Regulation of Genome Editing in Human IPS Cells : A Comparative Legal Analysis of National Regulatory Frameworks for IPSC-based Cell/Gene Therapies

The book provides a concise overview of currently applicable regulatory frameworks of states which are among the world leaders in research and development (R & D) of cell and gene therapies. Developments in genome editing are expected to lead to new possibilities for the treatment of hereditary diseases in humans. The treatment of such often severe but hitherto uncurable diseases can be based on genome-edited induced pluripotent stem cells (iPS cells). Such treatments constitute combined cell/gene therapies. These therapies need to be governed by a regulatory framework which ensures quality, safety, and efficacy of the relevant therapeutic products. On the other hand, such regulations may retard product approval and impede R & D. Accordingly, national regulations for therapies based on genome-edited iPS cells are an important and, as the case may be, decisive factor for both researchers and industry regarding their decision where to locate their R & D activities. Therefore, regulatory frameworks impact significantly on the competitiveness of states and their economies. This is why a comparative analysis of laws and regulations of different countries matters. Such a comparative legal analysis provides an important insight into regulatory concepts which, in turn, may inspire adjustments of, or amendments to, domestic legal regimes. For this purpose, experts present country reports on France, Germany, Japan, South Korea, Switzerland, and the USA. The reports on France and Germany also refer to the parameters and implications arising from pertinent EU law. This contributed volume is aimed at researchers, but also at, e.g., legal scholars, lawmakers, regulators, and political decision makers Preface Contents Editors and Contributors Chapter 1: Introductory Remarks 1.1 Introduction 1.2 Background to This Volume 1.2.1 The REALiGN-HD Research Consortium 1.2.2 Treatment of Hereditary Diseases: Two Scenarios 1.2.3 Regulatory Competition Between States 1.2.4 Anticipating the (Near) Future 1.3 Overview of the Volume 1.3.1 Scientific Foundations 1.3.2 EU Member States: France and Germany 1.3.3 Switzerland 1.3.4 United States 1.3.5 Japan 1.3.6 Korea 1.3.7 Comparative Analysis References Chapter 2: Introduction to Genome Editing in Induced Pluripotent Stem Cells, Gametes, and Embryos 2.1 Reprogramming and Induced Pluripotent Stem Cells 2.2 iPSC-Based Therapies 2.3 iPSC-Derived Gametes 2.4 Gene Correction in iPSCs Targeting Hereditary Diseases 2.5 Scenarios 2.5.1 Scenario 1: Gene Editing at the Endogenous Gene Locus of CFTR 2.5.2 Scenario 2: One-Generation Germline Therapy References Chapter 3: Regulation of Genome Editing in Human iPS Cells: Germany 3.1 Introduction 3.1.1 Gene Therapy and Cell Therapy in Figures 3.1.2 Historical Development of ATMP Legislation 3.2 Genome Editing in Human iPS Cells: An Overview of the Regulatory Framework 3.2.1 The National Framework of the Federal Republic of Germany 3.2.2 The Supranational Framework of the European Union 3.2.3 Applicability of the EU ́s Pharmaceutical Legislation 3.2.4 Classification of Genome-Edited iPS Cells as ATMPs 3.2.5 Classification of Genome-Edited iPS Cells as GMOs 3.3 Regulatory Prerequisites for Combined Gene/Cell Therapy Using Genome-Edited Human iPS Cells to Be Differentiated into Soma... 3.3.1 Cell Procurement 3.3.2 Manufacture 3.3.3 Placement on the Market 3.3.3.1 Centralised Marketing Authorisation 3.3.3.2 Special Programmes 3.3.3.3 Clinical Trials 3.3.4 Administration