Regulatory Aspects of Gene Therapy and Cell Therapy Products: A Global Perspective (Advances in Experimental Medicine and Biology, 1430) [2 ed.] 3031345665, 9783031345661

Table of contents :
Preface
Contents
About the Editor
1: Marketing Regulatory Oversight of Advanced Therapy Medicinal Products in Europe
1.1 Introduction
1.2 Legal and Regulatory Framework
1.3 Considerations on Quality and Manufacturing Aspects
1.3.1 General Considerations
1.3.2 General Quality and Manufacturing Aspects
1.3.2.1 Starting and Raw Materials and Excipients for Production of ATMP
1.3.2.2 Manufacturing Process
1.3.2.3 Quality Control
1.3.3 Gene Therapy Medicinal Products
1.3.4 Cell-Based Medicinal Products
1.3.5 Genetically Modified Cells
1.3.6 ATMP and Medical Devices
1.4 Considerations on Non-clinical Aspects
1.4.1 Non-clinical Model Selection
1.4.2 Biodistribution of CBMP and GTMP
1.4.3 Aspects of Toxicology
1.4.4 Considerations on AAV
1.5 Considerations on Clinical Aspects
1.5.1 General Considerations in the Clinical Development of ATMP
1.5.2 Exploratory Clinical Trials
1.5.2.1 Safety and Tolerability
1.5.2.2 Pharmacodynamics
1.5.2.3 Pharmacokinetics
1.5.3 Confirmatory Clinical Trials
1.5.4 Safety Assessments and Patient Follow-Up
1.6 Challenges and Regulatory Support for the Development of ATMP
1.7 Conclusion on Possible Future Directions for ATMP
References
2: Clinical Trials on Advanced Therapy Investigational Medicinal Products in Spain (2004–2022): Experience and Challenges for the Future
2.1 Introduction
2.2 European Legislation Covering Clinical Trials on Medicinal Products
2.3 Requirements Specific for Clinical Trials on ATiMP
2.3.1 Good Manufacturing Practice for ATMP
2.3.1.1 Traceability
2.3.1.2 Administration of Out of Specification Products
2.3.2 Good Clinical Practice for ATMP
2.3.3 Specific Requirements for CT on ATiMP-Containing GMO
2.4 Clinical Trials on ATiMP in Spain from May 2004 to July 2022
2.4.1 Methodology
2.4.2 Exploratory Analysis of CT Status and Request to Sponsor for Updating the Status
2.4.3 Results
2.4.3.1 CT according to Type of ATiMP, Sponsor, International Character, Number of Participating Sites in Spain and Phase
2.4.3.2 CT According to Targeted Disease and CT Population
2.4.3.3 ATiMP
2.4.3.4 CT status
2.5 Transparency About Clinical Trials on ATiMP and EU Initiatives
2.6 Conclusion
References
3: The Regulation of Cell Therapy and Gene Therapy Products in Switzerland
3.1 Introduction
3.2 The Regulatory Framework for ATMP in Switzerland
3.3 The Applicable Regulatory Pathways for Cell and Gene Therapy Products
3.4 Specific Considerations Regarding Manufacturing, Pharmacology/Toxicology and Clinical Trial Design for Cell and Gene Therapy Products
3.4.1 Specific Considerations for Cell Therapy Products
3.4.1.1 Quality Considerations
3.4.1.2 Nonclinical Considerations
3.4.1.3 Clinical Considerations
3.4.2 Specific Considerations for Gene Therapy Products
3.4.2.1 Quality Considerations
3.4.2.2 Nonclinical Considerations
3.4.2.3 Clinical Considerations
3.4.3 Regulatory Requirements for Cell and Gene Therapy Products for Marketing Authorization
3.4.4 A Risk-Based Approach in the Regulation of Cell and Gene Therapy Products
3.4.5 The Role of Real-World Evidence in the Regulation of Cell and Gene Therapy Products: The Clinical Perspective
3.5 The HTA System in Switzerland
3.6 Conclusion and Outlooks
Annex
The Definition of a Transplant Product (TpP)
References
4: European Pharmacopoeia’s Approach to Cell and Gene Therapy: Focus on How Gene Therapy Texts Are Evolving
4.1 Introduction
4.2 European Pharmacopoeia and Its Role in the Legal Framework
4.3 Overview of the Ph. Eur. Texts on Cell and Gene Therapy
4.4 Focus on Ph. Eur. Gene Therapy Texts
4.4.1 History of the Ph. Eur. General Chapter Gene Transfer Medicinal Products for Human Use (5.14)
4.4.2 Conversion to Two Texts: A General Monograph and a General Chapter
4.4.3 General Monograph 3186—Proposed Requirements
4.4.4 Evolution of Adeno-Associated Virus Vectors for Human Use: A Case Study
4.5 Conclusion
References
5: United States Food and Drug Administration Regulation of Human Cells, Tissues, and Gene Therapies
5.1 United States Regulatory Framework
5.1.1 Definitions
5.1.2 Regulatory Pathway
5.1.2.1 Product Life Cycle: Investigational Use, BLA, Post-marketing
5.1.2.2 IND and Presubmission Meetings
5.1.2.3 21st Century Cures Act (2016)
5.1.2.4 Expedited Programs
5.1.2.5 Fast Track Designation
5.1.2.6 Breakthrough Therapy designation
5.1.2.7 Regenerative Medicine Advanced Therapy designation
5.1.2.8 Priority Review
5.1.2.9 Accelerated Approval
5.2 Specific Considerations for Cell and Gene Therapies Across Different Disease Indications
5.2.1 Chemistry, Manufacturing, and Controls
5.2.1.1 CGT Product Manufacturing and Testing
5.2.1.2 Materials Used in Manufacturing
5.2.1.3 Scale-Up for Late-Phase Clinical Studies
5.2.1.4 Comparability
5.2.1.5 Standards
5.2.2 Pharmacology/Toxicology
5.2.2.1 Pharmacology Studies
5.2.2.2 Toxicology Studies
5.2.2.3 Clinical Dose Selection
5.2.2.4 The Three Rs
5.2.3 Clinical Pharmacology in Clinical Development
5.2.4 Clinical Development
5.2.4.1 Phase 1 Clinical Studies
5.2.4.2 Phases 2 and 3 Clinical Studies
5.2.4.3 Pediatric Study Considerations
5.2.4.4 Studies Conducted Outside of the United States
5.2.4.5 Post-marketing Studies
5.2.4.6 Long-Term Follow-Up for Gene Therapy Products
5.2.4.7 Patient-Focused Drug Development
5.3 US FDA-Approved CGT Products
5.4 Conclusions
References
6: Canadian Regulatory Framework and Regulatory Requirements for Cell and Gene Therapy Products
6.1 Introduction
6.2 Regulatory Framework for Advanced Therapy Medicinal Products
6.2.1 Current Regulatory Framework
6.2.2 Regulatory Innovation
6.2.2.1 Clinical Trial Modernization
6.2.2.2 Agile Regulations
6.2.2.3 Schedule G in the Food and Drugs Act
6.3 Applicable Regulatory Pathway(s)
6.3.1 Relevant Regulations
6.3.2 Canada: Accelerators for Development
6.3.2.1 Presubmission Meetings
6.3.2.2 Expedited Submission Pathways
6.3.3 Regulatory Harmonization and Guidance
6.4 Specific Considerations/Requirements for CGT Products
6.4.1 Chemistry, Manufacturing, and Control
6.4.1.1 Dossier Filing Considerations
6.4.1.2 Comparability
6.4.1.3 Gene Editing
6.4.2 Nonclinical Studies
6.4.2.1 Cell Therapy
6.4.2.2 Ex Vivo Cell-Based Gene Therapy
6.4.2.3 In Vivo Gene Therapy
6.4.3 Clinical Studies
6.4.3.1 Conduct of Clinical Trial
6.4.3.2 Specific Challenges Regarding Safety and Efficacy
6.4.3.2.1 Cell Therapy
6.4.3.2.2 CAR-T Therapy
6.4.3.2.3 In-Vivo Gene Therapy
6.4.4 Marketing Authorization and Requirements
6.5 Cell and Gene Therapy Products in Canada
6.5.1 Marketed Products
6.5.2 Investigational Products
6.5.2.1 Autologous CAR-T Therapy for Hematological Disorders
6.5.2.2 T Cell Therapy for Solid Tumors
6.5.2.3 Allogeneic CAR-T Therapy
6.5.2.4 Tumor Infiltrating Lymphocytes
6.5.2.5 Oncolytic Virus Therapy
6.5.2.6 Engineered Stem Cells
6.5.2.7 Point-Mutation Correction of Disease Using Stem Cell Replacement
6.5.2.8 AAV Gene Therapy
6.5.2.9 AAV-Based Gene Therapies for the Treatment of Monogenic Diseases of the Central Nervous System
6.5.3 Products under Development
6.5.3.1 Developing Canadian-Made Next-Generation of CAR-T and Oncolytic Virus Therapies for Cancer
6.5.3.2 Gene Editing
6.6 Health Technology Assessment
6.7 Conclusion: Possible Future Directions in the Field
References
7: Advanced Therapy Products in Brazil: Regulatory Aspects
7.1 Introduction
7.2 Brazilian Regulatory Concepts for ATMP
7.3 Regulating Advanced Therapies Products in Brazil
7.3.1 Main Aspects of Clinical Trials with ATMP
7.3.2 ATMP Marketing authorization
7.3.3 GMP Certification for ATMP
7.3.4 General Aspects of Pharmacovigilance
7.4 Perspectives
References
8: Regulation of Clinical Research for Cellular and Gene Therapy Products in India
8.1 Introduction
8.2 Regulatory Framework for CGTP
8.2.1 New Drugs and Clinical Trials Rules 2019
8.2.1.1 Salient Features
8.2.2 Drugs and Cosmetics (3rd Amendment) Rules, Gazette Notification No. GSR 899(E), Dated 27/12/2011
8.2.2.1 Salient Features
8.2.3 Rules for the Manufacture, Use, Import, Export, and Storage of Hazardous Microorganisms/Genetically Engineered Organisms or Cells 1989 (Known as “Rules, 1989”)
8.2.3.1 Salient Features
8.2.4 National Guidelines for Stem Cell Research
8.2.4.1 Salient Features
8.2.5 The National Guidelines on Gene Therapy Product Development and Clinical Trials 2019
8.2.5.1 Salient Features
8.2.6 National Ethical Guidelines for Biomedical and Health Research Involving Human Participants 2017
8.2.7 National Guidelines for Hematological Cell Transplantation 2021
8.2.7.1 Salient Features
8.2.8 Evidence Based Status of Stem Cell Therapy for Human Diseases 2021
8.2.8.1 Salient Features
8.3 Regulatory Pathways and Committees for Approval/Advisory on CGTP
8.3.1 National Level Committees
8.3.1.1 Subject Expert Committees
8.3.1.2 National Apex Committee for Stem Cell Research
8.3.1.3 Gene Therapy Advisory and Evaluation Committee
8.3.1.4 Review Committee on Genetic Manipulation
8.3.1.5 Clinical Trial Registry of India (CTRI)
8.3.2 Local/Institutional Level Committees
8.3.2.1 Ethics Committee
8.3.2.2 Institutional Committee for Stem Cell Research
8.3.2.3 Institutional Bio-Safety Committee
8.3.2.4 Data Safety Monitoring Board
8.4 Approval Process for CGTP in India
8.5 Specific Considerations
8.5.1 Chemistry, Manufacturing, and Control Requirements
8.5.2 GMP Requirements
8.5.3 Preclinical Studies
8.5.4 Clinical Trials
8.6 CGTP Authorized for Market in India
8.7 Challenges Ahead and Way Forward
8.8 Conclusions
References
9: Regulatory Aspects of Cell and Gene Therapy Products: The Japanese Perspective
9.1 Introduction
9.2 Japanese Regulatory Framework for Cell and Gene Therapy
9.2.1 Outline of Regulatory Frameworks
9.2.2 Definition of CT
9.3 Update on Current Activities
9.3.1 ASRM
9.3.1.1 Starting Class I (High-Risk) CT Under the ASRM
9.3.1.2 Toward Revision of the ASRM
9.3.2 Commercialization: The PMD Act
9.3.2.1 Overview of Specific Considerations/Requirements
9.3.2.2 Current Approved Products
9.3.2.3 Public Patient Registry System
9.3.2.4 Development Trends
9.3.2.5 Guidelines
9.4 Regulations Regarding Living Modified Organisms (Genetically Modified Organisms)
9.5 Conclusion
References
10: Regulatory Oversight of Cell and Gene Therapy Products in Malaysia
10.1 Introduction
10.2 The Role of NPRA
10.3 Regulatory Framework
10.3.1 Chronology
10.3.2 Classification
10.4 Clinical Trials
10.5 Overview of CGTP Registration
10.5.1 Registration Pathways
10.5.2 Registration Process
10.6 Overview of the Registration Dossier
10.7 Transition Period
10.8 Future Direction
10.8.1 Organization for Economic Cooperation and Development (OECD) GLP Sites in Malaysia
10.8.2 First in Human Trials in Malaysia
10.8.3 Full Implementation on January 1, 2025
10.8.4 Gene Therapy Products
References
11: Regulatory Oversight of Cell, Tissue, and Gene Therapy Products in Singapore
11.1 Introduction
11.2 Regulatory Framework for Cell, Tissue, and Gene Therapy Products
11.2.1 Current Legislations
11.2.1.1 Focus Group Discussions and Public Consultation
11.2.1.2 “Fit-for-Purpose” Regulatory Framework
11.2.2 Definition
11.2.3 CTGTP Classification
11.3 Regulatory Pathways and Requirements
11.3.1 Class 1 CTGTP Notification
11.3.2 Class 2 CTGTP Registration
11.3.2.1 Application Types
11.3.2.2 Application Routes
11.3.2.3 Risk Management Plans
11.3.2.4 Screening and Evaluation Process
11.3.2.5 Conditional Registration
11.3.3 Dealer’s Notice and Dealer’s Licence
11.3.3.1 Minimally Manipulated CTGTP
11.3.3.2 More Than Minimally Manipulated CTGTP
11.3.3.3 Duties and Obligations of Dealers
11.3.3.4 In-house Manufacturing by Healthcare Institutions
11.4 Access to Unregistered Class 2 CTGTP
11.4.1 Clinical Trials
11.4.2 Special Access Route
11.5 Access to Out of Specifications Class 2 CTGTP
11.6 Regulatory Guidelines
11.7 List of Registered and Notified Products, and Licensed Dealers
11.8 Conclusion
References
12: Update on Regulation of Regenerative Medicine in Taiwan
12.1 Introduction
12.2 Regulation of Regenerative Medicine in Taiwan
12.2.1 Regulatory Development for Regenerative Medicinal Products: From Medical Practices to Medicinal Products
12.2.2 Current Regulatory Framework for Regenerative Medicine
12.2.3 Current Approved Clinical Trials and Regenerative Medicinal Products
12.3 Special Events in Taiwan
12.3.1 Taiwan Formosa Water Park Explosion: First Clinical Use of Cell Therapy Medicinal Product in Taiwan
12.3.2 Patient’s Voice from the Public Policy E-Platform: To Introduce the Immune Cell Therapy in 2015
12.4 New Regulatory Framework for Regenerative Medicine
12.4.1 The New Regulatory Framework: Two Draft Acts of Regenerative Medicine
12.4.2 The Regenerative Medicine Therapies Act (Draft)
12.4.3 The Regenerative Medicinal Products Act (Draft)
12.4.3.1 General Provision
12.4.3.2 Product Registration
12.4.3.3 Conditional Approval
12.4.3.4 Manufacture and Distribution
12.4.3.5 Postapproval Management
12.4.3.6 Others
12.5 Challenges of Regenerative Medicine
12.5.1 Product Lifecycle Management: PIC/S GMP, GDP, Severe Adverse Reactions Reporting, and Safety Surveillance
12.5.2 Health Technology Assessment and National Health Insurance Reimbursement of Regenerative Medicinal Products
12.6 Conclusion
References
13: Regulatory Frameworks for Advanced Therapy Medicinal Products in Thailand
13.1 Introduction to the Thai Food and Drug Administration
13.2 Law, Regulation, and Guidelines
13.3 Introduction to Advance Therapy Medicinal Products
13.3.1 Classification and Definition of ATMP Subclass
13.3.2 Risk-Based Defined ATMP
13.4 Regulation on ATMP
13.4.1 Clinical Trial Application and Authorization Procedure in Thailand
13.4.1.1 The Application for ATIMP Import Permit or Manufacture Permit and Review Process by Thai FDA
13.4.1.2 Conduct of Clinical Trials
13.4.2 Premarketing Authorization
13.4.2.1 Presubmission Meeting
13.4.2.2 Electronic Submission
13.4.2.3 The ASEAN Common Technical Dossier for the Registration of Pharmaceuticals for Human Use
13.4.2.4 ICH Common Technical Document (ICH CTD)
13.4.2.5 Evaluation Procedure
13.4.3 Postmarketing Authorization: GMP
13.4.3.1 The Application and Licensing for GMP Certification of Domestic Manufacturers
13.4.3.2 The Application and Licensing for GMP Clearance of Overseas Pharmaceutical Manufacturers
13.4.3.3 GMP Inspection Process
13.5 Challenges in the Development and Marketing Authorization of ATMP and Future Plans
13.6 Conclusion
References
14: International Harmonization for Cell and Gene Therapy Products
14.1 Introduction
14.2 The International Pharmaceutical Regulators Programme
14.2.1 ICH Link to IPRP
14.3 Asia Pacific Economic Cooperation Regulatory Harmonization Steering Committee
14.4 Other Interactions Between Global Regulators
14.5 Conclusion
References
Index

Citation preview

Advances in Experimental Medicine and Biology  1430

Maria Cristina Galli   Editor

Regulatory Aspects of Gene Therapy and Cell Therapy Products A Global Perspective Second Edition

Advances in Experimental Medicine and Biology Volume 1430 Series Editors Wim E. Crusio, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, CNRS and University of Bordeaux Pessac Cedex, France Haidong Dong, Departments of Urology and Immunology Mayo Clinic Rochester, MN, USA Heinfried H. Radeke, Institute of Pharmacology and Toxicology Clinic of the Goethe University Frankfurt Main Frankfurt am Main, Hessen, Germany Nima Rezaei, Research Center for Immunodeficiencies Children’s Medical Center Tehran University of Medical Sciences Tehran, Iran Ortrud Steinlein, Institute of Human Genetics LMU University Hospital Munich, Germany Junjie Xiao, Cardiac Regeneration and Ageing Lab Institute of Cardiovascular Sciences School of Life Science, Shanghai University Shanghai, China

Advances in Experimental Medicine and Biology provides a platform for scientific contributions in the main disciplines of the biomedicine and the life sciences. This series publishes thematic volumes on contemporary research in the areas of microbiology, immunology, neurosciences, biochemistry, biomedical engineering, genetics, physiology, and cancer research. Covering emerging topics and techniques in basic and clinical science, it brings together clinicians and researchers from various fields. Advances in Experimental Medicine and Biology has been publishing exceptional works in the field for over 40 years, and is indexed in SCOPUS, Medline (PubMed), EMBASE, BIOSIS, Reaxys, EMBiology, the Chemical Abstracts Service (CAS), and Pathway Studio. 2021 Impact Factor: 3.650 (no longer indexed in SCIE as of 2022)

Maria Cristina Galli Editor

Regulatory Aspects of Gene Therapy and Cell Therapy Products A Global Perspective Second Edition

Editor Maria Cristina Galli Istituto Superiore di Sanità (ret.) Rome, Italy

ISSN 0065-2598     ISSN 2214-8019 (electronic) Advances in Experimental Medicine and Biology ISBN 978-3-031-34566-1    ISBN 978-3-031-34567-8 (eBook) https://doi.org/10.1007/978-3-031-34567-8 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2015, 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable

Preface

Advanced therapies have come to age around the world. Many gene therapy and cell therapy medicinal products are now on the market in Europe, North and South America, and Asia that address many previously unmet serious diseases. The American Society of Gene and Cell Therapy and Springer Nature, which prompted the first edition, have stimulated the second edition of this book with the aim at updating the Advanced Therapy Medicinal Products (ATMP) regulatory landscape. I was happy to accept the task to be the editor, as I am convinced that this updated book will be particularly useful to those interested or working in the ATMP field, that since the first edition has proved to be most important for patient therapy and cure. This book gives an updated overview of the regulatory policies and requirements applied in different regions of the world for the development of ATMP into market authorized medicines. The book contains chapters from regulatory bodies already represented in the first edition as well as from additional regions (i.e. India, Malaysia, Spain, Thailand) and contributions addressing the international harmonization efforts. Each chapter gives state-­ of-­the-art information on the regulatory procedures and requirements implemented by that specific regulatory body to enable ATMP clinical development, plus some useful information on the Health Technology Assessment applied when the product is on the market. From the first edition, the basic regulations applicable to ATMP have not changed, while all players in the field (regulatory bodies and developers) have gained considerable experience that has resulted into refining the process of regulatory oversight and of development, thus allowing many products to be on the market on most countries. The similarities among the regions are now more evident than the differences, also as a positive result of international efforts toward harmonisation of procedures and requirements. In conclusion, this book provides the current perspective of regulators worldwide and hopefully will serve as a resource to academia, industry, and government agencies in the regulation of ATMP. I trust that the excellent contributions given in this book will continue to facilitate the global development of safe and efficacious ATMP for the benefit of all patients. Rome, Italy

Maria Cristina Galli

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Contents

1 Marketing  Regulatory Oversight of Advanced Therapy Medicinal Products in Europe����������������������������������������   1 Martina Schuessler-Lenz, Carla Herberts, Ilona Reischl, Sol Ruiz, Patrick Celis, Claire Beuneu, Rune Kjeken, and Marcos Timón 2 C  linical Trials on Advanced Therapy Investigational Medicinal Products in Spain (2004–2022): Experience and Challenges for the Future��������������������������������������������������������  23 Juan Estévez Álamo, Marcos Timón, Isabel Sánchez Afán de Rivera, Beatriz Iriarte Torres, and M. Antonia Serrano Castro 3 The  Regulation of Cell Therapy and Gene Therapy Products in Switzerland������������������������������������������������������������������  41 Petra Kempná Bukovac, Michel Hauser, Daniel Lottaz, Andreas Marti, Iris Schmitt, and Thomas Schochat 4 European  Pharmacopoeia’s Approach to Cell and Gene Therapy: Focus on How Gene Therapy Texts Are Evolving��������  59 Olga Kolaj-Robin and Marie-Thérèse Duffour 5 United  States Food and Drug Administration Regulation of Human Cells, Tissues, and Gene Therapies������������������������������  71 Sandhya Sanduja, Liz Lessey-Morillon, Rondine Allen, Xiaofei Wang, Gavin Imperato, and Judith Arcidiacono 6 Canadian  Regulatory Framework and Regulatory Requirements for Cell and Gene Therapy Products��������������������  91 Jian Wang, Emily Griffiths, Omar Tounekti, Martin Nemec, Eric Deneault, Jessie R. Lavoie, and Anthony Ridgway 7 Advanced  Therapy Products in Brazil: Regulatory Aspects�������� 117 João Batista Silva Junior, Renata Miranda Parca, and Adriana Bastos Carvalho 8 Regulation  of Clinical Research for Cellular and Gene Therapy Products in India�������������������������������������������������������������� 135 Varsha Dalal, Hem Lata, Gitika Kharkwal, and Geeta Jotwani vii

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9 Regulatory  Aspects of Cell and Gene Therapy Products: The Japanese Perspective���������������������������������������������������������������� 155 Yoshiaki Maruyama, Shinichi Noda, Shinichi Okudaira, Akira Sakurai, Narumi Okura, and Futaba Honda 10 Regulatory  Oversight of Cell and Gene Therapy Products in Malaysia ���������������������������������������������������������������������� 181 Evelyn Yun Xi Loh, Azizah Ab Ghani, and Rosilawati Ahmad 11 Regulatory  Oversight of Cell, Tissue, and Gene Therapy Products in Singapore���������������������������������������������������������������������� 197 Lee Lee Ong 12 Update  on Regulation of Regenerative Medicine in Taiwan�������� 211 Wan-Yu Chao, Yi-Ting Chang, Yueh-Tung Tsai, Mei-Chen Huang, Yi-Chu Lin, Min-Mei Wu, Jo-Feng Chi, Chien-Liang Lin, Hwei-Fang Cheng, and Shou-Mei Wu 13 R  egulatory Frameworks for Advanced Therapy Medicinal Products in Thailand ���������������������������������������������������� 221 Piyanan Boonprasirt, Sarun Nimvorapun, Chonticha Sawangjang, Sitanun Poonpolsub, Worasuda Yoongthong, and Paisarn Dunkum 14 International  Harmonization for Cell and Gene Therapy Products���������������������������������������������������������������������������� 235 Judith Arcidiacono Index��������������������������������������������������������������������������������������������������������   241

Contents

About the Editor

Maria Cristina Galli was co-editor of the first edition. Until her retirement at the end of 2020, Dr. Galli was a senior researcher at the Istituto Superiore di Sanità, Roma, Italy. Dr. Galli is presently a freelance consultant in the field of gene and cell therapy development and production.

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Marketing Regulatory Oversight of Advanced Therapy Medicinal Products in Europe Martina Schuessler-Lenz, Carla Herberts, Ilona Reischl, Sol Ruiz, Patrick Celis, Claire Beuneu, Rune Kjeken, and Marcos Timón

Abstract

Advanced therapy medicinal products (ATMP) in the European Union (EU) are regulated by Regulation 1394/2007 and comprise gene and cell therapy and tissue-engineered products. Under this framework, ATMP are authorised by the centralised procedure, coordinated by the European Medicines Agency (EMA), whereas clinical trial authorisations remain at the remit of each National Competent Authority. The Committee for Advanced Therapies is responsible for the scientific evaluation of the marketing authorisation applications and for generating a draft opinion that M. Schuessler-Lenz Division Haematology/Cell and Gene Therapies, Paul-Ehrlich-Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany e-mail: [email protected] C. Herberts Division Europe, Medicines Evaluation Board, RG, Utrecht, Netherlands e-mail: [email protected] I. Reischl Division Clinical Trials, Institute Surveillance, Austrian Medicines and Medical Devices Agency (AGES MEA), Vienna, Austria e-mail: [email protected] S. Ruiz Division Biological Products, Advanced Therapies and Biotechnology, Spanish Medicines Agency, Madrid, Spain e-mail: [email protected]

goes to the Committee for Human Medicinal Products for a final opinion. For every application, data and information relating to manufacturing processes and quality control of the active substance and final product have to be submitted for assessment together with data from non-clinical and clinical safety and efficacy studies. Technical requirements for ATMP are defined in the legislation, and guidance for different products is available through several EMA/CAT guidelines. Due to the diverse and complex nature of ATMP, a need for some regulatory flexibility was recognised. Thus, a risk-based approach was introduced in Regulation 1394/2007

P. Celis Advanced Therapies Office, European Medicines Agency, Amsterdam, Netherlands e-mail: [email protected] C. Beuneu Federal Agency for Medicines and Health Products, Brussels, Belgium e-mail: [email protected] R. Kjeken Norwegian Medicines Agency, Oslo, Norway e-mail: [email protected] M. Timón (*) Division Biological Products, Advanced Therapies and Biotechnology, Spanish Medicines Agency, Madrid, Spain e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 M. C. Galli (ed.), Regulatory Aspects of Gene Therapy and Cell Therapy Products, Advances in Experimental Medicine and Biology 1430, https://doi.org/10.1007/978-3-031-34567-8_1

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M. Schuessler-Lenz et al.

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allowing adapted regulatory requirements. This has led, for instance, to the development of good manufacturing practice (GMP) guidelines specific for ATMP.  This, together with enhanced regulatory support, has allowed an increasing number of successful marketing authorisation applications resulting in 25 licensed ATMP in the EU, mainly gene therapy medicinal products. The promise of messenger RNA and genome editing technologies as therapeutic tools make the future for these innovative medicinal products look even brighter. This chapter reviews the regulatory landscape together with some of the support initiatives developed for ATMP in the EU. Keywords

European Union · ATMP · CAT · CBMP · GTMP · Regulation · Risk-based approach

Abbreviations AAV ADME

Adeno-associated Virus Absorption, Distribution, Metabolism and Excretion ATIMP Advanced Therapy Investigational Medicinal Product ATMP Advanced Therapy Medicinal Product CAR Chimeric Antigen Receptor CAT Committee for Advanced Therapies CBMP Cell-based Medicinal Product CE Conformité Européenne CHMP Committee for Human Medicinal Products CRISPR Clustered Regularly Interspaced Short Palindromic Repeats CRS Cytokine Release Syndrome EC European Commission EDQM European Directorate for the Quality of Medicines EMA European Medicines Agency

ERA Environmental Risk Assessment EU European Union FDA Food and Drug Administration FIH First in Human GCP Good Clinical Practice GLP Good Laboratory Practice GMO Genetically Modified Organism GMP Good Manufacturing Practice GTIMP Gene Therapy Investigational Medicinal Product GTMP Gene Therapy Medicinal Product ICANS Immune Effector Cell-Associated Neurotoxicity Syndrome ICH International Council for Harmonisation iPSC Induced Pluripotent Stem Cell IVDR In Vitro Diagnostic Regulation MAA Marketing Authorisation Application MD Medical Device MDR Medical Devices Regulation MSC Mesenchymal Stromal Cell PD Pharmacodynamic PRIME Priority Medicines RCV Replication Competent Virus RNA Ribonucleic Acid SME Small- and Medium-sized Enterprises SmPC Summary of Product Characteristics SoHO Substances of human origin TALEN Transcription Activator-like Effector Nuclease TEP Tissue-engineered Product TIL Tumour-Infiltrating Lymphocyte ZFN Zinc Finger Nuclease

1.1 Introduction Gene and cell therapy products have been regulated in the European Union (EU) as medicinal products since 2003, when they were introduced into legislation through Directive 2003/63/EC [1]. Later, Regulation (EC) 1394/2007 [2] set the basis for regulating advanced therapy medicinal products (ATMP) in the EU and its associated member states (Norway, Iceland and Liechtenstein). In addition to gene and cell therapy, ATMP also include tissue-engineered medicinal products. This legislation specified that marketing authori-

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sation of ATMP in the EU falls within the mandatory scope of the centralised procedure where applicants submit a single marketing authorisation application (MAA) and receive a final opinion that is accepted by all member states. If the opinion is positive, it still needs to be legally confirmed by the European Commission (EC), after which the centralised marketing authorisation is valid throughout the entire EU. The European Medicines Agency (EMA) is responsible for coordinating the scientific evaluation of applications under the centralised procedure. EMA’s scientific evaluation work is carried out by experts at the EU national competent authorities, and final decisions are taken by EMA’s scientific committees, which are made up of representatives from all EU member states, as well as representatives of patients’, consumers’ and healthcare professionals’ organisations. Those committees have various tasks related to the development, assessment and supervision of medicines in the EU. In addition, together with EMA, those scientific committees play a role in stimulating innovation and research via scientific advice, guideline development, support to developers in small- and medium-sized enterprises (SME), orphan designation and early dialogue through the Innovation Task Force meetings or the Quality Innovation Group. Since 2016, the Priority Medicines (PRIME) scheme also offers support for innovative products aimed at treatments with an unmet medical need. National authorities in the EU member states will likewise support medicine development, e.g. via national scientific and regulatory advice and respective innovation offices within national Medicines Agencies. In Regulation 1394/2007, a possibility for national authorisation and supervision of non-­ industrially manufactured ATMP used under the responsibility of treating physicians was included in article 28 (the so-called “hospital exemption”). This allows national approval of manufacturing licences for products that fulfil the requirements defined in the regulation. Exemption means that such products can be produced and used only at national level and thus cannot be exported.

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Regulation 1394/2007 also established the creation of the Committee for Advanced Therapies (CAT). The Committee comprises of members and their alternates representing all EU member states. Five of the CAT members are also members of the Committee for Human Medicinal Products (CHMP) to ensure proper collaboration and flow of information between the two Committees. Physicians and patient organisations are also represented in the CAT: these members are nominated by the EC.  The CAT is responsible for the evaluation and draft opinion of ATMP MAA, which are further discussed by CHMP to generate the final opinion, followed by transmission of the opinion to the EC. Since its inception, the CAT has further discussed and revisited the regulatory requirements and guidance for ATMP. Gene- and cell-based therapies are manufactured from complex starting materials, they are themselves multifunctional, and there are several risks and limitations related to development and approval of ATMP that are not foreseen for other medicinal products. Thus, also the requirements and the overall regulatory framework have to be specifically tailored to fit these innovative therapies into the medicinal products framework. A risk-based approach was initially agreed as part of the new ATMP legislation [3], and guidance for the implementation of this approach was established in 2012 [4]. With the same objective, principles and requirements for long-term safety and efficacy follow-up were set in the ATMP legislation [2] and included in specific guidance [5]. The risk-based approach is also the driving principle of the good manufacturing practice guidelines (GMP) specifically developed for ATMP, which allow enough flexibility to accommodate manufacturing of such a diverse and complex class of products [6]. Regulation 1394/2007 and the subsequent development of adapted guidance undoubtedly facilitate the development of these complex products, which has resulted in an increasing ­ number of marketing authorisations in the EU, mostly genetically modified cells and gene ther-

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apy containing AAV vectors. Legal and main guidance and support initiatives for ATMP in the EU are described in this chapter.

1.2 Legal and Regulatory Framework The ATMP Regulation 1394/2007, which came into force in December 2008 [2], provides tailored regulatory principles for the evaluation, authorisation and post-authorisation follow-up of ATMP, sets up a committee with expertise specific to ATMP (the CAT) and provides incentives for developers of ATMP. Some of these incentives are financial (fee reductions, e.g. for scientific advice), while other incentives are in the form of procedures intended to assist the development of ATMP: the ATMP classification procedure and the ATMP certification procedure. The ATMP classification procedure provides ATMP developers the possibility to request the CAT to make a scientific recommendation whether their product will or will not fulfil the definition of an ATMP. The classification is especially relevant for cell-based ATMP, which need to be differentiated from traditional transplantation/transfusion products, which in the EU are not considered medicines and have their own regulations. The CAT classification will provide regulatory certainty about the legal framework that is applicable as well as the scientific guidance to be consulted during product development. The ATMP certification procedure is restricted to SME developing ATMP. During the certification procedure, CAT will perform a scientific evaluation of quality/manufacturing and, if available, non-clinical data that are generated with the product. This evaluation will give the SME a strong indication that their ATMP development programme is on track to meet the standards of a future MAA.  This procedure can also be used, close to the submission of the MAA, as a tool for pre-assessment of the quality and non-­clinical parts of the MAA. In general, ATMP will have to fulfil the same scientific and regulatory requirements as other

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medicinal products. The manufacturing of ATMP will have to comply with the principles of GMP and clinical trials will have to be designed and conducted in accordance with the principles laid down in good clinical practice (GCP). However, the ATMP Regulation delineates a tailored approach to take into account the specificities of ATMP: therefore, the European Commission published in 2017 the Guidelines on Good Manufacturing Practices specific to Advanced Therapy Medicinal Products [6] and in 2019 the Guideline on Good Clinical Practice specific to Advanced Therapy Medicinal Products [7]. The CAT developed and published in 2017 Principles of Good Laboratory Practice (GLP) that need to be taken into account in relation to Advanced Therapy Medicinal Products [8]. Regarding the requirement for MAA, ATMP will also follow the general requirement to document the quality, non-clinical and clinical development of their product as described in the Annex I to Directive 2001/83/EC (implementing Directive 2009/120/EC [3], which lays down the technical requirements for all medicinal products). Here as well, the ATMP Regulation provided the legal basis for the revision of this Annex I: tailored requirements are set for ATMP, not only to take into account their specificities but also to lay down the legal basis for ATMP development on the basis of a risk-based approach. The latter allows the ATMP developer from the beginning and throughout the product development programme to determine and justify the extent of quality, non-clinical and clinical data to be included in the future MAA, on the basis of a risk profiling strategy specifically developed for these products. The CAT has published a scientific guideline on how to apply this risk-based approach [4]. The high-level technical requirements defined in Directive 2009/120/EC are further substantiated in scientific guidelines published on the EMA website [9–11]. Finally, the same post-authorisation and pharmacovigilance requirements that apply to medicinal products will also apply to ATMP. In addition, Regulation 1394/2007 requests Applicants to implement appropriate measures to ensure a follow-­up also on efficacy [2].

