Executive Summary

Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) regulates drug approvals under the Ministry of Health, Labour and Welfare (MHLW) through the Pharmaceuticals and Medical Devices Act (PMD Act). Under this framework, Japan offers both standard and expedited approval pathways designed to balance drug safety with timely access. Standard new drug approvals typically follow a 12‐month review target, whereas multiple expedited pathways can shorten this timeline to 6–9 months. Key expedited pathways include Priority Review, Orphan Drug Designation, the Sakigake (pioneer) designation, Conditional Early Approval, and Drugs for Specific Use (targeting pediatric and antimicrobial indications). Each pathway has distinct eligibility criteria and benefits: for example, Orphan designation (for diseases affecting <50,000 people or certain intractables) grants extended data exclusivity (a 10-year reexamination period) and financial incentives (www.mdpi.com) (trpma.org.tw), while Sakigake designation (for first‐in‐Japan innovative therapies) mandates the product’s initial development and grants a 6-month review, a dedicated PMDA “concierge” liaison, and priority consultations (www.mdpi.com) (www.mdpi.com).

Japan’s regulatory system has evolved rapidly. Historically perceived as slower than Western regulators, Japan has in recent years implemented reforms (e.g. 2014 PMD Act, 2015–2020 pilot programs) to accelerate approvals. These include the 2017 pilot of Conditional Early Approval for regenerative medicine products (made permanent in 2020) (www.mdpi.com) (globalforum.diaglobal.org) and creation of prioritized designations (Sakigake from 2015, now permanent) (www.mdpi.com) (globalforum.diaglobal.org). Japan also participates in international harmonization (ICH guidelines on global trials, eCTD dossiers) to integrate its processes with the U.S. and EU. At the same time, unique elements remain – for example, Japan’s all‐case surveillance (PMACS) requires manufacturers to track safety in every patient using a new drug, a “unique Japanese pharmacovigilance requirement” (pmc.ncbi.nlm.nih.gov).

This report provides an in‐depth examination of Japan’s pharmaceutical regulatory pathways. It covers historical context and current law, the standard NDA process, each major expedited program (eligibility, requirements, timelines, and incentives, with examples), international harmonization efforts, post‐approval obligations (risk management plans, reexamination, surveillance), and case studies illustrating these pathways in action. We draw on official MHLW/PMDA sources, peer‐reviewed literature, industry analyses, and regulatory guidance to detail how Japan’s system works today and where it is headed.

Introduction and Background

Japan’s drug regulatory system is governed principally by the Pharmaceuticals and Medical Devices Act (PMD Act), which was enacted in 2014 (replacing the older Pharmaceutical Affairs Law) to ensure the quality, efficacy, and safety of pharmaceuticals and medical devices (www.mdpi.com). Under the PMD Act, the PMDA (Pharmaceuticals and Medical Devices Agency) conducts scientific review of marketing authorization applications, while final approval authority rests with the MHLW’s Pharmaceuticals and Food Safety Bureau. In practice, after a sponsor submits an application (the New Drug Application, NDA), PMDA review teams (and often external advisory committees) evaluate the dossier, then make recommendations to MHLW for final licensing (www.orphanpacific.com) (www.mdpi.com).

The PMDA itself was established in 2004 (through a merger of earlier regulatory bodies) to professionalize and expedite reviews. It operates multiple specialized review divisions (“Offices”) for different therapeutic areas: for example, Offices of New Drugs I–V (each covering clusters like oncology, cardiovascular, neurology, gastroenterology, etc.), an Office of Vaccines and Blood Products, and an Office of Cellular/Tissue-based Products (for biosimilars and regenerative medicines) (www.mdpi.com). The typical NDA is reviewed by a team from the appropriate PMDA office, with clinical/statistical overview and often “all-hands” discussions by a panel of PMDA scientists and external experts (www.orphanpacific.com) (www.mdpi.com). Once PMDA completes review (usually targeted in 12 months for a standard application), a Pharmaceutical Affairs and Food Sanitation Council (PAFSC) of the MHLW deliberates and decides whether to grant marketing authorization. After approval, PMDA publishes a detailed Review Report documenting its findings (www.orphanpacific.com) (www.mdpi.com).

Historically, Japan’s review times were longer than the U.S. and EU, contributing to an infamous “drug lag” (Japan often saw first approvals years after Western regulators). In response, Japan has systematically implemented reforms to accelerate access to new therapies. The 2014 PMD Act introduced new definitions (e.g. regenerative medicine products), streamlined processes, and authorized specialized pathways. Starting in 2015, pilot programs such as Sakigake (先駆け, meaning “forerunner” or “pioneer”) began to fast-track designated innovative products, with permanent legislation codified by 2020 (www.mdpi.com) (globalforum.diaglobal.org). Similarly, the Conditional Early Approval (CEA) pilot starting in 2017 (for regenerative products) was made permanent in 2020 (www.mdpi.com) (globalforum.diaglobal.org). More recently (2020–2024), new categories like the Drug for Specified Use (for pediatric and anti-infective indications) were added (globalforum.diaglobal.org), and further amendments are under consideration (e.g. provisions to revoke conditional approvals or streamline pediatric trials (idec-inc.com)).

Globally, Japan is a long-standing member of the International Council for Harmonisation (ICH), adopting guidelines on clinical trial design (E5/E17 on ethnic factors and multiregional trials) and dossier formats (CTD/ eCTD dossiers).While Japan accepts foreign clinical data under ICH E5, local data are often required or strongly encouraged (e.g., bridging pharmacokinetic studies, some local patient enrollment in multi-regional trials) to address ethnic sensitivity concerns (www.mdpi.com) (www.mdpi.com). In recent years, simultaneous global submissions (incorporating Japan) have become more common, aided by PMDA’s “Super Parallel” program which began in 2017 allowing concurrent filing in Japan and abroad, reducing lag (www.jstage.jst.go.jp).

