Introduction

According to the news (ドラッグ・ロス、まず78品目を解決　　国主導で、新たに発生した品目も | 日刊薬業 – 医薬品産業の総合情報サイト) released by NIKKAN YAKUGYO on 11/25/2024, Japan’s Ministry of Health, Labour and Welfare (MHLW) has launched a proactive initiative to address “drug loss,” focusing on unmet needs for rare and pediatric medicines. The government aims to clarify the drugs that are in urgent need and categorize them. The government starts to facilitate its development planning through structured requests and public calls for proposals.

Targeting 78 Drug Loss Items

The government initially started the work for 78 drugs identified in a 2023 survey. A particular research group led by PMDA expert Jun Sato collaborates with over 30 academic societies to assess medical necessity, gather evidence, and rank priorities. Reports will be submitted to MHLW, which will engage companies in addressing development challenges.

Structured Development Requests

Starting in May 2024, the “Unapproved and Off-Label Drugs Review Conference” will discuss high-priority drugs. Development will proceed through public proposals, with incentives for companies to participate.

Expanding the Framework

The framework will also address newly identified drug loss cases, with funding included in the 2025 budget. Gaps in the original list, such as older approvals, will continue to be handled under traditional processes.

Conclusion

This initiative offers a unique opportunity for international pharmaceutical companies to align with Japan’s rare and pediatric drug development priorities. By addressing critical gaps, MHLW aims to ensure broader access to essential medicines.

Introduction to New Approval Guidelines 

According to the news (日本人症例なしで申請可能なケースを通知　　超希少疾患が対象、審査課 | 日刊薬業 – 医薬品産業の総合情報サイト) released by NIKKAN YAKUGYO on 10/23/2024, Japan’s Ministry of Health, Labour and Welfare (MHLW) issued new guidelines on October 23, allowing for orphan drug approval in Japan without the clinical data in Japanese patients dependent upon the status of the medical practice/needs. This shift aims to improve Japanese patients’ access to critical medications by avoiding unnecessary delays caused by implementing additional local clinical trials. 

Conditions for Approval Without Japanese Clinical Data 

The new guidelines detail three key conditions under which an orphan drug can be approved without Japanese patient data: 

1. Completed Multi–regional Global Trials: If the primary clinical trials for the drug have been appropriately conducted globally, Japan’s health authority may accept the data without requiring local trials in Japan. 

1. Limited Patient Populations: Additional clinical trials may be impractical or impossible for rare diseases with extremely small patient populations. 

1. Benefit-Risk Favorability for Japanese Patients: If available evidence strongly suggests the drug’s benefits outweigh its risks for Japanese patients, Japan’s health authority will consider approval without Japanese patient data. 

Emphasis on Japanese Clinical Trials for Broader Approvals 

While this change offers flexibility, the MHLW reiterates that Japanese drug approvals should, as a rule, be based on clinical trials conducted either domestically or through multi-national studies involving Japan. When clinical or pharmacological differences exist between Japanese and non-Japanese populations, additional clinical trials may be required to ensure safety, dosing accuracy, and efficacy. 

Conclusion  

Japan’s updated guidelines for orphan drug approval underscore its commitment to improving patient access to critical treatments. By allowing some flexibility on the requirement for Japanese-specific clinical data, these guidelines aim to streamline access to vital medications for Japanese patients with rare diseases. This shift could benefit international pharmaceutical companies seeking to bring orphan drugs to the Japanese market more efficiently. 

Introduction to Regulatory Revisions 

According to the news (薬機法改正、審査の7論点を了承　　制度部会、条件付き承認の見直しなど | 日刊薬業 – 医薬品産業の総合情報サイト) released by NIKKAN YAKUGYO on Oct/03/2024, Japan’s Ministry of Health, Labour and Welfare (MHLW) presented seven key proposals to revise the Pharmaceutical and Medical Device Act during a meeting of the Pharmaceutical Affairs and Food Sanitation Council. These proposals include improvements to the conditional approval system for prescription drugs, strategies to address drug loss in pediatric medicines, discussions on GMP inspections, and stable drug supply. The council will finalize the revision proposals by December, with legal amendments following. 