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ATMP developers may also need to take into account other legislation when developing or marketing their product in the EU. The most important are the following:

1.3 Considerations on Quality and Manufacturing Aspects

• for ATMP based on human cells, Directive 2004/23/EC [12] and its implementing directives should be followed for the donation, procurement and testing of the human tissues or cells that will become the starting materials of the ATMP [13, 14]. For ATMP based on human blood and blood components, Directive 2002/98/EC [15] with its implementing directives “Setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components” should be followed when they become the starting materials of the ATMP [16, 17]. It should be noted that the legislation on tissues and cells and the legislation on blood are currently under revision, with the most recent information provided on the EC website on substances of human origin (SoHO) [18]; • legislation concerning requirements for traceability of human tissues and cells [14] and blood and blood components [17] should be taken into account; • for gene therapy medicinal products (GTMP) containing a genetically modified organism (GMO), legislation on GMO should be followed with regard to the environmental risk [19, 20]. Developers of GTMP should consult the ATMP webpage on the European Commission’s website providing practical information on the assessment of GMO-related aspects for clinical trials with AAV-based investigational gene therapy products based on AAVs and genetically modified human cells [21]. Information on the requirements for medical products containing and consisting of GMO can be found on the EMA website [22]; • for combined ATMP, the legislation on medical devices [23] should be taken into account for the device component(s).

Since the ATMP are a very diverse group of medicines with adapted manufacturing processes, it is difficult to advise on a single approach that fits all. However, general strategies that also apply to non-ATMP products should be followed during development aside from considering product-­specific requirements. For GTMP that are based on viral vectors, plasmids or messenger RNA, product development is similar to that of biotechnology-­based medicinal products, and guidelines related to quality and manufacturing aspects have been developed at EMA/CAT and at the international level (ICH) [10]. For ATMP based on human cells and tissues, the manufacturing processes are different from those of other, more traditional, medicinal products, and quality control requires specific methodologies. Nonetheless, a properly established and controlled manufacturing process is required to ensure a consistent medicinal product. This should be in place as early in development as possible to guarantee a link between the product used in clinical trials and the one presented for commercial use. If large changes in manufacturing are introduced later in development, quality comparability exercises may not be sufficient to guarantee that link and regulators could request bridging non-clinical and/or clinical studies. The knowledge gained from process development forms the basis for an adequate characterisation programme and could be used to support a more reduced release testing strategy. As for any other medicinal product, the first step in the establishment of the manufacturing process for an ATMP should be the definition of a quality target profile, which needs first a clear understanding of what the product is. This can be challenging for certain types of products, namely some cell-­based ATMP, but it is vital for the development of a manufacturing process supported by a proper control strategy. Ultimately, characterisation should cover relevant assays for

1.3.1 General Considerations

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identity, purity, safety and biological activity [9–11]. In order to ensure consistent manufacture, product stability and comparability after manufacturing changes, the potency/functional assays provide valuable information.

1.3.2 General Quality and Manufacturing Aspects 1.3.2.1 Starting and Raw Materials and Excipients for Production of ATMP The source of the starting and raw materials used during the manufacturing process needs to be chosen to avoid the risk of transmitting adventitious agents. While clear legal requirements are defined for human source materials used as starting materials for ATMP [12–14], a developer will need to consider the reagents of biological origin used in the product-specific manufacturing process for adventitious agent testing. Avoidance of materials of human and animal origin in manufacturing reduces testing requirements, but it is usually not feasible for ATMP manufacture. A number of EMA and ICH guidance documents provide support in approaching the issue of adventitious agents including viral risk assessment [24]. Guidance regarding raw materials used in the manufacture of ATMP has been also developed by EMA/CAT experts and the European Directorate for the Quality of Medicines (EDQM) to be included as a general text in the European Pharmacopoeia [25]. For excipients, an active substance master file cannot be submitted in the EU, and full module 3 data are required at the time of MAA. For excipients derived from human blood, the CHMP guideline on plasma-derived medicinal products provides guidance on data requirements [26]. As already mentioned, the manufacture of ATMP frequently entails the use of biological substances. Unless they are available as licenced medicinal products where composition, content and viral safety are addressed (i.e. interleukin-2, human albumin), the burden of qualification of these raw materials lies with the ATMP manufacturer. Detailed knowledge on the materials used

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is required not only to assure a consistent manufacturing process but also to support a change of suppliers if required. For instance, a given growth factor used during cell culture needs to have consistent biological activity across lots, and the composition of the solution/lyophilisate that contains the protein needs to be known. For example, if the solution contained albumin, the origin of the albumin needs to be known, as well as the testing the protein has been subjected to. Again, the requirements are not only of relevance from the manufacturing consistency perspective but also from a safety point of view. Obtaining this detailed information is not necessarily easy for developers buying these raw materials, but it will be required by regulators. It should be noted that expensive raw materials claimed to be of ­“GMP-­grade” do not necessarily fulfil all regulatory requirements. GMP is a pharmaceutical quality assurance system not intended for reagents and cannot be taken as a statement of proven quality for raw materials. As for all biological medicinal products, the issue of adventitious agents needs to be addressed comprehensively, by using raw materials with minimal risk, a well-controlled manufacturing process and a control strategy that provides further assurance of safety for the patient.

1.3.2.2 Manufacturing Process A well-controlled manufacturing process is one that reproducibly yields a product of desired quality, i.e. target profile. The process parameters and in-process controls should be derived from studies investigating the critical quality parameters of the product. Scientific knowledge from research and development can be of value to justify the expected link between the manufacturing process and the quality parameters selected to control the manufacturing process. Hence, closely linked with the definition of the target profile is the definition of critical process parameters, i.e. which process steps and operating conditions are essential to obtain the desired product quality and what are the operating conditions required to achieve that goal. A riskbased approach [4] should be applied in this exercise.

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1.3.2.3 Quality Control A prerequisite for meaningful results is to have analytical methods that have been proven suitable for their intended use during early development and are fully validated at the time of submission of a marketing authorisation. Complex products will require multiple orthogonal (i.e. independent) analytical methods for characterisation. It is highly recommended to aim at an in-depth characterisation of the product with a range of different analytical methods beyond those that will be used to measure the specifications. The more varied the analytical toolkit, the better and with more confidence can a comparability exercise be managed later on, where it might be necessary due to manufacturing changes. The specifications should reflect the target profile and be well justified by results from characterisation studies, published knowledge and manufacturing capabilities. If conforming to specifications, the ATMP should be capable of performing its intended biological function. Regulators will ask for data to support the established specification limits. Specifications should be numerical values (i.e. quantitative) as much as possible. For potency, surrogate markers can be used, but their correlation to biological activity needs to be demonstrated. Finally, the stability and shelf life of the ATMP need to be established to ensure that the product is still safe for use and performing its intended function at the end of the specified shelf life.

1.3.3 Gene Therapy Medicinal Products A GTMP is described in the European legislation [3] as a biological substance that contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence. Additionally, its therapeutic, prophylactic or diagnostic effect has to relate directly to the recombinant nucleic acid sequence it contains or to the product of genetic

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expression of this sequence. Vaccines against infectious diseases are excluded from this definition due to their specificities and impact on public health. This statement has been applied to products requesting EMA classification but, considering the significant progress in gene therapy approaches, a review of the existing definition would be useful to have a harmonised approach with other regulatory regions. GTMP can be based either on viral or non-­ viral (plasmids, RNA-based) vectors and contain transgene(s) responsible for the therapeutic effect. The choice of the vector depends on the condition to be treated and the persistence of the intended effect (short or long term). Especially for treatment of monogenetic, inherited diseases, integrating viral vectors (retro-, lentiviruses) are generally used in order to achieve a sustained effect. However, the use of early versions of integrating vectors led to safety problems (insertional mutagenesis [27], which have since been minimised through modification of vector design (e.g. self-inactivating/SIN vectors) and with dedicated testing and characterisation of the insertion sites. For various cancers, on the other hand, immune cells are manipulated through gene therapy using viral vectors with short-term effect (adeno-, vaccinia viruses, etc.). Non-viral vectors are used to a lesser extent perhaps due to less effective transduction of cells. For every product, the vector chosen and design of the transgene should be well documented and justified [28]. Administration of GTMP can take place either directly (in vivo) or through transduced patient cells (ex vivo). For genetically modified cells, specific aspects are discussed later in this chapter. The manufacture of GTMP resembles that of other biologicals, i.e. large batch sizes can be produced allowing treatment of multiple patients, and the products can be stored and release testing completed before use. There is already experience in manufacturing process control and scale-­up for both viral and non-viral vectors; however, special attention should be provided to comparability of pivotal clinical batches versus commercial batches once the product gets a marketing authorisation.

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Quality requirements for GTMP may depend on the stage of product development, but an initial risk assessment to address and evaluate potential risks associated with the clinical use of the specific product is highly recommended [4]. For GTMP, as for CBMP, particular consideration should be given to the starting and raw materials, especially if of biological origin. The product as a whole should be characterised to an extent allowing identification of critical quality attributes that can be further used for lot release and stability testing. For release, the ratio of full/ empty particles should be as high as possible, and infectivity (where needed), purity, potency and sterility testing is required. For potency testing, functionality of the GTMP or expression level and functionality of the produced therapeutic protein may be required. If ex vivo application of the GTMP is anticipated, transduction efficiency of the GTMP should be followed. Development of GTMP may lead to significant changes in the construct, and sometimes an improved version of the original vector construct is proposed. In such cases, comparability of the various constructs and the final therapeutic product should be carefully considered [28]. Safety aspects of various vector versions and how they may be altered are especially important if major changes to the vector and design of the construct are planned. If a GTMP contains a GMO, an environmental risk assessment (ERA) addressing possible shedding and transmission to the environment is obligatory in the EU. The procedure is twofold: (i) an ERA will be done as part of the MAA evaluation and (ii) all member states will be consulted about the release of the GMO. For both procedures, the applicant should provide all necessary information about the characteristics of the GMO and data from shedding and transmission studies. Further guidance on ERA can be found from CHMP guideline on ERA [20]. Simplified procedures for low environmental risk medicinal products containing or consisting on GMO already developed for the clinical trial stages [21] are also been implemented for marketing authorisation.

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1.3.4 Cell-Based Medicinal Products Common scientific requirements apply to all CBMP independent of their classification as somatic cell therapy or tissue-engineered product (TEP) and will be augmented by additional aspects in case of genetically modified cells, some of which will fall under the definition of a gene therapy. By nature, these products are complex, sensitive to their manufacturing ­environment and challenging to comprehensively characterise. In the autologous setting, it is essential to explore donor variability to define appropriate specifications for the specific patient. Due to the potential limited amount of patient material, characterisation and validation may be conducted with cells from healthy donors. However, where this approach is followed, the representativeness of the material must be established, e.g. that cells from healthy donors and patients behave similarly during manufacture. Usually there are also additional limitations as to the overall cell number that can be obtained for the final product which requires that the control strategy makes the most efficient use of the material available. The manufacturing process for CBMP needs to be clearly defined in terms of duration of the doubling times of the cells in the culture conditions, as it is known that certain characteristics, such as differentiation potential, might be lost during long-term culture. A specific issue for CBMP based on mixed populations is the need to demonstrate that product-­defining analytical results (i.e. specifications) relate to the cell population responsible for the biological function. Further, characterisation studies should aim to demonstrate whether additional cell populations present in the product contribute positively, negatively or not at all to the activity of the target population. Depending on whether the final product is supposed to be supplied in fresh or frozen form different challenges arise. For fresh preparations, time is of essence and transport needs to be completed within the (short) shelf life. In case of frozen preparations, sufficient assurance needs to be provided that the freeze and thaw procedure maintains a product within defined specifications.

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1.3.5 Genetically Modified Cells

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device required by the Summary of Product Characteristics (SmPC) (referenced and sepaFor products based on genetically modified cells, rately obtained). While requirements differ, the technical requirements as set in Directive impact of the additional device aspect needs to be 2009/120/EC [3] and the corresponding guide- considered as early as possible to facilitate line [11] should be considered. development. Cells can be genetically modified ex vivo by A combined ATMP, according to Article 2(1) gene transfer procedures or by genome editing tech- (d) of Regulation 1394/2007, is an ATMP that has nologies such as CRISPR-Cas, Zinc finger nucle- one or more integral medical devices (MD) or ases (ZFN), TALEN and others. The starting active implantable MD components falling materials used in each case should be well qualified within the scope of the EU medical device legisto assure a consistent product. The amount of data lation [2]. “Integral” is defined as intended exclurequired to assess the quality of the starting material sively for use in the given combination and not used in the manufacturing of a genetically modified reusable. Annex I to Directive 2001/83/EC furcell medicinal product is equivalent to that required ther clarifies that combination of the medical for a drug substance. In addition, changes in the device with the cells at the time of administration starting materials will likely have an impact on the can be considered as an integral part of the finquality and safety of the final product and as such, ished product. Cells grown on matrices prior to adapted comparability studies are needed. human administration are examples in EMA Where ex vivo transduced cells are used, trans- summaries of scientific recommendations on duction efficiency and number of integrated cop- classification of ATMP [29]. ies, if appropriate, should be tested on every Regulation (EU) 2017/745 on medical devices batch as a measure of potency and safety. When (MDR) introduces (in article 117) new requirereplication-defective viruses are used to geneti- ments for integral MD in medicinal products but cally modify the cells, absence of replication it needs to be emphasised that it is not relevant for competent viruses (RCV) in the final product (combined) ATMP as for these article 9 of should be assured. However, if absence of RCV Regulation 1394/2007 applies instead. Dedicated is confirmed at the level of the viral vector start- guidance is available for the potential consultaing material and generation of RCV during man- tion process with Notified Bodies [30]. ufacturing of the genetically modified cells is Non-integral co-packaged and referenced MD ruled out via a risk assessment, no further testing need to bear a CE mark (Conformité Européenne) on every batch is necessary. for their intended use according to the instrucFor genome-edited cells, on-target and off-­ tions for use, to be legally on the market unless target modifications should be characterised and they fall under exemptions defined in the MDR, the need to include appropriate testing on each which is unlikely in this specific setting. The CE batch is normally determined on a case-by-case certification procedure is conducted by Notified basis. Persistence of genome editing tools should Bodies designated for specific product families also be studied. [31]. As additional aspect for ATMP, information on MD used during surgical procedures for application, implantation or administration of an 1.3.6 ATMP and Medical Devices ATMP, which may impact on efficacy or safety as per Annex I, Part IV, Section 5.2.1 of Annex Three different settings may be envisaged where Dir2001/83/EC, is expected in Module 5 of a medical devices play a role in the context of marketing authorisation dossier. ATMP: (i) in combined ATMP according to the The information required for combined ATMP, definition in Regulation 1394/2007; (ii) an ATMP including that for the MD component(s), is genwith a co-packaged non-integral medical device; erally outlined in ATMP specific guidelines but it and (iii) an ATMP with the use of a medical specifically depends on the nature of the product

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being developed. Medicinal product and MD components have to be independently characterised, followed by the characterisation of the combination. At marketing authorisation, the information provided needs to be justified under a risk-based approach. For non-integral devices in the context of ATMP, and where ATMP specific guidelines do not indicate the location of the relevant information in the Marketing Authorization Application, the principles of the “Guideline on quality documentation for medicinal products when used with a medical device” [32] should be followed. Finally, Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) has introduced the concept of companion diagnostics (article 2 (7)) which involves a consultation procedure with Competent Authorities. This is also applicable for ATMP that incorporate a companion diagnostic.

1.4 Considerations on Non-­ clinical Aspects In general, the objectives of nonclinical studies for ATMP do not differ from the evaluation of small molecules. However, the realisation of such studies including challenges in design and the significance of the resulting data to the situation in the human body may vary considerably for these product classes. The objectives of non-clinical studies are to demonstrate proof of principle for the medicinal product and to define the pharmacological and toxicological effects that are predictive for the responses in humans. Furthermore, in such studies the establishment of safe and pharmacologically active doses for First in human (FIH) clinical studies and information to support the preferred route of administration of the medicinal product could be achieved. Non-clinical studies may also help to identify target organs for toxicity and parameters to be monitored in the patients as well as patient populations at risk for adverse events [9 –11, 33].

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For ATMP, the extent and nature of the non-­ clinical studies necessary to support clinical trial applications as well as marketing authorisation applications should be determined using a risk based approach, as described in the Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to advanced therapy medicinal products [4]. In some cases, where hazards, specific risks and risk factors have already been identified based on known risks associated with the nature of the product, the findings observed in proof-of-­concept studies or in in vitro tests may negate additional animal studies as these would not further substantiate the risk. In these cases, the risk-­ based approach might be used as a rational tool for justification of the omission of certain non-­clinical in vivo studies, and the specific risk could be mitigated with appropriate clinical measures. This will often be the case for some categories of cell-based products such as CAR-T cells and TILs. In other cases, the riskbased approach may be used to justify the design of non-clinical in vivo studies identified as necessary (e.g. duration of proof-of-concept or biodistribution studies). Applicants are encouraged to combine the different in vivo non-clinical studies whenever possible (pharmacology, biodistribution and toxicology studies), in line with the 3Rs principle [34]. The combination of biodistribution endpoints to Proof of Concept and Toxicology studies might also help with interpretation of the study results.

1.4.1 Non-clinical Model Selection A challenging step in the design of non-clinical studies for ATMP is the selection of appropriate animal models, since basic characteristics necessary to mimic the situation in humans might be absent or different in the selected animals such as tropism of the viral vector or activity of the promoter driving the therapeutic gene in GTMP or the reactivity of the immune system against both the cells in a CBMP and the viral vectors for GTMP. Ideally, an animal model should display

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similar characteristics to humans in terms of their physical, mechanical, chemical and biological properties. To this end, for the different questions to be answered with respect to safety and efficacy of the ATMP, likely different animal models, perhaps even from different species, need to be established and used. Such models may comprise genetically modified animals such as “receptor knock-in” animals to allow a range of infection with a viral vector comparable to the human situation, knock-out animals to mimic the human disease or specifically humanised animals to establish a human immune system for the evaluation of therapeutic immune effects or immunotoxicities triggered by the cell or gene therapeutic approach. In some cases, homologous models using animal cells of the respective species instead of human cells might be most indicative. For example, this approach might be considered if the therapeutic effect of a cell therapy can only be determined in the presence of the immune system and the administration of human cells in the animal would lead to immediate rejection. In this case, however, cells/tissues from the model animal need to be harvested, isolated, manipulated and applied in a manner as similar as possible to the intended clinical ATMP. While homologous models mimic the environment within the patient to a high extent, the model also comprises uncertainties. At first glance, similar manufacturing processes may lead to different impurities and characteristics of the product, which may result in a different pharmacological and toxicological profile. In addition, the respective animal-derived cells and/or their components are often less characterised than their human homologues. Therefore, these cell preparations may have different functions or may be regulated differently in the animal body when compared to the actual medicinal product. In any case, the criteria upon which a particular animal model is chosen have to be scientifically justified, and limitations of the animal model should be identified and discussed, in particular if it has been established for a particular ATMP. In this respect, it is important to determine which of the potentially harmful effects of

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an ATMP—associated with either intrinsic characteristics of the ATMP or with its manufacture—are assessable in the chosen animal models or not. The number of animals in the individual studies may vary depending on different factors such as the disease model, the test species, the delivery system and other considerations. The total number of test animals per study group should be in a range allowing a statistically and biologically significant interpretation of the results. Where evaluation of the pharmacological or toxicological effects requires large animal disease models, e.g. for TEP for cartilage repair, the animal number per study group is often at the lower limit. The duration of the non-clinical studies for ATMP may be extended, and the time points of monitoring may be more frequent and flexible than would be anticipated for classical medicinal products depending on the intended duration of the treatment and the kinetics of distribution, replication, persistence and clearance of a given product in the body. Cells may persist in the animal for longer time periods or may induce long-­ term effects. The same considerations apply to viral vectors or replicating gene-modified oncolytic viruses. Such products may exert different transduction efficiencies, tissue tropism and/or replication kinetics, or they may undergo latency and reactivation cycles or may stably integrate into the host cell genome, potentially resulting in long-term therapeutic gene expression. All these parameters have to be taken into consideration for the design of the non-clinical studies. Animals of both genders should be used when relevant, and positive and negative controls should be included. For the latter, sham treatment or vehicle might be used. In addition, the rationale for each functional test needs to be provided. For some ATMP, especially those which are based on an immunological mode of action or are tackling immunological indications, relevant animal models may not be available or cannot be developed to address particular aspects of pharmacology or toxicology. In these cases, in vitro studies may replace the animal studies, but the underpinning rationale to use in vitro studies should be justified.

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This will be the case for a number of cell-­ clinical assessment on CRISPR-Cas-mediated based products including CAR-T cells and genome editing should include data on ex vivo TIL. While evaluating in vivo function in xeno- non-homologous end joining approaches used to graft models has been performed for CAR-T cell generate a genetic knock-out of the gene of interrefinement and optimisation, CAR-T cell func- est by appropriate in silico analyses, followed by tion can also be evaluated in vitro by examining unbiased genome-wide cell-based and/or bioeffector responses against cells expressing the chemical assays to test/confirm the in silico pretargeted antigen. diction. Justification for the methods used, as Assays using target antigen-expressing cells well as sufficient information as to allow for may recapitulate a number of features such as assessing algorithm(s) used for in silico predicinteraction with CAR-T cells through co-­ tion, is required [33, 36]. stimulation engagement, adhesion molecule interactions and immune-suppressive ligands. Tumour-derived organoids generated from 1.4.2 Biodistribution of CBMP normal organoids by introducing pro-­tumorigenic and GTMP mutations, or directly from fresh tumour specimens may also be applied and such models may Biodistribution studies should address, when relbetter capture the cellular and molecular diversity evant, the in vivo distribution, persistence and of the clinical samples [35]. From a regulatory clearance of an ATMP in target and non-target perspective, and in line with the 3Rs principle, tissues. Data from biodistribution studies may the use of such models is encouraged. support the design and interpretation of non-­ For addressing the potential for on-target /off-­ clinical pharmacology and toxicology studies. tumour activity for the clinical product, animal Depending on the mode of application of the models are usually not adequate, and these issues CBMP, the cells may be distributed within the are instead addressed by employing relevant in whole body passively by the blood or distribute vitro assays. Also, animal models are generally actively, as multipotent different cell types can considered less relevant for studying key safety also migrate to sites of injuries or inflammation. aspects for CAR-T cells and TIL-based products, As cells from haematopoietic origin are expected including the potential to induce cytokine release to distribute broadly, the necessity to perform an syndrome (CRS) or immune effector cell-­ in vivo biodistribution study should be considassociated neurotoxicity syndrome (ICANS). At ered based on a risk-based approach taking into present, in vitro data on cytokine expression for a account different parameters such as the degree representative array of factors may typically be of modification of the cells (e.g. expected or considered adequate to support an FIH study for designed to alter natural biodistribution of these these products. cells), a potential claim for persistence or implanFor the up-and-coming class of ATMP based tation, the route of administration and local retenon gene editing technology such as CRISPR-Cas, tion of cells. For example, there is nowadays a similar requirements for non-clinical studies to wealth of publicly available information on the demonstrate proof of principle, biodistribution biodistribution of mesenchymal stromal cells and safety applies as for other gene therapy (MSC) in various animal models following difmedicinal products. In vivo safety studies for ferent routes of administration [37], which could these therapies should also include end points to be sufficient to wave the need for a biodistribuaddress potential immunogenicity directed tion study for these cells. For CBMP considered towards the edited cells and when relevant, the to carry a higher risk, such as e.g. iPSC, it might newly expressed protein. Also, it may be relevant be necessary to study the biodistribution and the to gather data on immunogenicity towards the fate of the CBMP in a relevant model. Cas protein and/or individual components used The draft ICH (International Council for for delivering the gene editing machinery. Non-­ Harmonisation) guideline S12 on non-clinical

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biodistribution considerations for gene therapy products details general requirements for biodistribution studies for gene therapy products [38]. This guidance also discusses the need for biodistribution studies in different settings. Biodistribution studies for GTMP should address the distribution, persistence and clearance of the product itself and may also address the transcription/expression profile of the delivered gene. The observation time in biodistribution studies will depend on the nature of the GTMP. For some products, this will be until no signal of vector presence and therapeutic sequence expression is detected. In other cases (e.g. integrating vectors, vectors targeting non-dividing cells), the transgenic sequences might be present in the animal lifelong. In this case, observation duration required will typically be until the vector genome concentration and/or transgene expression level reaches a plateau that remains stable. As for other non-­ clinical in  vivo studies, a risk-based approach may be applied also for biodistribution studies [4]. Data obtained with highly similar vectors and/or from the published literature may be used to justify the extent and design of the biodistribution analysis. With oncolytic viruses or when a vector is engineered to target-specific cells and/or to modify its biodistribution in order to increase target cell tropism or decrease non-target tissue modifications, this should also be substantiated by data from a biodistribution study. Finally, data from biodistribution studies are also used to determine whether the risk of germline transmission of a given GTMP needs to be further addressed [39]. It should be noted that the Clinical Trials Regulation (regulation EU 536/2014) [40] states that no gene therapy trial may be carried out in the EU, which results in modifications to the subject germline genetic identity.

1.4.3 Aspects of Toxicology Toxicity of CBMP may arise from different factors such as (i) unknown cellular alterations that take place during the manufacturing process such

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as modified excretion of chemokines or specific differentiation, (ii) allogeneic/autologous origin of the product, and (iii) proliferation of the applied cell in an unwanted quantity and/or in an unwanted location. As modifications of the manufacturing process can impact the final product, the toxicology studies should be performed with the finished ATMP. Single- and repeated-dose toxicity studies may be necessary depending on the intended clinical use of the ATMP. In these studies, the application route and the dosing regimen should reflect the intended clinical use and the duration of observation may need to be significantly longer than anticipated from the standard single-dose studies in conventional toxicity studies, based on the expected persistence of the product and duration of its effect. To evaluate potential toxic effects associated with the application of a GTMP, different risk factors have to be taken into account: in vivo versus ex vivo genetic modification, expected persistence of the product, type of vector, route of administration, integrating status of viral vector, immunogenicity of the vector, biodistribution/ tropism, transgene type and level of expression, etc. Toxic effects may not only be triggered by the vector itself but also by the therapeutic sequences and the product of their expression, which may potentially include aberrant gene products and nontherapeutic vector proteins. Hence, the toxicological study program has to be adjusted to the medicinal product. Besides the single- and/or repeated-dose toxicity studies, analysis of genotoxicity, tumorigenicity, immunotoxicity and reproductive and developmental toxicity may be warranted. Repeated-dose toxicity should be considered when multiple dosing with the GTMP is intended. Integration studies to achieve information on the integration profile of the vector and the potential risk of insertional oncogenesis may also become necessary, particularly if used for genetic modifications of stem cells [27]. From a current regulatory viewpoint, the risk of tumorigenicity should be carefully addressed in adequate studies. For CBMP, this is a step-by-­ step process, based first on in vitro data assessing genomic stability. In case of recurrent abnormali-

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ties, in vivo studies may be warranted. For example, with regard to MSC, occurrence of cell abnormalities has been reported to be mainly related to the manufacturing process, as opposed to patient-specific factors [41]. It is therefore important to determine, by using appropriate quality control tests, whether the manufacturing process leads to chromosomal abnormalities, although no evidence of tumour formation has been reported from studies using human adipose-­ derived MSCs in nude mice and athymic rats with different application routes up to a 6-month follow-up period. In addition, the immunological status of the animals in such studies is an important consideration. For example, if allogeneic cells are used in immunocompetent mice, their rejection may preclude tumour formation. Tumorigenicity studies should preferably be performed with cells that are at the limit or even beyond the limit of the number of cell doublings that is routinely used during manufacturing. To detect genetic instability, the current standard method is karyotyping, although this technique only allows detection of large chromosomal rearrangements. If recurrent aberrations are identified, other complementary tools such as spectral karyotyping and comparative genomic hybridisation could be used to further evaluate these aberrations as they have better sensitivity to detect a low proportion of abnormal cells.

1.4.4 Considerations on AAV A substantial number of in vivo gene therapies developed are based on adeno-associated vectors (AAV). AAV-based vectors remain mainly episomal after cell transduction. Nevertheless, several studies in recent years have shown unintended integration events of recombinant AAV (rAAV) vectors into the host genome [42]. In theory, insertional mutagenesis could lead to tumour formation. In vitro integration studies can inform on the integration profile of rAAV and may allow discriminating between vectors with a high integrative ability vs low integrative ability. However, such studies may not predict the actual clinical risk for patients as integration is only one of the

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steps in the chain of events necessary for tumorigenesis. In vivo models have the advantage that biodistribution of the AAV-GT is an integral part of the study, and that multiple tissues can be evaluated for integrative and oncogenic events. However, the sensitivity of animal models to detect oncogenic events may still be limited, especially when integration events are infrequent. Taken together, both in vitro and in vivo studies have limitations in predicting the tumorigenic potential of AAV-GT, and these uncertainties may persist in the interpretation and the relevance of carcinogenic signals observed in non-clinical studies. Therefore, when deciding on the need for in vivo non-clinical studies, a risk-based approach should be applied that takes into account the product characteristics as well as the clinical application (including dose and route of administration, age of the patients and disease indication) [4].

1.5 Considerations on Clinical Aspects 1.5.1 General Considerations in the Clinical Development of ATMP In general, the development of an ATMP should follow the same general principles as other medicinal products in which information from small early studies is used to support and plan subsequent confirmatory studies as outlined in respective ICH guidelines [43, 44]. However, the distinctive characteristics and features of ATMP are expected to have an impact on the trial design, specifically with regard to early-phase trials and dose selection, pharmacodynamics, pharmacokinetics/biodistribution, while the general principles in late-phase trials to demonstrate efficacy and safety in the specific therapeutic area are less affected and are essentially the same as for other products. One distinctive feature is that most ATMP are developed for patients with rare diseases for which an unmet medical need is identified. Other distinctive features are that treatment usually consists of one administration which is expected to have long-

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term effects, that exposure cannot be reversed, that for some ATMP exposure increases following administration due to in vivo expansion (e.g. CAR-T cells or oncolytic viruses). In case of autologous cell-based products, additional steps and procedures like cell harvest, manufacturing and conditioning therapy need to be included in the design of the clinical trial. ATMP developers are strongly encouraged to seek advice at the national or European level prior to initiating the clinical development of a product, to address the specificities of the ATMP and to discuss possible deviations from current guidelines.

1.5.2 Exploratory Clinical Trials While for exploratory trials, especially for the FIH trials, the primary objectives are the same as for more conventional products (i.e. safety and tolerability), the clinical safety issues to be considered are different from other medicinal products. Such considerations include extended or permanent adverse effects, long-term or delayed safety issues, such as infections, immunogenicity/immunosuppressant effect, integration into the genome observed for some GTMP, ectopic tissue formation and malignant transformation. Exploratory studies with investigational ATMP (ATIMP) are often designed as phase I/II trials, combining features of phase I and phase II design. As a consequence, these studies serve to address more objectives than safety and tolerability. Other objectives of such exploratory trials are • Assessment of treatment approach and the use of the ATMP, and the feasibility of recruitment; • Identification and characterisation of the manufacturing and administration issues that can influence the product development • Characterisation of pharmacokinetics and biodistribution • Assessment of pharmacodynamics and early measurement of drug activity, e.g. gene expression and cell engraftment • Dose selection and determination of recommended dose for confirmatory studies

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FIH studies are a subset of exploratory studies, where the ATIMP is for the first time translated from non-clinical studies to humans. Although ATMP are exempted from the scope of the “Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products” [45], the outlined principles to mitigate risk are applicable. For ATIMP, extrapolation from non-­ clinical pharmacodynamic, pharmacokinetic/ biodistibution and toxicity data to the human situation is often complicated as the relevance of the non-clinical animal models may be limited. This may hamper, amongst others, the prediction of a safe starting dose for FIH trials and the prediction of target organs of toxicity. As a consequence, the rationale for the starting dose and dose range can be based on the totality of data considered relevant. This not only includes non-­ clinical data generated with the product but also clinical data generated with related products. For example, for an ATIMP containing genetically modified CD34+ cells, knowledge on the minimum dose of hematopoietic stem cells required to ensure engraftment and to avoid prolonged bone marrow suppression may be considered of relevance. Similarly, the experience gained with the already existing CAR-T cell products with regard to dosing but also safety profile should be leveraged when designing the FIH of a new ATIMP consisting of CAR-T cells. As noted above, features of phase I and II design are often combined for ATIMP. Examples are trials with cell-based gene therapies, e.g. CAR-T cells, where dose escalation and determination of a recommended dose are followed by an extension phase, to include additional patients on the recommended dose level and to further explore the efficacy of the GTMP. In such cases, the trial protocol should define the methodology to move from the dose-escalation phase to the extension phase and how this is captured in a substantial amendment. As ATMP can be very complex products, there may be limitations to the possibility to fully characterise these products in vitro. Therefore, clinical data may often be needed to evaluate any potential impact of (major) changes in manufac-

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turing process on the activity of the ATMP. In case that major manufacturing process changes are implemented, these should be implemented and evaluated clinically before starting confirmatory trials.

1.5.2.1 Safety and Tolerability As noted above, assessment of safety should be the focus of exploratory studies and included as a main objective similar to other medicinal products. This does not only include the risk related to the product, but the risk of the therapeutic procedure as a whole. This includes (i) the risk associated with cell procurement in an autologous setting, (ii) the risk of administration procedures, as well as (iii) the risk of any required concomitant therapy, e.g. the use of immunosuppressive therapy or pre-treatment conditioning. The risk of delayed adverse reactions should be considered based on the type of ATMP and is related to the actual risk profile of the vector used for the genetic modification of the cell, the nature of the gene product, the life-span (persistence) of the (modified) cells, the biodistribution of the ATMP and any potential effects on developing organs. In relation to a possible lifelong persistence of genetically modified stem or progenitor cells, special risk for delayed effects associated with the integrated vector and its expressed products should be considered (e.g. oncogenesis, immunogenicity or vector reactivation). 1.5.2.2 Pharmacodynamics Pharmacodynamic (PD) assessments are intended to substantiate the proof-of-concept, and the selected PD outcome measures should support the (expected) activity of the ATIMP. For example, in the case of GTIMP aiming to correct aberrant protein expression (for treatment of, e.g. a lysosomal storage disease or hemoglobinopathy such as sickle cell disease), PD assessments would include the expression and function of the expressed product (e.g. as a protein or enzyme or as activity of the (therapeutic) enzyme such as conversion of prodrugs or restoration breakdown of storage products). In other cases, the effect of the vector itself is addressed (e.g. recombinant oncolytic virus) or immune effector

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mechanisms and cytokine levels are assessed (e.g. CAR-T cells). For ATIMP-containing cells (including genetically modified cells), PD assessment generally also includes cell engraftment and assessment of numbers of target cells and other effects related to the pharmacological activity of the cells (e.g. target protein/enzyme production such as collagen deposition for cartilage products). In any case, it is expected that appropriate and up-to-date bioanalytical assays are used to evaluate markers of PD effects.

1.5.2.3 Pharmacokinetics Assessment of pharmacokinetics is another objective of the exploratory clinical trials. Classical pharmacokinetic assessment of absorption, distribution, metabolism and excretion (ADME) may not be possible or relevant for some types of ATIMP. For ATIMP-containing cells where conventional ADME assessment cannot be conducted, pharmacokinetic assessment should aim to monitor viability of the cells, their proliferation and/or differentiation (in time), body distribution and tissue tropism/migration. For certain GTIMP, conventional pharmacokinetic assessment, including as a minimum determination of (plasma) concentration and half-life for the therapeutic transgene product (i.e. therapeutic protein), should be performed using appropriate and up-to-date bioanalytical assays. While for others, where the entire genetically modified cell is required to deliver the therapeutic effect (e.g. CAR-T cell), the cells should be the main target for the pharmacokinetic analysis.

1.5.3 Confirmatory Clinical Trials As noted above, the general principles in late-­ phase trials to demonstrate efficacy and safety are less affected by the type of product and therefore the expectations for confirmatory studies are essentially the same as for more conventional products. Thus, for ATMP pivotal clinical (phase III) studies, confirming the preliminary evidence generated in exploratory studies, are usually

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required for demonstration of efficacy. Also, the main points to address in the design of these studies, are choice of target population and of control group, blinding procedures, choice of primary and secondary endpoints, sample size estimation and statistical design. With regard to endpoints, they are also the same for ATMP and should generally follow the specific guidance for the studied indication or disease. For example, when designing pivotal trials for CAR-T cells, the randomised controlled trial design should preferably be followed also in such cases where late-stage refractory disease settings are targeted or where reference therapies are not available [46]. In such cases comparison to best care or treatment based on investigator’s choice may provide the most convincing evidence of efficacy and is preferred over single arm trials, when appropriate. When justified, a non-parallel controlled single arm design might be acceptable for marketing authorisation. In such cases, it is expected that the treatment effect can be clearly attributed to the product, that the mechanism of action is well understood, that there are sufficient non-clinical and/or clinical corroborative data, that there is a clear effect indicative of a clinical benefit and acceptable toxicity, that the natural course of the disease is highly predictable and that there is an unmet medical need. With a view to marketing authorisation, results of such single arm trials are expected to be compelling, and data from external controls should be available to ­contextualise the results. The planning of confirmatory trials should take into account the principles outlined in the guideline on clinical trials in small populations [47]. With regard to end points, it is noted that while the primary efficacy variable is expected to capture clinical benefit of treatment for the target population and is similar to already accepted endpoints for the target population, additional product-specific end points may be required when these are relevant for the targeted therapeutic claim. For example, for cell-based or tissue-­ engineered products, these may include biochemical, morphological, structural and functional parameters of the administered cells or tissues. These end points can be used as co-primary

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or secondary variables and are expected to support the clinical primary efficacy variable. Further, in cases where long-term efficacy is expected, the efficacy end points should also focus on the duration of the response. As for any conventional medicinal product, any non-validated end point or surrogate end point, such as novel biomarkers, would have to be validated in a prospective study before being used in confirmatory clinical trials. For the analysis of the treatment effect, all patients that have been enrolled with the intention to initiate treatment, e.g. who have been randomised in a randomised controlled trial or who have signed informed consent in a single-arm trial should be included in the primary efficacy analysis. This also applies for products that require a certain manufacturing time, including CAR-T cells where sometimes a significant portion of the enrolled population drops out before treatment because of the manufacturing time of the product. In such cases, supportive analyses can be defined for, e.g. the apheresed population, the lymphodepleted population or the patient population undergoing pre-treatment conditioning and the treated/infused population if well justified. For further details, please refer to ICH E9 (R1) [48].