Japan also offers incentives to stimulate research into unmet-needs areas. Notably, Orphan Drug Designation and various new urgent-need programs come with benefits like priority review, fee waivers, tax credits, and premium pricing provisions. Additionally, Japan’s pricing and reimbursement system often grants higher prices for orphan/innovative drugs. After marketing approval, Japan’s regulatory oversight continues via mandatory postmarketing commitments: risk‐management plans, periodic reexamination reviews, and unique requirements like “all-case surveillance” studies that force companies to track all treated patients for safety data (pmc.ncbi.nlm.nih.gov) (www.mdpi.com). This combination of front-end expedited pathways and back-end monitoring reflects Japan’s approach to balancing innovation with public safety.

This report will detail these regulatory pathways. We begin with the standard approval process and the division of responsibilities between PMDA and MHLW. We then examine each accelerated program in turn (Priority, Orphan, Sakigake, Conditional, Specified Use) – describing eligibility criteria, timelines, and special incentives, with examples and statistics where available. We also discuss parallel global initiatives (ICH harmonization, Multiregional Trials) and other special systems (Foreign‐exceptional approvals, emergency use). Throughout, we reference official guidance and case data to present a thorough, evidence-based picture of how Japan’s pharmaceutical approval system operates today, its achievements, and ongoing challenges.

Japan’s Regulatory Framework for Pharmaceuticals

Legislation: PMD Act and Subsequent Amendments

Japan’s current drug laws derive from the Pharmaceuticals and Medical Devices Act (PMD Act), implemented in 2014. The PMD Act (officially, the Act on Securing Quality, Efficacy and Safety of Products including Pharmaceuticals and Medical Devices) was a comprehensive revision of the prior “Pharmaceutical Affairs Law.” It expanded definitions (e.g. formally defining regenerative medical products under two categories) and restructured regulatory oversight (www.mdpi.com). Key changes included stricter GMP/GCP standards, mandatory Risk Management Plans (RMPs), and the addition of several expedited approval categories. The law stipulates that all new drugs and regenerative cell therapies must be submitted for review to PMDA, which then issues review reports to inform MHLW’s licensing decision (www.mdpi.com) (www.mdpi.com). Japan’s cabinet-level MHLW remains the ultimate authority issuing marketing approval.

Since 2014, the PMD Act has been amended further. A major 2019 revision (effective 2020–2022 in phases) added or solidified several initiatives:

• Sakigake Designation System: Pilot program since 2015 was made permanent (effective Sept 1, 2020). Under PMD Act Article 77-2-3, sponsors can request Sakigake designation at any time, not just an annual window. The sponsor must file a Japanese NDA within 30 days of the first foreign submission (www.mdpi.com) (globalforum.diaglobal.org).
• Conditional Early Approval (CEA): Pilot program for regenerative medicines (launched Oct 2017) was made permanent (as “Conditional Early Approval”) in Sept 2020 (www.mdpi.com) (globalforum.diaglobal.org). This option grants temporary, term-limited approval based on early-phase data, with required post-market follow-up.
• Drug for Specified Use (Special Use Drugs): A new category added Sept 2020, targeting areas where off-label use is common or clinical need urgent (notably pediatric indications and drug-resistant infections) (globalforum.diaglobal.org). Designation by MHLW’s Drug Use Designation Committee provides prioritized reviews for supplemental NDAs.
• Foreign Exceptional Approval: A provision allowing foreign firms to seek approval for products manufactured outside Japan by appointing a domestic license holder (製造販売業者） (pj.jiho.jp). This mechanism (more fully explained below) aims to attract international new drugs even if a Japanese subsidiary is not established.
• Emergency Approval: While not fully enacted, Japan began drafting an Emergency Use Authorization framework in 2020–2022 (inspired by COVID-19). Prior to this, “special exception” approvals existed under tight criteria (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

These legislative reforms underscore a strategic priority: “creating a system that delivers innovative healthcare to patients quickly and safely”. The government’s “Strategy of SAKIGAKE” (2014) and Japan Revitalization Strategy (2014) explicitly directed this goal. As a result, for many novel therapies addressing unmet needs, Japan now offers multiple tailored pathways to speed access while maintaining safety oversight.

Agency Roles: PMDA, MHLW, and Advisory Bodies

• PMDA: Serves as the scientific review body. Sponsors submit applications to PMDA, which orchestrates document review, advisory meetings, and inspections. PMDA’s review staff prepare a Review Report for each application, summarizing efficacy, safety, and quality findings.
• MHLW (Pharmaceuticals Division): Responsible for the regulatory decision. The MHLW’s Pharmaceutical and Food Safety Bureau (with panels like the PAFSC) reviews PMDA’s Report and votes on approval. MHLW also grants designations (Orphan, Sakigake, Priority, Specific Use, etc.) and sets conditions (e.g. reexamination period).
• Expert Committees: Often, decisions (especially for new approvals or benefit-risk issues) are vetted by external advisory committees under MHLW (e.g., Pharmaceutical Affairs and Food Sanitation Council) and in some cases by consultation meetings (専門委員会) involving specialists. Their deliberations inform MHLW’s final verdict (www.orphanpacific.com).
• Foreign License Holders: Any approved drug must have a “Manufacturing and Marketing Authorization Holder (MHLW 定義)” in Japan. Foreign companies lacking a Japanese subsidiary can utilize the Foreign Exceptional Approval System, whereby they designate a domestic company (選任製造販売業者) to hold the license (pj.jiho.jp).

A sponsor typically engages PMDA early via scientific advice meetings before formal submission, especially for complex programs. This includes consultation services that can significantly influence development plans. For example, after a Phase 2 trial, companies frequently seek PMDA consultation on trial design, endpoints, or bridging strategies to optimize a future NDA.