Changes to the Conditional Approval System  

Unlike the US and European conditional approval systems, no regulation to revoke conditional approval after its commercialization has been set in the Japanese conditional approval system. This is why Japan has a higher hurdle to obtaining market approval, and there have been only a few cases in which the conditional approval system has been applied in Japan, unlike in the US and Europe. The government plans to introduce a revocation rule for the proposed revisions. In addition, the requirement to apply the system is revised from “cases shown clear effects in exploratory trials” to “cases reasonably predictable clinical usefulness “. This would allow us to expand the usage of the system and potentially speed up drug approvals. 

Facilitating Expanded Clinical Trials  

Japan also aims to simplify the procedures for expanded trials, ensuring better patient access to experimental treatments. This will streamline clinical trial processes, supporting local and international drug development efforts. 

Extended Re-Examination Periods for Pediatric Medicines  

To deal with the drug loss issue in pediatric medicines, MHLW proposes that pharmaceutical companies be obligated to establish pediatric drug development plans when applying for drug approvals. The re-examination period for such pediatric drugs would be extended by two years—normal drugs from eight to ten years and orphan drugs from ten to twelve years—offering incentives for companies to invest in pediatric drug development. 

Recognition of Real-World Data in Drug Applications  

MHLW is also working to enhance the use of real-world data (RWD)  in drug approval applications. The ministry intends to amend the law to clarify that RWD can be used in regulatory submissions, raising awareness of RWD’s potential to support faster approvals. 

Addressing Drug Supply Shortages  

To mitigate the impact of drug shortages, Japan plans to introduce new regulations allowing the fast-tracked approval and distribution of alternative overseas products during critical shortages. Special measures will also allow the use of foreign-language packaging for a limited time. These steps aim to prevent supply disruptions in the healthcare system. 

Streamlining Manufacturing Change Approvals  

Revisions are proposed to shorten the review period for moderate-risk changes in drug manufacturing processes from six months to 40 days. Additionally, the cap on monthly applications for process changes would be lifted, facilitating faster implementation of manufacturing improvements. 

Advancing Harmonization with Foreign Pharmacopeias  

Japan is working to harmonize its pharmacopeial standards with international ones, addressing bottlenecks faced by companies importing foreign-made drugs. This will simplify the approval and supply process for imported pharmaceuticals, ensuring timely patient access to medicines. 

Enhanced Access to Regenerative Medicine  

In a humanitarian move, Japan will allow pharmaceutical companies to provide regenerative medicine products that fall outside the usual standards if they meet specific criteria, improving patient access to advanced treatments. The government’s safety relief program will also cover such cases. 

Conclusion  

Japan’s proposed Pharmaceutical and Medical Device Act revisions aim to modernize the regulatory environment, enhance drug accessibility, and foster innovation. These changes will benefit domestic and global pharmaceutical companies by creating a more efficient drug development and approval pathway. The next meeting to discuss these proposals is scheduled for October 31st. 

Overview: Japan’s Ministry of Health, Labour, and Welfare (MHLW) has developed specific regulatory pathways to expedite the review and approval of innovative drugs. These systems aim to address unmet medical needs and provide patients quicker access to essential treatments. Ow, we explore three key systems: Orphan Drug Designation, the Sakigake Designation System, and the Conditional Approval System. Please also refer to the attached table for a detailed comparison of these systems (to get the higher-resolution image, please contact Eliquent Japan at info@idec-inc.com). 

1. Orphan Drug Designation System (ODD)  

The Orphan Drug Designation System supports the development of treatments for rare diseases. To qualify for this designation, a drug must be intended to treat a disease affecting fewer than 50,000 patients in Japan. Additionally, the drug must address serious conditions with high unmet medical needs. Key features of this system include: 

• Priority review with a shortened approval timeline of 9 months. 
• Financial support for development costs. 
• Extended market exclusivity for 10 years post-approval. 
• Price premium. 

