Reimagining Early‐Phase Clinical Development in Japan: From Regulatory Obligation to Global Acceleration

ABSTRACT

Japan has faced persistent challenges of “Drug Lag” and “Drug Loss”, partly due to the regulatory requirement for Japanese Phase I studies prior to global trial participation. However, recent regulatory reforms have introduced flexibility, creating new opportunities for Japan to strategically contribute to global drug development. This study redefined the value of Japanese Phase I by evaluating three options during the early development phase: the Japanese Phase I waiver, the first‐in‐human study conducted in Japan, and multifunctional Japanese Phase I studies. We analyzed 12 internal cases of Japanese Phase I waiver consultations and conducted a nationwide survey at early phase clinical trial sites. Our findings highlight Japan's robust clinical trial infrastructure for early phase trials. Japanese clinical trial sites have not only accumulated extensive experience in early phase trials but have also conducted specialized evaluations and enrolled diverse populations (e.g., non‐Japanese Asians, Caucasians, and patients). The cycle time analysis showed that trials in Japan could be initiated within globally competitive timelines, often faster than those in the EU. These strengths position Japan as a key location for first‐in‐human and early phase trials, enabling earlier access to investigational therapies and supporting global development strategies. We propose a flexible, case‐by‐case approach that leverages Japan's clinical research capabilities. This strategy not only preserves Japan's clinical trial infrastructure but also aligns with national initiatives to strengthen the “Drug‐Discovery Ecosystem”. By integrating Japan into early phase development, pharmaceutical companies can accelerate global innovation while improving access to Japanese patients.

Study Highlights

• What is the current knowledge on the topic?

  • ○
    Drug lag and drug loss have become a significant issue in Japan. Recently, the government has taken steps to address these concerns, and both regulators and pharmaceutical companies are actively working to resolve them.
• What question did this study address?

  • ○
    What approaches can pharmaceutical companies take to help address drug lag/loss?
• What does this study add to our knowledge?

  • ○
    Regulators have clarified its stance in Phase I trials in Japan. While this has facilitated Japan's smoother participation in multiregional clinical trials, there is concern that opportunities to conduct early phase clinical trials in Japan may decline. Our investigation has shown that Japanese clinical trial sites possess sufficient experience and capability to conduct early phase trials in Japan.
• How might this change clinical phamacology or translational science?

  • ○
    By leveraging Japan's strong clinical trial infrastructure and capabilities, pharmaceutical companies can actively conduct early phase trials. This contributes to global drug development and helps resolve drug lag/loss.

1. Introduction

The growing issues of “Drug Lag” (when development of a drug approved overseas is delayed in Japan) and “Drug Loss” (when development is not initiated in Japan, and it will never be approved) have become a serious concern. Of the 265 new drugs approved in the United States (US) or Europe between 2010 and 2020, only 31% underwent development in Japan [1, 2]. Among the 244 orphan drugs approved in the US between 2005 and 2021, 120 drugs (49%) had not been approved in Japan, and 86 drugs (35%) had not been developed [3]. Among the 136 anti‐cancer drugs approved in the US between 2011 and 2022, the median time to approval in Japan was 1278 days after their approval in the US [4]. Consequently, Japanese patients were unable to access appropriate treatments for 3 years. When using an unapproved drug in Japan, the cost of the treatment is not covered by the public health insurance system. Furthermore, if an adverse reaction occurs, the patient will not be eligible for compensation under the relief system for sufferers from adverse drug reactions [2].

With the aim of ensuring the early launch of innovative drugs and those with high medical needs in Japan, the Ministry of Health, Labour and Welfare convened “The Advisory Council on Comprehensive Measures to Realize Prompt and Stable Supply of Drugs” in 2023 [5, 6]. The council facilitated broad discussions on key issues, particularly the elimination of drug lag/loss. Furthermore, “The Review Meeting on Pharmaceutical Regulations for Strengthening Drug Discovery Capacity and Securing Stable Supply” was held from 2023 to 2024, which discussed measures to address matters related to pharmaceutical regulations [5, 7].