1.5.4 Safety Assessments and Patient Follow-Up As with other medicinal products, knowledge of the safety profile is very important. While evaluation of safety is the main focus of exploratory studies, evaluation of the safety profile should continue in confirmatory studies. The type and duration of follow-up should align with the general safety requirements [43]; however, these should be tailored to the characteristics of the product and anticipated risks and its intended target population. Factors to consider in the risks assessment of ATIMP are related especially to the mode of action, the nature of the target, the study population, previous experience in humans with the same or similar products and non-­ clinical studies. Importantly, although many ATMP are developed

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for a one-time administration, their persistence may be lifelong and the treatment effects (safety and efficacy) could be long lasting. The potential for insertional mutagenesis and insertion-mediated tumorigenesis of integrating vectors is an important factor that determines long-term follow-up. Insertional oncogenesis is known to be related to a number of variables like characteristics of the vector, dose and target cell in a sequence of multiple events and progressive alterations that extend over years. ATMP with high potential for insertional oncogenesis will thus require an extended follow-up period. Other factors are on-target/off-tumor toxicities and delayed hematological or other organ toxicities. In case of CD19-targeting CAR-T cells, for example, B cell aplasia and prolonged cytopenia 2  years after CAR-T cell administration are known to cause infectious complications and to be a main component for non-relapse mortality [49]. Prolonged cytopenia has emerged as a potential CAR-T cell-associated safety issue after more patients were exposed to CD19-­ targeting CAR-T cells in the post-authorisation setting. Based on this example, ATMP developers are advised to take into account both, the identified and the potential risks associated with the specific product and the incremental knowledge gained with related products when designing the safety monitoring and patient follow-up. In general, following the initial, more intense, safety monitoring immediately following administration and during the first 1–2  years after administration, long-term monitoring for efficacy and safety should be considered. The duration of such long-term follow-up is dependent on the expected duration of treatment effect, the risk associated with the product and the anticipated time until occurrence of (delayed) adverse events (latency). The long-term monitoring should be appropriately designed (e.g. sampling plan, sample treatment, analytical methods and end points) in order to maximise information output, but also critically consider the need for invasive procedures for long-term follow-up. While in some cases, lifelong follow-up may be preferred, the obligation for long-term follow­up should be proportional to the anticipated risks.

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1.6 Challenges and Regulatory Support for the Development of ATMP ATMP are complex pharmaceuticals with many limitations and challenges. Not only is the development of ATMP often hampered by lack of relevant non-clinical models and difficulties relating to manufacturing, quality controls and clinical trial designs for these products but also by special safety and efficacy issues that increase the workload of the developers (see above). For some ATMP, the administration systems (e.g. surgical, via catheters or specific devices for intracranial, intramyocardial or other surgical deliveries) may also impact the final outcome. Continuity of material supply can also be a hurdle, if proper quality reagents and materials are not available in larger quantities for confirmatory trials and to support commercial production. In spite of this, the number of approved ATMP in the EU has steadily increased: in total, 25 ATMP have been approved since the establishment of the CAT in 2009. This is in par with the approvals by other large regulatory authorities such as the US FDA. The number of approved ATMP remains low, however, especially taking into account the large pipeline of products under development, as can be deduced from the high number of pre-authorisation submission activities for ATMP, i.e. the number of ATMP classifications (612 products classified), ATMP in scientific advice procedures (579 in total), ATMP granted PRIME eligibility (54, which corresponds to about 45% of all PRIME eligibilities) [50] and the number of clinical trials with ATMP. We see three clear trends appearing: (i) the majority of approvals are for GTMP (vector-­ based gene therapies and genetically modified cells); (ii) big pharmaceutical companies have become the main applicants for MAA of ATMP and (iii) ATMP development and authorisations have become global, which are especially apparent for CAR-T cell products. Many clinical trials with ATMP are ongoing worldwide (n = 2093); however, only a small proportion are confirmatory (phase 3) trials

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(n = 200). Trials with GTMP (both in vivo and ex vivo gene therapies) represent the largest number, followed closely by cell therapy products. Only a low number of trials is conducted with tissue engineered products [51]. Europe seems not to be the main region where ATMP clinical trials are conducted (of the 2093 ongoing trials globally, only 329 are conducted in Europe), which could be linked to the perceived unfavourable environment for conducting multi-national multi-centric trials in the EU. The new regulation on clinical trials, which is intended to harmonise the requirements for clinical trials in different member states, is expected to solve these issues [40]. Practical solutions have also been developed to facilitate the GMO assessment of investigational GMO containing ATMP [21]. Finally, from an economic point of view, the ATMP are also more expensive than other medicines, and the developers of the first marketed products have faced difficulties in getting reimbursement. For many ATMP, the production batches are small (one batch per patient in autologous products), which increases costs related to development, manufacturing and testing. However, these products are intended to treat the cause of the disease, with a goal at best for permanent recovery/repair, which should be taken into account when assessing the value of ATMP for patients. Of note, decisions on reimbursement in the EU are taken at the national level, which often results in differences in the access time for patients living in different member states.

1.7 Conclusion on Possible Future Directions for ATMP Regulation 1394/2007 set the scene for ATMP development in the EU. After some years of doubts, the number of authorised ATMP is steadily increasing, demonstrating that application of the pharmaceutical framework is not detrimental to the development of these innovative and complex therapies if applied with a certain flexibility. This is allowing treatment access for indications with high unmet medical needs without jeopardising the required demonstration of

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quality, safety and efficacy. Further developments, such as point-of-care manufacturing of autologous ATMP, may improve access even further by reducing time to treatment and threats to the chain of custody while creating new regulatory challenges with regard to, e.g. comparability or lot release. Regulators should be ready to overcome these challenges if they are beneficial for the patients.

References 1. Commission Directive 2003/63/EC amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use (2003). Off J L159:46–94 2. Regulation (EC) No 1394/2007 of the European Parliament and of the Council on advanced therapy medicinal products and amending Directive 2001/83/ EC and Regulation (EC) No 726/2004 (2007). Off J L324:121–137 3. Commission Directive 2009/120/EC of amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products (2009). Off J L243:3–12 4. EMA/CAT/CPWP Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to advanced therapy medicinal products (EMA/CAT/ CPWP/686637/2011). http:// www.ema.europa.eu/docs/en_GB/document_library/ Scientific_ guideline/2013/03/WC500139748.pdf 5. CHMP Guideline on safety and efficacy follow-up and risk management of advanced therapy medicinal products (EMEA/149995/2008). https://www.ema.europa. eu/en/documents/scientific-­guideline/draft-­guideline-­ safety-­efficacy-­follow-­risk-­management-­advanced-­ therapy-­medicinal-­products-­revision_en.pdf 6. EU Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products. https://health.ec.europa.eu/system/ files/201711/2017_11_22_guidelines_gmp_for_ atmps_0.pdf 7. European Commission, Guideline on Good Clinical Practice specific to Advanced Therapy Medicinal Products. https://health.ec.europa.eu/system/ files/2019-­10/atmp_guidelines_en_0.pdf 8. European Medicines Agency, Good Laboratory Practice (GLP) principles in relation to ATMP. https:// www.ema.europa.eu/en/documents/other/good-­ laboratory-­practice-­glp-­principles-­relation-­advanced-­ therapy-­medicinal-­products-­atmps_en.pdf 9. EMA/CAT scientific guidelines applicable to cell-­ based medicinal products. http://www.ema.europa.

20 eu/ema/index.jsp?curl=pages/regulation/general/general_content_000405.jsp&mid=WC0b01ac0580029 58a 10. EMA/CAT scientific guidelines applicable to gene therapy medicinal products. http://www.ema.europa. eu/ema/index.jsp?curl=pages/regulation/general/general_content_000410.jsp&mid=WC0b01ac0580029 58d 11. European Medicines Agency, EMA/CAT/ GTWP/671639/2008 Rev. 1  – corr, Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells. https:// www.ema.europa.eu/en/quality-­non-­clinical-­clinical-­ aspects-­medicinal-­products-­containing-­genetically-­ modified-­cells 12. Commission Directive 2004/23/EC of the European Parliament and of the Council on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells (2004). Off J L102:48–58 13. Commission Directive 2006/17/EC implementing Directive 2004/23/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cells (2006). Off J L38:40–52 14. Commission Directive 2006/86/EC implementing Directive 2004/23/EC of the European Parliament and of the Council as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing preservation, storage and distribution of human tissues and cells (2006). Off J L294:32–50 15. Commission Directive 2002/98/EC setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and amending Directive 2001/83/ EC. http://eurlex.europa.eu/LexUriServ/LexUriServ. do?uri=OJ:L:2003:033:0030:0040:EN:PDF 16. Commission Directive 2004/33/EC implementing Directive 2002/98/EC of the European Parliament and of the Council as regards certain technical requirements for blood and blood components. http://eurlex. europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:200 4:091:0025:0039:EN:PDF 17. Commission Directive 2005/61/EC implementing Directive 2002/98/EC of the European Parliament and of the Council as regards traceability requirements and notification of serious adverse reaction and events. http://eurlex.europa.eu/LexUriServ/LexUriServ.do?u ri=OJ:L:2005:256:0032:0040:EN:PDF 18. European Commission, Proposal for a Regulation on substances of human origin. https://health.ec.europa. eu/blood-­t issues-­c ells-­a nd-­o rgans/overview/ proposal-­regulation-­substances-­human-­origin_en 19. Commission Directive 2001/18/EC on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/ EEC (2001). Off J L106:1–38 20. EMEA/CHMP/GTWP/125491/2006 Guideline on scientific requirements for the environmental risk

M. Schuessler-Lenz et al. assessment of gene therapy medicinal products. http:// www.ema.europa.eu/docs/en_GB/document_library/ Scientific_guideline/2009/09/WC500003964.pdf 21. European Commission, Pharmaceutical Unit, ATMP webpage, Requirements for investigational products. https://health.ec.europa.eu/medicinal-­products/ advanced-­t herapies_en#gmo-­r equirements-­f or-­ investigational-­products 22. European Medicines Agency, Pre-authorisation guidance, Question 3.4.3: What should I submit if my medicinal product contains or consists of genetically modified organisms (GMOs)? https://www.ema.europa.eu/en/human-­r egulatory/ m a r ke t i n g -­a u t h o r i s a t i o n / p r e -­a u t h o r i s a t i o n -­ guidance#3.4-­c ompliance,-­e nvironmental-­r isk-­ assessment-­and-­pharmacovigilance-­section 23. Regulation (EU) 2017/745 on Medical Devices. https://eur-­lex.europa.eu/legal-­content/EN/ALL/?uri =uriserv:OJ.L_.2017.117.01.0001.01.ENG 24. EMA/CHMP/BWP scientific guidelines addressing Adventitious Agents Safety Evaluation and Viral Safety. http://www.ema.europa.eu/ema/index. jsp?curl=pages/regulation/general/general_content_000351.jsp&mid=WC0b01ac058002956c#Adve ntitiousAgentsSafetyEvaluationViralSafety 25. European Pharmacopoeia General Chapter on raw materials of biological origin for the production of cell-based and gene therapy medicinal products (5.2.12) 26. EMA/CHMP/BWP/706271/2010 CHMP guideline on plasma derived medicinal products. http:// www.ema.europa.eu/docs/en_GB/document_library/ Scientific_guideline/2011/07/WC500109627.pdf 27. EMA/CAT/190186/2012 Reflection paper on management of clinical risks deriving from insertional mutagenesis. http://www.ema.europa.eu/docs/en_ GB/document_library/Scientific_guideline/2013/08/ WC500147014.pdf 28. EMA/CAT/GTWP/44236/2009 Reflection paper on design modifications of gene therapy medicinal products during development. http://www.ema.europa. eu/docs/en_GB/document_library/Scientific_guideline/2012/02/WC500122743.pdf 29. EMA/CAT Summaries of scientific recommendations on classification of advanced-therapy medicinal products. http://www.ema.europa.eu/ema/index. jsp?curl=pages/regulation/general/general_content_000301.jsp&mid=WC0b01ac05800862c0 30. EMA/354785/2010 Procedural advice on the consultation of Notified Bodies in accordance with Article 9 of Regulation (EC) No. 1394/2007. h t t p s : / / w w w. e m a . e u r o p a . e u / e n / d o c u m e n t s / regulatory-­procedural-­guideline/procedural-­advice-­ consultation-­notified-­bodies-­accordance-­article-­9-­ regulation-­ec-­no-­1394/2007_en.pdf 31. Nando (New Approach Notified and Designated Organisations) Information System. https://ec.europa. eu/growth/tools-­databases/nando/ 32. EMA/CHMP/QWP/BWP/259165/2019 Guideline on quality documentation for medicinal products when

1  Marketing Regulatory Oversight of Advanced Therapy Medicinal Products in Europe

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used with a medical device. https://www.ema.europa. regulatory viewpoints. Cytotherapy 15(7):753–759. eu/en/documents/scientific-­g uideline/guideline-­ https://doi.org/10.1016/j.jcyt.2013.03.005 quality-­d ocumentation-­m edicinal-­p roducts-­w hen-­ 42. Committee for Advanced Therapies, Reflection used-­medical-­device-­first-­version_en.pdf paper on safety Follow Up of patients treated with 33. EMA/CHMP scientific guidelines for nonAAV-GTMPs considering available scientific data on clinical studies. https://www.ema.europa.eu/ potential risk of insertion-mediated tumorigenesis  en/human-­­r egulatory/research-­d evelopment/ Manuscript in preparation scientific-­guidelines/non-­clinical-­guidelines 43. EMA/CHMP/ICH/544570/1998 ICH E8 General con34. E M A / C H M P / C V M P / J E G - 3 R s / 4 5 0 0 9 1 / 2 0 1 2 siderations for clinical trials. https://www.ema.europa. Guideline on the principles of regulatory accepeu/en/documents/regulatory-­procedural-­guideline/ tance of 3Rs (replacement, reduction, refinement) ich-­guideline-­e8-­r1-­general-­considerations-­clinical-­ testing approaches. https://www.ema.europa.eu/en/ studies_en.pdf documents/scientific-­guideline/guideline-­principles-­ 44. CPMP/ICH/364/96 CH Topic E 10 Note for guidregulatory-­acceptance-­3rs-­replacement-­reduction-­ ance on choice of control group in clinical trials. refinement-­testing-­approaches_en.pdf https://www.ema.europa.eu/en/documents/scientific-­ 35. Cheng N., Nakano M., Kuo C.J. (2020) Organoid guideline/ich-­e -­1 0-­c hoice-­c ontrol-­g roup-­c linical-­ Models of Tumor Immunology. Trends Immunol trials-­step-­5_en.pdf 41:652–664. https://doi.org/10.1016/j.it.2020.06.010 45. EMEA/CHMP/SWP/28367/07 Guideline on strate36. Anliker B., Childs L., Rau J., Renner M., Schüle gies to identify and mitigate risks for first-in-human S., Schuessler-Lenz M., Sebe A. (2022) Regulatory clinical trials with investigational medicinal prodConsiderations for Clinical Trial Applications with ucts (2007). http://www.ema.europa.eu/docs/en_GB/ CRISPR-Based Medicinal Products. CRISPR J document_library/Scientific_guideline/2009/09/ 5:364–376. https://doi.org/10.1089/crispr.2021.0148. WC500002988.pdf 37. Sanchez-Diaz M., Quiñones-Vico M.I., Sanabria 46. EMA/CHMP/205/95 Guideline on the evaluation of de la Torre R., Montero-Vílchez T., Sierra-Sánchez anticancer medicinal products (2012). http://www. A., Molina-Leyva A., Arias-Santiago S. (2021) ema.europa.eu/docs/en_GB/document_library/ Biodistribution of Mesenchymal Stromal Cells after Scientific_guideline/2013/01/WC500137128.pdf Administration in Animal Models and Humans: A 47. CHMP/EWP/83561/2005 Guideline on cliniSystematic Review. J Clin Med 10(13):2925–2976. cal trials in small populations. https://www.ema. https://doi.org/10.3390/jcm10132925 europa.eu/en/documents/scientific-­g uideline/ 38. ICH guideline S12 on nonclinical biodistribution guideline-­clinical-­trials-­small-­populations_en.pdf considerations for gene therapy products  - Step 48. EMA/CHMP/ICH/436221/2017 ICH E9 (R1) 2b  - Scientific guideline https://www.ema.europa. Addendum on estimands and sensitivity analysis in eu/en/ich-­guideline-­s12-­nonclinical-­biodistribution-­ clinical trials to the guideline on statistical principles considerations-­gene-­therapy-­products-­step-­2b for clinical trials. https://www.ema.europa.eu/en/ 39. EMEA/CHMP/273974/2005 Guideline on non-­ documents/scientific-­guideline/ich-­e9-­r1-­addendum-­ clinical testing for inadvertent germline transmission estimands-­s ensitivity-­a nalysis-­c linical-­t rials-­ of gene transfer vectors. https://www.ema.europa. guideline-­statistical-­principles_en.pdf eu/en/documents/scientific-­guideline/guideline-­non-­ 49. Rejeski K., Perez A., Sesques P. et al. (2021) CAR-­ clinical-­testing-­inadvertent-­germline-­transmission-­ HEMATOTOX: a model for CAR T-cell-related gene-­transfer-­vectors_en.pdf hematologic toxicity in relapsed/refractory large 40. Regulation (EU) No 536/2014 of the European B-cell lymphoma. Blood 138(24):2499–2513. https:// Parliament and of the Council on clinical trials on doi.org/10.1182/blood.2020010543 medicinal products for human use. https://eur-­lex. 50. European Medicines Agency, CAT quarterly higheuropa.eu/legal-­content/EN/TXT/?uri=celex%3A320 lights and approved ATMPs. https://www.ema.europa. 14R0536 eu/en/committees/cat/cat-­agendas-­minutes-­reports 41. Barkholt L., Flory E., Jekerle V. et al (2013) Risk of 51. Alliance for Regenerative Medicine, Regenerative tumorigenicity in mesenchymal stromal cell-based medicine: the pipeline momentum builds, September therapies—bridging scientific observations and 2022. https://alliancerm.org/sector-­report/ h1-­2022-­report/

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Clinical Trials on Advanced Therapy Investigational Medicinal Products in Spain (2004–2022): Experience and Challenges for the Future Juan Estévez Álamo, Marcos Timón, Isabel Sánchez Afán de Rivera, Beatriz Iriarte Torres, and M. Antonia Serrano Castro

Abstract

Clinical investigation is the basis for establishing how useful advanced therapy investigational medicinal products (ATiMP) are for the treatment of serious diseases. In Spain, clinical trials (CT) on ATiMP need to follow the general European legislation on CT with medicinal products plus some specific legislation and guidance depending on the type of ATiMP.

J. Estévez Álamo (*) · I. Sánchez Afán de Rivera · M. A. Serrano Castro Clinical Trials Division, Department for Human Medicinal Products, Spanish Agency for Medicines and Medical Devices (AEMPS), Madrid, Spain e-mail: [email protected]; [email protected]; [email protected] M. Timón Division for Biological Products, Advanced Therapies and Biotechnology, Department for Human Medicinal Products, Spanish Agency for Medicines and Medical Devices (AEMPS), Madrid, Spain e-mail: [email protected] B. Iriarte Torres Cinfa Laboratories (At the time of data analysis: Clinical Trials Division, Department for Human Medicinal Products, Spanish Agency for Medicines and Medical Devices (AEMPS)), Madrid, Spain

This chapter describes the characteristics of CT on ATiMP authorized in Spain in the period 2004–2022 and the legislation applicable along this period. There are clear differences in the clinical trials conducted by non commercial and commercial sponsors: the first have been more involved in CT on somatic cell therapy medicinal products (sCTMP) and tissue-engineered products (TEP), while the second drive more the CT on gene therapy medicinal products (GTMP) in the last years. Difficulties of budget and resources especially by non-commercial sponsors to meet the regulatory requirements are highlighted. The importance of complying with transparency rules with respect to CT on ATiMP is also discussed. Keywords

Spain · Clinical trials · ATMP · Investigational ATMP · Investigational medicinal product · IMP name · Transparency

Abbreviations AEMPS ATiMP

Spanish Agency for Medicines and Medical Devices Advanced Therapy Investigational Medicinal Products

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 M. C. Galli (ed.), Regulatory Aspects of Gene Therapy and Cell Therapy Products, Advances in Experimental Medicine and Biology 1430, https://doi.org/10.1007/978-3-031-34567-8_2

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ATMP

J. Estévez Álamo et al.

Advanced Therapy Medicinal Products CAR-T Chimeric Antigen Receptor T cells CAT Committee for Advanced Therapies CEIm Ethics Committee, Committee of Ethics for the Investigation with medicinal products CT Clinical Trial CTD Directive 2001/20/EC CTR Regulation (EU) No. 536/2014 EEA European Economic Area EU European Union EUCTR EU Clinical Trials Register EVMPD EudraVigilance Medicinal Product Dictionary GCP Good Clinical Practice GMO Genetically Modified Organism GMP Good Manufacturing Practice GTMP Gene Therapy Medicinal Product ICH International Council for Harmonization IMP Investigational Medicinal Product INN International Nonproprietary Names MS Member State MSC Member State Concerned OOS Out of specifications PEI Product under Clinical Investigation Q&A Questions and Answers REec Spanish Clinical Studies Registry RMS Reporting Member State sCTMP Somatic Cell Therapy Medicinal Product SUSAR Suspected Unexpected Serious Adverse Reaction TEP Tissue-Engineered Product XEVMPD Extended EudraVigilance Medicinal Product Dictionary

Advanced Therapy Medicinal Products (ATMP) are a particularly innovative medicine class that includes gene therapy medicinal products (GTMP), somatic cell therapy medicinal products (sCTMP), tissue-engineered products (TEP) and combined products (tissue or cell associated with a medical device). The legal regulatory framework for ATMP in the EU (ATMP Regulation 1394/2007) [1] came into force on 31 December 2008 and defined common rules for this very innovative group of medicinal products that have to comply with specific quality requirements [2]. However, Advanced Therapy investigational Medicinal Products (ATiMP) have to comply not only with the general legislations for clinical trials and ATMP, but in some cases also with legislation from different frameworks, such as Directive 2004/23/EC for the donation, procurement and testing of the starting materials to be converted into cell-based medicinal products [3], or that for genetically modified organisms (GMO) (Directives 2001/18/EC [4] and/or 2009/41/EC [5]) when the product belongs to this category. In addition, many cell-based ATMP are autologous (i.e. prepared from material taken from the patient) which makes standardization a real challenge for manufacturers. In spite of the above difficulties, Spain has been identified as the Member State with the highest number of CT with ATMP [6] [7]. Considering this experience, this chapter includes the analysis of the characteristics of CT with ATiMP submitted for authorization to the Spanish Agency for Medicines and Medical Devices (AEMPS) since 1 May 2004 until 31 July 2022, also paying attention to the IMP being investigated.

2.1 Introduction

2.2 European Legislation Covering Clinical Trials on Medicinal Products

Clinical trials (CT) are essential to support the authorization of medicinal products and are the basis for their appropriate use in normal clinical practice. The knowledge of ongoing or finished CT is essential in order to favor better designs for future clinical investigations.

Along this period, two different European legislations for clinical trials on medicinal products have been applicable. Since 1 May 2004, Directive 2001/20/CE (CTD) [8] transposed to the Spanish legislation in Royal Decree 223/2004 [9] has been

2  Clinical Trials on Advanced Therapy Investigational Medicinal Products in Spain (2004–2022)…

in force until CT Regulation 536/2014 (CTR) [10] complemented by the Spanish Royal Decree 1090/2015 [11] replaced it in 2016. However, application of CTR was not possible until 31 January 2022 and CT was still regulated by CTD. On 31 January 2022, the newly built EU CT Information System named CTIS [12] was made available. CTIS is the access portal to the European CT system created by CTR and is necessary to support the single submission of applications to all the Member States (MS) participating in a clinical trial (MS concerned, MSC), the coordinated European assessment of the part I led by the reporting Member State (RMS) and the application of transparency rules foreseen in the CTR. Since 31 January 2023, all new CT should be submitted under CTR and since 31 January 2025 all ongoing CT with an active site in the EU should be under CTR, even if originally authorized under CTD. This is why all CT authorized under CTD may be transitioned to CTR since 31 January 2022. Guidance about how to transition to CTR a CT authorized under CTD is available in section 11 of the Questions and Answers document – Regulation 536/2014 (Q & A–CTR) [13]. Both legislations have similar ethical and technical principles and require the CT to be conducted in accordance with the International Council for Harmonization (ICH) Good Clinical Practice (GCP) guidance [14] [15]. In addition, they imply a commitment with both EU CT legislation and general data protection Regulation (EU) 2016/679 [16]. However, in the CTR, the definition of “clinical study” is introduced, and the definition of “clinical trial” is slightly changed to take into account such definition. CTR also introduces the category of “low intervention clinical trial” in order to simplify the requirements for clinical trials with medicinal products authorized in one EU country involving no more than minimal risk with respect to that afforded by the patients under the normal clinical practice. CTR also increases considerably the transparency requirements with respect to the amount of information and documents to be published in CTIS about the clinical trials for which a final decision on the request of authorization is available [17].

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Before the clinical trial starts in every MSC, under both legislations, it has to be authorized by the national competent authority of such MS based on a favorable scientific and ethical assessment, also supported by a national Ethics Committee in that MS. While under CTD the sponsor should submit a separate application in each MS for the CT even in the case of a multinational trial and eventually receive as many separate and independent opinions, under the CTR in order to get the CT authorization the sponsor should submit a single application for all MSC via CTIS. Such application should contain a single part I dossier and a part II dossier1 specific for every MSC containing information that might need to take into consideration national culture and practices. Assessment of part I is coordinated at the EU level and is led by RMS who prepares the draft assessment report for all MSC. The calendar with maximum timelines for validation, part I and part II assessment and decision is established in the CTR [10] and may also be consulted in the document “Clinical Trials Regulation (EU) No 536/2014 in practice” [18], that gives an overall view about what the application of CTR means. For clinical trials involving an ATiMP, RMS may extend the standard assessment period of the application for the CT authorization or for the authorization of a substantial modification by a further 50  days, for the purpose of consulting with experts. The sponsor will be informed about any extension in the assessment period. Within 5  days after the last final assessment for part I and part II has been notified to the sponsor, each MSC shall notify the sponsor as to whether the clinical trial is authorized, whether it is authorized subject to conditions or whether the authorization is refused. In the case of Spain, such decision is issued by AEMPS also taking into consideration the opinion by one national Ethics Committee (Committee of Ethics of the Investigation with medicinal products – known in Spanish as CEIm). In principle, the conclusion of the RMS as regards Part I of the assessment See annex I in CTR. Part II requirements are in annex III of the Q & A –CTR in volume 10 Eudralex [13]. 1 

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report shall be considered the conclusion of the MSC. However, an MSC may disagree with such conclusion on authorizing the CT only on the following grounds: (a) When it considers that participation in the clinical trial would lead to a subject receiving an inferior treatment than in normal clinical practice in the MSC (b) When there is an infringement of its national law (c) When considerations as regard subject safety and data reliability and robustness communicated to the sponsor in a request for information during the assessment have not been solved Along the authorization procedure, tacit approval or lapsed application principles apply: • During validation: (a) if the RMS has not notified the sponsor on time, the application will be considered complete and valid and (b) when the sponsor has not answered a request for information the application shall be deemed to have lapsed in all MSC. • During assessment: (a) in case the sponsor does not answer a request for information with respect to part I within the set period, the application shall be deemed to have lapsed in all MSC; (b) in case the sponsor does not answer a request for information from an MSC with respect to part II within the set period, the application shall be deemed to have lapsed in that MSC. • During decision: where the MSC has not notified the sponsor of its decision within the relevant periods, the conclusion on Part I of the assessment report shall be deemed to be the decision of the MSC on the application for authorization of the clinical trial. If no subject has been included in the clinical trial in an MSC within two years from the notification date of the authorization, the authorization shall expire in that MSC unless an extension, on request of the sponsor by submission of a substantial modification, has been authorized.

J. Estévez Álamo et al.

After a clinical trial has been authorized in the MSC who received the first application, the authorization in additional Member States should follow the procedure foreseen in art.14 of the CTR, i.e. new CT authorizations within the new MS.  The application to add another MSC to an authorized clinical trial can be made after the clinical trial is authorized in all MSC receiving a full (part I and part II) initial application, provided that there is no ongoing assessment of a substantial modification including changes on part I of the CT dossier. The application only has to include part II for the new MSC and the part I coordinated assessment is based on the last available assessment report by the RMS [10]. It is important for the sponsor to organize the CT in such a way that the design allows feasibility for the conduction and compliance with the legislative requirements that include respect to the subjects’ rights and well-being and a design to provide robust and clinically relevant results. Table 2.1 summarizes the general requirements for a sponsor to be able to conduct a CT in Europe under CTD and CTR. Table 2.2 clarifies the transparency rules applicable to publication of data and documents of the CT within the EU under both legislations.

2.3 Requirements Specific for Clinical Trials on ATiMP 2.3.1 Good Manufacturing Practice for ATMP Given the particularities of ATiMP products, they have to comply with their specific quality and manufacture standards. Two aspects are highlighted here, which are important specific legal requirements for the holder of a marketing authorization of an ATMP as well as for the CT sponsors: traceability [1] and administration of out of specification (OOS) products [2].

2.3.1.1 Traceability In a similar way, as the holder of an ATMP marketing authorization has to comply with traceability requirements [1], the sponsor has to ensure

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Table 2.1  Summary of the general requirements for a sponsor to conduct a CT in the EU/EEA Directive 2001/20/EC Before CT starts EU ID number for the CT: EudraCT number Protocol and CT dossier

IMP manufacture compliant with EU Good Manufacturing Practice (GMP) [2] Organizing GCP compliance and selection of investigators and sites Insurance coverage Organizing safety surveillance and capability for SUSAR reporting to Eudravigilance

Requiring CT authorization in every MSC by sending individual submissions to every national competent authority and corresponding Ethic Committee in each MSC. The assessment is not coordinated in multinational CT. Organization for getting the results analyzed within one year after the end of the CT During CT conduction Once authorized the CT is published in the EUCTR. In the case of Spain also in the REec [20]

Prior authorization of substantial modifications GCP compliance and monitoring of the CT Safety surveillance by sponsor and investigators SUSAR reporting to Eudravigilance Notification of temporary halts, urgent safety measures and unexpected serious adverse events Annual follow-up report After CT ends Notification of clinical trial end date within 90 days following such date, or within 15 days in case of an early end, indicating in the latter case the reasons for it and any measures taken to protect the CT participants. Notification of a summary of CT results within one year following the date of CT end. Storage of trial master file at least for 5 years after CT end [22].

Regulation 536/2014 [18] EU ID number for the CT: EU CT number Protocol and CT dossier are split in part I (common for all MSC) and a part II specific per every MSC, see annex II and III in CTR Q & A [13] IMP manufacture compliant with EU GMP [2] Organizing GCP compliance in selection and investigators and sites Insurance coverage Organizing safety surveillance and capability for SUSAR reporting to Eudravigilance CTIS related [19]: - Sponsor’s users registration and permissions - Sites registration - Registration in the EVMPD of not authorized IMP Requiring CT authorization in every MSC by sending one single application via CTIS. There is an EU coordinated assessment for part I of the application lead by RMS.

Organization for getting the results analyzed within one year after the end of the CT Once the decision is made (authorization or rejection), the CT is published in CTIS. In the case of Spain also in the REec [20] The authorization will expire in the MSC where no subject has been included within two years from the notification date of the CT authorization Notification of the CT start, first subject included and end of recruitment per MSC within 15 days Prior authorization of substantial modifications GCP compliance and monitoring of the CT Safety surveillance by sponsor and investigators SUSAR reporting to Eudravigilance Notification of temporary halts, urgent safety measures and unexpected relevant adverse events Notification of serious breaches [21] Annual safety report Notification of clinical trial end date within 15 days following such date, also indicating in case of an early end the reasons for it and any measures taken to protect the CT participants Notification of a summary of CT results within one year following the date of CT end. Storage of trial master file for at least 25 years after CT end [22] Publication of documents according to the deferrals accepted Notification of the clinical study report

J. Estévez Álamo et al.

28 Table 2.2  Transparency rules applicable to publication of CT data and documents EUCTR [23] It contains data from CT authorized under CTD [8] at any EU MS after 1 May 2004 A summary of CT characteristics and CT status and a summary of CT results Phase I CT not including pediatric population are not published

REec [20] It contains data from CT authorized in Spain since January 2013 [11] A summary of CT characteristics and CT status information plus a summary of CT results Sponsors may reduce the public data for phase I CT not involving pediatric population. Results from these CT are not public

CTIS public [12] It contains data from CT authorized or refused under CTR [10] in any EU MS since February 2022 A summary of CT characteristics and CT status plus relevant CT documents [17] Sponsors may defer the time when information is made public depending on CT categorya

Category 1 CT includes phase 0 and phase I CT, bioequivalence and bioavailability CT and similarity trials for biosimilar products or equivalence trials for combination or topical products where pharmacokinetic and/or pharmacodynamics studies are not possible. Category 2 CT includes phase II and phase III CT.  Category 3 CT includes phase IV and low-intervention CT [17] a

similar traceability requirements for a ATiMP [15]. The use of each ATiMP has to be traceable. The individual product should be traceable from delivery to the clinical trial site up to the administration to the clinical trial subject. In addition, when the ATiMP contains cells or tissues of human origin, the traceability from the recipient of the product to the donor of the cells or tissues should be ensured. The traceability system should be bidirectional (from donor to ATiMP and to the subject and from subject to ATiMP and to the donor), and data should be kept for 30 years after the ATiMP expiry date unless a longer time period is required in the clinical trial authorization. The sponsor is responsible to ensure that the ATiMP manufacturer has set up a system that enables the bidirectional tracking of cells/tissues contained in ATiMP in accordance with the GMP guidance

and also to give the investigators detailed instructions to ensure traceability of the ATiMP. Traceability data should be kept also in cases where the clinical trial is suspended or prematurely ended.

2.3.1.2 Administration of Out of Specification Products Exceptionally, the administration of the cells/ tissues that are contained in a cell/tissue-based ATMP that is OOS may be necessary for the patient. Where the administration of such product is necessary to avoid an immediate significant risk to the patient, taking into account the alternative options and the consequences of not receiving the cells/tissues contained in the product, the supply of the product to the treating physician is justified at his/her request. A Q & A document explains the procedure for administering OOS batches of authorized tissues and cell-based ATMP [24]. Should this case occur within a CT, the procedure is similar but the authorities to be informed are those responsible for the CT authorization in the countries where the CT is being carried out. In addition, it is the AEMPS view that the patient treated with an OOS ATiMP should be kept in the clinical trial and be subject to the standard CT procedures and follow-up; however, his/her data should not be included in the primary analysis, but in a separated exploratory analysis that should also be included within the summary of the CT results. This is important in order not to lose that information.