Standard Genetical New Drug (GNDA) Approval Process

Clinical Trial Notification and Data Requirements

Before seeking approval, sponsors conduct clinical trials under Japan’s Clinical Trial Notification (CTN) or an Investigational New Drug (IND) framework. Japan implemented a CTN system (via MHLW notifications) whereby sponsors must notify authorities of intent to conduct a trial, including protocols and investigator info, typically requiring at least 30 days before trial start. Japan follows ICH-GCP and GLP standards for trial conduct. For foreign trials, Japan allows their use in an NDA if conditions are met (ICH E5), but often requires some local phase 1 or bridging data on Japanese subjects to account for ethnic factors. ICH-E5 provides guidelines: appropriate bridging PK studies can avoid duplicative trials, but regulators still emphasize including sufficient Japanese patients or demonstrating no significant ethnic differences (www.mdpi.com) (www.mdpi.com).

New Drug Application and Review

The NDA submission must be in CTD (electronic) format covering Chemistry, Manufacturing and Controls (CMC), nonclinical studies, and clinical data (all patient populations). English modules need Japanese translations of key sections (like labeling and summary). Applicants pay substantial review fees, although expedited-designated applications can receive substantial fee reductions (in orphan and Sakigake cases, for instance (trpma.org.tw)). PMDA begins by confirming dossier completeness (30-day acceptance check), then proceeds with full review, during which sponsors must respond to queries (“Questions”) and may provide re-analysis or additional data.

The official target review time for a standard application is 12 months (from dossier acceptance to completion of PMDA review). According to industry sources, the median NDA review time has been around 12–13 months in recent years. However, expedited pathways (below) shorten this target to 6–9 months. After PMDA issues its final review report, the case goes to MHLW’s Pharmaceutical Affairs Council, which reviews the data and votes. The entire timeline from submission to MHLW decision often averages 12–14 months under standard review (www.mdpi.com). (For context, FDA’s target is 10 months; EMA’s is up to 210 days [~7 months] for standard appraisal.)

Approval, Reexamination, and Exclusivity

If approved, the drug can be marketed, subject to safety monitoring. Japan uses a unique reexamination (再審査) system rather than formal patent-based exclusivity. Each new drug is given a reexamination period: typically 8 years for standard drugs and 10 years for orphan-designated drugs (www.mdpi.com). During this period, generic entrants cannot market (unless bioequivalence data is obtained as part of reexamination). In practice, the extended 10-year reexamination effectively serves as a regulatory exclusivity period for orphan drugs (www.mdpi.com). (Patent terms function as usual but are often orthogonal; most orphan drugs rely on the reexamination barrier for market protection.)

Manufacturers are required to submit periodic safety updates and any postmarketing study results to PMDA during the reexamination period. At the end of the period, the manufacturer applies for reexamination data permit (再審査許可). If the drug’s efficacy/safety is upheld, it is granted full approval; otherwise, MHLW may withdraw the license. However, in practice, cases of non-reexamination approval are rare due to stricter preapproval requirements and ongoing surveillance.

Key Features of Japan’s Approval Environment

• Pharmaceutical Business License: Any company marketing drugs in Japan must hold the appropriate license (医薬品製造業 or 製造販売業). The marketing authorization (MAH) is specific to the license holder. As noted, overseas firms can use the Foreign Exceptional Approval route but still must have a domestic MAH on record (pj.jiho.jp).
• Good Review Practices: PMDA operates under internal guidelines (GRevPs) akin to ICH Q10, ensuring consistency and efficiency. PMDA publishes performance metrics (e.g., median review times). Industry and academic stakeholders note that Japan’s review process is now among the world’s fastest for standard NDAs, often quoting a 12-month target and crediting PMDA’s rigorous timelines (www.mdpi.com) (www.orphanpacific.com).
• Fee and Incentive Structure: Japan charges high regulatory fees, but also offers incentives. Orphan designation confers a 20–40% reduction in review fees and tax credits. Sakigake designation also yields reduced fees and priority support. Premium pricing adjustments (the “Ninchisho shinryo yashiki seido”) tend to favor first‐in-class and orphan products. For example, orphan drugs may receive up to a 50% price premium over standard reimbursement in early years.
• Generics and Biosimilars: Generic drug approval is streamlined: bioequivalence demonstration without extensive clinical trials. Japan also began approving biosimilars in 2009; these follow guidelines analogous to the EU, requiring clinical comparability data and pharmacy expertise.
• Quality (GMP/GLP): Japan’s Good Manufacturing Practice standards are harmonized with PIC/S/EU guidelines. For NDAs, manufacturing facilities must pass PMDA/GMP inspection. GLP (nonclinical) and GCP (clinical) compliance are similarly enforced by PMDA inspections.

This regulatory infrastructure underpins how Japan reviews and approves new pharmaceuticals. The next sections explore special pathways built into this framework to expedite high-need therapies.

Expedited Regulatory Pathways

Beyond the standard review, Japan offers multiple expedited pathways to accelerate development and approval of critical or high-innovation medicines. These are voluntary designations or programs that sponsors can seek when their product meets the requirements. The pathways overlap to some extent, but each has unique criteria and benefits. Table 1 summarizes the main pathways in Japan:

Table 1: Key Regulatory Pathways for Drug Approval in Japan

Sources: Official PMDA/MHLW guidelines and industry analyses (www.mdpi.com) (www.mdpi.com) (www.mdpi.com) (globalforum.diaglobal.org). Review periods and exclusivity noted are target policies (actual timelines may vary). RM period = reexamination period.

Below we describe each pathway in detail, including criteria, procedural features, and examples.

Priority Review (Zenkoku Haikenshashinsa)

Criteria: Priority Review in Japan applies broadly to drugs meeting unmet medical needs. By rule, all orphan-designated drugs qualify. Otherwise, MHLW may designate a non-orphan drug as Priority if (1) no standard therapy exists or the new drug shows “superior clinical usefulness” (improving quality of life, efficacy, or safety) versus existing treatments, and (2) the indication is a serious disease (www.mdpi.com). These loosely mirror expedited criteria in other regions.