One of the factors behind drug lag/loss is major pharmaceutical companies' growing reliance on emerging biotech firms for technologies that serve as seeds for drug discovery. Emerging biotech firms in the US and Europe rarely initiate development in Japan in the early stage, therefore major pharmaceutical companies often begin drug development in Japan after acquiring the biotech products. Additionally, according to the notification issued in 2014 [8], prior to participation in a multi‐regional clinical trial (MRCT) from Japan, a Phase I study of healthy Japanese volunteers (J‐Ph1) must be conducted if safety data specific to the Japanese population have not been obtained. Conducting a J‐Ph1 requires time and funding, therefore this may delay MRCTs, or development in Japan may be abandoned altogether to avoid such delays, ultimately contributing to drug lag/loss [7].

It was stated that the Pharmaceuticals and Medical Devices Agency (PMDA) did not always require J‐Ph1 prior to an MRCT [9]. Instead, the necessity of such studies was assessed on a case‐by‐case basis considering the pharmacokinetic (PK)/pharmacodynamic (PD) properties and drug safety, along with data from preceding overseas studies, information on drugs with similar modes of action (MoA), disease characteristics, and specific features of the investigational product. The PMDA explained that participating in an MRCT without a J‐Ph1 was acceptable if there were no significant ethnic differences [9]. However, according to a survey conducted in 2023 by the Japan Pharmaceutical Manufacturers Association (JPMA), Pharmaceutical Research and Manufacturers of America (PhRMA), and European Federation of Pharmaceutical Industries and Associations (EFPIA) targeting 38 pharmaceutical companies, there were two cases in the US and one in the European Union (EU) in which a country did not participate in the first‐in‐human (FIH) study and instead conducted an additional Ph1 study domestically to join an MRCT. In contrast, Japan recorded 62 cases [10]. This suggests that the assumption that a J‐Ph1 is essential prior to participation in an MRCT might be ingrained in pharmaceutical companies.

Many antibody drugs approved in Japan since 2001 exhibit no significant ethnic differences in PK and immunogenicity [11, 12], and the same dosage is generally used in both Japan and the US [13]. We investigated the ethnic differences between Japanese and non‐Japanese regarding the safety and PK of Novartis compounds approved between 2010 and 2018 [14]. Only one of the 25 compounds investigated showed an ethnic difference that required dose adjustment. Furthermore, the EFPIA Japan reported similar findings [15]. These reports raise concerns that requiring a J‐Ph1 before joining an MRCT, even if non‐Japanese Ph1 data is already available, may result in missed opportunities for participation in MRCT.

Under these circumstances, the new notification was issued in 2023 [16], past related notification has been revised, and a current standpoint of the regulators has been announced. Although the previous notification stated that J‐Ph1 was required before an MRCT “in principle”, the new notification clarifies that an additional J‐Ph1 is not required unless deemed necessary. This updated stance reflects perspectives aimed at minimizing the disadvantages of excluding Japanese participants from drug development.

Subsequently, the Japan Association of Contract Institutes for Clinical Pharmacology (JACIC) warned that a decline in opportunities to conduct early clinical trials in Japan could undermine the established capabilities for evaluating new drugs. This may lead to the erosion of industrial, academic, and human resource development infrastructure in Japan [17]. There is a dilemma while clarifying the necessity of a J‐Ph1 could be valuable for reducing delays in drug development in Japan, this may raise concerns relating to fewer clinical trial opportunities in Japan and a potential weakening of the drug development infrastructure. This study aimed to redefine the value of J‐Ph1 and explore its strategic application, focused on non‐oncology drug development.

2. Methods

Figure 1 showed the options for handling J‐Ph1 data prior to participation in an MRCT. Each option has its own merits and values; therefore, we conducted detailed investigations of each option.

