Japan: the new strategic launchpad for accelerating global rare disease development

Introduction

In the past, rigid local Phase 1 requirements made Japan a late-stage hurdle in global drug development. This paradigm shifted with the landmark December 2023 Ministry of Health, Labour and Welfare (MHLW) Notification (PSB/PED No. 1225-2), which relaxed the requirement for a standalone Japanese Phase 1 study before initiating multi-regional clinical trials (MRCTs). Today, the Pharmaceuticals and Medical Devices Agency (PMDA) offers a balanced, data-driven pathway to integrate Japanese cohorts into global programs much earlier, positioning Japan as a strategic launchpad for early-phase and rare-disease trials¹. 

Translating this regulatory shift into clinical practice requires specialized medical insight & local operational infrastructure, including academic super-hubs, private networks, and decentralized clinical trial (DCT) components such as home nursing solutions, in line with the March 2026 MHLW guidelines. A recent first-in-human (FIH) MCRT for a rare genetic metabolic disorder exemplifies this modernized framework. By implementing an integrated, cross-functional operational strategy, Parexel aligned complex global protocol requirements with local clinical execution, establishing a template for navigating Japan's updated clinical landscape.

Section 1: Japan as a strategic hub for rare disease development 

1.1 Regulatory advantage: removal of the mandatory Japan Phase-1 data requirement offers more strategic flexibility for global developers

Japan has a long-standing drug-loss and drug-lag problem, where Japanese patients face a significant delay in accessing the most innovative drugs available in other developed markets.  The PMDA is now working to address this problem by clarifying the circumstances under which sufficient scientific justification may provide a basis for waiving Japan Phase 1 study before global MRCT participation, for example, based on the totality of available non-clinical, clinical, pharmacokinetic, and ethnic sensitivity data. The sufficiency of data depends on: Safety and Tolerability: robust nonclinical data or historical clinical data to demonstrate acceptable safety margins of study drugs; and Pharmacokinetics and Interethnic Sensitivity: pharmacokinetics (PK) and ethnic difference analysis, to demonstrate no significant difference between Japanese and foreign subject populations. When a Japan Phase 1 study is waived, Japanese patient safety is managed through mitigation strategies, including safety cohorts (e.g., a localized Japanese "run-in" cohort with predefined observational intervals) and other safeguards, such as more frequent clinical visits for close monitoring of safety, tolerability, and PK signals. 

For rare-disease drugs demonstrating high unmet medical needs in Japan, PMDA’s Conditional Approval pathway represents a significant opportunity for sponsors, allowing early market authorization based on foreign clinical data in exchange for post-marketing surveillance commitments, such as observational registry studies to confirm the therapy's real-world safety and efficacy in the Japanese population. In addition, programs such as the Sakigake (Pioneering) designation and Priority Review enable faster development and approval timelines for breakthrough therapies. Approved orphan drugs in Japan typically receive 10 years of data exclusivity, providing a secure commercial window for high-cost rare-disease treatments. 

In March 2026, the MHLW issued guidance clarifying the use of partner medical institutions in DCTs, providing a clearer regulatory framework for remote trial activities. This is expected to facilitate clinical trial participation for patients who face geographic barriers to accessing study sites, particularly benefiting therapeutic areas where patient recruitment is challenging, such as rare diseases and pediatric diseases.

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

1.2 Early phase infrastructure: experienced Super-hubs and private facilities accelerate execution

In parallel with the changes described in Section 1.1, backed by government policies to support early-phase and rare-disease trials, Japan’s early-phase clinical trial infrastructure is internationally competitive. This infrastructure fosters collaboration among academic, public, and private research institutions and ensures clinical research standards are aligned with international development requirements.

Over the years, Japan has accumulated extensive experience in early-phase and rare-disease clinical trials. Based on the survey of 13 Japanese clinical sites affiliated with JACIC (Japan Association of Contract Institutes for Clinical Pharmacology ), approximately 400 Phase1 studies were conducted in Japan between 2020 and 2024; of these, about 30% were First-in-Human (FIH) trials, about 20% were First-in-Japan (FIJ) trials, and about 50% were clinical pharmacology studies.

