Japan's regulatory landscape for pharmaceuticals and medical devices underwent a significant transformation with the enactment of the "Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices" (医薬品、医療機器等の品質、有効性及び安全性の確保等に関する法律 - Iyakuhin, Iryōkiki tō no Hinshitsu, Yūkōsei oyobi Anzensei no Kakuho tō ni Kansuru Hōritsu). Commonly referred to as the PMD Act or Yakkiho (薬機法), this legislation, which came into effect on November 25, 2014, replaced the longstanding Pharmaceutical Affairs Law (PAL or former Yakujihō - 薬事法). This overhaul was driven by the need to address rapid advancements in medical science and technology, particularly in the fields of medical devices and regenerative medicine, and to further enhance patient safety. The PMD Act introduced several pivotal changes, fundamentally altering the regulatory environment for companies involved in the research, development, manufacturing, and marketing of pharmaceutical products, medical devices, and regenerative medicine products in Japan.

The Shift from Pharmaceutical Affairs Law (PAL) to the PMD Act (Yakkiho)

The previous Pharmaceutical Affairs Law had been the cornerstone of pharmaceutical regulation in Japan for decades. However, the evolving healthcare landscape, characterized by increasingly sophisticated medical devices, the emergence of innovative therapeutic modalities like regenerative medicine, and a heightened global focus on product safety, necessitated a more adaptive and comprehensive regulatory framework.

The primary objectives behind the transition to the PMD Act were:

1. Strengthening Safety Measures: To enhance the safety net for pharmaceuticals and medical devices throughout their lifecycle.
2. Establishing a Regulatory Framework Tailored to Medical Devices: To recognize the unique characteristics of medical devices compared to pharmaceuticals and implement a more appropriate regulatory system.
3. Introducing a New Framework for Regenerative Medicine Products: To foster innovation while ensuring the safety and efficacy of these cutting-edge products.

The name change itself, from "Pharmaceutical Affairs Law" to the "Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices," underscores the expanded scope and the increased emphasis on medical devices as a distinct regulatory category.

Key Change 1: Enhanced Safety Measures for Pharmaceuticals and Medical Devices

A central tenet of the PMD Act is the fortification of safety measures. This involves several key components aimed at ensuring patient protection from the pre-market stage through post-market surveillance.

Mandatory Notification of Package Inserts (添付文書の届出制)

Package inserts (添付文書 - tenpu bunsho) are critical documents that provide healthcare professionals and patients with essential information regarding the proper use, dosage, contraindications, and potential side effects of pharmaceuticals and medical devices. Under the PMD Act, the system for package inserts was significantly revised.

For designated pharmaceuticals (primarily prescription drugs and "guidance-requiring pharmaceuticals" - 要指導医薬品) and medical devices, Marketing Authorization Holders (MAHs) are now required to prepare package inserts based on the latest scientific knowledge and officially notify the Ministry of Health, Labour and Welfare (MHLW) before commencing marketing or when making changes to the content (PMD Act, Article 52-2, Paragraph 1; Article 63-2, Paragraph 1, applying mutatis mutandis Article 52-2). Once notified, the MAH must promptly make the contents of the package insert publicly available, typically via the website of the Pharmaceuticals and Medical Devices Agency (PMDA) (PMD Act, Article 52-2, Paragraph 2; Article 63-2, Paragraph 1, applying mutatis mutandis Article 52-2, Paragraph 2).

This notification system aims to increase transparency and ensure that the information provided is up-to-date and reflects current scientific understanding, thereby contributing to the safer use of medical products. The content and format of package inserts have also undergone revisions, with a notable update to the "Guidance on Package Inserts for Prescription Drugs, etc." (医療用医薬品の添付文書等の記載要領について) issued on June 8, 2017 (Iyaku Seikatsu Eisei Kyoku-cho Hatsu 0608 Dai 1-go), further standardizing and clarifying the information provided.