1. Participate in MRCT without conducting a J‐Ph1 study (“J‐Ph1 waiver”).

2. Conduct a FIH in Japan (with the option to include Japanese participants in a global FIH study).

3. Conduct a standalone J‐Ph1 study.

FIGURE 1.

Typical drug development process and timeline of Japan Phase I options before joining the MRCT.

2.1. Investigation of J‐Ph1 Waiver Acceptability

The acceptability of J‐Ph1 waiver depends on several factors outlined in the relevant notifications and is currently under discussion among professionals within industry, regulators, and academia [18]. The relationship between the outcomes of the J‐Ph1 waiver consultation and the characteristics of each product were investigated using internal cases conducted between 2018 and 2025.

Twelve products with PMDA consultations on the necessity of J‐Ph1 prior to participation in the MRCT were analyzed. All products had (1) sufficient non‐clinical and non‐Japanese clinical data or study data from drugs with similar MoAs, (2) a wide safety margin confirmed by non‐clinical and non‐Japanese clinical data, and (3) no expected ethnic differences in PK based on non‐clinical data or the characteristics of the modalities. Each product was classified according to the items listed below, and the outcomes of the J‐Ph1 waiver consultation were summarized for each item. “Acceptance of the J‐Ph1 waiver” was defined as exemption from conducting a standalone J‐Ph1 prior to participation in an MRCT, including cases in which safety evaluation in Japanese participants was required in the MRCT.

1. Timing of consultation (before or after the issuance of the new notification)

2. Origin (internal or in‐licensed)

3. Modality

4. Therapeutic area

5. Target disease population (rare or non‐rare)

6. Whether there was sufficient time to conduct J‐Ph1 prior to the MRCT

2.2. Survey of the Clinical Trial Infrastructure and Timeline for FIH Trials in Japan

“FIH in Japan” enables Japan to contribute to global drug development process from earlier timing. We investigated two key perspectives that are important for the implementation of FIH studies in Japan.

2.2.1. Site Capability

To assess the potential for conducting clinical trials in Japan, we surveyed the capabilities of early phase clinical trial sites. Among the clinical research organization sites in Japan that are members of the JACIC, nine were assessed for the items below over 10 years (As of February 2024 for most items):

We investigated whether the following studies had been conducted on each site:

• FIH studies (including cases where special evaluation items were added to the FIH)

• Drug–drug interaction (DDI) studies

• Thorough QT (TQT) studies.

• Organ (hepatic and renal) impairment studies (as of June 2025)

• Elderly population (≥ 65 years of age) studies (as of June 2025)

Additionally, we investigated whether the following items were possible at each site:

• Enrollment of Asian (non‐Japanese)

• Enrollment of Caucasian

• Enrollment of patients

• Collection of cerebrospinal fluid (CSF) from healthy volunteers (HV)

2.2.2. Cycle Time

To clarify the ease of managing the study schedule, the number of days required from the submission of the clinical trial notification (CTN) to the start of the clinical trial (i.e., the first participant first visit, FPFV) was investigated. Among the nine sites mentioned above, one clinical site, SOUSEIKAI Medical Group (“SOUSEIKAI”), was selected for this investigation. SOUSEIKAI routinely tracks the CTN submission dates provided by sponsors, which makes this survey possible. The FIH and first‐in‐Japanese (FIJ) studies conducted at SOUSEIKAI between 2022 and June 2025 were used in the investigation.

2.3. Analysis of the Strategically Implemented Multifunctional J‐Ph1 Studies

The background and details of the J‐Ph1 conducted over the past 10 years, in which other evaluation items were included along with the safety and PK in Japanese participants, were investigated. The studies were classified based on the characteristics of the additional evaluation items, and the features of each characteristic were explored.

3. Results

3.1. Investigation of J‐Ph1 Study Waiver Acceptability

Table 1 provides a breakdown of each item among the 12 products that were applied for the J‐Ph1 waiver consultation. The J‐Ph1 waiver cases that were either accepted or not accepted are illustrated in Figure 2 by evaluation items. The details of each case are provided in Table S1.