This system ensures pharmaceutical companies can develop treatments for rare diseases with a shortened approval timeline. 

2. Sakigake Designation System  

The Sakigake (Pioneering) Designation System accelerates the approval of breakthrough therapies developed in Japan and shows prominent effectiveness in early-stage trials. Drugs under this system can expect: 

• Priority review with a 6-month approval timeline. 
• A designated PMDA manager who acts as a concierge, guiding the company through the regulatory process. 
• Early consultation with the PMDA, even before the formal submission of the Common Technical Document (CTD). 
• Price premium. 

This system is tailored for drugs developed first in Japan, which show significant potential compared to existing therapies.

3. Conditional Approval System  

The Conditional Approval System is designed for drugs that treat serious diseases but face challenges in completing large-scale clinical trials. It allows for early market entry based on limited clinical data, with conditions that must be met post-approval. Important aspects include: 

• Priority review with a 9-month approval timeline.
• Approval based on interim clinical results, with full approval granted after post-marketing studies confirm efficacy and safety. 

This system enables patients with life-threatening diseases to access new treatments earlier while additional clinical data is collected. 

Conclusion: These regulatory pathways highlight Japan’s proactive stance in promoting the development of innovative treatments, especially in areas with unmet needs. For pharmaceutical companies operating internationally, understanding and utilizing these systems can significantly shorten the time-to-market for new therapies, benefiting patients and healthcare systems alike. 

Introduction to Japan’s New Drug Development Initiative

According to the news (FIH試験体制整備、29年度稼働目指す　　世界の創薬シーズ呼び込む構想、厚労省 | 日刊薬業 – 医薬品産業の総合情報サイト (jiho.jp)) released by NIKKAN YAKUGYO on Sep/04/2024, the Japanese Ministry of Health, Labour and Welfare (MHLW) has recently announced an ambitious project aimed at establishing a state-of-the-art facility for First-In-Human (FIH) trials, which also includes Good Manufacturing Practice (GMP) compliant drug production capabilities and comprehensive research infrastructure. This new project, incorporated into the 2025 fiscal budget request as a ¥790 million initiative, reflects the ministry’s multi-year plan to bolster Japan’s drug development ecosystem. The ministry aims to complete the “specification design” of the facility by 2025 and have the FIH trial center operational by 2029.

Phased Approach to Facility Development

According to MHLW’s clinical trial promotion division, the primary focus for 2025 will be the detailed design of the FIH trial center. This phase involves determining the physical layout, functional roles, and necessary human resources to ensure the facility meets global standards for early-phase clinical trials. The ministry plans to move forward with construction in 2028, setting a target for the facility’s launch in 2029. The vision behind this center is to create a hub not only for Japanese drug development but also to support international pharmaceutical companies by fostering innovative drug candidates, thereby attracting more global collaborative trials to Japan.

A One-Stop Service for Consultation for International Clinical Trials

In addition to the FIH facility, MHLW has included in its budget request a separate initiative: the “One-Stop Consultation Center for International Clinical Trials” (¥270 million). This center will be a gateway for foreign biotech firms, especially those without a local presence in Japan, to navigate Japan’s regulatory landscape and healthcare environment. Positioned within the National Center for Advanced and Specialized Medical Care, the center will offer English-language consultations, helping engage overseas companies with appropriate Japanese medical institutions for clinical development programs. This initiative addresses a common challenge overseas ventures face: the lack of familiarity with Japan’s regulatory processes. The consultation hub will offer a preliminary exchange of information on trial feasibility, such as potential patient populations and trial site capabilities. Even companies not yet committed to conducting trials in Japan can seek advice through remote means such as phone, email, or virtual meetings. The goal is to reduce entry barriers and stimulate more clinical development activity within Japan.