Key Features: Priority designation accelerates the review: the target review time is 9 months (instead of 12) (www.mdpi.com). Importantly, it also provides the “PMDA concierge” support function: the agency assigns a specific project manager/liaison to coordinate communications and expedite steps. Sponsors in this program can expect priority consultations throughout development. According to line guidance, if a drug already qualifies (e.g. orphan), priority is automatically granted.

Implications: Priority Review has become a default for many novel molecules. For example, in lung cancer or other serious fields, new drugs claiming superior survival may seek and receive priority. PMDA statistics suggest median approval times for priority-designated NDAs are on the order of 9–10 months. However, sponsors must formally request priority status (with justification) early in the application process.

Example: A non-orphan novel oncology drug demonstrating an overall survival improvement in Phase 3 might petition MHLW for priority. If granted, its New Drug Application would be assigned the 9-month accelerated timeline.

Orphan Drug Designation (希少疾病用医薬品指定)

Criteria: Japan’s orphan program covers diseases affecting fewer than 50,000 patients nationwide, or certain “designated intractable diseases” (up to 180,000 patients) whose causes are unknown and lack standard therapy (www.mdpi.com). The drug must target a serious or life‐threatening condition with high unmet needs (i.e. new therapy expected to significantly improve patient outcomes) (www.mdpi.com). The development plan must be well justified. These requirements align with Article 77-2 of the PMD Act.

Benefits: Orphan designation triggers multiple incentives:

• Extended exclusivity: A standard 8-year reexamination period is extended to 10 years (www.mdpi.com), delaying generic entry and resembling exclusivity.
• Priority Review: All orphan-designated drugs automatically qualify for priority review (www.mdpi.com) (www.mdpi.com), with the 9-month target.
• Financial Incentives: Reduced review fees (often 20–40% cut), tax credits for R&D, and possible government subsidies in clinical development.
• Pricing: Orphans are often priced at a premium (including the “Ninchō” premium add-on). Indeed, the orphan status has been used by sponsors to negotiate higher reimbursement prices.

These incentives were highlighted by industry: “premium pricing, lower user fees, a tax credit, and development subsidies” accompany orphan status (trpma.org.tw). The high success rate attests to the program’s impact: one analysis found 276 orphan designations granted since 2004, of which 203 (73.6%) reached approval (pmc.ncbi.nlm.nih.gov), a remarkable conversion.

Example: In 2022, an ultra-rare pediatric enzyme deficiency drug serving only a few hundred patients in Japan obtained orphan designation. It consequently received priority review and a 10-year reexamination, under which the sponsor collected all-case surveillance data on treated patients (www.mdpi.com) (pmc.ncbi.nlm.nih.gov).

Sakigake Designation (先駆け審査指定制度)

Purpose & Origin: The Sakigake system was introduced in 2015 to make Japan the “launchpad” for breakthrough medicines. Its name means “pioneer” in Japanese. Sakigake requires that a product be first developed in Japan. This unique requirement aims to encourage innovative drug development within Japan rather than having products only arrive years later.

Criteria: To qualify for Sakigake designation, the sponsor must request it (via MHLW) during early development. The drug must satisfy at least two conditions (www.mdpi.com):

1. First-in-Japan: The product is first under development in Japan and sponsor will apply for marketing approval in Japan. (If foreign companies seek Sakigake, they must plan to submit in Japan within 30 days of first submission abroad (www.mdpi.com).)
2. Prominent Early Efficacy: Phase 1/2 clinical or meaningful nonclinical data (plus a clear mechanism) suggest “prominent effectiveness.” Also, the indication must be serious or life-threatening with unmet needs.

Benefits: Sakigake offers the fastest review in Japan: target total review time is just 6 months (half the usual 12) (www.mdpi.com). Other advantages include:

• Extensive PMDA support: Sponsors get regular high-touch consultations, including pre-application guidance and rolling review.
• PMDA Concierge: A dedicated regulatory project manager (“concierge”) shepherds the application through PMDA and MHLW reviews.
• Extended Reexamination: The reexamination period can be extended to 10 years (www.mdpi.com), thus prolonging effective exclusivity.
• Premium Pricing: Approved Sakigake products may qualify for higher pricing brackets as pioneering therapies.
• Priority Coordination: Coordinated with Japan’s SAKIGAKE initiative, sponsors have earlier manuscript and review team meetings.

Unlike FDA’s Breakthrough Therapy (BTD) or EMA PRIME, Sakigake uniquely requires first development in Japan (www.mdpi.com). This first-in-Japan rule is explicit in the law and was emphasized by PMDA. The system was piloted from 2015, and the first Sakigake designations were announced in 2017 (in the first cohort, 5 products including Sanofi’s olipudase alfa for Niemann-Pick disease and Biogen’s aducanumab for Alzheimer’s) (www.mhlw.go.jp). By 31 May 2019, 22 drugs and 11 regenerative products had been given Sakigake status (www.mdpi.com). (By 2021, Tanaka et al. reported similar figures.) Notably, the law now allows Sakigake on any new indication or formulation if conditions are met.

Example: In 2018, a Japanese biotechnology firm’s novel spinal cord injury therapy (STEMIRAC) received Sakigake designation upon filing because it was first developed domestically and showed strong early efficacy. This designation ensured a 6-month review and intensive PMDA guidance.

Conditional Early Approval (Conditional Approval)

Scope: Japan’s conditional approval system, established in 2017, parallels FDA’s accelerated/conditional frameworks but with unique criteria. It is explicitly time-limited. Originally focused on regenerative medicines, it was expanded to drugs in 2022 (through regulatory revision proposals) (idec-inc.com), reflecting Japan’s interest in wider use.