TABLE 1.

Classification of each product submitted for J‐Ph1 waiver consultation by PMDA.

Items	Class
Timing of consultation	Before new notification	10
	After new notification	2
Origin	Internal	7
	In‐licensed	5
Modality	Gene therapy	2
	Oligonucleotide therapeutics	3
	Therapeutic protein	2
	Monoclonal antibody (mAb)	2
	Low molecular weight (LMW)	3
Therapeutic area	Ophthalmology	3
	Neurosciences	2
	Cardiovascular, Renal and Metabolism	4
	Immunology	3
Target disease population	Rare	3
	Non‐Rare	9
Lacking sufficient time to conduct J‐Ph1 prior to the MRCT	No sufficient time	6
	Have sufficient time	6

FIGURE 2.

Outcomes of the J‐Ph1 waiver consultation with PMDA in Novartis cases from 2018 to 2024.

(a) Timing of consultation (before or after the issuance of the new notification)

• Although it was categorized a non‐rare disease, two cases consulted after the issuance of the new notification were accepted. No additional assessments were required before the global Ph2b trial.

• Of the five cases accepted before the issuance of the new notification, three were rare diseases.

• One of the remaining cases lacked sufficient time to conduct the J‐Ph1 before the MRCT; however, a safety evaluation of Japanese participants was required to add to the MRCT.

• The other case involved oligonucleotide therapeutics for non‐rare diseases with sufficient time to conduct J‐Ph1. It was presumed that owing to the nature of the modality, there would be no major ethnic differences and no significant relationship between PK and PD. However, Japanese PK data was required for new drug applications (NDA).

(b) Origin (internal or in‐licensed)

• All five in‐licensed products were accepted. In three cases, late‐phase trials had already been scheduled, leaving insufficient time for a J‐Ph1 to be conducted before the MRCT. Although one case had sufficient time for J‐Ph1, it was categorized a rare disease. The other case involved the oligonucleotide therapeutics mentioned above.

• Of the seven internally originated products, two were accepted. In both cases, there was insufficient time to conduct J‐Ph1 before the MRCT.

(c) Modality

• All five cases of oligonucleotide and gene therapies were accepted. It was presumed that due to the nature of these modalities, ethnic differences in PK were unlikely; therefore, the safety concerns specific to Japanese patients were considered low.

• None of the three low molecular weight (LMW) projects was accepted. The reason in all cases was that safety concerns specific to the Japanese participants could not be ruled out.

• Of the two monoclonal antibody (mAb) and two therapeutic protein cases, one from each category lacking sufficient time for a J‐Ph1 to be conducted was accepted. The J‐Ph1 waiver was not accepted for cases where there was sufficient time to conduct a J‐Ph1, even if the compound was not an LMW because the effects of ethnic differences could not be ruled out.

(d) Therapeutic area

• No trend was observed associated with the therapeutic area.

(e) Target disease population (rare or non‐rare)

• All three rare disease cases were accepted. This was considered to be because the disease had no alternative treatment options and administering the drug to the HV would pose a risk.

• Of the cases that accepted non‐rare diseases, three out of four lacked sufficient time to conduct J‐Ph1 before MRCT. The other case involved oligonucleotide therapeutics, as mentioned in the section titled “Timing of consultation”.

(f) Whether there was sufficient time to conduct J‐Ph1 prior to the MRCT

• Of the six products for which there was insufficient time to conduct J‐Ph1, five were accepted. This may reflect a consideration to avoid the risk of missing the opportunity to participate in the MRCT by conducting the J‐Ph1, which could potentially result in drug lag/loss.

• Despite the lack of sufficient time to conduct J‐Ph1 before MRCT, one case of an LMW compound with central nervous system safety risks was not accepted because of concerns about safety in Japanese participants.

• Of the six products with sufficient time to conduct the J‐Ph1, only two were accepted, one of which was a rare disease. The other case involved oligonucleotide therapeutics, as mentioned in the section titled “Timing of consultation”.

