Article

Regulatory and Clinical Trial Systems in Japan

Mamiko Satake and Natsuko Hosoda, Quintiles Transnational Japan KK, Tokyo, Japan

Introduction

  • Historical Context of Drug Regulation in Japan

    • Drug regulation began in early 18th-century Japan, particularly during the Edo era.

    • Establishment of drug inspection facilities in five major cities for traditional herbal medicines.

    • Drugs that failed inspection were banned from sale (1).

  • Meiji Restoration Impact

    • Post-1868, several laws enacted to regulate drug sales:

    • 1870: Regulation on drug sales.

    • 1873: Regulation on pharmaceutical drugs.

    • 1877: Regulation on toxic and poisonous drugs.

    • Focus shifted towards Western medicine, declining the traditional medicine industry (2).

  • The Japanese Pharmacopoeia

    • Promulgated in 1886, enforced from 1887, key element for regulating drug properties and qualities (3).

  • 'Yaku-Ritsu' Law

    • Enacted on 16 March 1889, enforced from March 1890.

    • Defined terms such as ‘pharmacist’, ‘pharmacy’, and ‘drug manufacturer’.

    • Prohibited sale of drugs non-compliant with the Japanese Pharmacopoeia.

    • Revised multiple times, notably in 1907, banning manufacture and display of prohibited drugs, marking it as a precursor to current regulations.

  • Regulatory Perspective Evolution

    • Initial focus on dangerous drugs evolved in 1910 to include drug efficacy, prompted by prior quality control measures (5).

Governing Law: Pharmaceutical Affairs Law (PAL)

  • Overview

    • The backbone of drug and medical devices regulation, enforced through ministerial ordinances from the Ministry of Health, Labour and Welfare (MHLW).

    • Covers safety, efficacy, quality through development, manufacturing, importation, and marketing via approval and licensing systems.

  • Life Cycle of a Drug Under PAL

    • From research and development to post-marketing through adherence to Good Laboratory Practice (GLP), Good Clinical Practice (GCP), and Good Manufacturing Practice (GMP).

Foreign Manufacturer Accreditation

  • Accreditation Requirements

    • Foreign manufacturers must be accredited similarly to domestic counterparts to export drugs to Japan.

    • The MHLW grants accreditation; the PMDA inspects manufacturing facilities.

  • Application Process

    • Japanese Marketing Authorization Holder (MAH) acts as an agent for foreign applicants.

    • Required documents include:

    1. Medical certificate regarding mental health or illegal drug addiction.

    2. Curriculum vitae of the manufacturing establishment's responsible person.

    3. List of products to be manufactured for export to Japan.

    4. Detailed documents on facility characteristics.

    5. Documentation on radiopharmaceuticals if exceeding MHLW thresholds.

    6. Copies of valid marketing/manufacturing licenses from the home country.

Historical Evolution of PAL

  • Key Revisions

    • Enacted in March 1943 (Law No. 48) merging previous laws with improvements in quality controls.

    • Revised in July 1948 to comply with the new Japanese Constitution, reducing governmental discretion.

    • Current version (1960 PAL/Law No.145) adjusted for universal health care under which quality health services are provided.

    • Major amendments in 2002 shifted focus from manufacturing to marketing approval, essential for aligning with Western standards.

Marketing Authorization Holder (MAH)

  • License Requirements

    • Type 1 license needed for MAHs of prescription drugs issued by prefectural governors.

    • Necessary roles include:

    • Quality control officer adhering to GQP.

    • Officer for post-marketing surveillance complying with GVP.

    • General manager with pharmacy qualifications overseeing compliance.

    • License valid for five years, renewable thereafter.

Marketing Approval Process

  • Submission to PMDA

    • The PMDA typically does not conduct on-site inspections; document confirmation is sufficient.

    • Accreditation of foreign manufacturers must occur before filing for Marketing Authorization Applications (MAAs).

Japanese Regulatory Framework: Key Organizations

  • Ministry of Health, Labour and Welfare (MHLW)

    • Keys to pharmaceutical regulatory affairs.

    • Pharmaceutical Affairs and Food Safety Bureau (PAFSB): Handles clinical development, approval, and post-marketing for drugs and devices.

    • Health Policy Bureau (HPB): Manages policy related to drug development, manufacturing, distribution, and pricing.

  • Pharmaceuticals and Medical Devices Agency (PMDA)

    • An independent body established in 2004 responsible for reviewing clinical trial notifications, MAAs, and ensuring compliance with quality standards.

    • Offices manage various drug classes and are structured to promote specialized review processes.

Key Advisory Committees

  • Pharmaceutical and Food Sanitation Council (PAFSC)

    • Reviews drug applications for marketing approval multiple times a year.

  • First and Second Committees on New Drugs

    • First reviews all new drugs, excluding those for oncology handled by the Second Committee.

