Regulation of Regenerative Medicines: A Global Perspective
v
Figure 10-4. Organizational Structure of the Division of Cellular and Gene Therapies
(March 2022). ...................................................................................................................105
Figure 10-5. Framework to Assess the Risk of Gene Therapy-Related Delayed Adverse Events. .........114
Figure 11-1. Legislation Relevant to ATMP Regulations.....................................................................118
Figure 11-2. MAA Process and Timelines. ...........................................................................................120
Figure 12-1. Responsibilities of Regulating CGT Products. .................................................................132
Figure 13-1. Laws and Regulations for Regenerative Medicines in Japan.............................................144
Figure 13-2. Process of Providing Regenerative Medicine Under the ASRM.......................................145
Figure 13-3. Risk-Based Classification of Regenerative Medicine Under the ASRM. .........................146
Figure 13-4. Conditional Expedited Approval System..........................................................................148
Figure 13-5. English Translation of the Overview of PMDA Consultations .......................................152
Figure 13-6. Application and Review Process for Regenerative Medicinal Products Under the
PMD Act. .........................................................................................................................156
Figure 14-1. Health Authorities in China Presiding Over Cell and Gene Therapy Regulations ..........165
Figure 14-2. CTA Procedures Overview. ..............................................................................................171
Figure 14-3. Marketing Authorization Procedures................................................................................172
Figure 15-1. TGA Review Pathways for Prescription Medicines and Biologicals.................................178
Figure 16-1. Application Process for a Class 1 CTGTP Notification. ..................................................194
Figure 16-2. Application Process for a Class 2 CTGTP New Drug Application (and MAV-1)...........195
Figure 16-3. Regulatory Roadmap for Class 2 CTGTP Clinical Trials. ...............................................200
Tables
Table 2-1. Regulation of Regenerative Medicine in the US, EU, and Japan..........................................6
Table 2-2. Current Laws for Conducting Embryonic Stem Cell and Cloning Research.......................7
Table 2-3. Development Timeline of Regenerative Medicine Guidances, Regulations, and Laws
in the US.............................................................................................................................14
Table 4-1. Types of Combination Products..........................................................................................31
Table 6-1. NIH Funding of Research Areas and Disease Conditions..................................................50
Table 7-1. Structure of Single European Code for Traceability. ..........................................................61
Table 7-2. Excipients Used in Marketed T-Cell Formulations. ...........................................................65
Table 8-1. Approved Products in Cell, Gene Therapy, and Tissue Engineering...................................72
Table 8-2. Product Types......................................................................................................................73
Table 8-3. Product-Specific Challenges for Each Product Type. .........................................................73
Table 8-4. Suggested Points to Consider and Guidance Documents...................................................82
Table 9-1. Comparison of Frozen and Fresh Conditions and Influence on Logistics. .........................91
Table 9-2. Relationship Between Temperature Conditions, Shelf-Life, and Manufacturing Site
Concept for Autologous Therapies......................................................................................92
Table 9-3. Relationship Between Temperature Conditions, Shelf-Life, and Manufacturing Site
Concept for Allogeneic Therapies. ......................................................................................93
Table 10-1. Donor Testing Requirements. ...........................................................................................109
Table 10-2. Propensity of Commonly Used Gene Therapy Products/Vectors to Modify the Host
Genome. ...........................................................................................................................113
Table 12-1. Approved Gene and Cell Therapy Products in Canada.....................................................130
Table 12-2. Key Regulatory Provisions for CGT Products in Canada.................................................131
Table 12-3. Product Definitions for Drug, Biologic, Cells, CTO, and Device. ....................................133
Table 13-1. Selected Regulations and Guidance Documents Related to Regenerative Medicine........157
Table 14-1. Overview of CGT Product Regulations (1993–January 2022). ........................................166
Table 14-2. Overview of Consultation Meetings With CDE..............................................................170
v
Figure 10-4. Organizational Structure of the Division of Cellular and Gene Therapies
(March 2022). ...................................................................................................................105
Figure 10-5. Framework to Assess the Risk of Gene Therapy-Related Delayed Adverse Events. .........114
Figure 11-1. Legislation Relevant to ATMP Regulations.....................................................................118
Figure 11-2. MAA Process and Timelines. ...........................................................................................120
Figure 12-1. Responsibilities of Regulating CGT Products. .................................................................132
Figure 13-1. Laws and Regulations for Regenerative Medicines in Japan.............................................144
Figure 13-2. Process of Providing Regenerative Medicine Under the ASRM.......................................145
Figure 13-3. Risk-Based Classification of Regenerative Medicine Under the ASRM. .........................146
Figure 13-4. Conditional Expedited Approval System..........................................................................148
Figure 13-5. English Translation of the Overview of PMDA Consultations .......................................152
Figure 13-6. Application and Review Process for Regenerative Medicinal Products Under the
PMD Act. .........................................................................................................................156
Figure 14-1. Health Authorities in China Presiding Over Cell and Gene Therapy Regulations ..........165
Figure 14-2. CTA Procedures Overview. ..............................................................................................171
Figure 14-3. Marketing Authorization Procedures................................................................................172
Figure 15-1. TGA Review Pathways for Prescription Medicines and Biologicals.................................178
Figure 16-1. Application Process for a Class 1 CTGTP Notification. ..................................................194
Figure 16-2. Application Process for a Class 2 CTGTP New Drug Application (and MAV-1)...........195
Figure 16-3. Regulatory Roadmap for Class 2 CTGTP Clinical Trials. ...............................................200
Tables
Table 2-1. Regulation of Regenerative Medicine in the US, EU, and Japan..........................................6
Table 2-2. Current Laws for Conducting Embryonic Stem Cell and Cloning Research.......................7
Table 2-3. Development Timeline of Regenerative Medicine Guidances, Regulations, and Laws
in the US.............................................................................................................................14
Table 4-1. Types of Combination Products..........................................................................................31
Table 6-1. NIH Funding of Research Areas and Disease Conditions..................................................50
Table 7-1. Structure of Single European Code for Traceability. ..........................................................61
Table 7-2. Excipients Used in Marketed T-Cell Formulations. ...........................................................65
Table 8-1. Approved Products in Cell, Gene Therapy, and Tissue Engineering...................................72
Table 8-2. Product Types......................................................................................................................73
Table 8-3. Product-Specific Challenges for Each Product Type. .........................................................73
Table 8-4. Suggested Points to Consider and Guidance Documents...................................................82
Table 9-1. Comparison of Frozen and Fresh Conditions and Influence on Logistics. .........................91
Table 9-2. Relationship Between Temperature Conditions, Shelf-Life, and Manufacturing Site
Concept for Autologous Therapies......................................................................................92
Table 9-3. Relationship Between Temperature Conditions, Shelf-Life, and Manufacturing Site
Concept for Allogeneic Therapies. ......................................................................................93
Table 10-1. Donor Testing Requirements. ...........................................................................................109
Table 10-2. Propensity of Commonly Used Gene Therapy Products/Vectors to Modify the Host
Genome. ...........................................................................................................................113
Table 12-1. Approved Gene and Cell Therapy Products in Canada.....................................................130
Table 12-2. Key Regulatory Provisions for CGT Products in Canada.................................................131
Table 12-3. Product Definitions for Drug, Biologic, Cells, CTO, and Device. ....................................133
Table 13-1. Selected Regulations and Guidance Documents Related to Regenerative Medicine........157
Table 14-1. Overview of CGT Product Regulations (1993–January 2022). ........................................166
Table 14-2. Overview of Consultation Meetings With CDE..............................................................170