3.2. Survey of the Clinical Trial Infrastructure and Timeline for FIH Trials in Japan

3.2.1. Capability

The results of the survey were shown in Figure 3a. It showed that all sites investigated had experience in conducting FIH studies in Japan. In total, 116 FIH studies were conducted, 87% of which were sponsored by domestic Japanese companies. All the sites had experience in conducting 92 DDI studies. Sixteen TQT studies were conducted at three of the nine sites. Six of the nine sites had experience in incorporating specific evaluation items (e.g., food effect, DDI, QT, elderly, and ethnic sensitivity assessments) into FIH studies. Forty‐two hepatic impairment studies involving patients classified as Child‐Pugh A and B were conducted at six of the nine sites. Nineteen renal impairment studies involving patients with mild‐to‐severe renal dysfunction were conducted at five of the nine sites. Seven sites had experience in conducting 88 elderly population studies.

FIGURE 3.

Results of questionnaire regarding the experiences and feasibility of early‐phase clinical trials at Japan clinical trial sites over the past 10 years. (a) The pie chart indicates the number of FIH studies in Japan. In total, 116 FIH studies were conducted by the evaluated sites. The colors indicate the sponsor category for the FIH studies (Red: Japanese domestic pharmaceutical company, Blue: Global pharmaceutical company, Green: Academia). (b) Of the sites able to enroll Caucasian participants, five out of seven had experience enrolling them (in total, 76 studies). Of the sites able to enroll Asian (Non‐Japanese) participants, one out of six had experience enrolling them (four studies).

Additionally, Figure 3b showed that six of the nine sites were able to enroll a healthy non‐Japanese Asian population and seven of the nine sites were able to enroll a healthy Caucasian population. All sites could enroll diverse patient populations (e.g., atopic dermatitis). Collection of the CSF from the HV was feasible at five of the nine sites.

3.2.2. Cycle Time

Figure 4 illustrates the distribution of the number of days from first CTN submission to FPFV for studies conducted by SOUSEIKAI between 2022 and June 2025. Fifty‐eight relevant studies were conducted. Approximately half (28) were initiated within 70 days of CTN submission. Several cases had notably longer durations, primarily due to clinical trial setup activities (such as adding extra tests, delays in PK/PD assay validation, or investigational drug preparation) rather than an extended review period.

FIGURE 4.

Distribution of the number of days from CTN submission to FPFV in clinical trials conducted for the first time in Japan. This investigation was conducted at the SOUSEIKAI clinical trial site. The numbers in each section of the pie chart indicate the number of studies conducted.

3.3. Analysis of the Strategically Implemented Multifunctional J‐Ph1 Studies

As conducting a separated study requires additional resources and HV data are often available, instead of conducting standalone J‐Ph1, leveraging the study as an opportunity to enrich the data for global filing by incorporating additional assessments should be considered. Examples of multifunctional J‐Ph1 studies are listed in Table 2. We identified 10 studies that included additional assessments beyond standard evaluations in Japanese. Based on their features, these studies were classified into three types: (1) J‐Ph1 studies with integrated additional assessments when further investigation is warranted based on prior study results. (2) J‐Ph1 studies including special population subgroups. (3) Japanese clinical pharmacology studies supporting global submission.

TABLE 2.

Multifunctional J‐Ph1 cases with additional assessment conducted by Novartis.