Support for Global Drug Development

The head of MHLW’s clinical trial promotion office, Yasuo Iimura, emphasized that these new initiatives position Japan as a pivotal player in global drug development. By investing in cutting-edge FIH trial capabilities and offering streamlined support for international clinical trials, Japan aims to increase its attractiveness as a destination for innovative research and drug development.

Through these efforts, MHLW hopes to build stronger international collaborations, enhance Japan’s reputation in the pharmaceutical sector, and support the growth of domestic and global drug pipelines.

Introduction to Japan’s Regulatory Budget Proposal

According to the news (PMDA審査官増員、手数料にも補助　　医薬局・25年度概算要求 | 日刊薬業 – 医薬品産業の総合情報サイト (jiho.jp)) released by NIKKAN YAKUGYO on Aug/28/2024, in the latest budget proposal for fiscal year 2025, the Pharmaceutical and Food Safety Bureau of Japan’s Ministry of Health, Labour and Welfare (MHLW) has requested ¥11.2 billion, an increase of ¥1.9 billion compared to the previous year. A key focus of this budget is addressing the drug lag and loss issues in Japan by supporting pharmaceutical companies through consultation fee subsidies and increasing the number of reviewers at the Pharmaceuticals and Medical Devices Agency (PMDA).

Enhanced Support for Unapproved and Orphan Drugs
One of the major initiatives within this budget includes ¥141 million to support a program to evaluate and promote the development of unapproved and off-label drugs without waiting for requests from medical societies. In line with this, seven new reviewers will be hired at PMDA to accelerate the evaluation of orphan drugs, partially funded by government subsidies.

Consultation Fee Waivers and Subsidies for Drug Development
The government plans to waive consultation fees for pediatric drug development to encourage more pharmaceutical companies to participate, particularly those developing pediatric and orphan drugs. Additionally, consultation fees will be subsidized by 50% for drugs related to the unapproved drug review system, orphan drugs, and investigator-initiated clinical trials. This effort aims to incentivize more companies to participate in developing critical therapies.

Expansion of PMDA’s International Presence
To facilitate drug development and regulatory submissions by overseas companies, including startups, Japan plans to expand PMDA’s US office by adding one more staff member. The budget for this expansion is set at ¥98 million, which will enhance PMDA’s ability to engage with foreign biotech companies and promote regulatory submissions in Japan.

This budget proposal underscores Japan’s commitment to reducing the drug lag and supporting the development of orphan drugs while enhancing international collaboration. For business development and regulatory professionals working outside Japan, these measures signal new opportunities for drug development and market entry in Japan.

Introduction to Regulatory Changes

According to the news (後発品の特許抵触で専門家照会制度を検討　　厚労省、25日の制度部会で提案へ | 日刊薬業 – 医薬品産業の総合情報サイト (jiho.jp)) released by NIKKAN YAKUGYO on July 24, 2024, the Ministry of Health, Labour and Welfare (MHLW) presented a proposal on July 25, 2024, at the Pharmaceutical Affairs and Food Sanitation Council’s subcommittee on Pharmaceutical and Medical Device Systems. The proposal focuses on improving the operation of the “Patent Linkage System”—a system that ensures generic and biosimilar drugs do not infringe on the patents of the original innovator drugs before they receive approval.

Clarification of Patent Definitions and Scope

The Ministry aims to clarify the definitions and scope of substance and use patents, which must be considered during the approval process. This move is intended to prevent discrepancies between innovators and generic/biosimilar drug companies that often lead to litigation. Such legal disputes can threaten the stable supply of generic and biosimilar drugs in Japan, a concern raised by industry stakeholders during a subcommittee hearing in May.

Proposal for Expert Consultation System

Given the complexities of patent law and the absence of a system for expert consultation, the MHLW acknowledges the difficulty in determining the extent of patent rights and whether a generic or biosimilar drug infringes upon them. To address this, the Ministry has proposed establishing a task force team to discuss the processes consulting patent infringement and the criteria for approving generics and biosimilars. This taskforce team would also explore mechanisms to incorporate expert opinions into the decision-making process, aiming to implement a formal system where third-party experts provide opinions on potential patent conflicts.