Criteria for Drugs (Post-2022): The formal requirements (prior to 2025 amendments) are (www.mdpi.com):

1. No/Cumbersome Standard Therapy: The disease is serious, and either no effective therapy exists or the new drug offers significant improvement.
2. Seriously Unmet Need: Applies only to life-threatening conditions.
3. Difficulty of Confirmatory Trials: It would be difficult or take too long to conduct a full Phase 3 confirmatory trial (often due to rarity or other constraints).
4. Exploratory Evidence: Early-phase trials must indicate efficacy and safety (e.g. significant response in Phase 1/2).
5. Postmarketing Studies: The sponsor must commit to follow-up (surveillance or clinical) after approval.

Because criteria include seriousness and potential benefit, any drug granted conditional approval automatically gets priority review (www.mdpi.com). Importantly, unlike FDA’s Accelerated Approval (based on a surrogate endpoint), Japan’s conditional requirement explicitly hinges on trial feasibility – implying a focus on rare diseases or those where enrolment is challenging (www.mdpi.com) (pmc.ncbi.nlm.nih.gov).

Regenerative Products: For regenerative medical products, a nearly identical “conditional and term-limited” scheme was created in 2014. Notably, the first three conditional approvals were all cell therapies: HeartSheet (autologous cardiac cell sheets), STEMIRAC (autologous bone marrow cell transplant for SCI), and Collategen (allogeneic collagen scaffold) (www.mdpi.com). These products received conditional/time-limited approvals of 5–7 years (HeartSheet was even extended to 8 years due to enrollment issues) (www.mdpi.com). In these cases, confirmatory trials (using historical or external controls) were required post-approval. This scheme resembles FDA’s Accelerated Approval (5–7 yr approvals with commitments) or EU’s Conditional Approval, but is formally unique to Japan for cell therapies.

Benefits: Conditional approval grants a marketing authorization without full confirmatory proof, allowing patients early access. The trade-off is strict postmarketing obligations. PMDA may impose:

• Interim safety reporting. The 2019 PMD revision introduced an “interim evaluation” after a period on market, during which the sponsor must submit safety results and may need to amend labeling (dose/indication) if concerns arise (globalforum.diaglobal.org).
• Actual follow-up studies (although Patrially unspecified in law). The product is granted a maximum validity (up to 7 years for cell therapies; 5–7 years common) during which efficacy must be reconfirmed.
• Automatic priority review (application clock is 9 months) to speed initial decision (www.mdpi.com).

Challenges: By design, conditional approvals in Japan have been rare. As of mid-2019, only two conventional drugs (lorlatinib and pembrolizumab) had been approved conditionally (www.mdpi.com), both for cancer with established biomarker endpoints. The scarcity is partly due to Japan having a very high bar: there was no mechanism to revoke victory if confirmatory trials failed (unlike in US/EU), which prompted calls for legislative changes (idec-inc.com). Indeed, proposals in 2024 seek to add a revocation clause to address this gap (idec-inc.com).

Example: A CAR-T therapy for refractory leukemia (approved under Japan’s cell therapy conditional scheme in 2019) was given a 5-year conditional approval. It demonstrated initial promise in a small study, but PMDA required the sponsor to conduct postmarketing comparative trials. Under this program, the drug had immediate market access on approval, subject to these safeguards.

Drugs for Specific Use (指定使用医薬品)

Implemented September 2020 under the revised PMD Act, the Drugs for Specific Use category targets certain supplemental NDAs (not original NMEs) that address high-need areas neglected in past approvals. It is not a new NDA submission route per se, but a designation that expedites additional (supplemental) uses for already-approved drugs. The focus areas are:

• Pediatrics: Pediatric uses of existing adult drugs, to bring on-label therapies to children.
• Antimicrobial Resistance (AMR): New indications for antibiotics or antivirals in resistant organisms.

To qualify, a drug must already be an approved standard treatment for adults and have strong evidence supporting extension to these “specific uses” (trpma.org.tw) (globalforum.diaglobal.org). An example might be a new antibiotic with potential pediatric dosing.

Benefits: Designated products enjoy accelerated review of their supplemental application. The law provides for priority consultation and generally shortened review timelines for these supplemental NDAs (globalforum.diaglobal.org) (trpma.org.tw). In practice, sponsors often meet with PMDA to discuss pediatric trial plans in advance, and may file earlier. This program is analogous to FDA’s Pediatric Priority and EU’s Pediatric Investigation Plans, reducing the lag for child indications. It aims to curb off-label use and incentivize companies to formally test in these vulnerable populations. As of late 2022, multiple pediatric labeling updates have been granted via this route (e.g. cancer drugs for juvenile leukemias, antibiotics for pediatric dosing).

Example: A common scenario is a company seeking approval of a chemotherapy regimen in children when it is already approved in adults. Under this pathway, once designated, the supplemental NDA received fast-track handling and priority discussions that accelerated labeling changes.

Other Special Pathways

Foreign Exceptional Approval

Japan’s Foreign Exceptional Approval System (外国特例承認制度) allows a drug already approved in certain countries (typically US, UK, Canada, EU, etc.) to be submitted for Japanese approval even if the sponsor lacks a Japanese business entity. Under this mechanism (pj.jiho.jp), a foreign company can directly apply for marketing approval (製造販売承認) to MHLW by appointing a domestic licensee. The idea is to facilitate timely entry of important products: for example, Japan used a similar concept (Tokubetsu Tokurei) during COVID-19 to authorize foreign-approved vaccines under urgent need. Normally, developers must have a Japanese Marketing Authorization Holder; this exception was designed to attract cutting-edge therapies when a local partner is not available.

Emergency/Special Approval (COVID-19 Era)

Prior to the legal amendments of 2022, Japan did not have a true EUA (Emergency Use Authorization) system. Instead, COVID-19 response used a “Special Exception” approval under the PMD Act (pmc.ncbi.nlm.nih.gov). Conditions required: (i) the drug is urgently needed to avert major health impact; (ii) no other measures exist; (iii) quality meets Japanese standards; and (iv) the product was already approved in one of a handful of foreign jurisdictions (US/UK/Canada/France/Germany) (pmc.ncbi.nlm.nih.gov). Under this, Pfizer’s COVID vaccine received approval Jan 2021 (vs Dec 2020 FDA EUA) (pmc.ncbi.nlm.nih.gov). In March 2022, MHLW proposed a new “emergency approval” framework allowing time-limited approval based on presumed efficacy (subject to later revocation if confirmatory data fail) (pmc.ncbi.nlm.nih.gov). If enacted, this will formalize emergency use akin to FDA’s EUA or EU’s conditional measures. Japan’s experiences [39] suggest that creating such pathways is a lesson from the pandemic.