Additional items	Background
Type 1: J‐Ph1 studies with integrated additional assessments in Japanese population
Enrich intensive QT sampling	A QT evaluation was conducted in the FIH outside Japan. However, due to insufficient data points, an additional QT evaluation was carried out in the J‐Ph1 trial, resulting in an enriched dataset for further analyses.
Biomarker assessment for new indication	Following the FIH outside Japan, a new indication was introduced, necessitating the investigation of specific biomarkers that were not assessed in the previous studies. These biomarkers were evaluated in the J‐Ph1 trial.
Higher dose beyond the FIH trial	Results from the FIH outside Japan indicated that higher exposures would be necessary for subsequent clinical trials. Therefore, higher doses than those used in the FIH trial were administered in the J‐Ph1 trial, and their PK and safety were evaluated.
Pharmacogenomics	CYP2C9 was identified as a major enzyme involved in the elimination of the drug. Population PK analysis indicated that clearance was reduced in poor metabolizers. Therefore, due to ethnic differences, the effect of CYP2C9 polymorphism on PK was evaluated in healthy Japanese participants.
Type 2: J‐Ph1 studies including special population subgroups
Non‐Japanese population	In the case of an in‐licensed product, the FIH trial had already been conducted by the licensor outside Japan. Following formulation changes made after the product was in‐licensed, the J‐Ph1 trial (being the first to use the new formulation) collected PK data from both Japanese and Caucasian participants.
Elderly population	As PK profiles may be different in the elderly, the J‐Ph1 trial included an evaluation of PK in this population.
Type 3: Japanese clinical pharmacology studies supporting global submission
Relative bioavailability	When a formulation was changed and a different PK from that of the original formulation was expected, these formulations were compared in the J‐Ph1 trial.
Effects of different injection site	Another administration route (s.c.) was introduced after completion of the FIH outside Japan using only intravenous dosing. The J‐Ph1 trial was conducted with s.c. dosing, and the data was incorporated into the PopPKPD model to improve the robustness of the model.
Food effects	A food effect assessment was included in the J‐Ph1 trial to evaluate the impact of food on PK of the new formulation.
Drug–drug interaction	Given the physicochemical properties of the compound, it was necessary to evaluate the DDI with antacids. J‐Ph1 was combined with a DDI study.

4. Discussion

“Drug lag” and “Drug loss” are a significant issue in Japan. Therefore, industry, government, and academic professionals are working together to address these issues. One example is the revision of the requirements for J‐Ph1 prior to MRCT, as outlined in the newly issued notification [16]. The J‐Ph1 waiver, which allows participation in MRCTs without obtaining J‐Ph1 data, is meaningful in terms of reducing the overall development resources and enabling Japan to participate in MRCTs in a timely manner.

4.1. J‐Ph1 Study Waiver

Based on our review of internal J‐Ph1 waiver consultations conducted before and after the issuance of the new notification [16], it was found that the PMDA accepted the J‐Ph1 waiver in cases such as those involving rare diseases or when there was insufficient time to conduct a J‐Ph1 prior to an MRCT (Figure 2). This reflects PMDA's intention to avoid missing opportunities to provide new treatment options for Japanese patients. For new modalities (i.e., oligonucleotide therapeutics and gene therapy), the J‐Ph1 waiver was accepted. This is likely because the effect of ethnic differences on PK and safety is low. Notably, the J‐Ph1 waiver was accepted in all five in‐licensed products. These products belonged to new modalities for which ethnic differences were generally not expected. Furthermore, for in‐licensed products, the FIH trial is often already completed at the time of in‐licensing, leaving insufficient time in many cases to conduct a J‐Ph1 study before late‐phase trials begin. These multifaceted factors likely contributed to waiver acceptance. Conversely, the J‐Ph1 waiver would not be accepted if there was sufficient time to conduct a J‐Ph1 or if safety concerns for Japanese patients could not be fully ruled out. As the PMDA stated, the necessity of conducting a J‐Ph1 prior to the MRCT was assessed on a case‐by‐case basis, even before the issuance of the new notification [9]. Furthermore, after the issuance of the new notification, there were two cases where participation in Ph2b was accepted without J‐Ph1, including for drugs for non‐rare disease. The analysis was based on only 12 cases, and subgrouping further reduced the sample size. While the data was insufficient to support robust or universally valid conclusions, the J‐Ph1 waiver remains a valuable option for drugs with completed FIH studies outside Japan.