Potential Impact on Drug Approvals

By establishing a more transparent framework and involving independent experts, the MHLW hopes to streamline the approval process for generics and biosimilars, minimize the risk of legal disputes, and ensure a more stable supply of affordable medicines in Japan. This initiative might also affect the strategies and timelines for overseas pharmaceutical companies entering the Japanese market.

The Ministry’s efforts to refine the Patent Linkage System reflect a broader commitment to balancing patent protection with the need for affordable medicines, making Japan an increasingly attractive market for global pharmaceutical companies.

Introduction to Regulatory Changes 

According to the news (厚労省、全例調査の除外規定を事務連絡　　Q＆Aを一部改正 | 日刊薬業 – 医薬品産業の総合情報サイト (jiho.jp)) released by NIKKAN YAKUGYO on 07/19/2024, significant changes have been made regarding the requirement for All Case Surveillance (ACS) as a condition for drug approval, and ACS will no longer be uniformly required. Instead, exceptions are now permitted based on specific criteria. This revision is part of the ongoing efforts to address drug lag and streamline regulatory processes. In the above context, the amendments of the Q&A on the regulation of ACS are available. 

Key Amendments to the Q&A 

The revised guidelines clarify that insufficient Japanese patient data in clinical trials should not be the sole reason for requiring ACS as part of the approval conditions. Examples where ACS may be reconsidered include: 

• Cases where, despite limited Japanese trial data, sufficient safety information is available from international trials, and there are no significant ethnic differences in safety concerns. 

• Cases where similar drugs with the same mechanism of action have established safety records, and consistent safety data is available. 

Background and Implications  

This policy shift is rooted in the findings of the April 24 report from the “Study Group on Pharmaceutical Regulations to Strengthen Drug Development and Ensure Stable Supply.” The MHLW aims to improve the efficiency of the drug approval process while ensuring safety and effectiveness. Reducing unnecessary ACS requirements alleviates the regulatory burden on pharmaceutical companies, potentially accelerating the introduction of new drugs to the Japanese market. 

Conclusion  

These changes mark a significant step towards optimizing Japan’s pharmaceutical regulatory framework. Pharmaceutical companies in the Japanese market should carefully review these updates to understand the new regulatory expectations and align their post-marketing surveillance strategies accordingly. 

Introduction to the New Regulatory Initiative

According to the news (小児薬の同時開発、新相談枠活用を　　PMDA、新センターが始動 | 日刊薬業 – 医薬品産業の総合情報サイト (jiho.jp)) released by NIKKAN YAKUGYO on 07/05/2024, on July 1st, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan launched the “Pediatric and Rare Disease Drug Consultation Center.” This center aims to support the development of drugs for pediatric and rare diseases, addressing the drug lag in these critical areas. The center also offers consultation services for the simultaneous development of adult and pediatric drugs, as Japan’s Ministry of Health, Labour and Welfare (MHLW) encourages.

Importance of Simultaneous Development

Director Hiroshi Suzuki highlighted the significance of simultaneous development, stating “Promoting simultaneous development of drugs for adult and pediatric populations will increase the number of medications suitable for children. We urge companies to utilize this new consultation framework.”

Regulatory Support and Fee Exemptions

MHLW’s recent notifications urge companies to develop pediatric drug plans along with adult drug development. Additionally, PMDA introduced a mechanism in the 2024 drug pricing reform to offer higher add-on rates for pediatric drugs approved through simultaneous development plans confirmed by PMDA. Consultation fees at the center are partially or fully subsidized. Notably, the “Pediatric Drug Development Plan Confirmation Consultation” fee is entirely waived for requests submitted between July 1st and January 8th of the following year.

Additional Services and Monitoring

The center also provides consultations for orphan drugs and public solicitation drugs. PMDA monitors the consultation status and has noted initial interest in non-pediatric drugs, with expectations for future pediatric consultations.