Central to this clinical ecosystem are academic super-hubs focused on early-phase development. Some examples are given below. The specialized Phase 1 Unit at a university hospital in Tokyo is embedded within the hospital’s clinical departments, ensuring close collaboration among departments and streamlining subject recruitment. Similarly, Kyoto University Hospital’s Ki-Connect — a Parexel Alliance Partner — specializes in early proof-of-concept (POC) studies in advanced therapies, across induced pluripotent stem (iPS) cell therapies, regenerative medicine, oncology, and intractable orphan diseases. In particular, Ki-Connect is capable of conducting a single clinical trial involving healthy volunteers and patients in a hybrid Phase Ia/ Ib setting.

Complementing the academic hubs are private early-phase clinical facilities with a strong track record. In particular, the SOUSEIKAI Medical Group has conducted more than 100 Phase 1 trials in healthy volunteers over a three-year period, comprising 31 FIH studies, 44 first-in-Japan trials, and 25 food-effect evaluations. These units support specialized pharmacology protocols, including Thorough QT study (TQT),  drug-drug interaction (DDI) evaluations, cerebrospinal fluid (CSF) sampling, and even mass balance studies. They also maintain the capability to recruit diverse populations, including Caucasian and non-Japanese Asian cohorts (such as Chinese and Korean), which facilitates clinical bridging and the assembly of studies in Japan.

Historically, implementing adaptive clinical trial designs (which incorporate both healthy volunteers and patient populations) in Japan has been challenging due to protocol and operation complexity. Now, with extensive experience gained from complex protocols, Japan Phase 1 clinical sites increasingly implement adaptive, more complex trials that integrate multi-ethnic populations and patient cohorts with healthy volunteer cohorts into FIH studies. This capability enables sponsors to evaluate efficacy and safety signals early in clinical development without separate standalone trials.

1.3 Country-specific medical insight and patient/site selection strategy to optimize trial execution 

Medical insight into the disease/treatment landscape and a robust patient/site selection and optimization strategy are critical before conducting early-phase rare disease trials. Depending on the specific disease area, Japan's healthcare system, diagnostic pathways, and standards of care can differ from other regions. Treatment access, reimbursement, availability of genetic testing, and the concentration of specialist expertise may also influence the identifiable and eligible patient population.  Specialist knowledge is therefore required to address specific challenges in a rare disease setting, including small patient populations, delayed diagnoses,  fragmented care pathways, high study burden and the needs of pediatric or medically complex patients and their caregivers.

Similarly, site and patient selection strategies need to be customized, involving patient pathways and population intelligence garnered from scientific associations, disease registries, patient organizations, publications, and real-world data. The strategy can be further optimized with insight from site-specific surveys and KOL interviews. Site feasibility should assess not only the number of potentially eligible patients but also referral reach, diagnostic and genetic testing capabilities, early-phase safety infrastructure, protocol-specific expertise, sample processing capacity, and the ability to support patients traveling long distances. A detailed understanding of sites and patients supports more reliable recruitment forecasting and early identification of screen-failure risks, competing studies, access barriers, and overlapping referral populations.  It also informs actionable mitigation strategies, such as referral network activation, pre-screening pathways, patient advocacy organization engagement, travel support, home health solutions, and targeted site training. 

Section 2: Case Study: 

A Rare Metabolic Disorder Multi-regional study (MRCT) – how a proactive and integrated approach enables fit-for-purpose strategy & operation solution 

Parexel recently worked on a multi-regional, FIH clinical trial of an investigational biologic therapy for a rare genetic metabolic disorder. The clinical protocol was complex, requiring a cohort dose-escalation design across several Asia-Pacific and Western territories and mandating daily clinical visits during the trial's initial phases. For patients with this progressive condition, who had impaired physical mobility, daily travel to an investigational site was an almost insurmountable barrier to recruitment and protocol compliance.

Proactive engagement is the first step. Parexel began by proactively engaging the sponsor’s study team, thoroughly exploring potential challenges in this complex study protocol and strategizing on country/site/patient selection options, as well as key operational aspects, including innovative approaches to home nursing. This early engagement has helped both teams establish early consensus and significantly streamline study execution.

With an understanding of the disease and the operational realities within the specific healthcare landscape, Parexel has identified three primary challenges in this study: 1) How do we build an evidence-based site and patient selection strategy, given the very limited number of patients in each country and site? 2) How to manage this complicated FIH protocol, which requires dose-escalation design and close cohort management? 3) What are clinically compliant and cost-effective solutions to reduce patient burden, as the study requires daily clinical visits?