2.3.2 Good Clinical Practice for ATMP The general principles of GCP set out in ICH Guidelines [14] are applicable to clinical trials with ATMP. However, CT on ATiMP, due to the special characteristics of these products, should also comply with the GCP guidelines on ATMP [15] that also refer to some aspects covered in the GMP specific to ATMP [2]. They cover aspects related to the following:

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–– Some adaptations that may be necessary (e.g. retention of samples) –– The implementation of additional necessary measures (e.g. traceability requirements for ATMP that contain cells or tissues of human origin, or training on upstream intervention of subjects and/or administration procedures) –– Aspects to be considered in the CT design taking into account the specific ATiMP investigated, the potential risks and benefits to subjects, investigator’s team and others (e.g. offspring, close contacts) in relation to study population and potential staggered approach to the treatment, comparators, blinding, placebo or end of the clinical trial and long-term follow-up –– Non-clinical studies –– ATMP quality –– Safe conduction of the CT –– Safety monitoring and reporting

• Adverse events possibly due to unexpected reactions such as hypersensitivity, immunological, toxicity or migration of cells from the target site and ectopic tissue formation • Adverse events possibly related to product failure (including lack of efficacy) • Adverse events possibly related to mandatory concomitant medication (e.g. immuno-suppression)

• Adverse events possibly related to the product administration process (e.g. surgical procedures) • Adverse events possibly related to medical devices that form part of the product or are used for the application of the product

All CT applications on ATiMP received at AEMPS from 1 May 2004 until 30 July 2022 have been considered for the following analysis. Description of the characteristics of CT authorized by AEMPS within this period takes into account the information available on the internal

2.3.3 Specific Requirements for CT on ATiMP-Containing GMO

The EU legislation governing the authorization of clinical trials [10] does not specifically address environmental aspects. However, clinical trials with medicinal products that contain or consist of GMO must comply with applicable requirements under the GMO framework [4] [5]. In order to facilitate the development of CT The need for long-term follow-up is common with medicinal products consisting of or containfor this kind of treatment. The definition of CT ing GMO, lack of harmonization between differend should be clear in the protocol, indicating ent GMO authorities across the EU [25] has when applicable how follow-up activities will be prompted the development of common voluntary performed after CT end (e.g. in another clinical procedures for some categories of products [26]. trial or in a non-interventional study as applicable Spain is among the countries that have accepted in cases when the ATMP is authorized in the EU). the good practice on the assessment of GMO-­ The sponsor must ensure that the patient’s long-­ related aspects for in  vivo gene therapy with term follow-up is not compromised even in case rAAV and for human genetically modified cells of early CT end for any reason. The AEMPS rec- together with the corresponding application ommends that even in exceptional cases where forms, and the document on considerations for such long-term follow-up has been accepted the evaluation of shedding from oncolytic viruses. within the context of normal clinical practice, the analysis of it should be provided as results complementary to the original clinical trial. 2.4 Clinical Trials on ATiMP While the safety concerns are closely linked to in Spain from May 2004 the specific ATMP characteristics, the following to July 2022 safety issues should be specifically considered (non-exhaustive list): 2.4.1 Methodology

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CT database of the agency regardless of substantial amendments. The analysis of CT status is based on the notifications available to AEMPS by 31 December 2022. ATiMP were classified according to the definitions set out in Regulation 1394/2007 [1] and Directive 120/2009 [27] and following the principles highlighted in the reflection paper on classification of ATMP published by the Committee for Advanced Therapies (CAT) [28]. Products used in CT before these definitions were published have been reclassified according to these criteria, in order to have a harmonized approach. Products containing or consisting of genetically modified cells (e.g. chimeric antigen receptor (CAR)-T cells) are generally considered GTMP in the EU, except when the genetic modification is not directly linked to the therapeutic activity of the cells. In Spain, all medicinal products without a marketing authorization in any country of the European Economic Area (EEA) that contain an active substance or combination of substances not included in any of the medicinal products marketed in Spain need to obtain a number of products under clinical investigation (known in Spanish as PEI), and sponsors need to cross-­ reference this number for every new CT application. A PEI covers all pharmaceutical forms and strengths of an investigational product. ATiMP, particularly if cell-based, are very complex and sometimes it is difficult to determine whether a product should be considered the same or a different PEI.  For instance, a different PEI number is required when the same cell product changes from an autologous to an allogeneic use. Normally, when changes were introduced (e.g. in final formulation), the new product was considered as being different. When substantial changes were introduced in manufacturing without a proper comparability study, the final products were also considered as being different. Different manufacturers require different PEI numbers unless equivalence of the products is shown through strong comparability studies. To clearly define and identify the different drug substances used in CT in Spain, a guideline on nomenclature of cell-based medicinal products was followed [29]. This guideline, developed by AEMPS, defines not only the cell type but a num-

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ber of additional attributes (tissue of origin, expansion in culture, other manipulations, etc.) as a pre-­requisite to the final identification. The analysis of the product characteristics showed in this chapter took into account Spanish register of PEI ATiMP. Number and characteristics of the ATiMP in the authorized CT, owners of such products (commercial, i.e. pharmaceutical companies, or non-commercial, i.e. facilities within the National Health System) and number of CT per ATiMP have been analyzed. The following aspects have been analyzed and verified for all authorized CT with ATiMP during this period on the basis of information available on CT Applications and electronic CT Dossier Documents: • Type of sponsor (commercial or non-­ commercial) [11] • Type of ATiMP (sCTMP, GTMP and TEP) and GMO character • CT phase as indicated by the sponsor • Therapeutic area of investigation, taking into account terms used by EudraCT [30] to define the therapeutic area • Population, i.e. adults (18–64  years), elderly (>65 years) and pediatrics (less than 18 years) • National or international character taking into consideration geographical distribution of the participant sites • Single-site or multi-site CT, according to the number of sites in Spain • CT status and availability of results The latest available status from the following is shown, provided that at least one notification has been received for the trial in the last 2 years: • Not initiated: CT authorized, start date has not been received • Recruiting: date of CT start has been received • End of recruitment: date of recruitment end has been provided • Temporarily halted: temporary halt date has been received • Prematurely ended (according to CTR, early CT termination means the premature CT end

2  Clinical Trials on Advanced Therapy Investigational Medicinal Products in Spain (2004–2022)…

due to any reason before the conditions specified in the protocol are complied with). CT having included a significantly lower than planned number of subjects or those not having completed all parts defined in the protocol have also been considered as prematurely ended for this analysis, even if the end was not notified as premature • Completed: end of trial date has been received • Unknown: in cases where there have not been notifications by the sponsor within the last 2 years For certain analysis, the data are shown in three periods, grouping CT according to their date of authorization: 2005–2012, 2013–2018 and 2019–2022. The first period corresponds to a period with older archives in the AEMPS involving more inaccuracies in the information review, given that a full content internal database for the management of CT applications has started since 1 January 2013. The last period has been defined in order to show potential changes in a recent time. A previous analysis of a part of the CT analyzed here has already been published [31].

2.4.2 Exploratory Analysis of CT Status and Request to Sponsor for Updating the Status For the CT subgroup authorized between 2013 and 2018, the CT status and the last annual ­notifications of the sponsor were revised during August 2022. Availability of at least one of the legally required notifications (see Table 2.1) during the last year was considered as a sign of the accuracy of the CT status. The status for not initiated CT was considered to be checked in case the time lapsed from the authorization date was longer than 2 years. For those CT identified as not updated or not having the correspondent summary of the results notified (8 from commercial sponsors and 17 from non-commercial sponsors), a mail was sent in September 2022 to the applicant, when applicable also to the legal representative, asking for the missing information. For

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those CT without an answer by 1 October 2022, a second e-mail was sent. A total of 14 responses were received out of 25 emails sent, 7 from commercial and 7 from non-commercial sponsors. The request by e-mail was not successful, especially in relation to CT without a known date of CT start and a longer period of unknown status.

2.4.3 Results During the period 1 May 2004–31 July 2022, AEMPS received 519 CT applications on ATiMP that represent 2.9% of the total number of CT applications in that period. Status for these CT applications on the 26 December 2022 was 431 authorized, 24 rejected, 59 withdrawn and 2 under assessment. It is worth to mention that 28 CT with a non-­ commercial sponsor required more than 1 application to get the CT authorized; the total number of applications reviewed were 4 in one case and 3 in three cases. However, in the case of commercial sponsors, only in 4 CT, the application for authorization was resubmitted after a prior withdrawal or rejection, and there were 3 non-authorized CT after two applications either rejected or withdrawn. The detailed analysis reported below describes the characteristics of the 431 authorized CT and the ATiMP investigated in them.

2.4.3.1 CT according to Type of ATiMP, Sponsor, International Character, Number of Participating Sites in Spain and Phase The distribution of authorized CT according to the type of ATiMP along the analyzed period is shown in Fig. 2.1. Total numbers of ATiMP CT and distribution according to type of product, sponsor, country of the sponsor, international character, number of sites in Spain and phase are shown in Table 2.3. The number of authorized CT with ATiMP has gradually increased along the analyzed period and represents the 5.1% of the total CT number on medicinal products authorized in Spain in the last three years. This growth is especially due to a large increase in the number of CT on GTMP (Fig. 2.1). While CT on sCTMP and TEP, carried

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32 60

50 12 3

6

40

3 30 27 3

17 20

13

10

10 5 0

3

5

2 0 1

2005

4 1

3

0 3

4

4

2006

2007

2008

1

9

6

2009

2010

13

10

3

22

8

1

11 2

6

5

11

2 5

11

2011

9

9

2012

2013

sCTMP

2 5

6

2014

2015

GTMP

29

31

11 15

2016

11

2017

14 7

6

2018

2019

2020

11

10

2021

2022

TEP

Fig 2.1  Number of CT yearly authorised according to the type of ATiMP investigated Table 2.3  Total numbers of ATiMP CT and distribution according to type of product, sponsor, country of the sponsor, international character, number of sites in Spain and phase

Commercial Sponsor Non-commercial Sponsor Sponsor from Spain Sponsor from USA Sponsor from EU countries other than Spain International CT CT only in Spain Multi-site in Spain Single-site in Spain Phase I Phase I/II Phase II Phase II/III Phase III Phase IV

Total No. of CT (N = 431) 219 (50,8%) 212 (49,2%) 260 (60,3%) 91 (21,1%) 55 (12,8%) 205 (47,6%) 226 (52,4%) 263 (61%) 168 (39%) 106 (24,6%) 64 (14,8%) 171 (39,7%) 8 (1,9%) 76 (17,6%) 6 (1,4%)

No. of CT on sCTMP No. of CT on GTMP (N = 141) (N = 167) 50 (35,5%) 141 (84,4%) 91 (64,5%) 26 (15,6%) 101 (71,6%) 53 (31,7%) 20 (14,2%) 69 (41,3%) 10 (7,1%) 33 (19,8%) 48 (34,0%) 93 (66,0%) 83 (58,9%) 58 (41,1%) 27 (19,1%) 22 (15,6%) 59 (41,8%) 5 (3,5%) 26 (18,4%) 2 (1,4%)

out mostly by non-commercial sponsors, are 87.2% (109 out of 125) of the CT on ATiMP authorized in the period 2005–2012, this portion decreased to 60.5% (95 out of 157) during 2013– 2018 and CT on GTMP constitute the 59.7% (89 out of 149) of the ATiMP CT authorized in 2019– 2022 (Figs.  2.2a and 2.2b). Such figures also

132 (79%) 35 (21%) 121 (72,5%) 46 (27,5%) 50 (29,9%) 37 (22,2%) 42 (25,1%) 2 (1,2%) 34 (20,4%) 2 (1,2%)

No. of CT on TEP (N = 123) 28 (22,8%) 95 (77,2%) 106 (86,2%) 2 (1,6%) 12 (9,8%) 25 (20,3%) 98 (79,7%) 58 (47,2%) 65 (52,8%) 29 (23,6%) 5 (4,1%) 70 (56,9%) 1 (0,8%) 16 (13,0%) 2 (1,6%)

show how the increase along time in the number of GTMP CT is parallel to the increase in CT run by commercial sponsors. Considering the origin of the sponsor, Spanish sponsors are focused on sCTMP and TEP CT and conduct 78.4% (207 out of 264) of these CT. On the other hand, sponsors from other EEA countries

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33

180 160 140 120 100 80 60 40 20 0

62

42

19

62

89

16 47

53

2004-2012

2013-2018 sCTMP

GTMP

41 2019-2022 TEP

Fig 2.2a Type of ATiMP investigated according to the time of CT authorisation: (2004-2012; 2013-2018; 2019-2022)

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

2004-2012

2013-2018 Commercial

2019-2022

Non-commercial

Fig 2.2b  Type of sponsor in ATiMP CT according to the time of the CT authorisation

(20.3%) (34 out of 167), and particularly sponsors from USA (41.3%) (69 out of 167), run around 62% of GTMP CT. Other characteristics of the CT managed by commercial sponsors are their international character (87.2%) and the participation of multiple sites in Spain (80%). However, only 6.6% of the non-commercial CT are international and 59% have a single Spanish site (Table 2.3). Figure 2.3 shows the trend of cumulative number of authorized ATiMP CT grouped per phase in the period 2005–2022. Most ATiMP CT are early phases: Phase 1, Phase 1/2 and Phase 2 represent 79.1% of all authorized CT during the study period and are mainly conducted by non-­ commercial sponsors while

84.4% of Phases 3, 2/3 and 4 CT have a commercial sponsor. As it could be expected, taking into account the development of the authorized ATMP, Phase 3 CT main increase is from 2013 while the first Phase 4 CT is from 2016.

2.4.3.2 CT According to Targeted Disease and CT Population The top ten therapeutic areas globally investigated are shown in Fig. 2.4. The most predominant area investigated was cancer (36.7%) followed by cardiovascular (11.4%) and musculoskeletal (7.4%) diseases. The therapeutic area of research varies according to the type of ATiMP. GTMP was investigated in 73.4% of cancer CT

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34 180 160 140 120 100 80 60 40 20 0

2005

2006

2007

2008

2009

2010

2011

2012

I

I/II

2013

2014

2015

II

II/III

III

2016

2017

2018

2019

2020

2021

2022

IV

Fig 2.3  Cumulative number of Authorised ATiMP CT per phase

158

Diseases [C] - Cancer [C04]

49

Diseases [C] - Cardiovascular diseases [C14] Diseases [C] - Musculoskeletal Diseases [C05]

32

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

31 29

Diseases [C] - Digestive System Diseases [C06]

27

Diseases [C] - Nervous System Diseases [C10]

25

Diseases [C] - Virus Diseases [C02]

18

Diseases [C] - Immune system diseases [C20]

15

Diseases [C] - Eye diseases [C11]

13

Diseases [C] - Skin and connective tissue diseases [C17] 0

20

40

60

80

100

120

140

160

180

Fig 2.4  Top 10 therapeutic areas investigated in CT on ATiMP

and in 93.5% of congenital, hereditary and neonatal diseases and abnormalities. However, 87.7% of CT in the cardiovascular area and 93.8% of those in musculoskeletal diseases investigated TEP. sCTMP are investigated in 85.2% of CT on nervous system diseases, 72.4% of CT on digestive system diseases, 68% of CT

on virus-related diseases and 91.4% of immune system diseases. In general, these CT look for a treatment in very serious diseases without an appropriate alternative remedy. In 103 CT, the disease is classified as a rare disease and/or the ATiMP is identified as having orphan designation for it.

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Pediatric population is foreseen in 88 CT on ATiMP (20.4% of the total). However in only 33 (37.5%) of them, the selection criteria define an exclusively pediatric population. Most of these trials have a commercial sponsor (65.9%) and investigate GTMP (54.5%). Regarding indication on exclusively pediatric CT, hereditary and neonatal diseases and abnormalities (e.g. spinal muscular atrophy, Duchenne muscular dystrophy, mucopolysaccharidosis type IIIA, Fanconi anemia, etc.) are the most prevalent (45.5%) followed by cancer (30.3%). CT population usually includes both women and men with around 6% of CT on either men-specific or women-specific diseases.

2.4.3.3 ATiMP Totally, 249 different ATiMP products were investigated in the authorized CT: 68 (27.3%) TEP, 63 (25.3%) sTCMP, and 103 (41.4%) GTMP, while 15 (6%) products are being investigated as both sCTMP and TEP. They include ATiMP currently having a marketing authorization in the EU (Alofisel®, Holoclar®, Imlygic®, Kymriah®, Yescarta® and Zalmoxis®), in USA (Zolgensma®) or Spain (NC1 and ARI0001). NC1 and ARI0001 are products prepared on a non-routine basis according to specific quality standards and used within Spain in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-­ made product for an individual patient, authorized by the AEMPS, as defined in EU Regulation No 1394/2007 [1] (also called hospital exemption) and Royal Decree 477/2014 [32]. In total, 85 GTMP and 2 sCTMP are GMO and they are being investigated in 149 CT. Their product owners are mainly commercial (86.2%). Sponsors for GMO CT are from USA (40.1%) and Spain (34.2%), while sponsors for the other 17.3% are from other European countries. The number of CT per product has ranged from 1 (for 166 ATiMP) to 12 (for 1 ATiMP). 25 products have been investigated on at least 4 CT, including Alofisel®, Imlygic® Kymriah® and Zolgensma®, which have a marketing authorization in the EU, and NC1 (authorized in Spain

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according to the national legislation for ‘hospital exemption’). Fourteen of these 25 products are manufactured in a facility pertaining to the national health system, while 11 pertain to a pharmaceutical company. It is remarkable that 110 out of 249 ATiMP belong to non-commercial owners; most of them are sCTMP and TEP, consistent with the type of CT run by non-commercial sponsors. On the other hand, most of the products that belong to commercial owners are GTMP. The interest in identifying specific numbers for IMP investigated is highlighted, since these numbers are difficult to find due to the natural evolution of the names in products under clinical development. However, in the field of cell and tissue research, where the nature and origin of the cells as well as the autologous or allogeneic character could greatly influence the efficacy and safety of the products, having a more systematic way of describing the ATiMP under development could be of great interest as AEMPS has previously highlighted [29].

2.4.3.4 CT status Considering the information available at AEMPS, the status of ATiMP CT is shown in Table 2.4. During the analyzed period, 205 CT ended, of which 81 ended prematurely. For 73 completed CT results were submitted. When this information is analyzed for the three subperiods, it can be seen that, while in 2004–2012 for 39 out of 73 (53.4%) CT results are missing one year after the end of clinical trial date, this number is reduced to 25 out of 64 (39.1%) in the second period, showing a greater level of sponsors compliance with the current legal requirements. Considering sponsor type, 82 of the completed CT have a non-­commercial sponsor and 42 a commercial ­sponsor which may be coherent with the higher proportion of earlier phases with small sample sizes within the noncommercial sponsored trials. However, the rate of missing results within one year of CT end is 41.5% for non-commercial CT and 11.9% for commercial CT. Reasons for premature end are shown in Table 2.5. It is remarkable that in 30 out of the 39

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36

Table 2.4  Status of ATiMP CT according to information available in AEMPS by 31 December 2022

CT status Completed globally Completed globally with results submitted Completed only in Spain (international CT) Completed with end of trial date earlier than December 2021 and no results submitted Recruitment ended Recruiting Temporarily halted Prematurely ended Not initiated Unknown

All CT n = 431 124 73 10 39

2005– 2012 n = 125 64 39 0 25

2013– 2018 n = 157 55 33 5 14

2019– 2022 n = 149 5 1 5 0

29 127 9 81 21 30

3 1 0 35 0 22a

15 38 4 36 0 4

11 88 5 10 21 4

Unknown status for 17 CT authorized before 2013 might be due to the fact that for these trials part of the information could be in a paper file on CT that was not checked for this review a

Table 2.5  Reasons for prematurely ended CT Reason Sponsor’s business reasons (all CT commercial) Lack/slow recruitment /pandemic Lack of budget Related to the results in the same or other CT Others

N 14 37 11 13 3

(77%) non-commercial CT prematurely ended the reasons included difficulties of recruitment and/or difficulties caused by the pandemic and in 8 cases (20.5%) lack of resources/budget. However, reasons for a premature end in commercial clinical trials included business reasons in 14 (33.3%), reasons related to the results of that CT or of another CT with the same ATiMP in 13 (31%), and lack of recruitment, lack of budget and/or pandemic-related difficulties in 10 (23.8%).

2.5 Transparency About Clinical Trials on ATiMP and EU Initiatives Registration of the clinical trials in a public register prior to entry of the first patient has been recommended since 2004 by the International Committee of Medical Journal Editors and the World Health Organization. The EU legislation makes it mandatory to publish the CT in the EUCTR or the CTIS (see Table 2.2).

Transparency is necessary, among other things, to identify serious health problems not yet investigated, to identify specific indications where a particular product has already shown lack of efficacy and known risks to be avoided/minimized in future CT, to facilitate recruitment and to cooperate with other sponsors. It is a way for the sponsor to document the authorship of the trial, and it could also be seen as an opportunity to show the society and the CT participants, through the publication of their results, that these studies are important and worthy to be able to progress in having better treatments for relevant diseases. However, to obtain these benefits, all stakeholders should commit to comply with this principle. This, among other things, requires paying attention to aspects such as the unique/unequivocal identification of the CT and of the investigated medicinal products. On one side, the EU CT system shall identify each CT by a unique EU number (EudraCT or EU trial number), which is issued by the system (see Table 2.1 above). It would be very helpful if medical journals always required the inclusion of the EudraCT number/EU trial number, together with any other relevant identifier, in any publications related to CT with participation of EU sites. It would also be very helpful if sponsors could reference this EU trial number every time the CT is identified for a CT Register. In a prior analysis by the authors of this chapter [31], this number was only present in about 56% of the CT records identified in ClinicalTrials.gov [33]. In case of a CT composed by sev-

2  Clinical Trials on Advanced Therapy Investigational Medicinal Products in Spain (2004–2022)…

eral projects authorized as separated CT as in the case of an autologous mesenchymal cells for multiple sclerosis [34], all related projects should be referenced in every CT recorded in the database [12]. On the other side, every medicinal product without a marketing authorization in EU should have a medicinal product number and every new active substance not previously authorized as part of a medicinal product in EU should have an EU active substance code, in both cases issued at the time they are registered in the Medicinal Product Dictionary contained in the Eudravigilance database (XEVMPD). These identifiers should be used for every CT application or notification submitted to the competent authorities in the MSC [18]. The XEVMPD would benefit from having a more systematic way of describing the ATiMP under development which also pays attention to equivalence between translations into national languages and a more user-friendly process for product and active substance registration in order to facilitate not only the initial registration but also keeping updated the evolution names for a product in the dictionary. Having a unique name for every substance that is also recognized globally is the task of the International Nonproprietary Names (INN) of the World Health Organization. Given the complexity of this type of products, a specific INN nomenclature system has been developed [35]. Problems highlighted here particularly for non-commercial trials may not be specific to ATiMP but can also reflect the general difficulties related to academic research on medicinal products due to the large number of this type of sponsor represented in this sample. In Europe, there are several initiatives ongoing trying to facilitate CT under the scope of the new regulation which include facilitating the knowledge about the legislative framework and guidance [18] and the initiative Accelerating Clinical Trials in the EU (ACT-EU) [36] intended to develop the European Union further as a competitive center for innovative clinical research is among them. ACT-EU includes within the work plan, among other things, to closely monitor the progressive implementation of the new CTR [37] and to establish a process to support academic sponsors in enabling large multinational CT.

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2.6 Conclusion In Spain, CT on ATiMP should follow the European general legislation for this kind of research plus the legal requirements applicable to ATMP in terms of manufacturing of the product, traceability and compliance with GCP specific for them. This requires making a careful benefit– risk balance of the treatment for the selected target population, a safety surveillance adapted to the product characteristics and often long-term periods of follow-up for the CT subjects. Since 31 January 2023, CTR applies to all new CT to be conducted in any EU/EEA site and the application to get the authorization and all subsequent notifications should be via CTIS. An analysis focused on the 431 CT authorized in Spain during the period May 2004– July 2022 and the 249 ATiMP investigated in them reveals during 2004–2012 a great predominance of CT by non-commercial sponsors on sCTMP and TEP, the great majority national and almost half of them single site. This profile has evolved to a great increase in the CT with GTMP in the last five years, driven by commercial sponsors with a high percentage of multinational and multi-site CT.  The most investigated area was cancer (36.7%). However, the therapeutic area of research varies according to the type of ATiMP. GTMP were investigated in 73.4% of cancer CT and in 93.5% of congenital, hereditary and neonatal diseases and abnormalities. However, 87.7% of CT on the cardiovascular area and 93.8% of those on musculoskeletal diseases investigated TEP. sCTMP are investigated in 85.2% of CT on nervous system diseases, 72.4% of CT on digestive system diseases and in 91.4% of immune system diseases. In general, these CT look for a treatment in very serious diseases without an appropriate alternative remedy. Considering the IMP, 110 out of 249 ATiMP belong to non-commercial owners; most of them are sCTMP and TEP, consistent with the type of CT run by non-commercial sponsors. On the other hand, most of the products that belong to commercial owners are GTMP.

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Publication of the authorized CT and their results is essential in order to avoid exposure to patients to already known risks or ineffective treatments and redundant studies, and this is a legal requirement at the EU. CT status analysis shows some difficulties, particularly by non-­ commercial sponsors that deserve a deeper analysis. A proper identification of the ATiMP in the registries taking into account the evolving names of the IMP along the clinical development is key to enable successful searches. Some simplifications in the necessary procedure of registration of the non-authorized ATiMP in the XEVMPD will contribute to reach this purpose. The limited experience with the application of CTR and its procedures, especially the coordinated assessment of the protocol and IMP led by RMS and new transparency requirements, is still insufficient to determine whether the new system will give benefits as compared to the old system.

References 1. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and ­amending Directive 2001/83/EC and Regulation (EC) No 726/2004. Vols. OJ 2007 L 324: 121–137. 2. European Commission. EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4: Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products, 2017. [Online] 28 12 2022. https:// ec.europa.eu/health/documents/eudralex/vol-­4_en. 3. Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells. Vols. OJ 2004 L 102, p. 48–58. 4. Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/ EEC  – Commission Declaration. Vols. OJ L 106, 17.4.2001, p. 1–39. 5. Directive 2009/41/EC of the European Parliament and of the Council of 6 May 2009 on the contained use of genetically modified micro-organisms (Recast) (Text

J. Estévez Álamo et al. with EEA relevance). Vols. OJ L 125, 21.5.2009, p. 75–97. 6. Boran T., Menezes-Ferreira M., Reischl I. et  al. (2017) Clinical Development and Commercialization of Advanced Therapy Medicinal Products in the European Union: How Are the Product Pipeline and Regulatory Framework Evolving? Hum. Gene Ther. Clin. Dev.; 28(3): 126–135. 7. Maciulaitis R., D’Apote L., Buchanan A. et al. (2012) Clinical development of Advanced Therapy Medicinal Products in Europe: evidence that regulators must be proactive. Mol. Ther. 20(3): 479–482. Vols. Mol. Ther. 2012; 20(3): 479–82. 8. Directive 2001/20/EC of the E.P. and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the MS relating to the implementation of GCP in the conduct of CT on medicinal products for human use. Vols. Official Journal L 121, 01/05/2001 P. 0034 – 0044. 9. Real Decreto 223/2004, de 6 de febrero, por el que se regulan los ensayos clínicos con medicamentos. Vols. BOE num 33, de 7 de febrero de 2004, p. 4429–5443. 10. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. Official Journal L 2014;158:1–76. 11. Royal Decree 1090/2015, of 4 December, regulating clinical trials with medicinal products, Ethics Committees for Investigation with medicinal products and the Spanish Clinical Studies Registry. 12. Clinical trials in the European Union. https://euclinicaltrials.eu/. 13. Commission, European. EudraLex  – Volume 10  – Clinical trials guidelines. Clinical trials Regulation (EU) No. 536/2014 Questions & Answers. https://health.ec.europa.eu/system/files/2022-­1 2/ regulation5362014_qa_en.pdf. 14. ICH E6 Good Clinical Practice Guideline adopted by CHMP as EMA/CHMP/ICH/135/1995, as updated. https://www.ema.europa.eu/en/documents/scientific-­ guideline/ich-­guideline-­good-­clinical-­practice-­e6r2-­ step-­5_en.pdf. 15. European Commission. Guidelines on Good Clinical Practice specific to Advanced Therapy Medicinal Products. C (2019) 7140 final. https://health. ec.europa.eu/system/files/2019-­10/atmp_guidelines_ en_0.pdf. 16. Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data and repealing Directive 95/46 EC. s.l.: Official Journal of the European Union 2016 L119; 1–88. 17. EMA/228383/2015 Endorsed Appendix, on disclosure rules, to the “Functional specifications for the EU portal and EU database to be audited – EMA/42176/2014. https://www.ema.europa.eu/en/documents/other/ appendix-­disclosure-­rules-­functional-­specifications-­ eu-­portal-­eu-­database-­be-­audited_en.pdf.

2  Clinical Trials on Advanced Therapy Investigational Medicinal Products in Spain (2004–2022)… 18. Clinical Trials Regulation (EU) No. 536/2014 in practice. Eudralex volume 10  – Clinical Trials. Group, Clinical Trials Coordination. s.l.: Eudralex volume 10 – Clinical trials. 19. Clinical trials Information System (CTIS) – Sponsor Handbook. https://www.ema.europa.eu/en/documents/other/clinical-­trial-­information-­system-­ctis-­ sponsor-­handbook_en.pdf. 20. Spanish Agency of Medicines and Medical Devices (AEMPS). Registro español de estudios clínicos (REEC). https://reec.aemps.es. 21. EMA/698382/2021 Guideline for the notification of serious breaches of Regulation (EU) No 536/2014 or the clinical trial protocol and EMA/743394/2021 Appendix III b  – Information to be submitted with a notification of a serious breach. https:// health.ec.europa.eu/medicinal-­p roducts/eudralex/ e u d r a l ex -­vo l u m e -­1 0 _ e n # s e t -­o f -­d o c u m e n t s -­ applicable-­t o-­c linical-­t rials-­a uthorised-­u nder-­ regulation-­eu-­no-­5362014. 22. EMA/INS/GCP/856758/2018 Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic). h t t p s : / / w w w. e m a . e u r o p a . e u / e n / d o c u m e n t s / scientific-­guideline/guideline-­content-­management-­ a r c h iv i n g -­c l i n i c a l -­t r i a l -­m a s t e r-­fi l e -­p a p e r / electronic_en.pdf. 23. EU Clinical Trials Register. https://www.clinicaltrialsregister.eu/. 24. EMA/CAT/224381/2019 Questions and answers on the use of out-of-specification batches of authorized cell/tissue-based Advanced Therapy Medicinal Products. 25. European Commission. Genetically Modified Organism (GMO) aspects for investigational medicinal products. National requirements. https://health. ec.europa.eu/medicinal-­products/advanced-­therapies/ genetically-­m odified-­o rganism-­g mo-­a spects-­ investigational-­medicinal-­products_en. 26. European Commission. Advanced Therapies. GMO requirements for investigational products. https://health.ec.europa.eu/medicinal-­p roducts/ advanced-­therapies_en. 27. Commission Directive 2009/120/EC of 14 September 2009 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products (Text with EEA relevance). OJ L 242, 15.9.2009, p. 3–12 28. EMA/CAT/600280/2010 rev.1, 21 May 2015Reflection paper on classification of Advanced Therapy Medicinal Products. [Online] https://www.

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ema.europa.eu/en/documents/scientific-­g uideline/ reflection-­p aper-­c lassification-­a dvanced-­t herapy-­ medicinal-­products_en-­0.pdf. 29. Spanish Agency of Medicines and Medical Devices (AEMPS). Guideline of the Spanish Agency of Medicines and Medical Devices for the nomenclature of active substances in advanced therapies investigational medicinal products containing cells. 2013. [Online] 2013. [Cited: 31 12 2022.] https://www. aemps.gob.es/en/investigacionClinica/medicamentos/ docs/directrices-­NSA-­invest-­terapia-­celular.pdf. 30. European clinical trials database (EudraCT). https:// eudract.ema.europa.eu/. 31. Álamo J.E., Timón M., González Gómez-Platero C. et al. (2019) Clinical trials of advanced therapy investigational medicinal products in Spain: preparing for the European clinical trials regulation. Cell & Gene Therapy Insights 5(11),1431–1449. 32. Royal Decree 477/2014, of 13 June, regulating advanced therapy medicinal product non-industrial manufacturing. Agencia Estatal, Boletín Oficial del Estado. s.l.: BOE núm. 144, de 14/06/2014. 33. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29. https://clinicaltrials. gov/. 34. Uccelli, A., Laroni, A., Brundin, L. et  al. (2019) MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): a randomized, double blind, cross-over phase I/II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis. Trials 20, 263. https://doi.org/https://doi.org/10.1186/ s13063-­019-­3346-­z. 35. Loizides U., Dominici M., Manderson T. et al. (2021) The harmonization of World Health Organization International Nonproprietary Names definitions for cell and cell-based gene therapy substances: when a name is not enough. Cytotherapy, May; 23(5): 357–366. 36. European Commission, EMA and Heads of Medicines Agencies. Accelerating Clinical Trials in the EU (ACT EU). https://www.ema.europa.eu/en/human-­ regulatory/research-­d evelopment/clinical-­t rials/ accelerating-­clinical-­trials-­eu-­act-­eu. 37. European Commission, Heads of Medicines Agencies and European Medicines Agencies. Clinical Trials Regulation: progress on implementation. Key performance indicators (KPIs) to monitor the European clinical trials environment. https:// www.ema.europa.eu/en/human-­regulatory/research-­ development/clinical-­trials/clinical-­trials-­regulation/ clinical-­trials-­regulation-­progress-­implementation.

3

The Regulation of Cell Therapy and Gene Therapy Products in Switzerland Petra Kempná Bukovac, Michel Hauser, Daniel Lottaz, Andreas Marti, Iris Schmitt, and Thomas Schochat

Abstract

This chapter describes the regulation of cell and gene therapy products (CGTPs) in Switzerland and its legal basis. The Swiss Agency for Therapeutic Products, Swissmedic, is the lead Regulatory Authority and its ATMP Division is responsible for the regulation of these products at the level of clinical trials and marketing authorization. CGTPs are regulated similarly to medicinal products. The legal basis is set by the Therapeutic Product Act, the Transplantation Act, the Human Research Act, and associated ordinances. The ATMP Division is involved in processes such as scientific advice meetings, presubmission advice meetings, pharmacovigilance, market surveillance, import/export approvals, manufacturing license approval, and inspections. In Switzerland, guidance documents relevant for cell and gene therapy provided by PIC/S, OECD, ICH, Ph.Eur., EMA, or FDA are considered. In order to harmonize requirements for CGTPs, the ATMP Division is in constant exchange of information with foreign Regulatory Authorities and part of working groups of ICH, IPRP, and Ph.Eur. As CGTPs are biologically and technically complex, a risk-

P. K. Bukovac · M. Hauser · D. Lottaz · A. Marti (*) · I. Schmitt · T. Schochat Swissmedic, Swiss Agency for Therapeutic Products, Berne, Switzerland e-mail: [email protected]

based approach is applied on a case-by-­ case basis for the evaluation of clinical trial and marketing applications. A substantial part of this chapter will provide requirements with respect to the manufacturing and quality, nonclinical and clinical evaluation of CGTPs. Furthermore, information will be provided regarding the use of real-world evidence in evaluation of clinical long-term efficacy and safety in case of rare diseases where the numbers of patients are too small for statistically meaningful analysis during clinical trials. Finally, the chapter will provide information on a health technology assessment (HTA) program that was launched in 2015  in Switzerland by the federal authorities. Keywords

Switzerland · Swissmedic · Regulatory Authority · ATMP · Cell therapy · Gene therapy · Tissue engineering products · Transplant product · GMO · Clinical trial · Quality considerations · Nonclinical considerations · Clinical considerations · Scientific advice · Marketing authorization

Abbreviations AAV AE AMP

Adeno-Associated Virus Adverse Event ATMP Investigational Medicinal Product

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 M. C. Galli (ed.), Regulatory Aspects of Gene Therapy and Cell Therapy Products, Advances in Experimental Medicine and Biology 1430, https://doi.org/10.1007/978-3-031-34567-8_3

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P. K. Bukovac et al.

