The Regulation on Cell Therapy Products in Japan Mayumi SHIKANO, Ph.D. Office of Biologics Pharmaceuticals and Medical Devices Agency May 1st 2004

Contents Changes in Regulation on Biologics in Recent Japan Revise of Pharmaceutical Affairs Law Establishment of Pharmaceuticals and Medical Devices Agency Specific Regulation for Cell Therapy Products May 1st 2004

Pharmaceuticals and Medical Devices Agency (PMDA) Establishment of PMDA Ministry of Health, Labour and Welfare (MHLW) The Organization of Pharmaceutical Safety and Research (OPSR) National Institute of Health Sciences (NIHS) Pharmaceuticals and Medical Devices Evaluation Center (PMDEC) Japan Association for the Advancement of Medical Equipment (JAAME) April 1st, 2004 Pharmaceuticals and Medical Devices Agency (PMDA)

Organization of PMDA Chief Executive Executive Directors Director, Center for Product Evaluation Chief Safety Officer Office of Compliance and Standard Office of Review Administration Office of General Affairs Office of New Drug I Office of Safety Office of New Drug II Office of Planning and Coordination Office of New Drug III Office of Relief Funds Office of Biologics Office of Medical Devices Office of R&D Promotion Office of OTC and Generics Office of Conformity Audit

Revise of Pharmaceutical Affairs Law Modification of Approval and Licensing System Including Enhancement of Safety Measures in PMS Enhancement of Safety Securing of Biologics Drastic Change of Safety Measures of Medical Devices Drug Master File Doctor-initiated Clinical Trials April 2005 July 2003 April 2005 April 2005 July 2003 May 1st 2004

Risks of Biologics Possibility of the Contamination of Unknown Infectious Agents High Risk of Infectious Contaminants for Materials Derived from Many and Unspecified Human or Animals Difficulty in Complete Clearance of Infectious Contaminants in Some Cases May 1st 2004

New Regulation on Biologics in the Revised Law Manufacturing Post-Marketing Labeling Informed consent Records of patient Periodical report of infection Control of raw materials Records of donors and raw materials Preservation of each lot Additional for Biologics According to Risk Basic Regulation on Drugs and Devices GMP; in order to manufacture the product of constant quality GPMSP; for quick and appropriate collection of adverse events information

Regulation on Development of Cell Therapy Products Drugs and Biologics Submission of Protocols NDA Non-Clinical Studies Clinical Studies Quality Studies Development Application for Confirmation of Quality and Safety Confirmation Additional for Cell Therapy Products

Guidelines for Cells and Tissues-derived Products in Japan Safety of Cell and Tissue-derived Products (7/30/’99,Not.#906) Quality and Safety of Pharmaceuticals Manufactured from Materials Derived from Human or Animals (12/26/’00, Not.#1314) Concept for treatment and use of cells and tissue-derived products Guideline for quality and safety of cells and tissue-derived products May 1st 2004

Cell Therapy Products Evaluation Prior to Clinical Studies (1) Collection of Cells or Tissues Donor Screening Facilities Record of Donors Transportation

Cell Therapy Products Evaluation Prior to Clinical Studies (2) Control of Manufacturing Process Control of Materials Validation and Control of Critical Steps Monitoring of Characteristics of Cells Virus Clearance SOP Facilities Record of Manufacturing Including Materials Staff Education and Management System May 1st 2004

Cell Therapy Products Evaluation Prior to Clinical Studies (3) Quality of Products Viability Identification Purity Process-derived Impurity Tests for Endotoxin, Bacteria, Mycoplasma and Viruses Unintended Factor from Cells Stability Transportation May 1st 2004

Cell Therapy Products Evaluation Prior to Clinical Studies (4) Non-Clinical Safety Studies Change of Product Characteristics Effect of Products on Normal Cells and Tissues Undesirable Immune-response by Products or by Factors Secreted from Products Non-Clinical Pharmacology Studies Pharmacology Studies Supporting Effects General Pharmacology Studies if Possible ADME Studies if Possible May 1st 2004

Cell Therapy Products Evaluation Prior to Clinical Studies (5) Information of Clinical Studies Summary of Clinical Experience if Available Information Regarding Target Disease Justification of the clinical use of the product Selection of Subjects Informed Consent Number of Subjects Treatment Procedure Primary and Secondary Endpoints Including Infection Plans for Analyses Records of Investigational Products Records of Subjects

Development of Cell Therapy Products in Japan Products being developed On review; 1 Confirmed; 4 (2 are discontinued) Products planned for clinical research; more than 200 May 1st 2004

Problem in the Future Not uniform regulation depending on the characteristics of the Product Promotion of clinical application of promising new technology including cell therapy Prevention measure of transmission of infectious agents via cell therapy products May 1st 2004

Review Team Organization Office Director Review Director Chief Chief Chief Sub-chief Quality Pharmacology Safety Clinical ADME Statistics

NDA Review Process in Japan 　PMDA Applicant PAFSC Interview Review Team Report (1) Report (1) Discussion Experts Interview Review Meeting on Key Issues Discussion Report (2) Committee on Drugs Report (1)&(2) Review Conclusion Review Conclusion Approval MHLW Advise