Without Marketing Authorisation 3.3.4.1 Compassionate Use 3.3.4.2 Hospital Exemption 3.3.4.3 Special Needs Exemption 3.3.4.4 Point-of-Care Treatment 3.4 Treatment of the Patient ́s Genetic Data 3.4.1 Special Status of Genetic Data 3.4.1.1 The Fundamental Right to Informational Self-Determination 3.4.1.2 Genetic Data in General Data Protection Law 3.4.2 Specific Provisions for Genetic Data 3.4.2.1 The Genetic Diagnostic Act 3.4.2.2 Protection of Genetic Data in Clinical Trials 3.5 Reform Efforts 3.6 Outlook: Human Germ Line Intervention through Genome Editing 3.7 Conclusion References Chapter 4: Regulation of Genome Editing in Human iPS Cells: France 4.1 Introduction 4.2 Genome Editing of Human iPS Cells: An Overview of the Regulatory Framework 4.2.1 Main Applicable Legal Texts 4.2.2 Competent Public Authorities 4.3 Regulatory Prerequisites for Combined Gene/Cell Therapy Using Genome Edited Human iPS Cells to Be Differentiated into Soma... 4.3.1 The ATMP Is Manufactured at an Industrial Scale to Be Marketed in the European Union 4.3.2 The ATMP Is Not Manufactured at an Industrial Scale 4.3.2.1 The ATMP Is Covered by the So-Called `Hospital Exemption ́ 4.3.2.2 The ATMP Is Covered by the Compassionate Use Schemes 4.3.3 The ATMP Is Investigational 4.3.4 If the Product Is Not Classified as an ATMP, the Regulatory Pathway Applicable to Tissues and Cells May Apply 4.4 Treatment of the Patient ́s Biological Data 4.5 Reform Efforts 4.6 Outlook: Human Germ Line Intervention Through Genome Editing 4.7 Conclusion References Chapter 5: Regulation of Genome Editing in Human iPS Cells: Switzerland 5.1 Introduction 5.1.1 Genome Editing in Human Cells 5.1.2 Research on Gene/Cell Therapies in Switzerland 5.1.3 Overview 5.2 Genome Editing of Human iPS Cells: An Overview of the Regulatory Framework 5.2.1 Regulatory Framework 5.2.1.1 The National Framework 5.2.1.1.1 Fundamental Rights in the Swiss Constitution 5.2.1.1.2 Historical Perspective on Constitutional Medical Regulation in Switzerland 5.2.1.1.3 Current National Framework of Medical Regulation 5.2.1.2 The Biomedicine Convention 5.2.2 Regulatory Authorities 5.2.2.1 Federal Office of Public Health 5.2.2.2 Swissmedic 5.2.2.3 Swiss Ethics Commissions 5.3 Regulatory Prerequisites for Combined Gene/Cell Therapy Using Genome Edited Human iPS Cells to be Differentiated into Soma... 5.3.1 The General Principle of Informed Consent 5.3.2 Clinical Trials 5.3.2.1 General Principles of Clinical Trials 5.3.2.2 In Particular: Preclinical Studies 5.3.2.3 Prior Research Approval 5.3.2.4 Conducting the Clinical Trial: Notification and Documentation 5.3.2.5 Manufacturing 5.3.2.6 Liability in Cases of Damage 5.3.3 Market Placement 5.3.4 Patentability 5.4 Human Germ Line Intervention Through Genome Editing 5.4.1 Forms of Germ Line Interventions 5.4.2 General Legal Framework 5.4.3 Further Legal Considerations 5.4.3.1 Germ Line Interventions on Embryos 5.4.3.2 Germ Line Interventions on Germ Cells 5.4.3.3 Germ Line Interventions on Stem Cells 5.4.3.3.1 Embryonic Stem Cells Used for Germ Line Intervention 5.4.3.3.2 Induced Pluripotent Stem Cells Used for Germ Line Intervention 5.4.3.4 Artificial Gametes 5.4.4 Conditions and Limits of Germ Line Interventions and of Dealing with Embryos and Embryonic Stem Cells 5.4.5 Discussion 5.5 Treatment of the Patient ́s Biological Data 5.5.1 Legal Framework 5.5.2 Requirements for Data Protection 5.5.2.1 Basic Principles of Data Protection 5.5.2.2 Selected Principles of Data Protection 5.5.2.2.1 Voluntary and Informed Consent 5.5.2.2.2 Secondary Use of Sampled Biological Data 5.5.2.2.3 Rules Concerning the Storage, Archiving