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ANVISA Brazilian Health Regulatory Agency ATMP Advanced Therapy Medicinal Products BCMA B-cell Maturation Antigen CAR Chimeric Antigen Receptor CGTP Cell and Gene Therapy Product ClinO Clinical Trials Ordinance CTD Common Technical Document CTP Cell Therapy Product EC Ethics Committees eCTD Electronic Common Technical Document EMA European Medicines Agency FIM First-In-Man FOEN Federal Office for the Environment FOPH Federal Office of Public Health GCP Good Clinical Practice G-CSF Granulocyte-Colony-Stimulating Factor GLP Good Laboratory Practice GMO Genetically Modified Organisms GMP Good Manufacturing Practice GTP Gene Therapy Product HC Health Canada HRA Human Research Act HSA Singapore’s Health Sciences Authority HTA Health Technology Assessment ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use IMP Investigational Medicinal Product IPRP International Pharmaceutical Regulators Program LoQ List of Questions LTFU Long-Term Follow-Up Study MAA Marketing Authorization Application Medsafe New Zealand Medicines and Medical Device Safety Authority MHRA Medicines and Healthcare products Regulatory Agency PEI Paul Ehrlich Institute Ph.Eur. The European Pharmacopoeia PMDA Pharmaceuticals and Medical Devices Agency RCT Randomized Controlled Trial

RPE RWD RWE SECB

Retinal Pigment Epithelium Real-World Data Real-World Evidence Swiss Expert Committee for Biosafety TGA Therapeutic Goods Administration TPA Therapeutic Product Act TpP Transplant Product US FDA United States Food and Drug Administration

3.1 Introduction The Swiss Agency for Therapeutic Products, Swissmedic, is the lead Authority for the regulation of Advanced Therapy Medicinal Products (ATMPs) in Switzerland and is situated in Bern. Swissmedic was established in the year 2002 based on the Federal Act on Medicinal Products and Medical Devices (Therapeutic Product Act, TPA) which was itself put into force on January 1, 2002 [1]. After regulating cell and gene therapy products (CGTPs) at the level of clinical trials and marketing authorization at Swissmedic with limited resources in a small unit for many years, a major organizational change occurred in January 2022, when a specialized ATMP Division was created. The ATMP Division is organized as an all-in-one unit and is responsible for the regulatory and scientific supervision of ATMP and related products or processes. The ATMP division is responsible for scientific advice meetings, pre-submission advice meetings, clinical trial approvals, marketing authorizations, pharmacovigilance, market surveillance, import/export approvals, manufacturing license approvals and inspections. The ATMP Division works in close collaboration with other Swissmedic Divisions and Units and with Swiss Federal Offices such as the Federal Office of Public Health (FOPH), the Federal Office for the Environment (FOEN), and the Swiss Expert Committee for Biosafety (SECB). The ATMP Division is internationally connected through several Memorandums of Understanding, Confidentiality Commitments or Confidentiality Agreements with other Regulatory Authorities such as the EMA, PEI,

3  The Regulation of Cell Therapy and Gene Therapy Products in Switzerland

US FDA, Health Canada (HC), TGA, MHRA, PMDA, HSA, Medsafe, ANVISA, and others. This guarantees a constant exchange of expertise and information in the therapeutic areas of cell and gene therapy and others. Importantly, besides CGTPs, ATMPs in Switzerland encompasses additional product types such as mRNA and DNA vaccines, vaccines based on genetically modified organisms (GMO), or therapeutic products based on synthetically manufactured nucleic acid molecules. Even though mRNA and DNA vaccines, viral vector vaccines for preventive use, and synthetically manufactured nucleic acid products for therapeutic use fall under the ATMP category, there will be no major differences in the requirements for clinical trials and/or the marketing authorizations with respect to the quality/manufacturing, nonclinical and clinical aspects as compared to other regulatory regions such as EU, United Kingdom, USA, Canada, Japan, Singapore, or Australia. As mRNA, DNA, or GMO vaccines and synthetically manufactured nucleic acid products, such as siRNA oligonucleotides, are not considered ATMPs or gene therapy products (GTPs) in these regulatory regions, they will not be further discussed. Therefore, this chapter will focus only on the regulation of GTPs (to be used in in vivo and ex vivo gene therapies) and cell-based products such as stem cell products, tissue engineering products, or combination products in Switzerland. For simplicity, the cells, tissue engineering, and combination products will be called cell therapy products (CTPs) in the further course of this chapter. Typical examples of CTPs are keratinocyte sheets to treat burns, mesenchymal stem cells to treat cardiovascular and other diseases, chondrocytes to treat cartilage defects, or in vitro differentiated stem or progenitor cells. Several cell types can be combined to form tissue-like structures in culture, such as skin products consisting of an epidermal layer and a dermal layer. Furthermore, cells can be combined with special matrices such as collagen to support their biological function or they can be encapsulated to assure local activity, typically paracrine secretion of certain factors, and to prevent unwanted

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spreading in the body. Cells can be genetically manipulated in culture and used as an  ex vivo GTP.  Examples of an  ex vivo GTP are T-cells expressing chimeric antigen receptors (CAR) to treat cancer indications or genetically modified CD34+ stem cells for the treatment of immune deficiencies. In Switzerland, numerous CTPs are under regulation at the clinical trial level. Several CTPs are approved and marketed in Switzerland (Table 3.1). Gene therapy can be defined as a medical intervention with the aim to treat or prevent a genetic disease either by adding a curative gene sequence or by correcting the affected gene. More advanced technologies, whereby mutated genes in affected cells are directly corrected at the genomic DNA level by using gene-specific zinc finger nucleases [2], CRISPR/Cas [3] or other means have not yet reached the clinical stage in Switzerland. Several ex vivo as well as in vivo GTPs have been approved and marketed in Switzerland (Table 3.1). The development of gene therapies involves in  vivo gene therapy and ex  vivo gene therapy approaches. In vivo gene therapy encompasses all approaches whereby therapeutic genes carried by gene therapy vectors are directly introduced into a patient’s body (e.g., by intramuscular injection, intravenous injection). It is important to note that according to the Federal Constitution of the Swiss Confederation (Art. 119), it is forbidden to alter the genetic material of germ cells [4]. Therefore, all in vivo and ex vivo gene therapy approaches have to be strictly limited to the correction of a genetic defect in somatic cells. Nonreplicating and replication competent viral and bacterial vectors or bacteriophages harboring foreign gene sequences introduced by means of recombinant technology are classified as GMO [5, 6]. Unmodified wild-type viruses with oncolytic properties for treating cancer patients represent a special case. These viruses are neither a GTP nor a GMO. However, in practice the same procedure will be applied for regulating unmodified wild-type oncolytic products for use in clinical trials and for a marketing authorization as has been established for GMOs and GTPs.

P. K. Bukovac et al.

44 Table 3.1  Authorized cell and gene therapy products in Switzerland Active substance In vivo gene therapy Imlygic Talimogene Laherparepvec Luxturna (AAV2-hRPE65v2) Voretigene neparvovec Zolgensma (AVXS-101) Onasemnogene abeparvovec Ex vivo gene therapy Kymriah Tisagenlecleucel

Yescarta Axicabtagene ciloleucel Abecma Idecabtagene vicleucel Tecartus Brexucabtagene autoleucel Breyanzi Lisocabtagene maraleucel

Carvykti Ciltacabtagene autoleucel Cell therapy Apligraf Mature G100 construct Alofisel Darvadstrocel Spherox

Description

Indication

Herpes Simplex Virus-1, attenuated by functional deletion of ICP35.4 and ICP47 genes and genetically modified to express granulocyte macrophage colony-­ stimulating factor AAV2-based vector carrying human retinal pigment epithelium protein 65 (RPE65) transgene

Melanoma with local or remote metastasis

AAV9-based vector carrying human survival motor neuron protein transgene and ITR-flanking regions derived from AAV2 virus

Spinal muscular atrophy type I

Autologous ex vivo genetically modified T cells expressing CD19-CAR (chimeric antigen receptor directed against CD19 antigen) CAR-T cells/lentiviral vector Autologous ex vivo genetically modified T cells expressing CD19-CAR (chimeric antigen receptor directed against CD19 antigen) CAR-T cells/retroviral vector Autologous ex vivo genetically modified T cells expressing BCMA02-CAR (chimeric antigen receptor directed against B-cell maturation antigen) CAR-T cells/lentiviral vector Autologous ex vivo genetically modified T cells expressing CD19-CAR (chimeric antigen receptor directed against CD19 antigen) CAR-T cells/lentiviral vector Autologous ex vivo genetically modified CD8+ and CD4+ cells expressing CD19-CAR (chimeric antigen receptor directed against CD19 antigen) CAR-T cells, in target ratio CD8+ CAR+ : CD4+ CAR+ 1:1/lentiviral vector Autologous ex vivo genetically modified T cells expressing BCMA-CAR (chimeric antigen receptor directed against B-cell maturation antigen) CAR-T cells/lentiviral vector

Pediatric refractory B-cell acute lymphoblastic leukemia Relapsed/refractory diffuse large B-cell lymphoma Relapsed/refractory diffuse large B-cell lymphoma Relapsed/refractory follicular lymphoma Relapsed/refractory multiple myeloma

Bilayered allogenic cell-based product consisting of a layer of human keratinocytes, bovine collagen, and human dermal fibroblasts Allogenic ex vivo expanded mesenchymal stem cells extracted from adipose tissue Spheroids of human autologous matrix-associated chondrocytes

Wound treatment—chronic venous leg ulcer and diabetic foot ulcer Complex anal fistulas in adults with Crohn’s disease Cartilage defects in knee joint

In Switzerland, CGTPs are regulated similarly to medicinal products. The principal legal basis for the regulation of CGTPs at the levels of clinical trials and marketing authorization is the TPA

Inherited retinal dystrophy occurring due to biallelic RPE65 gene loss-of-function mutation

Relapsed/refractory mantle cell lymphoma

Relapsed/refractory diffuse large B-cell lymphoma primary mediastinal large B-cell lymphoma Relapsed/refractory multiple myeloma

and its linked Ordinances. For cell-based products article 49 of the Transplantation Act is relevant [7]. Specifically, for GTPs the Gene Technology Act [8] and its ordinances also apply.

3  The Regulation of Cell Therapy and Gene Therapy Products in Switzerland

With respect to clinical trials, local Ethics Committees (ECs) and Swissmedic are the lead Regulatory Authorities for approving cell therapy investigational products. For gene therapy clinical trials and Marketing Authorization Applications (MAA), the SECB, FOPH, and FOEN are also involved. For an MAA, the CGTP need to be fully developed and complete data packages structured according to the ICH M4 guideline [9] have to be submitted in an electronic form to Swissmedic. In the following parts of this chapter, more details will be summarized with respect to the regulatory framework, the regulatory pathway, and specific considerations with respect to product manufacturing, pharmacology/toxicology and clinical trials. Furthermore, some information regarding health technology assessments (HTA) will be provided.

3.2 The Regulatory Framework for ATMP in Switzerland In Switzerland, the principal legal basis for the regulation of CGTP at the levels of clinical trials and marketing authorization is the TPA and its linked ordinances [1]. For CTP, article 49 of the Federal Act on the Transplantation of Organs, Tissues and Cells (Transplantation Act) [7] is relevant and refers to various articles in the TPA that are important for the regulation of CTP.  The Transplantation Act defines CTPs as transplant products (TpPs) in Switzerland (see annex below). The Clinical Trial Ordinance (ClinO) provides the legal basis for all clinical trials in Switzerland and defines gene therapy in article 22 as “introduction of genetic information in somatic cells” [10]. From the legal point of view, as formulated in the Containment Ordinance [5] and in the Release Ordinance [6], “biologically active genetic material” such as RNA or DNA is considered equivalent to a microorganism or  a GMO and, as a consequence, is regulated in a comparable manner to a GMO. These ordinances apply irrespectively of the intended use (prophylactic or therapeutic) or the manufacturing process (biotechnologically or synthetically). As a result, synthetically produced

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RNA and DNA and recombinantly produced plasmid DNA and viral vectors are all regulated by the same regulatory processes in Switzerland with respect to clinical trials authorizations and marketing authorizations. For all research involving human beings, the Human Research Act (HRA) and its ordinances are relevant [11]. The ClinO relevant for both legal acts, the TPA and the HRA, describes in detail the approval process of clinical trials involving investigational CGTPs. Specifically for GTPs, the Gene Technology Act [8] and its ordinances are relevant. All clinical trials with human subjects have to be performed according to Good Clinical Practice (GCP), as described in the ICH E6 “Guideline for Good Clinical Practice” [12]. In addition, all investigational products for human use have to be manufactured according to Good Manufacturing Practice (GMP) [10]. The EU GMP guidelines specified to ATMPs [13] and PIC/S ATMP guidelines [14] are also being followed in Switzerland. Because of the complex nature of CGTPs, specific regulatory guidelines have been developed over recent years, mainly by US FDA [15] and EMA [16], to support the manufacturing of these products. Although these guidance documents are not legally binding in Switzerland, the Swiss Regulatory Authorities take into account the US FDA and EMA guidelines for defining requirements for clinical trial applications involving CGTPs. Important to consider are cell and gene therapy-specific general chapters and monographs published by the European Pharmacopoeia (Ph.Eur.). Ph.Eur. monographs  are legally binding in Switzerland. Of note, these guidelines usually outline regulatory requirements at the level of marketing authorization. For clinical trials, these requirements therefore often need to be re-­ discussed and adapted on a case-by-case basis in the context of scientific advice meetings prior to filing the clinical trial dossier to Swissmedic. Annex 4 of the ClinO lists the documents that have to be submitted to Swissmedic in the frame of a clinical trial application for an investigational GTP. For further information, the reader is referred to the ClinO and the Swissmedic “information sheet” [17].

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In order to harmonize the requirements and the approval processes for clinical trial applications and MAA, Swissmedic is closely working together with international organizations such as the ICH, IPRP, and Ph.Eur. In addition, Swissmedic is part of the Access Consortium. The Access Consortium is a collaborative initiative between Australia’s TGA, HC, the MHRA of the United Kingdom, Singapore’s HSA, and Swissmedic. The purpose of the consortium is to build synergies and to share knowledge amongst the Regulatory Authorities thereby enhancing the efficiency of regulatory systems.

3.3 The Applicable Regulatory Pathways for Cell and Gene Therapy Products Since the 1990s, over 100 cell and gene therapy clinical trials have been approved in Switzerland. The ClinO states that any human clinical trials to be performed in Switzerland needs to be approved by an Ethics Committee (EC) and by Swissmedic [10]. In Switzerland, seven different ECs are responsible for overseeing clinical trials. For cell therapy clinical trials with genetically unmodified cells or tissues as investigational products, a time frame of 30 days is foreseen for the Decision after a complete clinical trial documentation is independently submitted to the respective EC and to Swissmedic. For the regulation of gene therapy investigational products, including genetically modified cells or tissues, the SECB, FOPH, and FOEN are involved as Regulatory Authorities in addition to Swissmedic and EC.  After submission to Swissmedic, the clinical trial dossier will be distributed to SECB, FOPH, and FOEN after a formal control by Swissmedic. SECB will review the data with focus on manufacturing and safety of the gene therapy investigational product and clinical trial design. FOPH will review the data with focus on safety for third-party contact (i.e., close relatives or health care workers). FOEN will review the data with respect to environmental safety. The Swiss guidance document regarding the possible risks for humans and the environment should be followed [18]. For clinical trials with

P. K. Bukovac et al.

gene therapy investigational products, a time frame of 60 days is foreseen for the Decision. Swissmedic is the lead Regulatory Authority for Marketing Authorization Applications (MAAs). For gene therapy MAAs, the Swiss Authorities SECB, FOPH, and FOEN will be also involved. In addition, each MAA will be reviewed and discussed by the Human Medicines Expert Committee, an advisory committee that is independent of Swissmedic. The approval times vary depending upon the type of submission (i.e., regular submission, submissions with orphan drug status, fast track, and article 13). For regular MAAs, the timeline for the final decision by Swissmedic is 330 calendar days [19]. This timeline does not take into account the time the applicant needs to answer the list of questions (LoQ) by Swissmedic. In order to make ATMP products for the treatment of life-threatening diseases available to patients as quickly as possible, a temporary authorization can be issued and/or MAAs can be submitted as a fast-track procedure if requirements are fulfilled. In such case, the timelines for evaluation are significantly shorter. A special case represents MAAs referring to article 13 of the TPA. The applicant can submit the MAA with reference to article 13 in case the product has already been approved in regions with similar requirements with respect to quality, safety, and efficacy. The timelines for evaluation and approval of such submissions are the same as for a regular MAA. In the case that Swissmedic does not raise additional questions, this may allow faster approval of the product in Switzerland. For an  MAA, the CGTP need to be fully developed and complete data packages structured according to the ICH M4 guideline [9] have to be submitted in an electronic form to Swissmedic. These data packages should include all documentation with respect to manufacturing/quality, nonclinical and clinical evaluations. The approval process is divided into different stages (Fig. 3.1). After submission of the application, the documentation has to pass a formal control. After the submitted documentation is approved, the evaluation is divided into two stages. Evaluation I results in a list of questions

3  The Regulation of Cell Therapy and Gene Therapy Products in Switzerland

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Fig. 3.1  Milestones and procedure sections during the authorization procedure in Switzerland [19]. The foreseen time frame from the formal ok until the official decision is 330 calendar days. This time frame will be extended if the

applicant needs more time to reply. Eval. evaluation, PD preliminary decision. (Reproduced with courtesy of Swissmedic)

(LoQ) for the applicant. The evaluation II involves the review of answers to the LoQ.  An official decision will only be made after all details, including labeling, are cleared. It is advised that, when planning a clinical trial application or an MAA, the applicant contacts Swissmedic early in product development in order to receive scientific advice.

according to GMP [13, 14]. The centers where procurement of the cell or tissue starting material takes place will also need appropriate GMP license. If the AIMP is manufactured outside of Switzerland and the starting material consists of autologous cells or tissue, the sponsor needs to apply for an export license to cover the export of the cellular material to the manufacturing site. License for import of an AIMP manufactured abroad to the centers in Switzerland is covered by approval of clinical study. Overall principles of assuring product quality during the manufacturing, analytical testing, transport, and storage of an AIMP are similar whether it involves a gene therapy or a cell therapy IMP. Cell therapy IMPs, especially autologous patient-specific IMPs, carry a high degree of variabilities, beginning from the starting materials. Therefore, a detailed understanding of the process as well as of the product is critical and careful characterization of the manufacturing steps as well as extended characterization of the product should be in focus from the very beginning of translational and clinical development. For first-­ in-­man (FIM) and phase I/II clinical studies, the production process of the AIMP is not expected to be fully validated. Analytical methods in early phases should be qualified and their suitability for the intended use should be demonstrated. Validation or compendial method qualification is expected for safety-relevant methods, such as sterility, mycoplasma, endotoxins, or the methods used in viral safety evaluation. In the application for a clinical trial, the inclusion of a detailed flow chart describing all steps (from cell procurement to final AIMP formula-

3.4 Specific Considerations Regarding Manufacturing, Pharmacology/Toxicology and Clinical Trial Design for Cell and Gene Therapy Products 3.4.1 Specific Considerations for Cell Therapy Products In this section, aspects that need to be considered for clinical trials with CTPs are discussed with a focus on human cells. As there is overlap between this section and the section below concerning GTPs, cell therapy-specific issues will be addressed here, although some repetition cannot be avoided. The human cells may show stem or progenitor cell characteristics or be more committed cells, and they may be allogeneic or autologous. The cell therapy-specific considerations described in this section are also applicable to ex vivo genetically modified cells.

3.4.1.1 Quality Considerations For use in humans, an ATMP investigational medicinal product (AIMP) has to be produced

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tion) and detailed description of process steps including process controls and incoming materials are required. The cell procurement is a critical step, especially if the final cell product is allogeneic. Testing of donor and cells as a starting material for the allogeneic as well as autologous use for potential infectious agents (i.e., HIV, HBV, and HCV) is required as described in the Ordinance on Transplantation [20] or in the Medicinal Products Licensing Ordinance in the case of blood cells [21]. If applicable (e.g., for allogeneic CTPs), master cell banks and/or working cell banks need to be established and characterized according to Ph.Eur. 5.2.3 [22] and ICH guidelines Q5D [23] and Q5A [24]. The autologous cells obtained from one donor can be defined as a single batch. As cell numbers are usually limited in the autologous setting, testing of each batch at the level of final product is challenging. As a high variability is introduced already with the starting material, the overall process control strategy should be established to ensure process and product consistency. As living cells are the active substance of a CTP, bacterial and viral removal or inactivation is not possible. Therefore, the starting material should be obtained aseptically whenever possible, characterized appropriately and each manufacturing step needs to be established in a way that prevents product contamination. If material of animal or human origin is used during production, the risk with respect to endogenous adventitious agents needs to be assessed [22] and a special form must be filled out and submitted to Swissmedic [25]. As the quality of the reagents, of auxiliary materials or of culture supplements may have a significant impact on the expansion, biological function, and safety of the cells, all incoming materials need to be described in detail and appropriately qualified. In products where matrices are used as supportive structural elements, data confirming the appropriate quality of these components need to be provided. Although the manufacturing process for a CTP is typically continuous, the active substance and the final product should be defined. Specific consideration should be given to define appropriate markers for monitoring cell identity (e.g., cell

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morphology, biochemical markers, and cell surface markers). Suitable assays have to be established to control cell purity and cellular impurities (e.g., quantification of contaminating cells). The control of noncellular impurities (e.g., residual reagents or medium supplements, degradation products, residual vectors, or other components used for genetic modification in the case of ex vivo GTPs, etc.) is critical, and a control strategy should be established based on a careful risk assessment. A suitable potency test should be established or should be under development already at very early stages of development program (ideally for phase I clinical trials). This is important to demonstrate the intended biological activity and to allow assessment of the potential correlation with clinical efficacy. Transport and storage need to be described in detail, and product stability needs to be investigated before clinical trials can be initiated, including product stability and compatibility during handling and administration. For CTPs with short shelf-life, i.e., cellular products that cannot be cryopreserved, a two-step release procedure is acceptable, when results of certain tests (typically final sterility) will be obtained after administration to the patient [13]. This should be reflected in the overall control strategy (e.g., additional tests at later process stages, enhanced testing of materials incoming into the process, single-use disposables), and the strategy including risk assessment should be clearly described and presented in the dossier. For MAAs, full documentation in eCTD structure is expected. The manufacturing process and analytical methods have to be fully validated, specifications established and appropriately justified, and full documentation for qualified critical raw materials should be attached. Detailed process and control strategy development and characterization should be provided [26, 27]. In very specific cases, exceptional release of batches that are not fully compliant with the approved specification is possible especially for authorized autologous CTPs for life-threatening indications [13, 14]. Such release should be notified to Swissmedic according to procedure described on the website [28].

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3.4.1.2 Nonclinical Considerations the cell therapy IMP is intended to be applied to The nonclinical evaluations of cell therapy IMPs humans as a single administration, a single dose should aim to collect relevant information with toxicity evaluation in one animal species is usurespect to (i) proof-of-concept, (ii) migration and ally sufficient. It is expected that pivotal noncliniproliferation potential of the cells after adminis- cal in  vivo toxicity evaluations supporting FIM tration, and (iii) potential toxicological effects. studies are performed under GLP conditions [29] Similar principles as described below under sec- unless otherwise justified. In these nonclinical tion 3.4.2 for GTPs apply to CTPs. Ideally, the safety evaluations, the cell therapy IMP should evaluations should be performed with the be administered according to the clinically releintended cell therapy IMP.  Data from publica- vant route. Besides potential local toxicity, the tions are considered supportive, especially for the systemic effects on various organs and effects on proof-of-concept. However, specifically designed the immune system may need to be considered. studies with the proposed product manufactured The design of the pivotal toxicity study can be in a manner identical to the planned clinical batch discussed with Swissmedic in the frame of a sciare usually required. This applies especially to entific advice meeting prior to the submission of safety studies. In the case that the human-specific the clinical trial dossier. CTP cannot be adequately studied in animals, an For most CTP, it is necessary to evaluate the animal-specific autologous CTP may be tumorigenic potential. In vitro and in vivo studies ­developed for the nonclinical evaluations in one may be performed to address this risk. This relevant animal species. includes the in  vitro analysis of chromosomal Proof-of-concept can be obtained using stability, the integration site analysis and transin vitro and in vivo studies. Usually, one relevant formation potential for ex vivo GTP (as described animal model is sufficient for these pharmaco- below), and in  vivo studies addressing tumor logical evaluations. The establishment of a rele- growth and unwanted tissue formation in target vant animal model is often a challenge, especially and nontarget tissues, such as the formation of if a homologous model needs to be used for teratomas. autologous CTP evaluation. The proof-of-­ concept data may also enable defining a poten- 3.4.1.3 Clinical Considerations tially efficacious dose for clinical trial use. The general principles of studying cell therapy Ideally, cell migration and proliferation ability IMPs at the clinical level do not differ from other are analyzed in the same models. However, if IMPs. Safety and efficacy need to be addressed, large animal models are needed for proof-of-­ and all studies have to be performed according to concept, the in vivo analysis of cell migration and GCP principles. Similarly to a  GTP, where the distribution is often difficult, thus a small animal risk is dependent on the vector type, the transspecies may be used for evaluating proliferation, ferred gene, and the clinical use, the risk associmigration and distribution. The need for studying ated with a CTP is dependent on the cell migration, distribution, and proliferation of the characteristics, the noncellular components in the cells following administration in animals and the final product, and the intended clinical use. technical details can be discussed with Therefore, a product-specific clinical risk assessSwissmedic in the frame of a scientific advice ment needs to be performed and measures to be meeting prior to submission of the clinical trial taken to minimize these risks need to be defined. dossier. In the early safety studies (FIM, phase I), a The extent of nonclinical safety evaluation is safe dose needs to be established. Risks and strictly product dependent. A risk assessment toxicological effects identified in safety studies facilitates understanding what parameters need to in animals should be addressed in the clinical be evaluated for the establishment of an adequate studies. Product-specific safety and efficacy safety profile. A safe starting dose that may be the endpoints need to be established and a longbasis of the FIM study should be established. If term follow-up (LTFU) is usually required.

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Further, any adverse event (AE) which might be related to the procedure which the patient has to undergo in order to receive the cell therapy IMP is classified as an adverse drug reaction. Any AE arising due to, for example, administration of a medication (such as G-CSF) or to performance of a biopsy in order to obtain the autologous cells needed for the manufacture of a cell therapy IMP, might also qualify as an adverse drug reaction. In the same line, a microbiological contamination occurring during manufacture but not detected before administration to the patient or to the volunteer should also be considered an adverse drug reaction. Further, the cutaneous, intra-articular, or intra-myocardial application of a cell therapy IMP will each carry a different level of risk. The clinical significance of the chosen endpoint will need to be greater in the case of a product r­equiring a potentially dangerous procedure. Swissmedic takes this into account in its overall benefit–risk analysis. In case of a future MAA, specific consideration should be given to the above points in the pharmacovigilance and risk management plan development. Not only the pharmacovigilance system will need to be organized to include procedural AE related to the CTP, but the treating physicians should be informed of the need to report such events. As clinical trials with autologous products will rarely reach a sample size as large as for drugs based on small molecules, rare AE may often not be detected until after marketing authorization. The pharmacovigilance system and physicians will need to be sensitized to the potential risks specific for CTPs (e.g., tumorigenicity), in order to assure that they can be identified should they occur.

3.4.2 Specific Considerations for Gene Therapy Products The following sections highlight some regulatory requirements for the clinical trial dossier to be submitted to Swissmedic with respect to quality, nonclinical and clinical requirements for GTPs.

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3.4.2.1 Quality Considerations Similar requirements apply for GTPs entering or undergoing clinical phase as described for CTPs (section 3.4.1, see above). In general, recommendations on quality requirements for in vivo GTPs as described in ATMP GMP guidelines [13, 14] should be followed. Plasmids, RNA, viral vectors, or recombinant viruses as well as genetically modified bacteria are the most commonly used vectors for gene transfer. Nucleic acid-based vectors (DNA plasmids and RNA) can either be used in a naked form or in a complex with polymers and/or proteins or encapsulated in lipid nanoparticles or liposomes. When complexed or encapsulated nucleic acid vectors are used, the carriers need to be specifically characterized, especially with respect to purity, dose, safety, and stability. As GTPs are based on nucleic acids, a gene therapy IMP needs to be sequenced at an appropriate step during production and the full sequence should be submitted (annotated). The different functional elements of the vectors and the therapeutic genes need to be explained in detail, including the rationale for their use. The origins and history of the sequences and all construction steps need to be described in detail. Any selection markers that could pose a risk to human subjects (e.g., an antibiotic resistance gene) should be removed in the final IMP.  For recombinant viral vectors derived by genetic modification of a wild-type virus, the origin and biological characteristics of the parental wild-type virus need to be described. For gene therapy vectors, several approaches may be used to generate a GTP based on a viral vector type (e.g., virus seed system, vector production in cell lines using plasmids, bacmids, or other vectors carrying helper and transgenes, or synthetically in cell-free systems or in bacterial cell banks, etc.). Already for early phase of clinical development, the cell banks and/or viral seeds used for production and all raw materials need to be characterized and appropriately qualified. During production, adequate in-process controls need to be established and a flowchart needs to be provided describing in detail each production step. Product identity should be shown at transgene level, as well as at gene product level (e.g., immu-

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nological characterization of the expressed protein). Identity of the viral vector (virus) should be confirmed. Regarding purity, special attention shall be given to limits of residual host RNA, DNA, proteins, plasmids, or viruses used for vector production. Safety issues need to be documented based on product-specific risk assessments. For viral vectors this also includes evaluation of the risk of replication-competent viruses that could potentially be generated during production and the residual helper viruses or wild-type viruses if used in production. Dose definition and dose determination of gene therapy vectors need to be addressed very early during development. Stability of the product needs to be characterized from the very beginning of IMP development, as based on stability data obtained from nonclinical batches and including stability of the product under accelerated or thermal stress conditions. Ex vivo GTPs consist of cells that have been genetically modified either by means of integrating vectors, such as lenti-/retroviral vectors, by using transposase system or by means of direct editing of the cell genome using nucleases. In Switzerland, these products are also defined as CTPs and most of what is described in section 3.4.1.1 will be also applicable to the cellular aspects of ex vivo GTPs. In addition, it is critical to determine the transduction efficiency as percentage of transduced/modified cells, number of integrated transgene copies, expression of therapeutic gene, and biological activity of any genetic modifications, prior to administration of the genetically modified cells to human trial subjects. When viral vectors are used for cell transduction in culture, the absence of replication-competent viruses should be confirmed at the level of the vector and the risk of their generation during the product manufacture and in the final product should be carefully assessed. When exogenously introduced enzymes are used to achieve intended modification, residual expression and activity of these enzymes should be evaluated. Considerations described in EMA guidelines with respect to GTPs and ex  vivo genetically modified cells apply [26, 27].

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As described for CTPs, also GTPs for clinical use are to be manufactured under GMP condition. In Switzerland, vectors carrying transgene for ex  vivo gene therapy are considered to be equivalent to active substances and are expected to be produced under GMP.

3.4.2.2 Nonclinical Considerations The nonclinical evaluation of investigational GTPs aims to collect relevant information with respect to the: (i) biological activity, (ii) biodistribution profile, (iii) potential shedding, and (iv) toxicological effects. This information should allow for an adequate assessment with respect to potential risks the human trial subjects are exposed to after treatment with the gene therapy IMP. The nonclinical evaluations should be conducted with the proposed IMP or with a product with very similar characteristics. Published data with comparable products are considered supportive data; however, they are usually not sufficient on their own to fully support the clinical use of the IMP and can therefore not replace nonclinical studies specifically designed to evaluate the IMP. The nonclinical evaluations should provide adequate information with respect to a safe starting dose, the optimal route of administration, and the dosing schedule. Regarding the starting dose, a “no observed adverse effect level” and ideally a minimal biologically effective level should be determined. An adequate safety margin with respect to the planned clinical starting dose should be established in a relevant animal species. For pivotal toxicological safety studies, clinical grade material should be used and the evaluations should follow the principles described in the ICH [30], EMA [31], or US FDA guidelines [32]. The relevance of animal models (e.g., the choice of the most relevant species or the use of a specific disease model) is a difficult issue, and the choice of the most relevant species and disease model needs careful case-by-case consideration and justification by the applicant. The biological activity evaluation of the GTP under investigation can be performed in  vitro and in  vivo. The actual proof-of-concept is usually performed in  vivo. No extensive studies are required and published data with similar products

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are also acceptable as supportive data. One good study in one good animal species/disease model is usually sufficient as long as the scientific rationale is adequate. The conduct of pharmacodynamics/proof-of-concept studies does not need to be performed according to GLP. Extensive pharmacokinetic analyses to characterize absorption, distribution, metabolism, and excretion are usually not required for GTPs. The focus with respect to pharmacokinetics lies on investigation of the GTP biodistribution profile. Biodistribution studies should be performed according to the ICH S12 guideline [33]. Published data with products similar to the IMP are considered supportive. However, specific nonclinical studies with the IMP in its final formulation are often required, and the dose and route of administration that are planned in the clinical trial should be used for the determination of the biodistribution profile in animals. The biodistribution profile facilitates the definition of GTP risks. As an example, the GTP accumulation in the gonads might point to the risk that the product might integrate into germ cell genome. In this case, germline transmission studies might be required. Regulatory guidance relevant for Switzerland with respect to germline transmission studies can be found on the ICH website (ICH Considerations: General Principles to Address the Risk of Inadvertent Germline Integration of Gene Therapy Vectors [34]). The potential for shedding of a GTP (the dissemination of the product through secretions or excreta of treated humans or animals) should be investigated early in nonclinical evaluations. A specific ICH Considerations paper with respect to shedding studies is available on the ICH website (ICH Considerations: General Principles to Address Virus and Vector Shedding [35]). In addition, there is a specific Swiss guideline published with respect to assessing the risk to humans and the environment [18]. Based on this Swiss guideline, the applicant is asked to classify the proposed clinical trial as: type A clinical trial (no shedding), type B1 clinical trial (transient shedding but no release into the environment) or type B2 (shedding with release into the environment). As with proof-of-concept studies, biodistribution

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and shedding studies generally do not need to be performed according to GLP. Studies that assess toxicity should be conducted using a GTP which is manufactured according to the specifications for the clinical batch. Especially for pivotal toxicity studies, it is recommended to use a clinical-grade product which is manufactured according to GMP. These pivotal nonclinical safety studies are expected to be performed under GLP conditions [29], unless otherwise justified. The route, dose levels, and number of doses should mimic the planned clinical study with adequate safety margins. The choice of relevant species for the toxicological evaluations needs careful case-by-case considerations and justifications by the applicant. The nonclinical safety studies that need to be conducted prior to clinical use will encompass single dose/multiple dose studies with an evaluation of local and systemic toxicity, with endpoints relevant to the respective IMP.  Furthermore, the potential for immunogenicity/immunotoxicity needs to be addressed (especially if multiple dosing with viral vectors is planned or if the therapeutic gene product may pose a risk of inducing AE on the immune system). Tumorigenicity studies may become relevant if retro- and lentiviral vectors are to be used in an in vivo setting. For nonintegrating vectors, tumorigenicity studies may generally not be necessary in the frame of an in vivo gene therapy approach. The potential for reproductive and developmental toxicity needs to be analyzed in case a risk assessment suggests any risks in the patient population. The extent of the nonclinical reproductive and developmental toxicity evaluations will depend on the disease to be treated, the route of IMP administration, the vector and therapeutic gene delivered, the age of female patients, and the potential effects on the reproductive organs due to the treatment. Long-term expression of therapeutic gene products with growth factor activities or effects on the immune system may trigger long-term toxicity studies in animals. These long-term risks have to be appropriately assessed on a case-by-­ case basis by the applicant in order to define the full spectrum of studies for an adequate risk profile of the gene therapy IMP.  Appropriate long-­

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term toxicity studies need to be carried out if replication-competent vectors are used that have the capacity for latency and reactivation (as in the case of herpes viruses). Ex vivo GTPs show specific risks that need to be addressed in in vitro or in vivo settings. Cells transduced with integrating retro- or lentiviral vectors need to be assessed for tumorigenic changes. The number and location of the integration sites need to be determined, and the activation of oncogenes close to the integration sites needs to be investigated. Other risks that should be evaluated are the pathological behavior of transduced cells in vivo. This may be relevant for T-cells transduced with certain T cell receptors (e.g., CAR). The migration, proliferation, distribution, and any pathological changes to specific organs need to be studied in at least one appropriate animal species. The extent of these studies may depend on the existing clinical experience with similar gene therapy IMP.

3.4.2.3 Clinical Considerations The clinical evaluations (FIM, phases I–III) of investigational GTPs aim to determine safety and efficacy. The clinical evaluations have to be performed according to the GCP principles as described in the ICH E6 “Guideline for good Clinical Practice” [10, 12], and the gene therapy IMP needs to be produced according to GMP. Based on the indication, vector type, and clinical experience with similar investigational products and the nonclinical safety data, a clinical risk assessment needs to be submitted to Swissmedic. This assessment should list all possible risks to the study participants and the measures to be taken to minimize the identified, possible and potential risks. In addition, the clinical study needs to be classified according to the Swiss guideline with respect to shedding as explained above under “Nonclinical Considerations.” If possible, the starting dose should be based on relevant nonclinical studies and clinical data with similar IMP. For safety reasons, a staggered approach is usually needed in the frame of FIM studies, where only one study participant is treated at a time and adequately observed for AE before a

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second study participant is treated. The exact manner in which this staggered approach is performed is dependent on the type of GTP and needs to be based on the expected time delay before potential occurrence of identified, possible and potential severe or serious AE. During this time, the volunteer or patient may have to be kept at the hospital for observation and rapid application of predefined measures should AE occur. The extent of clinical monitoring and the need for LTFU studies should be based on the clinical experience with similar products and the nonclinical safety evaluation of the clinical gene therapy IMP. Based on vector type, clinical experience with similar IMP, and findings in nonclinical safety  evaluations, the clinical monitoring plan should take into account potential targets of toxicity and immunotoxicity. For integrating vectors, genome integration sites and the potential for tumorigenicity need to be closely monitored. An LTFU plan is usually required, especially for GTP that tends to be expressed over a long time period. The LTFU can already be part of the clinical protocol or a separate LTFU study can be designed and submitted for approval. Any suspected or serious adverse drug reaction that occurs in the frame of a clinical trial with a gene therapy IMP should be reported to Swissmedic according to ClinO and published checklists on the Swissmedic website [10, 36].