Strengthened Post-Marketing Safety Measures (GVP)

The PMD Act places a strong emphasis on robust post-marketing safety surveillance. MAHs are responsible for collecting, evaluating, and acting upon safety information after their products are on the market. The standards for these activities are outlined in the Good Vigilance Practice (GVP) ordinance (医薬品、医薬部外品、化粧品及び医療機器の製造販売後安全管理の基準に関する省令 - Iyakuhin, Iyaku Bugaihin, Keshouhin oyobi Iryoukiki no Seizōhanbaigo Anzen Kanri no Kijun ni Kansuru Shōrei).

The PMD Act reinforces the MAH's obligations under GVP, requiring them to:

• Collect information on adverse drug reactions, medical device malfunctions, and infections suspected to be caused by their products.
• Evaluate the collected information and, if necessary, plan and implement safety-enhancing measures, such as revising package inserts or issuing warnings.
• Report serious adverse reactions and malfunctions to the MHLW via the PMDA within specified timelines (PMD Act, Article 68-10). For instance, fatal cases or those leading to disability generally require reporting within 15 days of the MAH becoming aware of them.

Failure to comply with these reporting obligations can result in administrative sanctions, including orders for business improvement or suspension of business operations.

Clarification of Responsibilities for Stakeholders

The PMD Act explicitly defines the roles and responsibilities of various stakeholders in ensuring the safety of pharmaceuticals and medical devices. This includes not only MAHs and manufacturers but also healthcare professionals (doctors, dentists, pharmacists), and even the national and local governments (PMD Act, Articles 1-2 to 1-6). This clarification aims to foster a collaborative approach to pharmacovigilance and device vigilance. For example, healthcare professionals are obligated to report information on suspected adverse drug reactions or device malfunctions if they deem it necessary to prevent the occurrence or spread of public health hazards (PMD Act, Article 68-10, Paragraph 2).

Enhanced Recall System

The PMD Act refines the system for product recalls. MAHs are obligated to take necessary measures, including recall, disposal, or suspension of sales, if they become aware of any health hazard risks associated with their products (PMD Act, Article 68-9). They must also report the initiation and status of recalls to the MHLW. The specific procedures and classifications for recalls (Class I, II, and III, based on the level of health risk) are detailed in administrative guidance.

Key Change 2: Regulatory Framework Tailored to Medical Devices

Recognizing that medical devices have distinct characteristics from pharmaceuticals, such as shorter product lifecycles and a wider range of risk profiles, the PMD Act introduced a dedicated chapter and a more nuanced regulatory approach for them.

Separate Chapter and Definition for Medical Devices

The PMD Act now contains a distinct chapter outlining the regulations specifically applicable to medical devices (Chapter V: Medical Devices and In-Vitro Diagnostics). This structural change acknowledges the unique aspects of device development, manufacturing, and marketing. Medical devices are defined as instruments, machines, appliances, or similar products (excluding regenerative medicine products) intended for use in the diagnosis, treatment, or prevention of diseases in humans or animals, or intended to affect the structure or functions of the body (PMD Act, Article 2, Paragraph 4).

Risk-Based Classification System

Medical devices are classified based on their risk to the human body. This risk-based classification determines the regulatory pathway for market approval:

• Class I (General Medical Devices): Devices with extremely low risk. These generally require self-declaration of conformity and marketing notification to the PMDA.
• Class II (Controlled Medical Devices): Devices with low to moderate risk. Many of these require certification by a third-party Registered Certification Body (RCB) accredited by the MHLW, unless designated as requiring MHLW approval.
• Class III (Specially Controlled Medical Devices): Devices with moderate to high risk, often implantable or life-sustaining. These typically require MHLW approval after review by the PMDA.
• Class IV (Specially Controlled Medical Devices): Devices with high risk, such as those that are highly invasive. These also require MHLW approval after PMDA review.

This tiered system aims to apply regulatory scrutiny commensurate with the potential risk of the device.