To address the first challenge, Parexel integrated tailored medical and feasibility insight into study design and recruitment strategy to drive operational excellence. To mitigate recruitment risk for this challenging study, our team conducted a detailed patient pool analysis using insights from customized sources, including a disease-specific registry, RWD, site surveys, and KOL interviews. Concurrently, medical experts in pediatric metabolic disease evaluated local standards of care, including regional use of newly approved targeted therapies, diagnostic and referral pathways, and treatment access, to model enrollment dynamics and project the realistically identifiable patient population in each target region. 

The analysis was subsequently validated at the site level, accounting for each site’s referral network, historical patient access and database, anticipated screen failure rates, and the ability to support pediatric patients and caregivers through an intensive early-phase study. This enabled more realistic recruitment forecasting and early development of targeted mitigation strategies. However, patients with rare diseases and expertise remain concentrated in a limited number of specialist centers, and access is highly disease-specific. 

To address the 2nd and 3rd challenges, Parexel identified DCT as an operational solution to reduce patient burden. For Japan, a proactive approach is required to identify a workable solution with detailed planning. Parexel is well-positioned for this, with significant experience working with leading early-phase sites and in DCT solution development. Rather than deploying costly global home-nursing vendors, Parexel partnered with the Ph1 unit at a university hospital, which is DCT-enabled, and our partner DCT site (Tokyo Center Clinic), which is also an experienced clinical research site. Staff at the partner clinic conducted compliant, localized home nursing visits and essential patient monitoring, which is cost-effective while maintaining full Good Clinical Practice (GCP) compliance. Combined with dedicated travel coordinators to manage patient transport, this localized solution ensured consistent cohort enrollment and protocol adherence in all the participating sites.

Section 3: Forward-Looking: what global rare disease sponsors should do 

Integrating Japan into early-phase clinical programs - the time to act is now

Integrating Japan into early-phase clinical programs is an active strategy to accelerate global rare disease programs and development timelines. Japan is now an attractive global trial destination for rare disease clinical development, driven by PMDA’s more flexible regulatory approach, Japan’s established specialist centers and growing use of disease registries and real-world data to support patient identification and clinical research (particularly in genetic, metabolic, neurological, cardiovascular and renal rare diseases) and its advanced academic and early-phase clinical trial infrastructure. Including Japan from the outset, rather than as a late-stage addition, can support more efficient global evidence generation, reduce downstream development gaps and enable earlier access for Japanese patients. With the right integrated strategy, Japan can shift from a traditionally later-stage market to a powerful accelerator of global rare disease development.  

At Parexel, we help sponsors: 

• Activate the Japan regulatory framework through coordinated global and local regulatory expertise, early PMDA engagement, and knowledge gained from past success 
• Deliver complex early phase protocols efficiently by leveraging expert site networks, different study strategies and patient populations, and 
• Integrate medical, regulatory, feasibility and operational expertise from Day 1, ensuring decisions are evidence-based, executable and tailored to the disease and patient population. 

For global rare disease sponsors, engaging early with Parexel and leveraging our end-to-end capabilities would help capitalize on these opportunities and ultimately bring life-saving therapies to patients across the globe faster. 

Resources

1. Ministry of Health, Labour and Welfare (MHLW)."Relaxation of Standalone Local Phase 1 Study Requirements for Multiregional Clinical Trials," PSB/PED Notification No. 1225-2, issued December 25, 2023.

2. Japan External Trade Organization (JETRO). Life Science Industry Overview: Attractive Markets, 2024.

3. MHLW."Operational Guidelines for Decentralized Clinical Trials (DCTs) and Partner-Site Home Nursing Execution," Notification No. [Insert specific March 2026 registry number], March 2026.

4. International Council for Harmonisation (ICH)."Ethnic Factors in the Acceptability of Foreign Clinical Data," Guidance for Industry, ICH E5(R1).

5. Pharmaceuticals and Medical Devices Agency (PMDA)."Conditional Early Approval System for Innovative Drugs and Medical Devices," Evaluation and Licensing Division Framework.

6. Kyoto University Hospital, Clinical Research Center for Medicine and Therapeutics."Ki-Connect Advanced Therapy and Proof-of-Concept Unit Capabilities Portfolio."

7. MHLW Ordinance No. 28."Ordinance on Good Clinical Practice (GCP) for Drugs," as amended to accommodate localized home nursing execution networks.

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