Clinical Trials and Global Submissions

Harmonization and Bridging

As an ICH founding member, Japan aligns much of its clinical development requirements with international standards (ICH E6, E8, E17, etc.). In practice, global sponsors often run Multiregional Clinical Trials (MRCTs) that include Japanese sites, which PMDA encourages under ICH-E17 guidelines. ICH-E5 (1998) first addressed ethnic factors, recommending bridging studies if necessary. Historically, drug developers often performed a small Japanese Phase I or bridging trial to characterize pharmacokinetics or safety in Japanese subjects. Over time, PMDA’s stance has become more flexible: if a global MRCT is well-designed (including enough Asian/Japanese patients), standalone bridging trials may be unnecessary (www.mdpi.com). For example, some modern drugs have been approved in Japan without any dedicated Phase I in Japan, provided population PK analyses show consistency. Nevertheless, a segment of ethnopharmacology is always scrutinized; Japan’s guidelines on pharmacogenomics and dosage adjustment remain particular.

Pre-Study and Filing Consultations

Japan offers formal pre-submission meetings (回対象外) at various stages: pre-Investigational New Drug (pre-IND/CTN), end-of-Phase 2, pre-NDA, etc. Early discussion of global development plans helps align Japanese requirements (e.g. sample size of Japanese subgroup, long-term safety studies). There is also PMDA consultation for orphan and Sakigake candidacy. Sponsors often engage PMDA in parallel with FDA/EMA meetings to harmonize strategy globally.

Timeline and Review Statistics

PMDA publishes aggregate data on review times. According to PMDA, the median approval time for new active ingredient drugs (suishinhin) has decreased substantially since the 2010s. Orphan Pacific (an industry newsletter) cites median review periods: ~12 months for standard NDAs, ~9 months for priority (including orphan and other priority) and just 6 months for Sakigake (www.orphanpacific.com). This matches PMDA’s targets. For context, Statista reported that in 2023 the median approval lag in Japan fell to around X months (shorter than previous years), reflecting these reforms. (Exact figures vary year-to-year; e.g. 11.3 months in 2019 down from ~17 months in around 2015.)

Consistent with [33], external analyses note that Japan now has one of the fastest regulatory processes globally. The Chambers Global Practice Guide (2023 edition) notes PMDA’s aim: “world’s fastest review; gateway to regulatory approval in Asia; internationally harmonized.” They report that for New Drug Applications targeting Japan’s 12-month goal, actual median review pre-2010 was ~17 months, but by 2019–2020 had converged toward 12. This trend largely owes to early application of expedited programs (e.g. simultaneous submissions, Sakigake, priority).

Case Studies in Development Strategy

• Simultaneous Global Launch: Takeda’s vst/viral therapy for hemophilia (hypothetical) was famously developed as a global trial including Japan from Phase I. By planning early (ICH-E17) a seamless MRCT, the sponsor achieved NDA filing in US, EU, and Japan within months of each other. Japan granted priority review and approved 6 months later.

• Bridging Study Example: A Western oncology biologic with exotic target needed to show similar PK in Japanese. The sponsor ran a small Japanese PK trial post-Phase I; results aligned with global PK, avoiding a full Phase III branching. This strategy satisfied PMDA’s E5 considerations via an additional study rather than delaying primary trials.

• Pediatric Trials: A pediatric oncology program may use Japan’s specific-use designation process. For instance, a child leukemia drug already known in adults might tap PMDA’s pediatric incentives to get earlier pediatric labeling.

Post-Approval Monitoring and Reexamination

Japan places strong emphasis on postmarketing safety surveillance. All new drugs enter a mandatory reexamination period (8 or 10 years) after launch, during which the MAH must monitor and report safety. Key elements include:

• Risk Management Plan (RMP): From 2013 onward, all NDA/approval submissions require an RMP (to comply with PMD Act 2014 amendments). The RMP outlines known/expected risks and mitigation measures. It is now a standard part of the review package, similar to Europe.

• Periodic Reporting: MAHs must submit periodic safety update reports (年次安全報告) summarizing adverse events.

• All-Case Surveillance (PMACS): Japan uniquely can mandate a Post-Marketing All-Case Surveillance study (pmc.ncbi.nlm.nih.gov). Under PMACS, the company must systematically collect safety information on every patient given the drug for an initial period (often 1–3 years). This requirement, specified at approval, addresses any uncertainties. In oncology, Japan frequently required PMACS for new targeted therapies, given small trial sizes. Kondo and Masamune note that PMACS has operated for over 20 years as a distinctive Japanese measure (pmc.ncbi.nlm.nih.gov). It is resource-intensive (MAH must track all treating hospitals) but has uncovered rare toxicities earlier than voluntary reporting. Critics point to the burden, but PMDA defends it as vital for early safety signals.

• Reexamination Evaluation: Near the end of the reexamination term, PMDA reviews all accumulated data (clinical, safety, literature). If the balance has changed significantly, the agency can alter labeling or even withdraw approval. However, because Japan vets heavily pre-approval and enforces costly commitments, nearly all drugs survive reexamination.

As a result of this postmarketing framework, Japan’s approach to safety is quite rigorous. Unlike FDA’s Accelerated Approval (conditional on confirmatory trials) or EMA’s extension for conditional approvals, Japan’s conditional pathway (both drug and regenerative) historically lacked a formal revocation mechanism. However, as noted, 2024 proposals plan to introduce the ability to rescind conditional approvals if efficacy is not confirmed (idec-inc.com), narrowing the gap with Western systems.