Introduction of Third-Party Certification

For many Class II medical devices (and some Class III devices not requiring MHLW approval), the PMD Act formalized and expanded the role of RCBs. Instead of direct MHLW approval, MAHs can obtain certification from these accredited bodies, potentially streamlining the market entry process for lower-risk devices. However, RCBs operate under strict MHLW oversight.

Quality Management System (QMS) Requirements

MAHs and manufacturers of medical devices must comply with the Quality Management System (QMS) ordinance (医療機器及び体外診断用医薬品の製造管理及び品質管理の基準に関する省令 - Iryōkiki oyobi Taigai Shindan'yō Iyakuhin no Seizō Kanri oyobi Hinshitsu Kanri no Kijun ni Kansuru Shōrei). This ordinance is based on the international standard ISO 13485 and mandates the establishment and maintenance of a QMS for the design, development, manufacturing, and distribution of medical devices. Compliance with the QMS ordinance is a prerequisite for obtaining marketing authorization and manufacturing licenses, and is subject to PMDA or RCB audits.

Regulation of Software as a Medical Device (SaMD)

The PMD Act explicitly includes "programs" (software) and "recorded media thereof" within the definition of medical devices if they are intended for diagnostic or therapeutic purposes (PMD Act, Article 2, Paragraphs 4 and 5). This has provided a clearer regulatory pathway for Software as a Medical Device (SaMD). Guidance has been issued on how to determine if a software program qualifies as a medical device and the applicable regulatory requirements, which generally follow the risk-based classification system. This is a rapidly evolving area, with continuous efforts to adapt regulations to the unique nature of software, including aspects like cybersecurity and version control.

Single-Unit Programs and Medical Device Manufacturing

The law also addresses the manufacturing of medical devices that are single-unit software programs. The act clarifies that acts such as the creation or modification of such programs, or their recording onto media for the purpose of marketing, fall under the definition of "manufacturing."

Key Change 3: New Framework for Regenerative Medicine Products

One of the most groundbreaking aspects of the PMD Act is the establishment of a dedicated regulatory framework for regenerative medicine products (再生医療等製品 - saisei iryō tō seihin). This was a response to the rapid advancements in cell therapy, gene therapy, and tissue engineering, aiming to facilitate the timely market entry of innovative treatments while ensuring patient safety.

Definition and Scope

Regenerative medicine products are defined as:

1. Processed human or animal cells/tissues intended for the reconstruction, repair, or formation of human body structures or functions, or for the treatment or prevention of human diseases.
2. Products intended for use in gene therapy (PMD Act, Article 2, Paragraph 9).

This category is distinct from pharmaceuticals and medical devices and has its own set of regulations.

Conditional and Time-Limited Approval System (早期承認制度)

Recognizing that extensive efficacy data might be difficult to obtain for some regenerative medicine products in the pre-market stage, particularly for those targeting rare diseases or having novel mechanisms of action, the PMD Act introduced a system for conditional and time-limited approval (条件及び期限付承認 - jōken oyobi kigen-tsuki shōnin) (PMD Act, Article 23-26).

Under this system, if a regenerative medicine product is presumed to be efficacious and its safety is confirmed based on available data (often from smaller-scale trials), it can receive marketing approval subject to certain conditions and for a limited period (e.g., up to 7 years). The conditions typically require the MAH to:

• Implement appropriate post-marketing risk management measures.
• Collect comprehensive post-marketing data on safety and efficacy from all treated patients.
• Re-apply for full approval within the specified timeframe by submitting the collected post-marketing data.

This "fast-track" pathway is designed to make promising regenerative therapies available to patients earlier, while still ensuring rigorous oversight and data collection to confirm their long-term benefit and risk profile. Failure to meet the conditions or demonstrate efficacy can lead to revocation of the approval.

Specific Manufacturing and Quality Control Standards (GCTP)

MAHs and manufacturers of regenerative medicine products must comply with Good Gene, Cellular, and Tissue-based Product Manufacturing Practice (GCTP) (再生医療等製品の製造管理及び品質管理の基準に関する省令 - Saisei Iryō tō Seihin no Seizō Kanri oyobi Hinshitsu Kanri no Kijun ni Kansuru Shōrei). GCTP standards address the unique challenges in manufacturing these complex products, such as ensuring sterility, preventing cross-contamination, managing donor variability, and maintaining cell viability and functionality.