Roadmap to Drug Launch

  • Definition of New Drugs

    • Includes new modes of action, chemical structure, new molecular entities (NMEs), dosage forms, or indications distinct from existing drugs.

  • Regulatory Consultation Process

    • Expedited consultations available from PMDA concerning drug reliability and compliance on a fee basis.

    • Increased evaluations since 2011 for traditional and orphan drugs to promote proactive evaluations.

Data Required for Approval Application

  • Application data must follow the Common Technical Document (CTD) format, adhering to international standards, especially since July 2003.

Required NDA Data Items

  1. Historical data and characteristics of the drug.

  2. Chemical structure and manufacturing methods.

  3. Stability testing.

  4. Pharmacological actions and supporting efficacy tests.

  5. Complete pharmacokinetic data (absorption, distribution, metabolism, excretion).

  6. Toxicology studies and clinical trial results.

  7. Administrative information and relevant documentation.

Review Process and Approval Timelines

  • Median NDA review time for standard applications decreased significantly to around 15.8 months, with priorities set for drugs crucial for serious conditions.

  • Priority Review Designations

    • Indicated for orphan drugs—criteria include patient population sizes under 50,000 and significant medical importance.

Post-Marketing Surveillance

  • Good Vigilance Practice (GVP)

    • A framework for ensuring drug safety post-launch involving continuous monitoring of adverse drug reactions (ADRs) (9).

  • Periodic Safety Update Reports (PSUR)

    • Submitted semi-annually and annually post-approval.

Conclusions

  • Ongoing reforms in Japan's drug regulatory and clinical trial systems aimed at harmonization with global standards continue to progress, addressing drug lag issues identified in outgoing and incoming market assessments.

  • Japan is proactively adapting to upcoming pharmaceutical technologies, aiming for a centralized Asian approval system while ensuring patient safety remains a core priority.

References

  • Cited articles and notifications relevant for the creation and enforcement of Pharmaceutical Affairs Law and additional regulatory requirements.

Drug lag refers to the delay between the approval of new drugs in one region (often the United States or Europe) and their subsequent availability in another country, such as Japan. This phenomenon can lead to patients not having access to potentially beneficial new treatments while they remain available elsewhere. Ongoing reforms in Japan's drug regulatory and clinical trial systems aim to address drug lag issues to better align with global standards and increase the pace of drug approvals.

Drug lag refers to the delay between the approval of new drugs in one region (often the United States or Europe) and their subsequent availability in another country, such as Japan. This phenomenon can lead to patients not having access to potentially beneficial new treatments while they remain available elsewhere. Ongoing reforms in Japan's drug regulatory and clinical trial systems aim to address drug lag issues to better align with global standards and increase the pace of drug approvals.

Drug lag in Japan specifically results in the following challenges:

  • Delayed Access to Treatments: Patients in Japan may experience delays in accessing new and innovative drugs, which can lead to poorer health outcomes compared to patients in regions where these drugs are available sooner.

  • Increased Healthcare Disparities: The lag can contribute to disparities in healthcare access between Japan and Western countries, where new treatments are more promptly approved and available.

  • Market Competitiveness: The prolonged approval process can hinder Japan's competitiveness in the global pharmaceutical market, potentially affecting both domestic and foreign investments in drug development.

  • Patient Experiences: Patients may have to wait longer for alternative treatments that could offer better efficacy or fewer side effects, impacting their quality of life during that time.

  • Regulatory Reforms: Ongoing reforms in Japan's drug regulatory systems are focused on addressing these lag issues, as the country aims to harmonize with global standards to expedite drug approvals and ensure better patient outcomes.

Ongoing reforms in Japan's drug regulatory and clinical trial systems are aimed at harmonizing with global standards to address drug lag issues identified in outgoing and incoming market assessments.

Key initiatives include:

  1. Increased Evaluation for New Drugs: Expedited evaluations for traditional and orphan drugs have been emphasized since 2011 to promote proactive assessments.

  2. Regulatory Consultation Process: The PMDA offers expedited consultations concerning drug reliability and compliance on a fee basis, which can help streamline the approval process.

  3. Priority Review Designations: Establishing criteria for priority reviews, particularly for orphan drugs, allowing for quicker access to treatment options for patients with serious conditions.

  4. Alignment with International Standards: Revisions in the Pharmaceutical Affairs Law focus on improving marketing approvals rather than solely on manufacturing, which helps align Japan's practices with Western markets and reduces delays in drug availability.

  5. Collaboration with Global Agencies: Improving collaboration with regulatory agencies worldwide to share insights and protocols can further expedite the approval process, reducing the time it takes for drugs to become available in Japan compared to other regions.

  6. Patient Access Initiatives: Initiatives aimed at ensuring timely access to new drugs that mitigate delays experienced by patients, ultimately resulting in improved healthcare outcomes.