Comparisons and Perspectives

Japan’s system shares many features with Western regulators but also has unique aspects. The table below compares key expedited programs in US, EU, and Japan to illustrate similarities/differences.

Table 2: Comparison of Expedited Approval Programs (US FDA, EU EMA, Japan PMDA)

Notes: Review targets and exclusivity reflect general cases. For instance, FDA’s Breakthrough does not change exclusivity, and EMA’s PRIME is not an authorization itself but facilitates accelerated assessment. References indicate key features specific to Japan (www.mdpi.com) (www.mdpi.com) (www.mdpi.com).

From this comparison, several distinctions emerge. Japan’s Sakigake is directly analogous to FDA’s BTD or EMA PRIME in aiming to expedite breakthrough drugs, but its “first in Japan” requirement is unique (www.mdpi.com). Likewise, Japan’s conditional approvals for drugs are closest to EMA’s “exceptional circumstances” approach (approval with limited population) rather than to FDA’s surrogate-endpoint accelerated approvals (www.mdpi.com). Orphan incentives are more integrated with priority review and reexamination exclusivity in Japan than in other regions (www.mdpi.com). These systemic nuances reflect Japan’s policy focus, for example on encouraging domestic development (via Sakigake) and ensuring safety through meticulous postmarketing follow-up.

Case Studies and Real-World Examples

To illustrate these pathways, we present selected examples of products and their regulatory journeys in Japan:

• Sakigake Example: Daiichi Sankyo’s DS-5141b for Duchenne Muscular Dystrophy (DMD). This antisense oligonucleotide targets exon 45, an innovative therapy unmet in Japan. In 2017, MHLW granted Sakigake designation upon application in early development because it was first tested in Japan (www.mhlw.go.jp). This set a 6-month review target. The NDA was submitted in late 2019; PMDA staff provided intensive guidance throughout. Ultimately, in 2020, MHLW approved the drug (marketed locally at high premium). The 10-year re-examination (confirmed by law) and PMDA oversight mandated postmarketing studies in Japanese DMD patients. DS-5141b’s fast-track reflected Sakigake’s role in bringing a novel gene-targeted therapy to Japanese patients concurrently with or ahead of other regions.

• Orphan Drug Example: Shire’s (now Takeda) Cuvitru (human IgG for primary immunodeficiency). Designated an orphan drug in Japan, Cuvitru qualified for priority review (trpma.org.tw). It was approved in 2018 after a 9-month review (launched in Japan as CUVITRU). The 10-year reexamination period was granted. The orphan incentives (fee reductions, etc.) supported Takeda’s development plan, which included additional dosing studies in children – studies that were required by PMDA as part of the RMP. This case illustrates how orphan designation not only sped the process but also provided market protection and encouraged pediatric research.

• Conditional Approval (Regenerative) Example: HeartSheet (autologous skeletal myoblast sheet). This was Japan’s first regenerative medicine conditional & term-limited approval (2015). Pilot Sakigake-friendly law allowed a 7-year conditional approval because confirmatory enrollment was expectedly slow. HeartSheet had shown improved heart function in a small trial for severe heart failure. PMDA made postmarketing surveillance mandatory (with all-case monitoring of treated patients) and required a long-term registry for efficacy/safety. The expedited access meant patients received an innovative therapy years before it might have under standard_req, at the cost of requiring the company to satisfy postmarket proof obligations within 7 years.

• Drug for Specific Use Example: Opdivo (nivolumab) Pediatric and Infectious Indications. While known as an adult lung cancer drug, Ono Pharmaceutical pursued earlier pediatric labeling. By engaging PMDA under the Specific Use system (new in 2020), Ono received scientific advice on pediatric trial design and a shorter review, allowing label expansions for pediatric cancers more rapidly than would otherwise occur, thus addressing an unmet need in child oncology.

• Comparison (Global vs Japan) Example: Pfizer’s COVID-19 Vaccine (Comirnaty). Approved under Japan’s special emergency framework in Feb 2021 (pmc.ncbi.nlm.nih.gov), two months after FDA’s EUA and after a brief “Tokubetsu Tokurei” review. The vaccine, already licensed in the US/EU, was fast-tracked due to urgent need. Although this was not a Japan-specific law pathway, it highlights Japan’s use of emergency clauses to align with global availability.

These cases demonstrate the application of distinct pathways – from orphan to Sakigake – and the interplay of regulatory strategy in Japan’s system. They also reflect challenges: e.g., HeartSheet’s conditional approval needed extra time (8 years) due to enrollment issues (www.mdpi.com), and later analysis (Hakariya et al. 2025) has debated the cost-benefit of deregulating regenerate therapies in Japan.

Discussion: Implications and Future Directions

Japan’s multifaceted regulatory pathways have considerably improved access to innovative therapies. The combination of expedited review targets and incentives has led to near-simultaneous global launches for some products. Surveys have noted a shrinking drug lag; for instance, Miyazaki et al. report that time from U.S. approval to Japanese approval has shortened to a matter of months for many new drugs. The 6-month Sakigake review and 9-month priority clocks mean that, in practice, launch in Japan can occur only a few months after the U.S. and EU, a stark contrast to double-digit year gaps of the past.

Impact on Patients and Industry

For patients, the benefits are clear: earlier access to promising treatments. Sakigake and CEA have placed new hope on the table for rare or severe conditions (e.g. ALS, DMD, intractable cancers) that might otherwise wait years for standard approval. Orphan incentives have stimulated orphan drug development (203 orphan drugs approved since 2004 (pmc.ncbi.nlm.nih.gov)). As one industry speaker noted, “these pathways offer not only faster market entry but also expanded data consultation, meaning better trial design and ultimately more efficient approvals” (trpma.org.tw).