However, we believe that applying the J‐Ph1 waiver to all projects is a suboptimal approach. Notably, the new notification only mentions “the concept of Japanese data before participation in MRCT” [16]. Therefore, considering the drug development process in Japan leading up to regulatory approval, the need to obtain data from the Japanese population to evaluate ethnic sensitivity remains unchanged. If J‐Ph1 is not conducted before MRCT, the following risks may arise:

(a) Potential for increased burden during late‐phase trials

• The requirement for safety measures (e.g., safety run‐in) and other procedures specific to Japanese participants in late‐phase trials makes it difficult to integrate additional elements into a global trial protocol.

• Requirements for intensive PK assessment of Japanese participants in late‐phase trials.

(b) Potential risk during the review process after NDA submission

• The enrollment of Japanese participants in late‐phase trials is more difficult than expected, ultimately resulting in a limited number of Japanese participants.

• Consequently, the limited data make it difficult to clearly assess the ethnic differences between Japanese and non‐Japanese.

(c) Potential risk impacting the global development plan

• Due to limited data from the Japanese population, the ability to utilize such data in discussions of ethnic differences for applications in other Asian regions is restricted.

If essential data are missing, this could ultimately delay the regulatory approval process. Therefore, the appropriateness of applying the J‐Ph1 waiver should be carefully considered on a case‐by‐case basis.

4.2. FIH Trials in Japan

“FIH in Japan” is considered a preferable approach that can mitigate these risks. Sufficient Japanese data for regulatory submission can be secured early while simultaneously making a direct contribution to global development. While our analysis was based on a limited dataset, our survey revealed that several early phase clinical trial sites in Japan possess sufficient experience and capability in conducting FIH studies locally (Figure 3). According to Furihata, 403 Ph1 trials were conducted in Japan between 2020 and 2024 at 13 sites affiliated with JACIC, comprised of 19.6% FIH studies, 28.3% FIJ studies, and 52.1% other clinical pharmacology trials [19]. Although the surveillance periods varied, 190 FIH studies were conducted at these sites, the majority (85%) of which were sponsored by Japanese domestic companies. Furthermore, 375 FIJ studies were conducted, 61% of which were sponsored by foreign pharmaceutical companies [19].

FIH studies are conducted swiftly in Japan. Under the Japanese regulatory system, the PMDA's reviews and document amendments are completed exactly 30 calendar days after the first CTN submission. As indicated by the typical timeline (Figure 5), we could contract with clinical sites on the 31st day and then start the FIH study in Japan. Therefore, anticipating the overall timeline up to FPFV in advance is easy. Similarly, in the US, according to the “Investigational New Drug (IND) Application” [20, 21], once the IND is submitted, the sponsor must wait 30 calendar days before initiating clinical trials. However, during this period, if there are concerns that participants will be subjected to unreasonable risk or if the study design is not acceptable, a clinical hold often occurs. This is unlikely to occur in Japan. In the EU, the minimum review period for a Clinical Trial Application (CTA) is 60 calendar days [22]. Consequently, the time required to initiate a clinical trial is estimated to be roughly twice as long as that in Japan. Furthermore, as extensions are permitted for each phase to accommodate inquiries and other related matters, managing the timeline during this period can be challenging (Figure 5). From the survey results of the FIH and FIJ studies conducted in Japan, approximately half of the studies investigated were initiated within 70 days of CTN submission (Figure 4). Given that CTA approval in the EU can take up to approximately 90 days, it may be possible to initiate studies in Japan within a short timeframe. In addition, it is essential to address in advance any factors that may impact the timeline (see Results section: “Cycle time”) to ensure prompt study initiation. As comparable international datasets were not accessible at the time, this analysis was based solely on data from Japanese sites. Future studies should incorporate cross‐regional comparisons to validate these findings.

FIGURE 5.

Typical regulatory process for the first clinical trial conducted in three regions: Japan, EU, and US.