and Destruction of Health and Genetic Data 5.5.2.2.4 The Right Not to Know 5.5.3 Discussion 5.6 Conclusion Legal Acts Material Swiss Federal Supreme Court Cases European Court of Human Rights Cases European Court of Justice References Chapter 6: Regulation of Genome Editing in Human iPS Cells: United States 6.1 Introduction 6.1.1 History of Cell-based Product Regulation in the U.S. 6.1.2 Current State of Cell and Gene Therapy Product Research in the U.S. 6.1.3 Current Regulation of iPSC-based Products in the U.S. 6.2 Regulatory Requirements for Investigating and Seeking Approval for Gene/Cell Therapy Products 6.2.1 General Recommendations for Preclinical Testing Programs for CGT 6.2.1.1 Specific Preclinical Study Design Considerations for Cell Therapy Products 6.2.1.2 Specific Preclinical Study Design Considerations for Gene Therapy Products 6.2.2 Considerations for Early Stage Clinical Trials with CGT Products 6.2.3 Manufacturing Considerations for Cell and Gene Therapy Products 6.2.4 Approval of CGT Products 6.2.4.1 Accelerated Approval: 21 C.F.R. § 314.601 6.2.4.2 Breakthrough Therapy Designation: 21 U.S.C. § 356(a) 6.2.4.3 Fast Track Review: 21 U.S.C. § 506(b) 6.2.4.4 Regenerative Medicine Advanced Therapy Designation: 21 U.S.C. § 356 6.3 Legal Protections for Patient Biological Data and Biospecimens 6.4 Legal Developments Relating to Ownership of Biospecimens 6.5 Future of Germline Intervention Therapeutics in the U.S. 6.6 Conclusion References Chapter 7: Regulation of Genome Editing in Human iPS Cells: Japan 7.1 Introduction 7.1.1 Support Programs and Implementation Schemes in Different Countries 7.1.2 Scientific Research Trends Within the Stem Cell Field (Fig. 7.1) 7.1.3 Bank for Clinically Applicable Pluripotent Stem Cells (Fig. 7.3) 7.1.4 Launch Status of Regenerative Medicine Products (Fig. 7.4) 7.1.5 Status of Clinical Trials Using Pluripotent Stem Cells 7.1.6 Clinical Trials and Clinical Applications 7.2 Genome Editing of Human iPS Cells: An Overview of the Regulatory Framework 7.2.1 Overview 7.2.2 History of the Adoption of Three Regenerative Medicine-Related Acts 7.2.3 The Regenerative Medicine Promotion Act 7.2.4 The PMD Act (Revised PAL) 7.2.4.1 History 7.2.4.2 Overview of the PMD Act 7.2.4.3 Regulatory Scientific Strategic Consultation 7.2.5 Regenerative Medicine Safety Act 7.2.5.1 History 7.2.5.2 Overview of the Regenerative Medicine Safety Act 7.2.5.3 Advanced Medical Care As an Exit from the Regenerative Medicine Safety Act 7.2.5.4 Tumorigenicity-Related Genes 7.2.5.5 Reasons for Reforming the Regulatory Framework in Japan 7.3 Regulatory Prerequisites for Combined Gene/Cell Therapy Using Genome-Edited Human iPS Cells to be Differentiated into Soma... 7.3.1 Regulatory Practice for Regenerative Cellular Products in the PMD Act 7.3.2 Quality Control 7.3.2.1 Overview 7.3.2.2 Quality Assurance from the Clinical Phase of Development to Manufacturing and Marketing 7.3.2.3 Change in Regulatory Attitudes Toward the Quality of Pharmaceutical Products 7.3.2.4 Common Technical Document (CTD) 7.3.2.5 Points for Regulatory Assessment of Quality and Quality-Related Documents Required for Approval 7.3.2.6 Ensuring Quality of Cellular and Tissue-Based Products 7.3.2.6.1 Ensuring Quality 7.3.2.6.2 Quality Control Items for Final Products 7.3.2.6.3 GCTP As an Essential Prerequisite for Quality 7.3.2.6.4 GCTP in Cellular and Tissue-Based Products 7.3.3 Pre-clinical Studies 7.3.3.1 Definition 7.3.3.2 Toxicity Studies 7.3.3.2.1 Objectives of Toxicity Studies 7.3.3.2.2 General Toxicity Studies and Cell-Based Medicinal Products 7.3.3.2.3 Special Toxicity Studies and