Post-Marketing Safety and Efficacy Reassessment

Given the novel nature of many regenerative medicine products and the conditional approval pathway, robust post-marketing surveillance and reassessment are crucial. MAHs have stringent obligations to monitor the long-term safety and efficacy of their products, including establishing patient registries where appropriate and reporting any adverse events. The data collected post-marketing forms the basis for the decision on full approval or continued marketing.

Safety Measures for Cellular and Tissue Products

The PMD Act, in conjunction with the "Act on the Safety of Regenerative Medicine" (再生医療等の安全性の確保等に関する法律 - Saisei Iryō tō no Anzensei no Kakuho tō ni Kansuru Hōritsu), which primarily regulates the provision of regenerative medicine by healthcare institutions, creates a comprehensive regulatory system. This dual framework aims to ensure safety from the product development stage through to clinical application.

Implications of the PMD Act Changes

The changes introduced by the PMD Act have significant implications for businesses operating in or seeking to enter the Japanese pharmaceutical, medical device, and regenerative medicine markets.

• Increased Compliance Burden: The enhanced safety measures and specific requirements for different product categories necessitate robust internal compliance systems and expertise in Japanese regulations.
• Strategic Regulatory Planning: Understanding the nuanced pathways for medical devices (risk classification, third-party certification) and regenerative medicine (conditional approval) is crucial for efficient market entry.
• Focus on Lifecycle Management: The Act emphasizes safety and efficacy throughout the product lifecycle, requiring strong post-marketing surveillance and risk management capabilities.
• Opportunities in New Fields: The dedicated framework for regenerative medicine products, including the conditional approval system, offers significant opportunities for companies developing innovative therapies in this area, though it comes with substantial post-marketing obligations.
• Importance of the Marketing Authorization Holder (MAH): The role of the MAH (製造販売業者 - seizō hanbai gyōsha) remains central. The MAH is legally responsible for product quality, safety, and efficacy in Japan, regardless of where the product is manufactured. Foreign companies typically need to partner with a Japanese MAH or establish their own licensed MAH in Japan.

Future Outlook and Continuous Improvement

The PMD Act includes a provision for review approximately every five years after its enforcement to ensure it remains effective and responsive to ongoing scientific and technological advancements, as well as societal needs. The first major set of amendments based on such a review was enacted in 2019 and came into effect in stages from September 2020. These 2019 amendments included:

• Strengthening Post-Marketing Safety Measures: Further refinements to GVP and other safety systems.
• Improving the Reliability of the Pharmaceutical Supply Chain: Measures related to traceability and preventing counterfeit drugs.
• Facilitating Faster Access to Innovative Products: Introduction of a "Sakigake" (先駆け) fast-track designation system for truly innovative products and a post-approval clinical trial system.
• Optimizing Pharmacy Functions: Revisions related to the role of pharmacists and pharmacies in patient care.

More recently, amendments in 2022 introduced an emergency approval system for pharmaceuticals and medical devices to address public health crises more swiftly. This continuous evolution signifies Japan's commitment to maintaining a robust and modern regulatory system.

Conclusion

The PMD Act (Yakkiho) represents a comprehensive modernization of Japan's regulatory framework for medical products. By strengthening safety measures, tailoring regulations to the specific characteristics of medical devices, and creating a pioneering framework for regenerative medicine, the Act aims to protect public health while fostering innovation. For businesses in the pharmaceutical, medical device, and regenerative medicine sectors, a thorough understanding of the PMD Act's provisions, its subsequent amendments, and its ongoing evolution is essential for successful navigation of the Japanese market. The emphasis on lifecycle management, product-specific regulatory pathways, and robust safety and quality systems requires a proactive and well-informed approach to compliance and market strategy.