Pharmacol. 2014 May;54(5):483-94. Available from: https://accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.231
8. Zhou et al. Oncology Therapy Drugs in China, Japan, and the United States: Pharmacokinetic Characteristics, Dose Regimens, and Development Strategies. Clin Pharmacol Ther. 2019 Jun;105(6):1303-1320. Available from: https://pubmed.ncbi.nlm.nih.gov/30802932/
9. Kijima S, Yoshida S, Ochiai Y. Activity and perspective on quantitative modeling and simulation in Japan: Update from the Pharmaceuticals and Medical Devices Agency. CPT Pharmacometrics Syst Pharmacol. 2022 Dec;11(12):1552-1555. https://ascpt.onlinelibrary.wiley.com/doi/epdf/10.1002/psp4.12868
Author Bio
Mayumi Hasegawa, PhD, is Senior Director, Drug Development Solutions at Certara. Mayumi has more than 20 years of drug development experience focused on clinical pharmacology and pharmacometrics in the Asia-Pacific region (Japan-Korea-Taiwan). Her expertise includes early- and late-stage development programs in oncology/immunology, rheumatoid arthritis, and cardiovascular disease and she has supported multiple filings to the FDA, EMA and PMDA.