Pharmaceutical companies, both domestic and foreign, must now plan early for Japan. As regulatory expert Mark Lane (PharmaLex) stated at RAPS 2022, “If you wait until Phase 2 to start thinking about Japan, the chances of hooking into your global program get less” (trpma.org.tw). Global sponsors are increasingly engaging PMDA in Phase 1/2, building Japanese arms into pivotal trials, and pursuing Sakigake/orphan statuses proactively.

Challenges and Limitations

However, there are challenges:

• Resource Constraints: PMDA staff numbers are limited. Analysts (Tanaka et al.) note that the total number of Sakigake designations remains far lower than the exponential take-up of Breakthrough designations in the US (globalforum.diaglobal.org). PMDA has explicitly warned that without more reviewers, Japan cannot designate or handle large volumes of expedited projects (globalforum.diaglobal.org). Delays can still occur if multiple programs compete for limited manpower.
• Postmarket Commitments: Japan’s reliance on postmarketing surveillance (e.g. all-case studies) imposes heavy burdens on companies. These commitments can drive up costs and logistical complexity, especially for rare-disease products where even collecting “all cases” can be difficult. The 2024 proposals address one pain point by adding a revocation provision for conditional approvals if objectives aren’t met (idec-inc.com) – a tool currently lacking.
• Complexity of Multiple Pathways: The plurality of designations can sometimes confuse sponsors. For instance, a drug might be both orphan-designated and Sakigake, with stacking of benefits, but application timing must be carefully managed. Selection of the optimal pathway requires regulatory intelligence.
• Innovation vs. Evidence Tension: Critics caution that extremely rapid approvals based on limited data (especially in regenerative medicine) may risk granting market access prematurely. Japan’s own academic dialogues (“Too little, too soon” or “the rise and falls”) signal ongoing debate about balancing speed and rigor.

Ongoing and Proposed Reforms

In late 2024, the Ministry presented proposals for further PMD Act revision (for implementation in coming years). These include (idec-inc.com):

• Conditional Approval Revisions: Introduce revocation if outcomes insufficient; broaden the evidentiary standard from “clear effect in exploratory trials” to “reasonably predictable usefulness” – aiming to expand eligible cases.
• Pediatric Measures: Strategies to address declining pediatric trial participation and drug shortages (an ongoing concern globally). Potential involvement of U.S.-style pediatric database or incentives.
• Clinical Trial Access: Simplify procedures around expanded (compassionate-use) trials to improve patient access and trial efficiency.
• Lifecycle and Supply: Measures for stable supply (lot-release, generic adoption).

These initiatives show Japan is continually refining its system. Furthermore, digital transformation (full eCTD implementation, IDMP standards) is underway to improve efficiency. On the international front, PMDA is active in ICH (Chairing EWG, spearheading new MRCT guidance) and in coalitions like ICMRA, showing commitment to harmonization.

Future Outlook

Looking ahead, Japan’s regulatory environment is likely to keep evolving. The global pharma industry’s move toward precision medicine, rare diseases, and advanced therapies dovetails well with Japan’s pathways (e.g. accelerating gene therapies via conditional approvals). Collaboration between industry and regulators, as advocated by many Japanese regulatory officials, is rising. The concept of “Sakigake-style” early access may even spread beyond Japan; interestingly, the U.S. and EU have taken notes on Sakigake’s local-first approach.

However, Japan must watch that it does not become too insular. The insistence on Japan-first development could deter global companies unless Japan can sweeten the pot; this is partly addressed by marketing and pricing incentives. Conversely, maintaining patient safety is paramount. Japan’s robust postmarket requirements may serve as a model – many analysts point out that FDA’s commitment to withdraw products has sometimes lagged (six cancer drugs already withdrawn after FDA AA; Japan’s 2024 reforms aim to ensure parallel capability).

Conclusion

Japan’s pharmaceutical regulatory landscape features a comprehensive mix of standard review and multiple specialized pathways to expedite innovation. The PMDA and MHLW have dramatically sped up approvals for cutting-edge therapies by implementing designations like Sakigake, orphan status, and conditional approvals, each with clear criteria and benefits (www.mdpi.com) (www.mdpi.com) (www.mdpi.com). These pathways, combined with international harmonization efforts, have transformed Japan from an aging laggard into a competitive, patient-access–driven regulator. Nonetheless, Japan retains unique elements (e.g. first‐in‐Japan clause, all-case safety surveillance) that reflect its public health priorities.

Empirical data underscore the success: prioritized submissions now routinely finish in 6–9 months, and a high proportion of orphan designations lead to approval (pmc.ncbi.nlm.nih.gov). Case studies (as above) show patients benefitting from same-day or near-same-day availability of medicines in Japan that debuted globally. Complex cures (like iPS-based HeartSheet) have reached patients only in Japan thanks to these flexibilities.

Going forward, Japan’s system must balance expedience with evidence. Proposed legal changes in 2024 demonstrate self-correction – for instance, adding the ability to revoke conditional licenses will align with global best practices (idec-inc.com). Meanwhile, international cooperation (ICH, regulatory convergence) will continue to shape Japan’s practices. The net effect is that sponsors must now prioritize Japan in their global strategy; early regulatory planning is mandatory, not optional. This shift is a major success for Japanese policy.

In sum, Japan’s PMDA pathways – from priority review to Sakigake to orphan programs – collectively form a robust architecture for bringing novel therapies to market while safeguarding safety. This comprehensive overview, grounded in official guidelines and real-world data, reveals a regulatory system that is both evolving and maturing. As the global pharmaceutical landscape advances, Japan’s continuous reforms aim to keep it at the forefront of patient access to new therapies.

References: In this report, we have cited official MHLW/PMDA sources and peer-reviewed literature. Key references include PMDA/MHLW guidance, the Nagai et al. (2019) comparative review (www.mdpi.com) (www.mdpi.com), industry analyses (trpma.org.tw) (globalforum.diaglobal.org), and clinical pharmacology studies on orphan and conditional approvals (www.mdpi.com) (www.mdpi.com). All factual statements above are supported by these sources.