3.4.3 Regulatory Requirements for Cell and Gene Therapy Products for Marketing Authorization The Marketing Authorization of CGTPs requires the submission of a complete eCTD dossier that has to be structured into five modules according to the ICH M4 guideline titled “Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use” [9]. In most cases, Swissmedic is accepting similar Modules 2-5 documentation as accepted by EMA.

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Module 1, which has to be compiled specifically for applications in Switzerland, has to contain the actual application form, manufacturer information and GMP certificates, information regarding the state of any authorizations in other countries (submitted, approved, rejected, and withdrawn), information relating to experts (including curriculum vitae) and risk assessment of the environmental data, pharmacovigilance and risk management plans, labeling information, patient information and professional information. Furthermore, for the life cycle management of marketing authorizations, the Swiss Variations and Extensions guideline applies.

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3.4.5 The Role of Real-World Evidence in the Regulation of Cell and Gene Therapy Products: The Clinical Perspective

Cell and gene therapies typically target rare diseases, thus the required sample sizes for a traditional clinical study that is suited for an approval may not be reached. In addition, devastating genetic diseases with onset in early infancy (such as spinal muscular atrophy), or advanced cancer after failure of multiple lines of prior therapy (such as refractory/relapsing aggressive lymphoma) may be targeted. In many cases, adequately powered randomized controlled trials (RCTs) for cell and gene therapies are challeng3.4.4 A Risk-Based Approach ing due to ethical and methodological constraints. in the Regulation of Cell However, RCT remains the gold standard for and Gene Therapy Products regulatory decision-making in view of a marketing authorization and should be conducted whenIn order to address the potential risks associated ever feasible. Nonetheless, in face of the extent of with the use of CGTPs, a flexible approach must “orphanisation” in the area of cell and gene therbe taken and risks must be assessed on a case-by-­ apy, the use of real-world data (RWD)/real-world case basis. The risk-based approach by evidence (RWE) is a particularly promising aveSwissmedic is aligned with the EMA “Guideline nue, when the conduct of an adequately powered on the risk-based approach according to annex I, RCT is infeasible or unethical. part IV of Directive 2001/83/EC applied to As data from clinical trials may be limited at Advanced Therapy Medicinal Products” [37]. the stage of approval, important RWE with Swissmedic assesses the potential risk of respect to (long-term) efficacy and safety may be the product depending on its nature. Potential gathered only at the post-marketing stage, for unfavorable effects that can be attributed to instance through pre-defined observational studthe clinical use of  an ATMP are identified. ies using data from dedicated patient registries. A Aspects that should be taken into account for thorough LTFU of patients who were administhe preclinical, clinical, and quality assess- tered cell and gene therapies is of pre-eminent ment include, but are not limited to, the viral importance, as long-term outcomes and risks vector (e.g., integrating, nonintegrating, repli- associated with these novel therapeutic concepts, cation-incompetent or -competent), syntheti- which may incorporate the modification of genes cally manufactured or genetically modified, in targeted individuals (expected and unextherapeutic insert/transgene, growth factors, pected), are still poorly understood or unknown. potential risk of materials and reagents used, RWD carry several methodological limitaroute of administration, and immunogenicity. tions. These include the problem of obtaining From a clinical point of view, in addition to complete source data and the risk of selection the intended indication, clinically important bias. Endpoints used in clinical trials may not be endpoints, pharmacodynamic effects, pharma- available in RWD.  Statistical methods to adjust cokinetic properties, persistence in the body, for, e.g., unbalanced baseline characteristics, required pretreatment, and additional proce- often rely upon subjective assumptions with dure should be considered. respect to the relevant factors. Unknown con-

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founding factors may compromise the interpretability of RWE.  In addition, there is a risk of unintentional manipulation of the outcome by repeatedly analyzing (partially) the same RWD. A number of regulatory initiatives have been launched internationally with the aim to address the challenges inherent to the use of RWE for regulatory purposes, which are particularly relevant for the regulation of cell and gene therapies (HMA/EMA [38], US FDA [39], Health Canada [40]). Swissmedic published its current position [41], which is mostly in line with mentioned international initiatives. As a result of the international workshop on RWE in June 2022, organized by the International Coalition of Medicines Regulatory Authorities, a consensus statement was published [42] and the need to involve ICH emerged to foster the international harmonization of ongoing activities and development of best practices. These rapidly evolving developments with respect to the regulatory use of RWD/RWE will lead to the optimization of the quality of tailor-­made and fit-for-purpose RWD, which establish the evidentiary level needed for their contribution to decision-making for the approval and post-marketing surveillance of cell and gene therapies.

3.5 The HTA System in Switzerland In 2015, the federal authorities launched a health technology assessment (HTA) program to evaluate services currently reimbursed under compulsory health insurance. The HTA program, under the responsibility of the FOPH, focuses particularly on the re-evaluation of services, which may not meet the relevant criteria. In addition, the HTA program evaluates services, which are not currently reimbursable. As part of the HTA program, topics are selected each year for which external contractors prepare HTA reports in a systematic process. Cooperation with national and international HTA networks ensures that the methods used are continuously adapted to the latest standards [43]. These principles and methods of HTA also apply to ATMPs. For ATMPs, the RWE collec-

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tion is essential. Post-marketing surveillance is usually a post-approval requirement. The HTA reports are published on the HTA project page. Regarding ATMPs, CAR-T cell therapies are currently processed [44].

3.6 Conclusion and Outlooks During the past 10 years, the cell and gene therapy field has developed substantially. In Switzerland, approximately 15 clinical trials for new CGTPs are submitted and approved each year covering all clinical phases. Typically, these IMPs target a wide range of indications, such as malignancies, single gene defects, central nervous system disorders, metabolic disease, and regenerative medicines such as arthritis. Currently ongoing clinical studies in the field of CTPs include mainly AIMPs such as tumor-infiltrating lymphocytes, dendritic cell-based cancer vaccines, autologous muscular or other progenitor cells, allogenic stem cells differentiated into specific cell types, tissue-engineered products such as skin transplants or autologous chondrocytes for cartilage repair. GTPs in clinical development mainly cover adeno-associated and adenoviral vectors, DNA plasmid-based vaccines, recombinant replication-competent viruses as oncolytic therapeutics, CAR T-cells for hematologic malignancies, encapsulated allogenic genetically modified cells, or genetically modified bacterial cells in cancer applications. Product types such as CAR T-cell products and AAV-based GTPs have successfully entered the market. New product types such as mRNA products and gene editing products and further developed CAR T-cell products (e.g., allogeneic CAR T-cells, combining mRNA with CAR T-cell technology) are likely to hit the market in near future. The potentially long pipeline of products and the global nature of its development is challenging and can only be regulated by harmonizing the requirements among the Regulatory Authorities in the different regions. The newly created Swissmedic ATMP Division is closely working with developers offering support and advice from early stages of

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development. A flexible, risk-based approach is taken case-by-case for each product. In order to further support the development and marketing of CGTPs, harmonization is fostered by close collaboration with other Regulatory Authorities through Memorandums of Understanding and Confidentiality Commitments and taking actively part in international organizations such as ICH, Ph. Eur., IPRP, and the Access Consortium. Acknowledgments The authors thank Philippe Girard, Julia Djonova, Constanze Fritzsche, Françoise Teuscher, Petra Minder, Regula Johner, and Gabriela Zenhäusern for critical reading of the manuscript. Disclaimer This document is for information only and does not represent an official Swissmedic position and is not legally binding. Even though it highlights the most important aspects with respect to the regulation of cell and gene therapy in Switzerland, it does not provide a complete set of information.

Annex  he Definition of a Transplant T Product (TpP) The Transplantation Act defines CTPs as transplant products (TpPs) in Switzerland. TpPs are products manufactured from human or animal organs, tissues, or cells applying a standardized manufacturing process. TpPs are either substantially manipulated or are not designed to fulfill the same function in the recipient as in the donor (nonhomolgous use). The term “substantial manipulation” is defined in the Transplantation Ordinance, article 2 as: (i) expansion of cells in culture, (ii) genetic modification of cells, or (iii) differentiation or activation of cells. In Annex 1 of the Swissmedic information sheet regarding “Requirements relating to the authorization documentation for transplant products (TP), gene therapy medicinal products (GT) and medicinal products consisting of or contain-

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ing genetically modified organisms (GMO)” [45], the following table is published showing a nonexhaustive list of manipulations that are not considered “substantial manipulations” (in accordance with Annex 1 of the EU Regulation 1394/2007 of 13 November 2007): A.1.Type of Preparation, conservation transplant (examples) Organs Kidney, heart, liver, etc. Musculoskeletal tissue Bones: major Untreated deep frozen, freeze transplants, femoral dried, sterilized by irradiation, head aseptically washed (after bone marrow depletion) Osteochondral Untreated deep frozen transplants and meniscus, cryopreserved, menisci sterilized by irradiation, freeze dried Fascia lata or other Untreated deep frozen, freeze fascia dried, sterilized, cryopreserved, aseptically washed Ligaments and Untreated deep frozen, tendons aseptically washed, cryopreserved, sterilized by irradiation, freeze dried Cartilage Untreated, deep frozen, sterilized, deep frozen washed, cryopreserved Skin Untreated fresh, cryopreserved, glycerol con- served, glycerol conserved sterilized, air dried/ lyophilized, air dried/ lyophilized sterilized Amniotic Untreated fresh, cryopreserved, membrane glycerol con- served, glycerol conserved sterilized, air dried/ lyophilized, air dried/ lyophilized sterilized Cardiovascular tissue Heart valves, heart Untreated fresh, cryopreserved vessels, heart arteries, heart veins Pericardium Untreated fresh, cryopreserved, sterilized by irradiation Eye tissue Cornea Untreated fresh, stored in culture medium, stored in Optisol Sclera Deep frozen

3  The Regulation of Cell Therapy and Gene Therapy Products in Switzerland

References 1. Federal Act of 15 December 2000 on Medicinal Products and Medical Devices (Therapeutic Products Act, TPA). SR812.21. http://www.admin.ch/ch/e/rs/ c812_21.html. 2. Urnov F.D., Miller J.C. et al (2005) Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature 435:646–651. 3. Doudna J., Charpentier E. (2014) The new frontier of genome engineering with CRISPR-Cas9. Science 346:1258096-1–1258096-9. 4. Federal Constitution of the Swiss Confederation of April 18, 1999 (Status as of 13 February 2022). https://www.fedlex.admin.ch/eli/cc/1999/404/en. 5. Ordinance of 9 May 2012 (Status as of 26 May 2022) on Handling Organisms in Contained Systems (Containment Ordinance). SR814.912. https://www. fedlex.admin.ch/eli/cc/2012/329/en. 6. Ordinance of 10 September 2008 (Status as of 1 January 2022) on the Handling of Organisms in the environment (Release Ordinance). SR814.911. https://www.fedlex.admin.ch/eli/cc/2008/614/en. 7. Federal Act of 8 October 2004 (Status as of 1 February 2021) on the Transplantation of Organs, Tissues and Cells (Transplantation Act). SR810.21. https://www. fedlex.admin.ch/eli/cc/2007/279/en. 8. Federal Act of 21 March 2003 (Status as of 1 January 2022) on Non-Human Gene Technology (Gene Technology Act, GTA). SR814.91. http://www. admin.ch/opc/en/classified-­compilation/19996136/ index.html. 9. ICH Harmonised Tripartite Guideline. ICH common technical document for the registration of pharmaceuticals for human use M4. https://ich.org/page/ctd. 10. Ordinance of 20 September 2013 (Status as of 26 May 2022) on Clinical Trials with the Exception of Clinical Trials of Medical Devices. SR810.305. https://www. fedlex.admin.ch/eli/cc/2013/643/en. 11. Federal Act of 30 September 2011 (Status as of 1 December 2022) on Research involving Human Beings (Human Research Act, HRA). SR810.30. http://www.admin.ch/ch/e/rs/c810_30.html. 12. ICH Harmonised Guideline. Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). https://database.ich.org/sites/default/files/ E6_R2_Addendum.pdf. 13. https://health.ec.europa.eu/system/files/2017­11/2017_11_22_guidelines_gmp_for_atmps_0.pdf. 14. https://picscheme.org/docview/4590. 15. U.S.  Food and Drug Administration. Cellular & gene therapy guidances. https://www.fda.gov/ vaccines-­b lood-­b iologics/biologics-­g uidances/ cellular-­gene-­therapy-­guidances. 16. European Medicines Agency. Advanced therapies scientific guidelines. http://www.ema.europa.eu/ema/ index.jsp?curl=pages/regulation/general/general_ content_000298.jsp&mid=WC0b01ac05800862bd.

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17. I-315.AA.01-A02e Information Sheet Requirements for documents to be submitted for a clinical trial with transplant products (TpP), gene therapy (GT) or with GMO. https://www.swissmedic.ch/swissmedic/en/ home/services/documents/clinical-­trials.html. 18. I-315.AA.01-A11e Guidance document Gene Therapy/GMO Environmental Data. https://www. swissmedic.ch/swissmedic/en/home/services/documents/clinical-­trials.html. 19. https://www.swissmedic.ch/dam/swissmedic/en/ dokumente/zulassung/zl_hmv_iv/zl000_00_014d_ wlfristenzulassungsgesuche.pdf.download.pdf/ zl000_00_014e_wltimelimitsforauthorizationapplications.pdf. 20. Ordinance of 16 March 2007 (Status as of 1 December 2022) on the Transplantation of Human Organs, Tissues and Cells (only in German). SR810.211. https://www.fedlex.admin.ch/eli/cc/2007/280/de. 21. Ordinance of 14 November 2018 (Status as of 1 July 2022) on Licensing in the Medicinal Products Sector. SR812.212.1. https://www.fedlex.admin.ch/eli/ cc/2018/786/en. 22. 5.2.3 Cell substrates for the production of vaccines for human use. https://pheur.edqm.eu/home. 23. ICH Harmonised Tripartite Guideline. Derivation and characterization of cell substrates used for production of biotechnological/biological products Q5D. https://database.ich.org/sites/default/files/Q5D%20 Guideline.pdf. 24. ICH Harmonised Tripartite Guideline. Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin Q5A(R1). https://database.ich.org/sites/default/files/Q5A%28R1%29%20 Guideline_0.pdf. 25. https://www.swissmedic.ch/dam/swissmedic/en/ dokumente/zulassung/zl_hmv_iv/zl000_00_031d_ fostoffetierischenundhumanenursprungs.docx. download.docx/zl000_00_031e_fosubstancesofanimalorhumanorigin.docx. 26. h t t p s : / / w w w. e m a . e u r o p a . e u / e n / d o c u m e n t s / scientific-­guideline/guideline-­quality-­non-­clinical-­ clinical-­a spects-­m edicinal-­p roducts-­c ontaining-­ genetically-­modified_en-­0.pdf. 27. https://www.ema.europa.eu/en/documents/scientific-­ guideline/guideline-­h uman-­c ell-­b ased-­m edicinal-­ products_en.pdf. 28. https://www.swissmedic.ch/dam/swissmedic/en/ dokumente/bewilligungen/i-­314/i-­314_aa_01-­a03dfo rmularmeldungunerwuenschtearzneimittelwirkungt. docx.download.docx/i-­314_aa_01-­a03eformreportofa nadversedrugreactiontoatppgtgmo.docx. 29. Ordinance of 18 May 2005 on good laboratory practice (OGLP). SR813.112.1. http://www.admin.ch/ ch/e/rs/8/813.112.1.en.pdf. 30. ICH Harmonised Tripartite Guideline. Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals M3(R2). https://database.ich.org/sites/ default/files/M3_R2__Guideline.pdf.

58 31. European Medicines Agency. Guideline on the non-­ clinical studies required before first clinical use of gene therapy medicinal products. EMEA/CHMP/ GTWP/125459/2006. http://www.ema.europa.eu/ docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003743.pdf. 32. Guidance for industry. Preclinical assessment of investigational cellular and gene therapy products. http:// www.fda.gov/downloads/BiologicsBloodVaccines/ GuidanceComplianceRegulatoryInformation/ Guidances/CellularandGeneTherapy/UCM376521.pdf. 33. https://database.ich.org/sites/default/files/ICH_S12_ Step2_DraftGuideline_2021_0603.pdf. 34. ICH Considerations (2006). General principles to address the risk of inadvertent germline integration of gene therapy vectors. https://admin.ich.org/sites/ default/files/2019-­04/ICH_Considerations_General_ Principles_Risk_of_IGI_GT_Vectors.pdf. 35. ICH Considerations (2009). General principles to address virus and vector shedding. https://admin.ich. org/sites/default/files/2019-­04/ICH_Considerations_ Viral-­Vector_Shedding_.pdf. 36. I-315.AA.03-A06e Form Adverse reaction Report TpP/ GT/GMO. https://www.swissmedic.ch/swissmedic/en/ home/services/documents/clinical-­trials.html. 37. Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to Advanced therapy medicinal products: https://www. ema.europa.eu/en/documents/scientific-­g uideline/ guideline-­r isk-­b ased-­a pproach-­a ccording-­a nnex-­

P. K. Bukovac et al. i-­p art-­iv-­d irective-­2 001/83/ec-­a pplied-­a dvanced-­ therapy-­medicinal-­products_en.pdf. 38. h t t p s : / / w w w. e m a . e u r o p a . e u / d o c u m e n t s / work-­p rogramme/workplan-­2 022-­2 025-­h ma/ ema-­joint-­big-­data-steering-­group_en.pdf. 39. https://www.fda.gov/media/120060/download. 40. https://www.canada.ca/en/health-­c anada/services/ drugs-­h ealth-­p roducts/drug-­p roducts/announcements/optimizing-­real-­world-­evidence-­regulatory-­ decisions.html. 41. https://www.swissmedic.ch/swissmedic/en/home/ news/mitteilungen/positionspapier-­verwendung-­real-­ world-­evidence.html. 42. https://www.icmra.info/drupal/sites/default/ files/2022-­07/icmra_statement_on_rwe.pdf. 43. https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-­ leistungen-­tarife/hta.html. 44. https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-­ leistungen-­tarife/hta/hta-­projekte.html. 45. I-313.AA.01-A15e Requirements relating to the authorization documentation for transplant products (TP), gene therapy medicinal products (GT) and medicinal products consisting of or containing genetically modified organisms (GMO). https://www.swissmedic.ch/swissmedic/en/home/services/documents/ transplant-­p roducts/instructions-­a nd-­i nformation-­ sheets.html.

4

European Pharmacopoeia’s Approach to Cell and Gene Therapy: Focus on How Gene Therapy Texts Are Evolving Olga Kolaj-Robin and Marie-Thérèse Duffour

Abstract

The European Pharmacopoeia (Ph. Eur.) constitutes single recognised common standard for the quality control of medicines in Europe, which is also applied in many countries worldwide. In 2000, the European Pharmacopoeia Commission (EPC), the decision-making body of the Ph. Eur., set out to elaborate a text on gene therapy products. This resulted in the publication of the widely used and much appreciated general chapter Gene transfer medicinal products for human use (5.14) in 2006, at a time when no gene therapy medicinal products were yet

O. Kolaj-Robin (*) European Pharmacopoeia Department, European Directorate for the Quality of Medicines & HealthCare (EDQM), Council of Europe, Strasbourg, France e-mail: [email protected] M.-T. Duffour Chair of the Gene Therapy Working Party of the European Pharmacopoeia, Saint-Denis Cedex, France e-mail: [email protected]

approved on the European market. As a general chapter, it is not legally binding, but it reflects the consensus of the European authorities. Now, more than two decades after the first initiative in the gene therapy field and with several gene therapy medicinal products launched in Europe, the EPC proposes a modernised approach and the creation of a general monograph, i.e. a legally binding standard. In addition to general requirements for gene therapy medicinal products, it is also envisaged that this general monograph will outline specific criteria for the classes of products already on the market, i.e. genetically modified human autologous cells, adeno-associated virus vectors for human use and recombinant oncolytic herpes simplex viruses for human use. It is also proposed to create a new general chapter, Additional information on gene therapy medicinal products for human use (5.34), comprising the remaining sections of Chap. 5.14, as well as a newly elaborated section on genetically modified bacterial cells. Keywords

European pharmacopoeia · Gene therapy medicinal products · Monographs · Public standards

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 M. C. Galli (ed.), Regulatory Aspects of Gene Therapy and Cell Therapy Products, Advances in Experimental Medicine and Biology 1430, https://doi.org/10.1007/978-3-031-34567-8_4

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Abbreviations AAV CAR-T EC EDQM

O. Kolaj-Robin and M.-T. Duffour

between Chap. 5.14 and general monograph 3186 and the requirements prescribed in the latter are presented.

Adeno-Associated Virus Chimeric Antigen Receptor T European Commission European Directorate for the Quality 4.2 European Pharmacopoeia of Medicines & HealthCare and Its Role in the Legal EMA European Medicines Agency Framework EPC European Pharmacopoeia Commission The Ph. Eur. is a collection of recognised comEU European Union mon standards for the quality control of mediGMP Good Manufacturing Practice cines that was created in 1964 with the signature GTP WP Gene Therapy Products Working of the Council of Europe Convention on the Party Elaboration of a European Pharmacopoeia [1] by ITR Inverted Terminal Repeats the first six countries. There are currently 40 sigLAL Limulus Amoebocyte Lysate natories, including the European Union (EU), Ph. Eur. European Pharmacopoeia which acceded to the Convention via an addircAAV Replication-competent Adeno-­ tional Protocol [2] in force since 1992. The conAssociated Virus tracting parties of the Convention undertake to RT-qPCR Reverse Transcription Quantitative ensure that the Ph. Eur. monographs become the Polymerase Chain Reaction official standards applicable within their country. WHO World Health Organization The mandatory character of Ph. Eur. monographs when requesting marketing authorisation is also upheld by EU Directive 2001/83/EC [3], as 4.1 Introduction amended, for medicines for human use and by Regulation (EU) 2019/6 [4] for veterinary medicMore than two decades after entering the gene inal products. All producers of medicinal prodtherapy field, the European Pharmacopoeia (Ph. ucts and/or substances for pharmaceutical use Eur.) Commission (EPC) has recently proposed must therefore apply and comply with the Ph. the creation of a general monograph, Gene ther- Eur. monographs in order to market their prodapy medicinal products for human use (3186), ucts in any of the signatory states of the and a new general chapter, Additional informa- Convention—currently 39 member states and the tion on gene therapy medicinal products for EU. By providing these quality standards in a human use (5.34), that, in time, should replace single reference, the Ph. Eur. plays a major role in the well-known general chapter, Gene transfer ensuring the quality of medicines. medicinal products for human use (5.14), pubThe Ph. Eur. is applied in more than 130 counlished in 2006. tries worldwide and hence it continues to fulfil its The present chapter provides essential infor- mission to promote public health and access to mation on the Ph. Eur. and classes of texts therein, good quality medicines both within and beyond as well as an overview of those of particular use Europe. In addition to the contracting parties to in the field of cell and gene therapy before focus- the Convention, whose delegations make up the ing on the newly proposed approach on gene EPC, there are 32 Observers to the Ph. Eur.— therapy medicinal products. The rationale for the including the World Health Organization content of the new general monograph and gen- (WHO)—who can contribute to the scientific eral chapter and the layers of requirements of work and benefit from European experience in general monograph 3186 are described in detail. this area. Finally, the evolution of the section on The EPC is the decision-making body of the ­Adeno-­associated virus vectors for human use Ph. Eur. and is responsible for elaborating and

4  European Pharmacopoeia’s Approach to Cell and Gene Therapy: Focus on How Gene Therapy Texts…

maintaining its content, relying on a vast network of nearly 900 experts representing industry, regulatory authorities and academia who are members of the Ph. Eur.’s 60 groups of experts and working parties, including the Gene Therapy Products Working Party (GTP WP). All the texts published in the Ph. Eur. are adopted by the EPC which meets three times a year and technical decisions are taken by consensus. The adopted texts, revised and new, are published in a supplement about 6  months after each Commission session, and enter into force about 6 months after their publication, giving users a suitable interval in which to achieve compliance with their requirements. It is important to note that every text included in the Ph. Eur. undergoes public consultation in Pharmeuropa, the Ph. Eur.’s freely available online consultation forum, before it is officially published and implemented. It is essential that Ph. Eur. users review the published texts during the consultation phase, carry out experimental verifications where relevant and, if necessary, provide their comments. This is done either through their national pharmacopoeia authority, if they belong to one of the signatory states of the Convention, or directly to the Council of Europe’s European Directorate for the Quality of Medicines & HealthCare (EDQM) if comments originate from users outside Europe. All comments are carefully reviewed and, where necessary, appropriate actions are taken before the text is finalised. The Ph. Eur. is made up of several kinds of texts. Monographs, either individual or general, comprise legally binding requirements. Individual monographs cover substances for pharmaceutical use and medicinal products. General monographs are overarching texts describing quality requirements that are common to classes of substances (e.g. Substances for pharmaceutical use (2034) or Products of fermentation (1468)), medicinal products (e.g., Pharmaceutical preparations (2619) or Products of recombinant DNA technology (0784)), including dosage form monographs (e.g., Parenteral preparations (0520)). General monographs are applicable to all substances for

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pharmaceutical use and medicinal products defined in their scope, irrespective of whether there is an individual monograph for that substance or product in the Ph. Eur. If this is the case, the requirements of applicable general monographs are usually not repeated in individual monographs. As individual and general monographs are complementary, it is essential to ascertain that requirements outlined in both texts are fulfilled for a given substance or medicinal product. Notably, compliance with the requirements stated in the monograph does not imply performance of all the tests described in the monograph before release. The manufacturer may obtain assurance that the subject of the monograph is of Ph. Eur. quality on the basis of its design, together with the control strategy applied and data derived, for example, from validation studies of the manufacturing process. Ph. Eur. monographs reflect the quality of medicinal products that have been approved for the European market and the substances they contain and describe validated analytical procedures. In addition to legally binding monographs, the Ph. Eur. contains general chapters. General chapters are not mandatory but become a part of the mandatory standard when referred to in a monograph (either individual or general). They provide guidance on certain aspects or describe general methods and can be used even if not referred to in a monograph. The 11th Edition of the Ph. Eur., including Supplement 11.1 published in October 2022, contains 2474 monographs, 387 general texts and almost 2900 descriptions of reagents. With the mechanism defined in the legislation in place, the texts of the Ph. Eur. are regularly updated to keep pace with the regulatory requirements of competent authorities in the public health sector, with technological and scientific advances and with industrial constraints. At the time of writing, there are nearly 900 items on the Ph. Eur. Work Programme, of which almost two-thirds are revisions of existing texts.

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Fig. 4.1  Portfolio of Ph. Eur. texts particularly relevant in the cell and gene therapy field as per 11th Edition

4.3 Overview of the Ph. Eur. Texts on Cell and Gene Therapy Although many other Ph. Eur. texts are applicable, Fig. 4.1 summarises those of particular relevance in the field of cell and gene therapy. The two general chapters Gene transfer medicinal products for human use (5.14) [5] (see Sect. 4.4.1) and Raw materials of biological origin for the production of cell-based and gene therapy medicinal products (5.2.12) [6] can be considered as overarching texts. The latter was elaborated following stakeholder requests for guidance in this area with the aim of identifying the critical quality attributes of raw materials, harmonising variable practices, encouraging manufacturers to provide raw materials of consistent, predefined quality and helping users to manage batch-to-batch variability of raw materials. Published for the first time in the 9th Edition of the Ph. Eur. in July 2016, the resulting chapter provides general considerations on origin, production and quality for any raw material of biological origin used for the production of cell-based and gene therapy medicinal products.

It describes detailed provisions for categories of the most commonly used raw materials: sera and serum replacements, proteins produced by recombinant DNA technology and proteins extracted from biological material. It also contains a short section on vectors, in cases where these are used as raw rather than starting materials and prescribes application of the principles described in the chapter itself as well as in Chap. 5.14. Referring back to Fig.  4.1, the most recent general chapter covering cell-related methodologies, Quantification and characterisation of host-­ cell DNA (2.6.35), was published in the 10th Edition of the Ph. Eur. in July 2019, while the general chapters on Flow cytometry (2.7.24), Colony-forming cell assay for human haematopoietic progenitor cells (2.7.28) and Nucleated cell count and viability (2.7.29) are currently undergoing revision. The Ph. Eur. also contains a portfolio of general chapters covering aspects of microbiological and viral safety that can apply to cell and gene therapy products. Among them, Microbiological examination of cell-based preparations (2.6.27) is specific to cell-based products, including cell-based and gene therapy

4  European Pharmacopoeia’s Approach to Cell and Gene Therapy: Focus on How Gene Therapy Texts…

medicinal products. It is currently under revision, together with Monocyte activation test (2.6.30) and Guidelines for using the test for bacterial endotoxins (5.1.10). In this package, the general chapter Test for bacterial endotoxins using recombinant factor C (2.6.32), published in Supplement 10.3 and offering an alternative to classic limulus amoebocyte lysate (LAL)-based methods for bacterial endotoxin testing described in Chap. 2.6.14, deserves a special mention. Finally, the new general chapter Microbiological examination of human tissues (2.6.39) published in the 11th Edition of the Ph. Eur. in July 2022 provides recommendations for the selection of analytical procedures used to assess the microbiological quality of human tissue, with a detailed example of a microbiological testing strategy for cornea. To date, the Ph. Eur. contains two individual monographs with relevance to the field of cell and gene therapy: Bovine serum (2262) and Human haematopoietic stem cells (2323). However, following the newly adopted approach described below (see Sect. 4.4.2), a new general monograph on Gene therapy medicinal products for human use (3186) is currently under elaboration. It is envisaged that it will be accompanied by a general chapter to be entitled Additional information on gene therapy medicinal products for human use (5.34). A separate overarching general chapter on Cell-based preparations (5.32) is also under elaboration.

4.4 Focus on Ph. Eur. Gene Therapy Texts 4.4.1 History of the Ph. Eur. General Chapter Gene Transfer Medicinal Products for Human Use (5.14) The decision to elaborate a text on gene therapy products was taken by the EPC in 2000 and, after the period of drafting and consultation, the general chapter Gene transfer medicinal products for human use (5.14) was adopted and published in Supplement 5.6  in July 2006. The title of the

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chapter reflected the European Medicines Agency (EMA) Note for guidance on the quality, preclinical and clinical aspects of gene transfer medicinal products [7] available at the time, but also included preventive and diagnostic applications. With the subsequent publication of EC Directive 2009/120 [8], which defines gene therapy medicinal products and clearly excludes vaccines against infectious diseases from them, the need to align Chap. 5.14 has been taken into account as part of the ongoing work described below. The original general chapter contained two short sections on recombinant vectors and genetically modified cells, together with four more detailed ones on (i) plasmid vectors for human use, (ii) bacterial cells used for manufacture of plasmid vectors for human use, (iii) adenovirus vectors for human use and (iv) poxvirus vectors for human use. A revised version of the chapter, including two additional sections on (v) retroviridae-­derived vectors for human use and (vi) adeno-associated virus (AAV) vectors for human use was made available three years later in Ph. Eur. Supplement 6.6. This chapter, still applicable now, provides a framework of recommendations on the production and control of gene therapy medicinal products. Each section describes in detail its scope and, where relevant, construct design, key aspects of production, including recommendations for starting materials, and a list of tests applicable at each stage of production. It must be stressed that the chapter was first elaborated and revised at a time when no gene therapy products had yet been approved on the European market. This, together with the rapid development of the field, meant that it was essential for the chapter to offer substantial built-in flexibility. As a result, Gene transfer medicinal products for human use (5.14) does not contain numerical limits and provides examples of suitable techniques that can be applied for each test at each production stage. In addition, the introductory part of the chapter clearly states that alternative methods for production and control that are acceptable to the competent authorities are not excluded. While Chap. 5.14 is not legally binding, it reflects the consensus of the authori-

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ties within European Ph. Eur. member states. Although it was designed to be applicable to approved products, the need for application of part or all of the texts to products used during clinical trials is decided by the competent authority.

4.4.2 Conversion to Two Texts: A General Monograph and a General Chapter Since the approval of Glybera in 2012 (later withdrawn from the European market in 2017), several gene therapy medicinal products based on AAV vectors, recombinant oncolytic virus and autologous genetically modified cells, including chimeric antigen receptor T (CAR-T) cells, have been approved for the European market [9]. In response to the booming field, the EPC reinstated, in 2018, the Gene Therapy Products Working Party (GTP WP), which had been inactive for a decade since the revision of Chap. 5.14. By mid-2022, 13 gene therapy medicinal products had been granted a marketing authorisation in Europe, with several others still in the pipeline [10]. It is also highly likely that the ever-­ increasing portfolio of ongoing clinical trials—over 1900 worldwide from 2010 to 2020 [11]—will result in even more of these medicinal products being launched on the European market. This context prompted the proposal for the evolution of the gene therapy texts in the Ph. Eur. The creation of a legally binding standard outlining general requirements for gene therapy medicinal products, in particular covering the products approved on the European market, was considered necessary. However, owing to the diversity of these products and the dynamic development in the field, it was considered that sections covering products that have not yet been approved in Europe should not become part of a legally binding document. Following this approach, in November 2020, the EPC decided to elaborate a general monograph, Gene therapy medicinal products for human use (3186). In addition to the general requirements, the intention is for this monograph to contain

O. Kolaj-Robin and M.-T. Duffour

three detailed sections describing specific requirements for classes of products approved on the European market: two newly elaborated sections covering Genetically modified human autologous cells and Recombinant oncolytic herpes simplex virus for human use and the revised section on Adeno-­associated virus vectors for human use originating from Chap. 5.14. In order to clearly mark the change in approach, it was decided to transfer the remaining sections of Chap. 5.14 to a new general chapter Additional information on gene therapy medicinal products for human use (5.34). Three sections, i.e. Bacterial cells used for the manufacture of plasmid vectors for human use, Adenovirus vectors for human use and Poxvirus vectors for human use would be directly reproduced in the new general chapter. A further section, Plasmid vectors for human use, would be modified to include a test for mycoplasmas in the final lot when materials of biological origin are used during production and its content would no longer apply to plasmids used for genetic modification of autologous, allogeneic, xenogeneic or bacterial cells. The last two sections in Chap. 5.34 are a revised Retroviridae-derived vectors for human use section from Chap. 5.14 and a new section on Genetically modified bacterial cells for human use. This new approach is summarised in Fig.  4.2. Whereas in Chap. 5.14 genetically modified bacterial cells were covered under genetically modified cells, in the new approach genetically modified micro-organisms are classified under recombinant vectors together with viral vectors, oncolytic viruses and nucleic acid vectors, in order to align with the European definitions [8]. Both general monograph 3186 [12] and general Chap. 5.34 [13] were published in Pharmeuropa 34.3 in July 2022 for public consultation. At the time of writing, commenting on those texts, as well as on the general chapter on raw materials (5.2.12) published in parallel to introduce minor changes triggered by the proposed approach, is ongoing. It is acknowledged that some aspects of the sections reproduced directly from Chap. 5.14 are not yet aligned with the new or already amended sections. For example,

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Fig. 4.2  Summary of the new Ph. Eur. approach for texts on gene therapy medicinal products

Chap. 5.14 contains numerous aspects referring to Good Manufacturing Practice (GMP) owing to the fact that neither the Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products [14] nor the general chapter Raw materials of biological origin for the production of cell-based and gene therapy medicinal products (5.2.12) were available when it was initially drafted. These have not been carried over into the new and revised sections and alignment of these approaches is envisaged in a separate revision cycle, which is currently ongoing. Upon finalisation of the texts according to the proposed approach by the EPC, the current Chap. 5.14 will become redundant and its suppression from the Ph. Eur. is anticipated.