Cell-Based Medicinal Products 7.3.3.2.4 Pluripotent Stem Cell Input Studies 7.3.3.3 Pharmacology Studies 7.3.3.3.1 Pharmacology Safety Studies 7.3.3.3.2 Primary Pharmacodynamics Studies 7.3.3.4 Pharmacokinetic Studies/Disposition Studies 7.3.4 Case Study 7.4 Treatment of the Patient ́s Biological Data 7.5 Reform Efforts 7.6 Outlook: Human Germ Line Intervention Through Genome Editing 7.7 Conclusion References Chapter 8: Regulation of Genome Editing in Human iPS Cells: Republic of Korea 8.1 Introduction 8.1.1 Clinical Trials for Somatic Gene Therapy in Korea 8.1.2 Marketing Authorisation for Somatic Gene and Cell Therapy Products 8.1.3 Research and Clinical Trials on Genome Editing 8.2 Genome Editing of Human iPS Cells: An Overview of the Regulatory Framework 8.3 Regulatory Prerequisites for Combined Gene/Cell Therapy Using Genome-Edited Human iPS Cells to Be Differentiated into Soma... 8.3.1 Administrative Authorities 8.3.2 Control Mechanisms 8.3.2.1 Non-Clinical Research Planning 8.3.2.2 Extraction of Human Materials 8.3.2.3 Non-Clinical Studies on Reprogramming, Genome Editing, Redifferentiation 8.3.2.4 Clinical Studies of Gene Therapies and Gene Therapy Products 8.3.2.5 Manufacture and Marketing of Gene Therapy Products 8.4 Treatment of Patient Biological Data 8.5 Reform Efforts 8.6 Outlook: Human Germ Line Intervention through Genome Editing 8.7 Conclusion References Chapter 9: Comparative Analysis 9.1 Introduction 9.2 General Aspects 9.2.1 Legal Frameworks 9.2.1.1 Formal Aspects 9.2.1.1.1 National Law 9.2.1.1.2 EU Law 9.2.1.1.3 International Law 9.2.1.1.4 Federal Systems 9.2.1.2 Substantive Aspects 9.2.1.2.1 Medicinal Products Regulation 9.2.1.2.2 GMO Regulation 9.2.1.2.3 Bioethics Regulation 9.2.1.2.4 Personal Data Protection Regulation 9.2.2 Competent Authorities 9.3 Clinical Trials 9.3.1 In Advance Control Mechanisms 9.3.1.1 Prior Authorization 9.3.1.2 Prior Notification 9.3.2 Time Limits for Review 9.3.3 Manufacturing Requirements 9.3.4 GMO-Specific Requirements 9.3.5 Consultation Mechanisms 9.3.6 Country-Specific Peculiarities 9.3.6.1 Japan 9.3.6.2 Korea 9.4 Placing on the Market 9.4.1 Pre-Marketing Control Mechanisms 9.4.2 Special Procedures 9.4.2.1 Intense Mentoring 9.4.2.2 Accelerated Review 9.4.2.3 Provisional Authorization 9.4.3 Manufacturing Requirements 9.4.4 GMO-Specific Requirements 9.5 Treatment Without Prior Marketing Authorization 9.5.1 Single-Patient Treatments 9.5.2 Treatments of Patient Groups 9.5.3 In-house Manufacturing and Administration 9.6 Patients ́ Biological Data 9.7 Germ Line Therapy 9.8 Conclusions 9.8.1 Best Regulatory Practices 9.8.1.1 Three-Layered Regulatory Framework 9.8.1.2 Regenerative Medicine-Specific Regulations 9.8.1.3 Centralized Bodies 9.8.1.4 Avoiding Undue GMO Regulation 9.8.1.5 Facilitated, or Differentiated, In Advance Control of Clinical Trials 9.8.1.6 Early Consultation Mechanisms 9.8.1.7 Expedited Marketing Authorization Procedures 9.8.1.8 Permissibility of Treatment Prior to Marketing Authorization 9.8.1.9 Abolishing the Additional Manufacturing Licence Requirement 9.8.1.10 Differentiated Prior Informed Consent Requirements 9.8.1.11 Moratorium on Germ Line Therapies 9.8.2 Additional Considerations References Appendix: Questionnaire Country Report: [please state your country] Introduction Genome Editing of Human iPS Cells: An Overview of the Regulatory Framework Regulatory Prerequisites for Combined Gene/Cell Therapy Using Genome Edited Human iPS Cells to be Differentiated into Somatic ... Treatment of the Patient ́s Biological Data Reform Efforts Outlook: Human Germ Line Intervention Through Genome Editing Conclusion