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

2. 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

3. 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)

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

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

18. 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