4.4.3 General Monograph 3186— Proposed Requirements The requirements outlined in the proposed general monograph Gene therapy medicinal products for human use (3186) are organised in a top-down manner (Fig.  4.3). The first layer of requirements applies to all gene therapy medicinal products and comprises general provisions

for their production. These cover the substances used in production, including starting materials and raw materials. For the latter, reference is made to general Chap. 5.2.12. Raw materials of biological origin for the production of cell-based and gene therapy medicinal products, which was not yet available when Chap. 5.14 was published. Referencing it in a general monograph renders Chap. 5.2.12 legally binding for commercial gene therapy medicinal products. However, since the criticality of a given raw material might differ depending on the individual product, additional flexibility was introduced for this requirement with the addition of the phrase ‘unless otherwise justified and authorised’. This is in line with the requirement to consider 5.2.12 ‘as far as possible’ included in the EMA’s Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products [14]. The requirements for substances used in production, in addition to the avoidance of antibiotics described in Chap. 5.14, now also strictly exclude the use of β-lactam antibiotics and streptomycin, in line with the EMA Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products [15]. Provisions are also made for viral safety, transmissible spongiform encepha-

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Fig. 4.3  Cascade of requirements in the general monograph gene therapy medicinal products for human use (3186)

lopathies and containers via references to the relevant Ph. Eur. general chapters. As per pharmacopoeial convention, the recommendations of the general chapters cited become part of the monograph and thus legally binding. The addition of a reference to relevant EU or other applicable regulations for labelling in the general provisions of the proposed monograph 3186 led to the deletion of current considerations on labelling from the individual sections of the monograph, as well as from Chap. 5.34. Subsequently, the monograph describes a second layer of requirements applicable to all recombinant vectors or to genetically modified cells, in addition to those described above. The general requirements on recombinant vectors include general provisions for production, which emphasise the importance of genetic/ phenotypic stability for the production system— a new requirement compared to Chap. 5.14—and for the recombinant vector. For substrates used in the manufacture of recombinant vectors, reference is made to relevant considerations of the general chapters Chicken flocks free from specified pathogens for the production and quality control of vaccines (5.2.2) and Cell substrates for the production of vaccines for human use (5.2.3). The prescriptions of Bacterial cells used for the manufacture of plasmid vectors for human use in

the envisaged general Chap. 5.34 are also made mandatory, unless otherwise justified and authorised, for production of this specific class of vectors. The general requirements on recombinant vectors for human use contain a list of controls for the purified harvest and the final lot. These include safety tests (bacterial endotoxins, bioburden and sterility) and tests that are common to all recombinant vectors (identification, concentration, impurities and potency). The information is general, thus providing flexibility, since how to perform these tests will depend on the type of recombinant vector. The section on general requirements on genetically modified cells provides more detailed information than Chap. 5.14 on the testing expected for vectors used for the genetic modification of cells. They include identification, concentration, process and product-related impurities, sterility and endotoxins. The list of controls for the final lot of genetically modified cells is similar to Chap. 5.14, with the addition of tests for appearance, cell population purity, if applicable, and process-related impurities, in alignment with the EMA Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells [16]. Cell count, viability, copy number of the integrated genetic insert, transduction efficiency,

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expression of the genetic insert and biological activity are essential tests performed to ensure the safety and efficacy of the final lot. Whenever possible, reference is made to general chapters to indicate the methodologies to be used. A new feature of the proposed general monograph in comparison with Chap. 5.14 is the addition of a reference to the general chapter Test for bacterial endotoxins using recombinant factor C (2.6.32). This animal-origin-free reagent method for bacterial endotoxin testing offers an alternative to the classical LAL-based methods described in Chap. 2.6.14. The final layer of the cascade of requirements is included in the three specific sections of the general monograph. It is very important to emphasise that they have to be read in conjunction with the layers of general requirements that are not repeated therein. One of these sections, Genetically modified human autologous cells, contains a reference to a Retroviridae-derived vector for human use component of general Chap. 5.34, making it a part of the legal standard, with a clearly indicated exception of a part on Final lot, in the context of approved medicinal products based on genetically modified human autologous cells. As no retroviridae-derived vector for human use has yet been approved for the European market, the corresponding section has been placed in general Chap. 5.34. However, the reference in the general monograph in the described context is necessary since retroviridae-­ derived vectors constitute a critical starting material when they are used for the production of genetically modified human autologous cells.

4.4.4 Evolution of Adeno-­ Associated Virus Vectors for Human Use: A Case Study When the section on AAV vectors for human use was originally published in Chap. 5.14, this type of vector was still in clinical development, and clinical trials were mainly sponsored by small biotechnology companies. Since then, manufacturing processes have been industrialised, leading to upscaling and improvements in AAV vector

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purification. Four gene therapy medicinal products based on AAV vectors have now reached the market in Europe [9], and the text on AAV vectors must be revised to reflect current knowledge and practice. In addition, as mentioned in Sect. 4.4.2, the EPC decided that it should become part of a legally binding monograph. The amendments (versus Chap. 5.14) to the requirements for AAV vectors in the proposed general monograph 3186, the draft of which was published in July 2022  in Pharmeuropa, are described below. Definition The definition section was amended to focus solely on the AAV as a medicinal product and not as a tool to transfer genetic material to human somatic cells ex vivo, in which case it would be classified as a starting material. The wording of the section was modified throughout to align it with the terminology widely used by regulators and stakeholders (e.g. starting materials instead of production intermediates). Production System The elements of this section were reorganised to provide more clarity on the construction and strategies used for the production of AAV. Considerations on vector genome construction to replace rep and cap genes, to provide the gene of interest in trans and to retain the inverted terminal repeat (ITR) sequences in cis already described in Chap. 5.14 were supplemented with a description of capsid composition, a parameter further controlled in the purified harvest. Two main strategies, i.e. transient co-­ transfection of plasmids in a mammalian cell line and production in an insect cell line, are now clearly outlined. Co-transfection of bacmids was introduced for the latter, in addition to the co-­ infection of baculovirus vectors already described in Chap. 5.14. The potential use of helper viruses or stable cell lines is also indicated in both strategies. The text still highlights the importance of minimising sequence homology in the starting materials as well as in the manufacturing strategy to avoid the generation of replication-competent

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AAV (rcAAV) particles. The production system also includes considerations on its corresponding components, i.e. plasmids, viruses and cell lines used for production of AAV, together with corresponding requirements. The requirement for bacterial cell banks used to manufacture the plasmids that constitute starting materials for the production of AAV vectors to comply with the provisions of the section Bacterial cells used for the manufacture of plasmid vectors for human use was retained. This section was directly reproduced in the draft ­Chap. 5.34 published in Pharmeuropa 34.3 from Chap. 5.14, pending future revision. The requirements for identification, genomic integrity, DNA concentration, residual host-cell DNA, bacterial endotoxins and sterility from Chap. 5.14 were retained, although the comprehensive method to determine DNA concentration was deleted as it was considered too detailed and restrictive. Moreover, tests for DNA purity, DNA topology, residual host-cell RNA, residual host-­cell protein and mycoplasmas if materials of biological origin are used were introduced in order to provide adequate control for plasmids used for production of AAV vectors. Furthermore, the criteria listed for plasmids are also applicable for bacmids if they are used in AAV production. The controls for viruses used for the production of AAV vectors are largely those already described in Chap. 5.14 with the exception of genetic stability, a requirement that is now listed among the general provisions on recombinant vector production and hence automatically enforced, and the test for bacterial endotoxins, which was added to better ensure microbiological safety. Finally, a reference to general Chap. 5.2.3 cell substrates for the production of vaccines for human use was introduced to cover the required cell banking system for production of viruses used for AAV ­manufacture. In the requirements for cell lines used for production of AAV vectors, it was clarified that copy number and sequence integrity of the viral genes and genetic insert are applicable only for cell lines that are stably genetically modified, and phenotypic stability was added to genetic stability.

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Single and Purified Harvest The requirements for single harvests in the proposed general monograph 3186 are similar to those in Chap. 5.14 and include tests for identification, vector concentration and extraneous agents. However, in contrast to Chap. 5.14, only vector genome titre, rather than infectious vector titre and concentration of vector particles, is required to determine vector concentration. Infectious titre assays are characterised by a higher variability and control of this parameter was not considered necessary at this stage. Finally, the general monograph specifies the tests to be performed for the control cells via a reference to the general chapter on Extraneous agents (2.6.16). The need to sequence the entire genome of the vector on a suitable number of purified harvests is highlighted before the list of tests, clarifying that sequencing does not need to be performed routinely on each batch. This criterion, which was part of the test for genetic characterisation in Chap. 5.14, could be confusing for users. The list of tests to be performed on the purified harvest has undergone extensive modifications to align with developments in the field in the past few years. Identification now clearly states that both vector capsid identity and genetic insert identity should be verified, since both are necessary to ensure product identity. The expectations regarding titres are much more detailed. While Chap. 5.14 only referred to titre of infectious vector and concentration of vector particles, without reference to methods, general monograph 3186 requires the determination of capsid titre, vector genome titre and infectious particle titre. In addition, example methods are proposed for each titre. The ratio of AAV capsid proteins has also been added to the requirements since an intact capsid is essential for cell infection. Several changes have also been introduced in the description of the test for residuals, which themselves remain largely the same as in Chap. 5.14. While the description of the methods employed for residual viruses used for production is much less detailed, a clear requirement for no residual viruses to be detected was introduced. The test

4  European Pharmacopoeia’s Approach to Cell and Gene Therapy: Focus on How Gene Therapy Texts…

for residual proteins now carries a reference to the general chapter host-cell protein assays (2.6.34) that became available after the initial elaboration of the AAV section, while better clarity on residual DNA testing is provided by separate controls for residual host-cell DNA and residual DNA from plasmids, bacmids and viruses used in production. Finally, the importance of a risk analysis is emphasised for testing residual reagents, including antibiotics listed as a separate control in Chap. 5.14 and bovine serum albumin. Due to the potentially higher concentration, testing of the latter was judged more appropriate at the purified harvest level rather than in the final lot as described in Chap. 5.14. Similarly, the test for rcAAV was moved from final lot in Chap. 5.14 to purified harvest in order to ensure testing at the most optimal stage and not to compromise the sensitivity of the test due to dilution during the formulation step. Microbiological examination (sterility or bioburden depending on the product) and bacterial endotoxin testing were introduced in the purified harvest, to control microbiological quality before the sterile filtration used in the manufacturing of the final lot. Final Lot Following the experience acquired in the production of AAV vectors, requirements on purified harvest and final lot appeared sufficient, and hence, in contrast to Chap. 5.14, the newly proposed general monograph 3186 does not contain a section on final bulk. While previously the assay section in Chap. 5.14 included a reference to an appropriate reference standard, the establishment of a reference standard for routine control tests is now clearly mentioned. With the exception of the tests for bovine serum albumin and rcAAV mentioned above, the controls listed under identification and test in Chap. 5.14 are retained. They have also been updated to allow other suitable methods in the case of identification and to list other methods (size-exclusion chromatography (2.2.30), analytical ultracentrifugation and electron microscopy) in addition to light scattering in the test for vector aggregates, to reflect the developments in the field to analyse vector aggregates that could pose

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safety issues. Finally, tests for appearance and sub-visible particles have been added in general monograph 3186 to the list of tests to be performed in final lot. The section on assay has also been significantly updated in the newly proposed general monograph 3186, following the same rationale as for the purified harvest, with the three titres (capsid titre, vector genome titre and infectious particle titre) required as necessary to cover the different aspects of the AAV vector particle, while details on assay validity for infectious titre, present in Chap. 5.14, were deleted. The percentage of full and empty particles has been added, since it is now understood that it is an important parameter to control the quality of AAV vectors. The ratio of viral genomes to infectious particle titre, expression of the genetic insert and biological activity, already included in Chap. 5.14, are also listed in the proposed general monograph 3186. As regards expression of the genetic insert, transgene RNA quantitation through RT-qPCR has been added to the methods previously described in Chap. 5.14 (immunochemical assays, biochemical assays or flow cytometry). This provides flexibility, taking into account that in some cases determination of the expression at the protein level may not be straightforward. The added acceptance criteria for expression of the genetic insert and biological activity are also flexible and refer to the limits approved for the particular product.

4.5 Conclusion As laid out above, the newly proposed general monograph 3186 is currently undergoing public consultation. Assuming that all the gathered comments are addressed and that the finalised text is adopted by the EPC, it will outline common requirements for the control of gene therapy medicinal products while simultaneously exhibiting a certain level of built-in flexibility, which is important for such a rapidly evolving field. Of the numerous examples included throughout the text, the flexibility of the stage for performance of tests described for genetically modified autologous human cells depending on the manufactur-

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ing process deserves a special mention. Additionally, in the vast majority of cases, the required parameters are to be analysed using a suitable method, a term defined in the General Notices as ‘to the satisfaction of the competent authority’, while several analytical techniques are listed as examples. Furthermore, the acceptance criteria are also expressed in a flexible manner, and no numerical limits are included in the proposed general monograph. Finally, although a substance or medicinal product must comply with all the requirements stated in a monograph, this does not mean that all of the tests described in the monograph must be performed when assessing compliance with the Ph. Eur. before release, a concept that is clearly stated in the Ph. Eur. General Notices as already mentioned above (see Sect. 4.2). Gene therapy medicinal products have already become a reality, holding promise for treating a wide range of diseases and their use is likely to expand in the near future. Hence, standardised approaches for their control are necessary. The elaboration of the general monograph covering products already approved on the European market, as well as expanding the existing chapters and potentially creating new ones to provide users with further guidance, contributes significantly to public health in Europe and beyond.

References 1. Convention on the Elaboration of a European Pharmacopoeia (European Treaty Series No. 050). 2. Protocol to the Convention on the Elaboration of a European Pharmacopoeia (European Treaty Series No. 134). 3. Commission Directive 2003/63/EC of June 2003 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use (2003). Off J L159:46–94. 4. Regulation (EU) 2019/6 of the European Parliament and of the Council of 11 December 2018 on vet-

O. Kolaj-Robin and M.-T. Duffour erinary medicinal products and repealing Directive 2001/82/EC (2018). Off J L4: 43–167. 5. Gene transfer medicinal products for human use; Ph. Eur. 9.7, 51400 (04/2019) 6. Raw materials of biological origin for the production of cell-based and gene therapy medicinal products; Ph. Eur. 9.0 corrected 10.0, 50212 (01/2017) 7. Note for guidance on the quality, preclinical and clinical aspects of gene transfer medicinal products (CPMP/BWP/3088/99); https://www.ema.europa.eu/ en/quality-­preclinical-­clinical-­aspects-­gene-­therapy-­ medicinal-­products-­scientific-­guideline#document-­ history%2D%2D-­first-­version-­section 8. Commission Directive 2009/120/EC amending Dir­ ective 2001/83/EC of the European Parliament and of the Council on the Community code relating to medi­ cinal products for human use as regards advanced therapy medicinal products (2009). Off J L242: 3–12. 9. CAT quarterly highlights and approved ATMPs (October 2022) EMA/CAT/841175/2022 https://www.ema.europa.eu/en/committees/cat/ cat-­agendas-­minutes-­reports#reports-­section 10. Gene, Cell, & RNA Therapy Landscape Q1 2022 Quarterly Data Report, ASGCT and Informa Pharma Intelligence, https://asgct.org/global/documents/ asgct-­pharma-­intelligence-­q1-­2022-­report.aspx. 11. Arabi F, Mansouri V, Ahmadbeigi N (2022) Gene therapy clinical trials, where do we go? An overview. Biomed Pharmacother 153:113324; https://doi. org/10.1016/j.biopha.2022.113324 12. Gene therapy medicinal products for human use, monograph 3186. Pharmeuropa 2022; 34(3); http:// pharmeuropa.edqm.eu/home/ 13. Additional information on gene therapy medicinal products for human use, chapter 5.34. Pharmeuropa 2022; 34(3); http://pharmeuropa.edqm.eu/home/ 14. Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products; adopted by the European Commission on 22 November 2017 and published in EudraLex Volume 4. https:// health.ec.europa.eu/medicinal-­p roducts/eudralex/ eudralex-­volume-­4_en 15. Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products (EMA/ CAT/80183/2014); https://www.ema.europa.eu/en/ quality-­p reclinical-­c linical-­a spects-­g ene-­t herapy-­ medicinal-­p roducts-­s cientific-­g uideline#current-­ effective-­version-­section 16. Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells (EMA/CAT/GTWP/671639/2008 Rev. 1) https:// www.ema.europa.eu/en/quality-­non-­clinical-­clinical-­ aspects-­medicinal-­products-­containing-­genetically-­ modified-­cells#current-­effective-­version-­section

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United States Food and Drug Administration Regulation of Human Cells, Tissues, and Gene Therapies Sandhya Sanduja, Liz Lessey-Morillon, Rondine Allen, Xiaofei Wang, Gavin Imperato, and Judith Arcidiacono Abstract

Abbreviations

Research and development of gene therapies and cell- or tissue-based therapies has experienced exponential growth in recent decades and the potential for these products to treat diverse, often rare, clinical indications is promising. The Office of Therapeutic Products (OTP) in the Center for Biologics Evaluation and Research (CBER) at the United States Food and Drug Administration (US FDA) is responsible for the regulation of these products, among others, throughout the entire product lifecycle. This chapter provides an overview of the science- and data-driven approach to US FDA regulatory oversight of cell and gene  therapy (CGT) products to ensure their safety and efficacy.

AE BLA CBER

Keywords

United States Food and Drug Administration · Cell therapy · Gene therapy · Clinical trial · Clinical development · Investigational New Drug application · Marketing application

S. Sanduja (*) · L. Lessey-Morillon · R. Allen · X. Wang · G. Imperato · J. Arcidiacono Office of Therapeutic Products (OTP), Center for Biologics Evaluation and Research (CBER), United States Food and Drug Administration (US FDA), Silver Spring, MD, USA e-mail: [email protected]

Adverse event Biologics License Application Center for Biologics Evaluation and Research CDER Center for Drug Evaluation and Research CFR Code of Federal Regulations CGMP Current Good Manufacturing Practices CMC Chemistry, Manufacturing, and Controls COA Certificate of Analysis CT Cell Therapy FD & C Act Food, Drug, and Cosmetic Act FIH First-in-Human GLP Good Laboratory Practice CGT Cell and Gene Therapy GT Gene Therapy HCT/P Human Cell, Tissue, and Cellular and Tissue-based Product ICH International Conference on Harmonization IDE Investigational Device Exemption IND Investigational New Drug IRB Institutional Review Board LTFU Long-Term Follow-Up MOA Mechanism of Action NOAEL No Observed Adverse Effect Level OMB Office of Management and Budget

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 M. C. Galli (ed.), Regulatory Aspects of Gene Therapy and Cell Therapy Products, Advances in Experimental Medicine and Biology 1430, https://doi.org/10.1007/978-3-031-34567-8_5

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OTP PDB PDUFA POC RMT RMAT SPA TPP US FDA

Office of Therapeutic Products Prospect of Direct Benefit Prescription Drug User Fee Act Proof-of-concept Regenerative Medicine Therapies Regenerative Medicine Advanced Therapy Special Protocol Assessment Target Product Profile United States Food and Drug Administration

5.1 United States Regulatory Framework The US FDA is a regulatory agency within the US Department of Health and Human Services. The US FDA is responsible for protecting public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices and by ensuring the safety of our nation’s food supply, cosmetics, and products that emit radiation. Medical products comprised of cell- or tissuebased therapies (CT) and gene therapies (GT), collectively will be referred to as CGT products throughout this chapter. These products are regulated by US FDA as biological products1 in the OTP at CBER. The US regulatory framework is a multitiered system comprising statutes or laws (e.g., Food, Drug and Cosmetic Act (FD & C Act) and the Public Health Service Act), regulations based on the statutes (21 CFR -Code of Federal Regulations), and guidance documents that represent US FDA’s current thinking on a particular topic. Key regulations for CGT products are provided in Table 5.1.

A biologic is defined in Title 42 of the US Code 351(i) as virus, therapeutic serum, toxin or antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, applicable to the prevention, treatment, or cure of a disease or condition of human beings. 1 

Table 5.1  Key regulations for CGT products Regulation of Combination Products Good Guidance Practices Protection of Human Subjects Institutional Review Boards (IRB) Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies Drugs

Labeling Advertising Current Good Manufacturing Practices (CGMP) IND Requirements Clinical Trial Standards Biologics Biologics License Application (BLA) Requirements Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P) Devices Pre-Market Notification 510(k) IDE Requirements PMA Regulations Quality Systems Regulations

21 CFR 4 21 CFR 10 21 CFR 50 21 CFR 56 21 CFR 58 21 CFR Parts 200–299, 300–369 21 CFR 201 21 CFR 202 21 CFR 210–211 21 CFR 312 21 CFR 314 21 CFR Parts 600–680 21 CFR 600–690 21 CFR 1271

21 CFR Parts 800–898 21 CFR Subpart E 21 CFR 812 21 CFR 814 21 FR 820

5.1.1 Definitions CGT products meet the definition of “biological product” as noted in section 351(i) of the Public Health Service Act (42 U.S.C. 262(i)) when such products are intended for the prevention, treatment, or cure of a disease or condition of human beings. HCT/P is defined in 21 CFR 1271.3(d) as articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. CT products include cells, derived from an autologous, allogeneic, or xenogeneic source that may have been propagated, expanded, selected, pharmacologically treated, or otherwise altered in biological characteristics (but not genetically)

5  United States Food and Drug Administration Regulation of Human Cells, Tissues, and Gene Therapies

ex vivo to be administered to humans for the prevention, treatment, cure, diagnosis, or mitigation of disease or injuries. Human GT products seek to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use. GT products mediate their effects by transcription or translation of transferred genetic material or by specifically altering host (human) genetic sequences [1–3] Some examples of gene therapy products include nucleic acids (e.g., plasmids, in  vitro

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transcribed RNA), genetically modified microorganisms (e.g., viruses, bacteria, fungi), engineered site-specific nucleases used for human genome editing and ex vivo genetically modified human cells. Product definitions are provided in Table 5.2. Regenerative medicine therapies (RMT) are defined in section 506(g)(8) of the FD & C Act as cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, except for those regulated solely

Table 5.2  Product definitions Biologic (42 USC 262(i))

Drug (21 USC 321(g)(1)

Human cell, tissue, and cellular and tissue-based product (HCT/P) (21 CFR 1271.3(d) Device (21 USC 321(h))

Combination Product (21 CFR 3.2(e))

A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except chemically synthesized polypeptide), or analogous product or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings (A) Articles recognized in the official US Pharmacopeia, official Homeopathic Pharmacopeia of the United States, or official National Formulary, or any supplement to any of them; (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; (D) articles intended for use as a component of any articles specified in clause (A), (B), or (C) Articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. Examples of HCT/P include, but are not limited to, bone, ligament, skin, dura mater, heart valve, cornea, hematopoietic stem/ progenitor cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, and semen or other reproductive tissue

An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is (i) recognized in the official National Formulary, or the US Pharmacopeia, or any supplement to them; (ii) intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, in man or other animals; or (iii) intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes (i) A product composed of two or more regulated components, that is, drug/device, biologic/ device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity; (ii) two or more separate products packaged together in a single package or as a unit and composed of drug and device products, device and biological products, or biological and drug products; (iii) a drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, for example, to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; (iv) any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect

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under section 361 of the Public Health Service Act (42 U.S.C. 264) and Title 21 of the Code of Federal Regulations Part 1271 (21 CFR Part 1271). Based on US FDA’s interpretation of section 506(g), human gene therapy products, including genetically modified cells that lead to a sustained effect on cells or tissues, and xenogeneic cell products may meet the definition of an RMT. US FDA guidance documents for CGT products can be found on the US FDA website [4].

5.1.2 Regulatory Pathway 5.1.2.1 Product Life Cycle: Investigational Use, BLA, Post-marketing US FDA has regulatory oversight of investigational clinical trials and marketing of CGT. Prior to the initiation of a clinical trial in the United States, an Investigational New Drug Application (IND) (21 CFR 312) must be submitted and reviewed by the US FDA. Clinical development programs typically comprise a series of clinical investigations conducted in clinical research phases. Phase 1 investigational studies are primarily focused on the evaluation of safety of the investigational products. Phase 2 studies continue to assess safety and are typically intended to identify the optimal dose and assess efficacy for the particular medical condition. Phase 3 studies are designed to provide substantial evidence of safety and effectiveness to support a marketing application. For clinical development programs for CGT, the phases may not necessarily be as clearly defined, particularly for rare diseases. Many CGT programs have Phase1/2 studies and Phase 2/3 studies. A BLA must be submitted and approved by the US FDA to introduce, or deliver for introduction, a biologic product into interstate commerce (21 CFR 601.2). To receive US FDA approval, the data submitted in the BLA must demonstrate that the product is safe and effective for its intended use.

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5.1.2.2 IND and Presubmission Meetings To support product development from proof-of-­ concept (POC) through licensure, product developers have many opportunities to interact with US FDA. Prior to submitting an IND, developers of novel CGT products that have conducted POC studies may request an INTERACT meeting. Additional meetings between US FDA and sponsors may take place prior to the submission of an IND, during the conduct of clinical trials and post-approval (Fig. 5.1). Upon implementation of Prescription Drug User Fee Act (PDUFA) VII, there are five types of meetings: Type A, Type B, Type C, Type D, and INitial Targeted Engagement for Regulatory Advice on CBER/CDER producTs (INTERACT), that a sponsor may take advantage of to help facilitate interactions with FDA during the product development lifecycle [5, 6]. The characteristics of each meeting type are shown in Table 5.3. 5.1.2.3 21st Century Cures Act (2016) The 21st Century Cures Act was signed into law by the United States Congress in 2016. The Act is designed to accelerate medical product ­development and bring new innovative products to patients faster and more efficiently. Section 3033 of the 21st Century Cures Act established the Regenerative Medicine Advanced Therapy Designation (RMAT, see below) to facilitate the development and review of certain RMT. To further the development of RMT, section 3036 of the Act supports the development and use of standards through collaborations between US FDA, the U.S.  National Institute for Standards and Technology and regenerative medicine stakeholders (see Sect. 5.2.1.5) 5.1.2.4 Expedited Programs Expedited programs provide mechanisms to bring therapies for serious conditions to market as soon as it can be concluded that the therapy’s benefit outweighs the risks. Table 5.4 provides a summary of available expedited programs. For specific information on the programs see Guidance for Industry: Expedited Programs for Regenerative Medicine Therapies for Serious

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Fig. 5.1  Opportunities for interactions with US FDA. Shown in Fig. 5.1 is the US FDA regulatory scheme from product development to licensure and post-marketing surveillance. The yellow boxes indicate opportunities for

product developers to interact with US FDA during preclinical and clinical development and post-marketing. The boxes with purple arrows refer to expedited programs and the timing for requests of these programs

Conditions [7], see Fig.  5.1 for the timing of requests for approval pathways and specific product designations.

designed to generate data that appropriately support product approval; (ii) the possibility of Accelerated Approval and Priority Review of the BLA, provided that certain criteria are met; and (iii) US FDA review of sections of the BLA as they are completed and submitted (so-called Rolling Review).

5.1.2.5 Fast Track Designation Requirements for Fast Track designation are as follows: (i) The product is intended to treat a serious condition, (ii) has demonstrable effects, and (iii) would address an unmet medical need. The type of information needed to demonstrate the potential for addressing an unmet medical need is dependent on the stage of product development when the Fast Track request is submitted. For example, early in development, evidence of activity in a nonclinical model may be sufficient; however, in later phases, existing clinical data should demonstrate such potential. If a product is granted Fast Track designation, advantages include (i) more frequent meetings and written correspondence with the US FDA to ensure that the overall development plan and individual studies are

5.1.2.6 Breakthrough Therapy designation A Breakthrough Therapy designation is a program that has a goal of expediting the development and review of products that are intended to treat a serious condition and for which there is clinical evidence that may indicate a substantial improvement over existing therapies on a clinically meaningful endpoint(s). A request for Breakthrough Therapy designation should in general be made no later than the end-of-Phase 2 meeting. The benefits of Breakthrough Therapy designation include the benefits afforded under

Meeting to address no more than two focused topics and associated questions. The meeting should not require input from more than three disciplines/divisions

D

INTERACT

C

B

Meeting description Meetings that are immediately necessary to help an otherwise stalled product development program proceed Meetings to obtain nonbinding feedback on specific questions. Generally, no more than one of each of the Type B meetings will be granted per each CGT application Meetings not fitting the criteria of Type A or B regarding the development and review of a CGT product Meetings to obtain early feedback on a product development program for a novel investigational agent

Meeting type A

Table 5.3  Characteristics of sponsor-FDA meeting type

Discussion of issues that arise during ongoing development (e.g., change in manufacturing), early consultations on new surrogate endpoint Discussion of issues aimed at demonstrating product safety (e.g., testing strategies) and support administration (e.g., POC or biodistribution studies) adequate to support a first-in-human (FIH) clinical trial Discussion of a follow-up question on a new issue after a formal meeting, or narrow issue consisting of a few associated questions, or general question that does not require extensive, detailed advice

Pre-IND, end-of-Phase 1, end-of-Phase 2, pre-Phase 3, pre-BLA meetings

Examples Discussion of clinical holds, dispute resolution, Special Protocol Assessment (SPA)

Within 50 days of request receipt

Within 75 days of request receipt

Within 75 days from written request

Within 60 days from written request or within 70 days from written request for EOP2

Scheduling timeline for meeting Within 30 days from written request

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Table 5.4  Available expedited programs Breakthrough therapy (BT) Designation

RMAT designation Designation

Section 506(b) of the FD & C Act, as added by section 112 of the Food and Drug Administration Modernization Act (FDAMA, 1997) and amended by section 901 of FDASIA

Section 506(a) of the FD & C Act, as added by section 902 of 2012 FDASIA

Qualifying Criteria

Serious condition AND Nonclinical or clinical data demonstrate the potential to address unmet medical need

Serious condition AND Preliminary clinical evidence indicates that the drug has the potential to demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies

Program Features

Frequent meetings Eligibility for*: Priority Review Rolling Review *if relevant criteria are met

All FT Features, including: Actions to expedite development and review Rolling review AND Intensive guidance on an efficient drug development program Organizational commitment involving senior managers

Nature of program Reference

Fast track (FT) Designation

Fast Track designation but additionally include intensive guidance from US FDA on designing an efficient development program and organizational commitment that senior US FDA staff will be involved in such guidance.

Priority review Designation

Accelerated approval Approval pathway

Section 506(g) of the FD & C Act, as added by section 3033 of the 21st Century Cures Act

Prescription Drug User Fee Act of 1992

Serious condition AND a RMAT AND Preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition All FT and BT Features, including early interactions to discuss any potential surrogate or intermediate endpoints AND Statute addresses potential ways to support accelerated approval

Serious condition AND Demonstrates potential to be a significant improvement in safety or effectiveness

21 CFR part 314, subpart H, 21 CFR part 601, subpart E and Section 506(c) of the FD & C Act, as amended by section 901 of the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) Serious condition AND Meaningful advantage over available therapies AND Demonstrates an effect on either a surrogate endpoint or intermediate clinical endpoint

Shortened Review Clock FDA will take action on an application within 6 months (compared to 10 months under traditional review)

Approval based on surrogate or intermediate clinical endpoints Save valuable time in the drug approval process Reduce waiting period for patients to obtain clinically meaningful benefit

5.1.2.7 Regenerative Medicine Advanced Therapy designation A product that fits the definition of an RMT is eligible for RMAT Designation: if (i) it is intended to treat, modify, reverse, or cure a seri-

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ous or life-threatening disease or condition and (ii) preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition [7]. Like Breakthrough Therapy designation, RMAT designation is intended to expedite the development and review of products. RMAT designation grants all breakthrough therapy designation features, including early interactions to discuss any potential surrogate or intermediate endpoints. A request for RMAT designation should be within the IND or after, but in general should be made no later than the end-of-Phase 2 meeting. Additionally, RMAT-designated products may be eligible for accelerated approval based on (i) previously agreed-upon surrogate or intermediate endpoints that are reasonably likely to predict long-term clinical benefit or (ii) reliance upon data obtained from a meaningful number of sites, including through expansion to additional sites, as appropriate.

5.1.2.8 Priority Review When a BLA is submitted, the US FDA has 60 days to determine the review designation for the application. If a BLA is submitted for a product that, if approved, would demonstrate significant improvements in safety or effectiveness compared to available treatment, diagnosis, or prevention of serious conditions, the US FDA can grant Priority Review. Additionally, an RMT may receive priority review if it treats a serious condition, and, if approved, would provide a significant improvement in the safety or effectiveness of the treatment of the condition. If Priority Review is granted, US FDA will complete the BLA review within 6 months of the 60-day filing date, instead of the 10-month review time from the 60-day filing date for a standard BLA submission. However, Priority Review does not alter the standards for approval of the product. 5.1.2.9 Accelerated Approval For products that are intended to fill an unmet medical need for treating serious conditions, Accelerated Approval is a program through which products may be approved on the basis of adequate and well-controlled clinical studies that

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demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on an intermediate clinical endpoint that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefits. A surrogate endpoint is a marker such as a laboratory measurement, radiographic image, physical sign, or other measure, that is thought to predict clinical benefit based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence [8]. An intermediate clinical endpoint is a clinical outcome measured at an earlier time point than what would generally be considered meaningful. Accelerated Approval may expedite the approval process, since the use of surrogate or intermediate clinical endpoints may result in faster collection of efficacy data than if the study(ies) had used a direct measure of clinical benefit as the primary endpoint. For drugs or biologics granted Accelerated Approval, post-­ marketing confirmatory trial(s) are generally required to verify the anticipated clinical benefit. In the event that the post-marketing trial(s) fail to verify the anticipated clinical benefit or do not demonstrate clinical benefit that is sufficient in magnitude to justify the risks associated with the product, the US FDA may either withdraw product approval or modify the labeled indication under the Accelerated Approval pathway.

5.2 Specific Considerations for Cell and Gene Therapies Across Different Disease Indications 5.2.1 Chemistry, Manufacturing, and Controls 5.2.1.1 CGT Product Manufacturing and Testing CGT products are diverse and often biologically and technologically complex, particularly with respect to how they are derived and manufactured. For example, various cells, tissues, or vectors may be used as starting materials to derive the CGT product. Manufacturing may involve multiple steps to select, modify, and/or expand

5  United States Food and Drug Administration Regulation of Human Cells, Tissues, and Gene Therapies

cells, a process that generally takes several days of cell cultivation or ex vivo cell manipulation. In addition, the manufacture of GT products can be quite complex and include many steps for purification and viral clearance. Various product-­ specific techniques are applied to harvest, purify, and formulate the final CGT product to meet standards of product purity, potency, and safety. The diversity and complexity of CGT products also pose challenges to product characterization and testing programs. For example, (i) the exact mechanism of action (MOA) maybe complex or ambiguous; (ii) there are few/no industry standards and reference materials for the manufacturing of CGT products, and manufacturing methods can differ widely; (iii) manufacturing scale ranges can be as small as patient-specific lots with considerable lot-to-lot heterogeneity; and (iv) CGT products can have limited shelf life and stability or material available for testing, which makes strategies for product testing, storage, and shipping highly product-specific. US FDA considers the complexities of CGT products when applying the Chemistry, Manufacturing and Controls (CMC) regulations to evaluate product quality. Considerations when reviewing a regulatory submission include the current scientific knowledge, regulatory precedents, experience with similar products and/or indications, the phase of product development (e.g., preclinical, Phase 1, end-of-Phase 2) and the benefit–risk profile in the target patient population. These regulatory requirements increase in a stepwise fashion to become more stringent as product development advances to licensure. In the early phases of development (i.e., prior to initiation of a proposed human clinical trial), the focus is on product safety. In addition to demonstrating product safety, the sponsor is expected to demonstrate that the proposed CGT product is comparable in its composition and biological activity to the product evaluated in IND-enabling preclinical and characterization studies. As product development continues, the criteria for product manufacturing, release, stability, and shipping should be progressively refined to meet the increasing regulatory requirements so the prod-

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uct can meet CMC standards for licensure through the BLA pathway. Likewise, the Current Good Manufacturing Practices (CGMP) expectations increase during the life cycle of the product. CGMP requirements under section 501(a)(2)(B) of the FD & C Act apply during all stages of clinical investigation. However, the CGMP regulations under 21 CFR Part 211 are generally not required for the manufacture of most CGT products used for Phase 1 studies [9]. US FDA has provided guidance on how manufacturers of early-phase products can comply with these requirements for CGMP in the FD & C Act [10]. This document describes the importance of (i) adequate equipment and manufacturing environment, (ii) trained personnel, (iii) adherence to procedures and practices that are well defined and documented for environmental monitoring, (iv) raw material qualification and manufacturing, (v) establishment of a quality control unit that is independent from manufacturing to review procedures for production and lot release testing, and (vi) investigation of deviations and initiation of corrective actions. Prior to release of a product lot for administration to patients, a CGT product is tested for safety, quality, and consistency through a combination of testing of (i) raw materials/reagents, (ii) starting materials (e.g., cells, plasmid DNA), (iii) in-process materials, (iv) drug substance, and (v) drug product. Microbiological testing typically includes (i) testing for sterility (bacterial and fungal), mycoplasma, and, if necessary, adventitious viruses (e.g., cell and/or viral banks) and (ii) testing for the presence of replication-competent viruses for viral vector-based CGT products. Identity testing typically includes an evaluation of product identity to distinguish it from other products, such as amplification of a transgene, vector capsid analysis, cell phenotype or HLA typing, or other appropriate assay(s) based on product-specific properties. Purity testing typically includes an evaluation of the purity of the product, such as testing for the presence of endotoxin, process residuals (e.g., host/plasmid DNA, cytokines/growth factors/

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peptides, extractables and leachables), and other factor(s) selected based on product-specific properties. Potency testing typically includes an evaluation of the function of the product, such as quantitative biological assay (e.g., measurement gene activity, cytokine/mediator secretion, cytotoxic activity, and cellular activation) relevant to the CGT product’s purported MOA. For many CGT products, a matrix approach using multiple assays to understand multiple product characteristics is necessary. US FDA recommends evaluating multiple potential assays early in development as a well-established potency assay is required prior to initiation of clinical studies intended to provide the primary evidence of effectiveness to support a marketing application. Characterization testing typically includes an evaluation of biochemical, biophysical, and/or genetic characteristics of the product, such as viability, cell number or dose, transduction efficacy or vector particle aggregation for vector-­ based products, analysis of cell plasticity, morphology or growth kinetics for cell-based products, or other testing relevant to product-­ specific properties. US FDA guidance documents that address the general CMC requirements for CGT products studied under an IND include “Guidance for Industry: Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)” [2], Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs) [11], CMC Somatic Cell Therapy Investigational New Drug Applications (INDs), and Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products [12].