Leveraging such robust Japanese data may enable its use in regulatory applications across other parts of Asia, the US, and the EU. Our investigation revealed that several clinical trial sites in Japan are capable of enrolling healthy Asian and Caucasian participants (Figure 3). For FIHs in Japan, a certain number of non‐Japanese participants in each cohort should be included to enable efficient early collection of non‐Japanese ethnic group data without requiring additional resources. The data obtained in this manner could be valuable for other Asian regions, such as China, to join the MRCT [23]. As stated in the guidance for oncology products, early stage MRCTs should be conducted in a diverse population [24]. Including Caucasian participants in FIH in Japan is a promising and feasible option, as it may be useful for future drug applications in other regions.

4.3. Multifunctional J‐Ph1 Studies

The additional assessment items incorporated into standalone J‐Ph1 studies rather than solely for safety and PK evaluation are highly valuable for enriching global submission packages as well as for fulfilling local regulatory requirements (Table 2). We considered that these cases could be classified into three types and demonstrate how J‐Ph1 studies can strategically supplement data gaps in FIH trials, for example, when new indications, formulations, or administration routes emerge post‐FIH.

4.4. Future Perspectives on Early‐Phase Clinical Trials in Japan

Based on the analysis of the three options reviewed, a flexible approach can be taken. Conducting FIH in Japan by leveraging Japan's robust clinical trial infrastructure could enable timely trial initiation. Alternatively, for in‐licensed products with limited time before late‐phase trials and where ethnic differences are not anticipated, a J‐Ph1 waiver would be an appropriate option. If ethnic differences and safety concerns for Japanese patients persist, conducting a J‐Ph1 study would be appropriate with consideration of how it can add value to the global development plan.

According to our surveys (Figure 3), it is possible to conduct early phase patient trials in Japan. All the evaluated clinical sites in Japan were capable of enrolling diverse patient populations. For diseases that are more prevalent Japan than in Europe and the US, conducting early phase patient trials in Japan may accelerate development. However, limited information is available on the investigational products in the early stages, and safety concerns may remain. The investigational product should be administered to patients under such conditions; therefore robust safety management and informed consent measures may be required. Thus, it is important to sustain these efforts through scientific support and expert collaboration to foster cooperation between pharmaceutical companies and academia.

In recent years, the Japanese government has made a strong commitment to developing “Drug‐Discovery Ecosystem” [25, 26]. This is a national initiative aimed at enhancing the overall drug discovery framework beyond the efforts of individual pharmaceutical companies. Its goal is to establish a clinical research implementation system that meets international standards through collaboration among all stakeholders, such as promoting industry‐government‐academia partnerships, fostering emerging biotech firms, and strengthening the foundational research capabilities of academic institutions. This initiative will enable the early delivery of new therapeutic drugs to Japanese patients, and the concept aligns with the direction that Japan should pursue, as outlined in this manuscript.

J‐Ph1 has been used to meet regulatory requirements in Japan, especially by global pharmaceutical companies. However, with ongoing national efforts to restructure the foundation of pharmaceutical development, it is essential to shift from a domestically focused mindset to one that leverages Japan's strengths to accelerate global development. There are several approaches available for managing J‐Ph1, such as the J‐Ph1 waiver and FIH in Japan or conducting multifunctional J‐Ph1 studies. By understanding each characteristic and engaging in global drug development from an early stage, Japan can enhance the robust drug discovery infrastructure, ultimately contributing to the elimination of drug lag/loss.

Author Contributions

Y.K. wrote the manuscript. Y.K., M.H., and M.S. designed the research. K.M., S.I., and H.T. performed the research. Y.K., K.M., S.I., O.M, and H.T. analyzed the data.

Funding

The authors have nothing to report.

Disclosure

All authors are employees of Novartis Pharma K.K.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: cts70467‐sup‐0001‐TableS1.pdf.

Kawakita Y., Matsumoto K., Hirano M., et al., “Reimagining Early‐Phase Clinical Development in Japan: From Regulatory Obligation to Global Acceleration,” Clinical and Translational Science 19, no. 1 (2026): e70467, 10.1111/cts.70467.