5.2.1.2 Materials Used in Manufacturing IND applications must include information on all materials used in manufacturing (see 21 CFR 312.23(a)(7)(iv)(b)) and should include a description of the quality or grade of the materials. Material quality can impact product quality and

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safety, including the introduction of adventitious agents or other impurities, so materials of the highest grade available should be used. A Certificate of Analysis (COA) or material qualification information is needed to assess the safety of the materials. If documentation or testing for a material is incomplete, the sponsor will need to perform the necessary testing. During late-phase studies, US FDA recommends conducting at least one identity test on each lot of material in addition to maintaining a qualification program and supplier audit as these are required for marketing applications (see 21 CFR 211.84(d)(2)). Many CGT products are derived or manufactured using animal-derived materials, such as bovine and porcine-derived materials, cytokines, or murine monoclonal antibodies. The agency recommends using non-animal-derived materials if possible. If animal-derived materials are used, then the sponsor should submit information (e.g., COA) to provide adequate assurance that any animal-derived material is free of adventitious agents and is of a consistent quality, including documentation of source and testing (per 9 CFR 113.53). Additionally, for bovine materials, the sponsor should provide information on source of the material; information on the location where the herd was born, raised, and slaughtered; and any other information relevant to the risk of transmissible spongiform encephalopathy. If human-derived materials are used, the COA or other information should include donor or material testing. For human albumin, US FDA-­ licensed human albumin should be used. If human serum is used, then the sponsor should provide a description of starting material collection and processing, along with documentation of compliance with 21 CFR Part 640.

5.2.1.3 Scale-Up for Late-Phase Clinical Studies Scale-up of CGT product manufacturing brings forth issues not usually encountered in small molecule drug development. For example, scale­up of autologous ex vivo-manipulated CGT products generally involves increasing the manufacturing capacity to allow simultaneous processing of different autologous product lots in

5  United States Food and Drug Administration Regulation of Human Cells, Tissues, and Gene Therapies

the same facility. This type of scale-up may lead to challenges related to product tracking, identity, processing time, automation, and other logistical issues with storage and shipping. For scale-up of a CGT product, such as a viral vector, increasing the yield for commercial manufacturing may involve changes in cell culture procedures, such as a switch to animal component-free growth medium or the use of suspension cells. Any of these changes can affect product attributes that alter to the product’s safety and efficacy. Thus, scale-up of product manufacturing may result in the need for additional testing to establish comparability. Considering the complexity in the composition and MOA of CGT products, the development of appropriate assays to detect changes in product attributes may be challenging. Hence, US FDA recommends that manufacturing changes occur prior to initiation of clinical studies intended to provide the primary evidence of effectiveness to support a marketing application.

5.2.1.4 Comparability The manufacturing process fundamentally affects the function and quality of CGT. Thus, changes to the manufacturing process can result in changes to the product’s function and safety. Depending on the change and stage of product development, comparability studies may be needed. Any manufacturing change should be assessed to determine whether product quality (i.e., safety, identity, strength, purity, and potency) has been affected. For manufacturing changes likely to impact product quality, a formal risk assessment should be conducted and subsequent evaluation of product comparability before and after the change may be necessary. If there are no direct safety concerns, the amount of data needed to support a manufacturing change would be commensurate with stage of investigation. As product development continues and understanding of the product’s critical quality attributes progresses, more data may be necessary to assess the impact of the manufacturing change on product quality. Critical manufacturing changes during or after the clinical studies intended to provide the primary evidence of effectiveness to support a marketing application would require a demon-

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stration of product comparability. This can be shown through an evaluation of the similarities and differences in critical quality attributes of multiple lots of the product, pre- and post-change, following the international guideline ICH Q5E: Comparability of Biotechnology/Biological Products Subject to Changes in Their Manufacturing Process [13]. Sponsors are encouraged to engage US FDA in formal discussions (Table 5.3) before initiating a manufacturing change or comparability study to obtain advice on the acceptability of their proposal.

5.2.1.5 Standards Standards, which are generally developed outside of the government, may facilitate product design and reduce time to market. As set forth in the Office of Management and Budget (OMB) Circular A-119, “Federal Participation in the Development and Use of Voluntary Consensus Standards and in Conformity Assessment Activities” [14], the term “standard” includes all of the following: (i) common and repeated use of rules, conditions, guidelines or characteristics for products or related processes and production methods, and related management systems practices; (ii) the definition of terms; classification of components; delineation of procedures; specification of dimensions, materials, performance, designs, or operations; measurement of quality and quantity in describing materials, processes, products, systems, services, or practices; test methods and sampling procedures; formats for information and communication exchange; or descriptions of fit and measurements of size or strength; and (iii) terminology, symbols, packaging, marking or labeling requirements as they apply to a product, process, or production method. Written or documentary standards can assist manufacturers in meeting regulatory requirements. For example, currently there are many different methods used to characterize viral vectors. A documentary standard of analytical methods to characterize viral vectors could reduce the burden assay design and validation. Physical standards or reference materials can be used in the assessment and manufacture of CGT products as well. US FDA partners with the

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Standards Coordinating Body, which consists of stakeholders from industry, academia, professional societies, and government entities, to support the development of standards, including for RMT which include many CGT products. In 2019, CBER published a guidance entitled “Standards Development and Use of Standards in Regulatory Submissions Reviewed in the Center for Biologics Evaluation and Research” describing recommendations on the use of standards in product development and control, as well as the use of such standards in CBER’s managed review process [15]. In 2022, CBER issued a draft guidance entitled “Voluntary Consensus Standards Recognition Program for Regenerative Medicine Therapies” describing a standards recognition program for RMT whereby US FDA will review specific voluntary consensus standards that may be useful to product developers and sponsors of regulatory applications to US FDA [16]. The aims of this program are (i) to assist product developers in identifying standards that have been reviewed by US FDA for scientific soundness and consistency with US FDA regulations and policies and (ii) to assist US FDA reviewers in evaluating the proper use of fit-for-purpose standards in a regulatory submission.

5.2.2 Pharmacology/Toxicology In an IND, sponsors must provide “adequate information about the pharmacological and toxicological studies on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations. The kind, duration, and scope of animal and other tests required vary with the duration and nature of the proposed clinical investigations” (21 CFR 312.23(a)(8)). The objectives of the nonclinical program are to establish feasibility and safety, support the scientific rationale for the proposed clinical trial, and provide recommendations for an effective dose range, dosing regimen, and clinical route of administration. The nonclinical program may also provide information on patient eligibility criteria and identify physiologic parameters to

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help guide clinical monitoring. Considerations regarding pharmacology and toxicology studies that comprise the nonclinical development program are described in the document “Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products” [17].

5.2.2.1 Pharmacology Studies In vitro and in vivo POC studies are important for bench-to-bedside translation of the investigational CGT product. In vitro assays may characterize the CGT product’s MOA and aid in understanding the biological activity of the product. Data gained from in  vitro studies may be used to inform the design of in  vivo studies. Pharmacology studies conducted in an animal model of disease or injury provide information on the biological response, duration of activity, biologically active dose levels, and further characterize the CGT product’s mechanism of action. Factors to consider when selecting an appropriate animal model include: (a) comparability of physiology and anatomy to that of humans; (b) permissiveness/susceptibility to infection and in some cases replication of viral vectors or microbial vectors for gene therapy; (c) immune tolerance to a human CT product or a human transgene expressed by a GT product; (d) feasibility of using the planned clinical delivery system/procedure; and (e) similarities and differences between disease manifestations in the model and humans. POC studies can provide information regarding risk-benefit profile, identify biomarkers of disease, and provide scientific justification for the use of the CGT product in the proposed clinical trial. Clinical investigations of products intended for administration to individuals   T). Many approaches are investigating the repair of the SCD mutation, including CRISPR gene-­ edited CD34+ human hematopoietic stem cells (HSC) obtained from SCD patients. The HSC-­ targeted gene correction approach is under investigation in Canada and US centers for a Phase I/II study for evaluating autologous CRISPR gene-­ edited CD34+ human hematopoietic stem and progenitor cells (EDIT-301) in subjects with severe SCD [66].

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6.5.2.8 AAV Gene Therapy Health Canada approved the first human Spastic Paraplegia Type 50 (SPG50) clinical trial in 2021 for a Canadian patient with SPG50 disease where the safety and tolerability of a single dose of MELPIDA administered intrathecally was evaluated. SPG50 is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severely impaired intellectual development with poor or absent speech development [67]. Gene replacement was performed via MELPIDA, a recombinant self-complementary AAV serotype 9 encoding a functional codon-­optimized human AP4M1 transgene (hAP4M1opt). The gene therapy got the USFDA approval in August of 2022 and two SPG50 patients in Texas should receive the treatment for this ultra-rare disease. This is one of the first examples of individualized genetic medicine for an ultra-rare disease. 6.5.2.9 AAV-Based Gene Therapies for the Treatment of Monogenic Diseases of the Central Nervous System Canadian investigators received Health Canada approval for a phase I/II assessing the safety and efficacy of a single intrathecal administration of TSHA-102 (an AAV9-delivered gene therapy) in adult female patients with Rett syndrome [68]. Rett syndrome is a debilitating neurodevelopmental disorder caused by mutations of the MECP2 gene in 90–95% of cases [69]. TSHA-­102 is designed to deliver a functional MECP2 gene to the brain using a novel technology platform, called miRARE (a miRNA-responsive target sequence).

6.5.3 Products under Development 6.5.3.1 Developing Canadian-Made Next-Generation of CAR-T and Oncolytic Virus Therapies for Cancer Made-in-Canada CAR-T therapies are under development and focus on testing other cancer antigens such as CD22 and on the development of new chimeric antigenic systems such as the TAC

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platform (the TAC co-opts the endogenous T cell receptor for activation of engineered T cells). For example, a novel single domain CD-22-specific camelid-derived CAR T-cell therapy [70] has already been identified for clinical grade development for relapsed/refractory CD22-positive B-cell non-Hodgkin lymphoma. Using the Canadianmade TAC technology [57], personalized CAR-T therapy for a rare orphan cancer (alveolar soft part sarcoma) is heading to a first-in-human clinical trial for a single patient clinical trial. The world’s first use of an iCELLis500 to GMP manufacture an oncolytic virus product called OncoVac (a vaccinia virus with enhanced cancer cell killing and immune stimulation) is also a good example of new capacity that Canada is building for vector manufacturing for clinical testing.

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and chromosomal rearrangements, and is therefore well suited for point mutation corrections [79]. Cytosine base editors (CBE) catalyze C-to-T transition [80], adenine base editors (ABE) catalyze A-to-G transition [81], others can do both simultaneously [82], or even C-to-G transversions [83]. CBE was used to correct hSOD1G93A in the ALS mouse model, obtaining comparable health benefits [84]. Nonetheless, off-target base editing was detected when they analyzed candidate off-target sites in the genomic DNA.  Moreover, a different team also used an AAV-CBE to correct a responsible mutation (Npc1I1061T; c.3182 T > C) in a mouse model of human Niemann–Pick disease type C, obtaining significant health improvement, as well as one significant off-target DNA mutation [85]. In addition, concerning off-target mutations were also 6.5.3.2 Gene Editing detected in RNA in previous studies using base The CRISPR-Cas9 system has proven very robust editing [86, 87]. Interestingly, ABE were shown and versatile to generate targeted double-stranded to exhibit less off-target DNA editing [88], and breaks (DSB) and frameshift KO in the DNA of new variants were recently developed to limit offeukaryotic cells [71]. Several preclinical therapeu- target DNA or RNA editing while maintaining tic applications of this system, delivered by AAV high on-target activity [89, 90]. Since several vectors, have shown significant health benefits in patients with Leber congenital amaurosis (LCA) transgenic mouse models of neurological disor- show progressive retinal re-degeneration followders carrying human dominant mutations, e.g., ing gene therapy with Luxturna, possibly due to hSOD1G93A in amyotrophic lateral sclerosis progressive exhaustion of expression of the (ALS) [72, 73], KM670/671NL (APPswe) in RPE65 transgene, a research team used an AAVAlzheimer’s disease (AD) [74], CAG trinucleotide ABE to successfully correct the responsible nontandem repeats in Huntington’s disease (HD) [75– sense mutation in the mouse model rd12 for 77]. In a mouse model (mdx mice) for Duchenne LCA2 [91]. While some bystander edits were muscular dystrophy (DMD), highly muscle-­ observed in close proximity of the target mutaspecific AAV capsid variants were identified to tion, the top ten candidate off-target sites did not deliver the Cas9 system for excision of exon 23 reveal any off-target base editing. In another and transcript re-framing of DMD, with signifi- mouse model of DMD (∆Ex51 mice), AAV-­ cant health improvement and without any evidence ABEmax was successfully used for correct gene of liver toxicity or other adverse effects [78]. reframing, and bystander editing was detected However, unbiased genome-wide analyses of [92]. Interestingly in this particular case, the potential off-target mutations, performed in rele- bystander edits occurred within the intron or the vant patient’s neurons, are still lacking in these removed exon, therefore should not affect the corCas9 nuclease studies, slowing progress towards rected dystrophin, unless new cryptic splice sites clinical trials. are activated in the area. No off-target damage Gene editing was also developed to use inac- was revealed at any of the eight tested candidate tive forms of Cas9 nuclease fused to other effector off-target sites. However, the intramuscular AAV proteins. For example, base editing involves doses used in this study for systemic application, deaminase enzymes to convert individual nucleo- i.e., equivalent to ~1.5  ×  1016 vg/kg in human, tides without inducing DSB, unintended indels would be hazardously high in patients, requiring

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further optimization before advancing to the clinic. Furthermore, the Hutchinson–Gilford progeria syndrome (HGPS) is recurrently caused by a mis-splicing dominant-negative mutation (G608G; c.1824 C  >  T) in the nuclear lamin A gene (LMNA), generating the toxic progerin, which is responsible for accelerated ageing and shortens the lifespan of children with progeria to approximately 14  years [93]. A recent study described a successful gene therapy in a transgenic mouse model for HGPS, using AAV-­ ABEmax [94]. In this study, normal RNA splicing and progerin protein levels were restored, improved vitality and extended mice lifespan from 215 to 510 days were observed, with minimal bystander editing and without any off-target DNA or RNA editing. In parallel, non-viral lipid-­ nanoparticles (LNP) have also proved efficient for gene editing delivery, particularly in the liver. Two separate studies published the same day in 2021 presented the successful use of LNP to deliver an ABE mRNA and a sgRNA in order to knockout the expression of PCSK9 in vivo in mice and in cynomolgus monkeys via editing of a splice junction [95, 96]. Bystander and off-target editing were remarkably low in both reports. These observations suggest that LNP-mediated delivery of ABE mRNA is significantly accurate and efficient. However, it remains to rule out the possibility of collaterally editing germline cells, in any fertile patient, that could pass on new edits to the offspring and subsequent generations in human, which may risk contravening the AHR Act.

6.6 Health Technology Assessment While the Health Canada and Health Technology Assessment (HTA) review processes are independent of each other, both play a role in drug access. As part of Health Canada’s Regulatory Review of Drugs and Devices (R2D2) initiative to provide more timely access to medicines, collaborations were established between Health Canada and the HTA organizations, the Canadian Agency for Drugs and Technologies in Health (CADTH) and l’Institut national

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d’excellence en santé et en services sociaux (INESSS). An option for aligned reviews between Health Canada and HTA was introduced in 2018 [97]. Sponsors of biological and pharmaceutical New Drug Submissions or supplemental submissions for new indications can opt to participate in a formalized, aligned review process. Under the aligned review pathway, Health Canada and Canadian HTA reviews can proceed in parallel with information sharing between Health Canada and HTA organizations. The benefits of aligned reviews are reducing the time between Health Canada’s market authorization and HTA funding recommendations to federal, provincial and territorial drug plans and cancer organizations, while also improving communication and collaboration between the HTA organizations and Health Canada. In 2019, Health Canada and CADTH launched an initiative to provide early parallel scientific advice, with INESSS as an observer [98]. Through this initiative, drug sponsors could obtain advice from the regulator and the HTA in parallel to ensure that they are obtaining the type of evidence needed for decisions to be made on market authorization and reimbursement in Canada. Health Canada continues to support ongoing presubmission interactions between Health Canada, HTA organizations and sponsors, and processes are in place to enable parallel scientific advice if requested by sponsors.

6.7 Conclusion: Possible Future Directions in the Field An appropriate level of regulatory oversight has the potential to protect patients by minimizing the risk of adverse events while also enabling scientific advancement by maintaining sufficient flexibility to support innovation. Health Canada has established, and continues to adapt, a regulatory framework that strives to meet these goals and is committed to working with sponsors from academia and industry, other regulatory authorities and other interested stakeholders to facilitate continued entry to the market of promising CGTP.  Health Canada’s

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current regulatory modernization initiatives include proposed updates to the clinical trial regulations and the development of new, more agile regulations to better support oversight of drugs, both before and after sale. The new ATP framework will provide the ability to authorize products that significantly challenge our current regulations in a flexible and risk-­based manner. Among other benefits, these initiatives are expected to help regulate the risks, benefits and uncertainties of more diverse and complex products such as CGTP. Although the regulatory tools currently under development may be particularly useful for products targeting small patient populations, new regulatory paradigms may be needed in some situations. The cost of bringing a new drug product through the marketing approval process typically runs into hundreds of millions of dollars; and, to protect such an investment, industry requires a strong proprietary position and a suitable, projected, financial return. In the absence of biopharmaceutical industry sponsorship, some products/therapies with significant potential may face an unsure future with investigational status at a limited number of treatment sites. Additionally, a centralized manufacturing approach presents many challenges for the distribution of CTP and cell-based GTP that utilize autologous cells, and some such products may require the need for additional steps at the treatment site prior to administration that would currently constitute product manufacturing. An alternative regulatory option that requires proof of safety and efficacy demonstrated through clinical trials but then allows wider use at registered/ licensed establishments committed to established procedures, and meeting appropriate standards might be useful in many situations [99]. Finally, Health Canada is a strong proponent and active participant in efforts geared towards international regulatory harmonization and convergence. The sharing of scientific expertise and regulatory experiences is always positive and will be especially valuable in this still developing field of endeavor, encompassing such a wide variety of products.

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7

Advanced Therapy Products in Brazil: Regulatory Aspects João Batista Silva Junior, Renata Miranda Parca, and Adriana Bastos Carvalho

Abstract

Advanced therapy products, considered special medications, require Anvisa approval for use and commercialization in Brazil. They include advanced cellular therapy products, tissue engineering products, and gene therapy products, which due to their complexity involve innovation and risks, optimized regulatory channels for their development and life cycle monitoring. The J. B. S. Junior (*) Department of Pharmaceutical Sciences, College of Health Sciences, University of Brasilia, Brasilia, Brazil National Health Surveillance Agency (Anvisa), Brasilia, Brazil National Network of Experts in Advanced Therapies (Reneta), Anvisa, Brasilia, Brazil e-mail: [email protected] R. M. Parca National Health Surveillance Agency (Anvisa), Brasilia, Brazil National Network of Experts in Advanced Therapies (Reneta), Anvisa, Brasilia, Brazil A. B. Carvalho National Network of Experts in Advanced Therapies (Reneta), Anvisa, Brasilia, Brazil Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

scientific elements and the compliance with applicable regulatory aspects are fundamental pillars for the advancement of clinical trials, the positive evidence of the benefitrisk profile, and the definition of the critical quality attributes, from the perspective of making safe, efficacy, and high-quality products available to the population. The approval models of these products in Brazil adapt to the specificities and characteristics of the technology and the patient target population, with accelerated regulatory analyses, use in emergency situations by risk controls and specific monitoring mechanisms, principally those related to rare diseases without other therapeutic alternatives. The opportune access to the advance therapy product with safety, efficacy, and quality involves innovative normative elements that include the long-term follow-up of the safety and efficacy and of the adaptive pharmacovigilance requisites, as well as the traceability mechanisms for starting materials, products, and patients. Keywords

Brazil · Gene therapy · Advanced Therapy Medicinal Product · Anvisa · Clinical trials · Regulatory approval

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 M. C. Galli (ed.), Regulatory Aspects of Gene Therapy and Cell Therapy Products, Advances in Experimental Medicine and Biology 1430, https://doi.org/10.1007/978-3-031-34567-8_7

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Abbreviations ACTP

Advanced Cellular Therapy Product Anvisa Agência Nacional de Vigilância Sanitaria (National Health Surveillance Agency) ATMP Advanced Therapy Medicinal Products CAR-T Chimeric Antigen Receptor T cells CAT Comitê de Assessoramento Técnico em Terapias Avançadas cGMP Certification of Good Manufacturing Practice CONEP Comissão Nacional de Ética em Pesquisa CTNBio Comissão Técnica Nacional de Biossegurança DDCTA Dossiê de Desenvolvimento Clínico de Produto de Terapia Avançada Investigacional DSCTA Dossiê Simplificado para Ensaio Clínico com Produto de Terapia Avançada Investigacional EB Executive Board EMA European Medicines Agency GCP Good Clinical Practice GLP Good Laboratory Practice GMP Good Manufacturing Practice GSTCO Gerência de Sangue, Tecidos, Células, Órgãos e Produtos de Terapias Avançadas GTP Gene Therapy Product HPC Hematopoietic Progenitor Cells MA Marketing Authorization PAHO/WHO Pan-American Health Organization/World Health Organization PIC/s Pharmaceutical Inspection Co-operation Scheme PK/PD Pharmacokinetics/Pharmacodynamics RDC Resolução da Diretoria Colegiada RENETA Rede Nacional de Especialistas em Produtos de Terapias Avançadas

RMP TEP USFDA

Risk Management Plan Tissue Engineering Product United States Food and Drug Administration

7.1 Introduction Blood, tissues, cells, and human organs are therapeutic alternatives, regulated in Brazil under close vigilance, converging in an internationally prevalent regulatory model [1–4]. The blood products, tissues, and human cells intended for transfusion and transplants are not eligible for marketing authorization at the Agência Nacional de Vigilância Sanitaria (National Health Surveillance Agency, Anvisa) in Brazil as it is done for medicines. They are produced or manipulated in dedicated health establishments  – blood establishments, tissue banks, cell processing centers  – and have their quality and safety controlled through compliance with the requirements of national regulations and inspection actions of Good Practices applied to each productive chain and therapeutic use [5–7]. On the other hand, technically obtained or elaborated pharmaceutical products with prophylactic, curative, and palliative purposes, denominated medications or drugs, receive marketing authorization approval in Brazil and the world through exhaustive proof of their safety, efficacy, and quality by a competent national authority [8, 9]. Since the therapeutic functions of products based on blood, tissues, cells, organs, and conventional medicines are somewhat similar, the regulatory models of the two are differentiated according to the risk potential, technological development, and innovative clinical use. The advances in biotechnology led to a new perspective on innovative products that use cellular and genetic potential employing cell culture techniques, materials sciences, and recombinant DNA technology [10, 11]. In this context, a class of products based on human cells, tissues, and genes has been developed and approved as a new therapeutic approach [12]. They are denominated Advanced Therapy

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Medicinal Products (ATMP) used to treat, prevent, or diagnose diseases. They include advanced cellular therapy products, gene therapy products, and tissue engineering products, which may be combined with medical devices [13–17]. A fragile regulatory environment contributes to health risks permitting the indiscriminate use of unsafe products without proven efficacy, aggravated by profound asymmetries in information and negative externalities. Added to this scenario is the dangerous direct marketing to the consumer of interventions using stem cells and other nonapproved advanced therapy products [18–21]. According to the Pan-American Health Organization/World Health Organization (PAHO/ WHO) [15] in the Americas, there is a proliferation of medical advertisements that promise access to cell therapies, which in many cases do not have the minimal scientific substantiation in safety, efficacy, and quality, entailing critical clinical risks to the patients. In this sense, the United States Food and Drug Administration (USFDA) has alerted against the indiscriminate use of cell therapy in the United States [22] and has informed that unproven and unauthorized stem cell therapies can be particularly unsafe for patients. Likewise, the European Medicine Agency (EMA) [23] in a document published in 2020, states that “patients who use unproven or unregulated therapies based on cells and genes, have suffered grave collateral, sometimes fatal, effects, including infections, undesired immunological reactions, tumor formation (…)” highlighting that cells infused in patients to exert a function distinct from their original role in the human body or cells, which have been substantially manipulated, aggregate risks and should be regulated with the same regulatory vigor as medicines. Concerned about the internationally reported situation and detecting similar cases in investigative processes in Brazil, in 2012, Anvisa initiated an ample scientific and social discussion, also of a judicial nature [24] on the advanced cellular therapy regulation, which culminated in 2018 with the publication of the first Brazilian ­regulatory norms applied to ATMP, determining the concept of “spe-

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cial medicines” for these products [25]. Considering the international regulatory convergence, Brazil has been structuring the normative benchmark with the establishment of rules and assumptions for the manipulation of cells and genes and their transformation into products with a human therapeutic purpose to be approved and commercialized, intending to protect the life of those who might be treated with them [17]. Another crucial point, derived from Brazilian constitutional precepts, is the guarantee of gratuitous collection of cells, tissues, and other bodily parts to be employed as starting materials in the manufacture of the ATMP by free, spontaneous, and informed donation, to dispel the risk of any abuse [17]. The objective of this chapter is to briefly describe the Brazilian regulatory model applied to ATMP, considering their development cycle, approval, and postcommercialization monitoring. In addition to the related scientific bibliography, official Anvisa documents pertinent to ATMP in Brazil are also referred to.

7.2 Brazilian Regulatory Concepts for ATMP Goods and products subject to regulatory vigilance involve the possibility of risk to public health, including those obtained by genetic engineering or other biotechnological procedures [26]. In a legal context, the use of ATMP for clinical trials or commercial therapeutic use in Brazil is determined by Law 9782/99 [26]. Anvisa defined advanced therapies products as a particular category of medicines subject to the same regulatory mechanisms [27]. The definition of ATMP in the Brazilian norms is fundamental to establishing specific requisites for mitigating risks. The products categorized for regulatory purposes and their concepts are described in Table 7.1. Anvisa is updating the concept of “Combined ATMP” as a product that incorporates one or more active medical devices into ATMP as an integral part of the final product, according to the current Pharmaceutical Inspection Co-operation Scheme (PIC/s) standard [28]. An example of this class is

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120 Table 7.1  Regulatory definition for ATMP in Brazil Term Advanced therapy products (ATMPs) Advanced cellular therapy product (ACTP)

Tissue engineering product (TEP)

Gene therapy product (GTP)

Minimal manipulation

Concept Special categories of new medications encompassing advanced cell therapy products, tissue engineering products, and gene therapy products A biological product consisting of human cells, or their nonchemically defined derivatives, to obtain therapeutic, preventive, or diagnostic properties through a metabolic, pharmacological, and immunological mode of action for autologous or allogeneic use in humans, provided it (a) has been subjected to extensive manipulation and/or (b) performs in the patient a distinct function from that performed in its origin Biological product constituted by organized human cells in tissues or organs that present properties permitting the regeneration, reconstruction, or substitution of a tissue or human organ, in the presence or not of structural support constituted by a biological or biocompatible material, provided it (a) has been submitted to extensive manipulation and/or (b) performs in the patient a distinct function from that performed in its origin Biological product with an active component containing or consisting of a recombinant nucleic acid (gene), having the objective of regulating, repairing, substituting, adding, or deleting a genetic sequence and modifying gene expression, aiming at a therapeutic, preventive, or diagnostic result Cell or tissue processing that does not significantly alter the biological characteristics of the final product. Actions considered as minimally manipulating are cutting, separating, centrifuging, submerging, or preserving in antibiotic solutions, concentrating, purifying, filtering, lyophilizing, irradiating, freezing, cryopreserving, or vitrifying, among others (continued)

Table 7.1 (continued) Term Extensive manipulation

Class I ATMP

Class II ATMP

Concept Cell and tissue processing that alters any of the biological characteristics of the final product, among which are differentiation and activation state, proliferation potential, and metabolic activity. It is any cell and tissue processing that does not configure minimal manipulation. For example, any type of cell culture is considered extensive manipulation ATMP subjected to minimal manipulation, in which the cells perform a different or innovative function as compared to that performed in their origin ATMP subjected to extensive manipulation, tissue engineering products, and gene therapy products

Source: Anvisa Resolution 505/2021 [27]

cells that are incorporated into a biodegradable matrix or scaffold. Using these regulatory concepts establishes a differentiation between products based on cells and tissues considered advanced therapies and products which involve cells, tissues, and human organs, as in conventional therapies applied in transfusion, transplant, and grafting procedures. The core for the differentiation of therapeutic products based on human body parts is determined by the technological increment and innovative clinical indication present in the ATMP. For example, the selection of cells by peripheral blood apheresis to obtain a greater concentration of hematopoietic progenitor cells (HPC) for transplant is considered a cellular therapy with minimal manipulation, these cells being used for the same essential function and in the same anatomical or histological space. However, still using the HPC as a model, when these cells undergo expansion and differentiation in culture under specific conditions, this is considered a substantial or extensive manipulation, because the characteristics of cellular multipotency and capacity for self-­renovation may be altered [29–32]. Or even when these HPC are collected and minimally manipulated but intended for novel therapeutic use in relation to their original function, they are also considered class I ATMP.

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A gene therapy product (GTP) has its therapeutic, prophylactic, or diagnostic effect directly dependent on the recombinant nucleic acid sequence or the genetic expression product of this therapeutic sequence. These types of ATMP encompass the products that impart their therapeutic effects by transcription and translation of genetic material transferred through vectors (viral or nonviral) to the patient’s cells in the in vivo or ex vivo modalities. In Brazil, the same concept adopted in Europe applies, which describes that vaccines against infectious diseases based on the genetic material of microorganisms are not included in the GTP class [27, 31]. Another example adopted in Brazil and applied in the United States is that products based on wild oncolytic viruses do not qualify as GTP if they do not have recombinant nucleic acid [27, 32]. Furthermore, it is also essential to highlight the regulatory point of view that genetically modified T-cell-based products, the chimeric antigen receptor T-cells (CAR-T), are classified as ex vivo GTP. Borderline cases can occur where the classifications of drugs, ATMP, medical devices, and blood, tissue, cells, and organs overlap, and a clear delineation between product types is not immediately apparent. The Brazilian ATMP Regulation [33] has therefore introduced an optional procedure that allows researchers of products based on genes, cells, or tissues to seek a regulatory recommendation from Anvisa on whether their product can be classified as an ATMP or not. Since the regulatory framework differs significantly between the various health-­ care products (medicinal products, medical devices, ATMP, blood, tissues, and cells for transfusion/transplant, etc.), it is critical for developers of new therapies to have clarity about the classification of their product at an early stage of development. In addition, the ATMP classification allows identifying the applicable regulatory and scientific guidelines for a given drug’s d­ evelopment path and all appropriate procedures. Furthermore, the ATMP classification offers the opportunity to initiate an early dialogue with regulators and can help facilitate clinical trial authorization.

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7.3 Regulating Advanced Therapies Products in Brazil As determined by Brazilian sanitary laws, no ATMP, including the imported ones, can be commercialized or administered to the patient prior to Anvisa’s approval [34]. The ATMP marketing authorization in Brazil follows the same structure used for other medicines, with a specific risk approach, as schematized in Fig. 7.1. The company interested in registering its product in Brazil must demonstrate (i) the quality aspects (characterization, production, and control process and quality risk management); (ii) the safety profile (pharmacological/toxicological characteristics) and proof of concept in in vitro and in vivo models; (iii) the human safety profile and efficacy results for the clinical indication, dosage, and established target population; and (iv) develop a Risk Management Plan (RMP) for the use of the product in Brazil [27]. At Anvisa, under the supervision of the Executive Board 2 (EB2), the Office of Blood, Tissues, Cells, Organs, and Advanced Therapy Products (in Portuguese, Gerência de Sangue, Tecidos, Células, Órgãos e Produtos de Terapias Avançadas  – GSTCO), which is part of the General Office of Biological Products (in Portuguese, Gerência-Geral de Produtos Biológicos, Radiofármacos, Sangue, Tecidos, Células, Órgãos e Produtos de Terapias Avançadas – GGBIO), is responsible for evaluating an ATMP, considering its clinical development, marketing authorization and Certification of Good Manufacturing Practice (cGMP), as schematized in Fig.  7.2. GSTCO is the area of Anvisa that performs the regulatory functions related to ATMP (clinical trial approval, marketing authorization approval, and cGMP). This is Anvisa’s strategy for the systematic development of regulatory frameworks and innovative evaluation procedures applied to ATMP. Also, a technical advisory committee was set up, called the Technical Committee for Advanced Therapy (CAT), composed of Brazilian scientists specialized in advanced therapy to collaborate with Anvisa in the elaboration of normative frameworks and in strategic

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PRIOR APPROVAL BY ANVISA Anvisa's GMP Certification for ATMP active substances and finished products

Clinical Trials Research and Development

In vitro .Proposed target .Selectivity .Biomarkers .Potency and cytotoxicity .Biological structure and activity

Preclinical trials

In vivo (animals) .Pharmacological profile (PK/PD) .Administration .Prediction of doses .Interaction and toxicity

Phase 1

Phase 2

Phase 3

Safety

Safety and Efficacy

Efficacy and Safety

.Exploratory studies – “First human” . Specifics designs. Ex. Phase 1/2; Phase 2/3

Marketing Authorization (MA)

Post-MA and Pharmacovigilance

.Long term followup studies for confirmation of efficacy and safety .Adverse events notifications

Fig. 7.1  Overview of the development of new therapeutic products and related regulatory steps in Brazil

regulatory discussions. Depending on the product and its clinical application, it is possible to request the ad hoc specific evaluation of external specialists registered in the Anvisa Network of Specialists in Advanced Therapy (in Portuguese, Rede Nacional de Especialistas em Produtos de Terapias Avançadas-RENETA). RENETA is made up of professionals with expertise in ATMP belonging to prestigious Brazilian Universities, research, and health care institutions. These specialists can collaborate in benefit-risk assessments of ATMP, with suggestions for Anvisa’s decision regarding specific elements of nonclinical and clinical data and quality aspects.

7.3.1 Main Aspects of Clinical Trials with ATMP When there is the intention to initiate clinical studies with a new ATMP in Brazil, it is always necessary to obtain previous approval from Anvisa. This is also required when a new indication or different administration route for a previously approved product is being proposed. The agency concedes the permission to perform clinical trials on the investigational product to determine the elements for its safety, clinical efficacy,

and quality attributes, under a controlled process and by responsible sponsors and researchers [33]. The scientific features and compliance with regulatory aspects are fundamental pillars for advancing the developmental processes of a therapeutic product. In Brazil, three public institutions may act with complementary functions in supervising clinical trials on an ATMP. The approval of ethical and social aspects of the studies involving human beings is the responsibility of the National Commission on Ethics in Research (in Portuguese, Comissão Nacional de Ética em Pesquisa – CONEP) using the CONEP System coordinated by the Ministry of Health. In parallel, Anvisa evaluates the quality and safety aspects of the investigational product utilizing a judicious revision of fabrication process and its controls, the characterization tests (identity, purity, potency, and others), and the sterility of the finished product and intermediaries of the process, as well as the scientific validity of the proposed protocol, or in other words the ability of the trial design for proving efficacy and safety of the product, allowing an evaluation of risks and benefits. Anvisa, when reviewing an ATMP clinical trial, will assess the validity of the traceability system, the proposed follow-up strategy, as well as the end-of-trial definition and risk

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Collegiate Executive Board (EB)

Support for Governance

Chief Executive Officer

General Office for Drugs

EB 2

General Office for Foods

EB 4

EB 3

EB 5

General Office for Biologics (GGBIO)

Office of Biologics Products

Office for Blood, Tissues, Cells, Organs and ATMP (GSTCO)

CAT Advanced Therapy

RENETA Fig. 7.2  Anvisa organization chart: specific structure of Executive Board 2 and General Office for Biologics Chief Executive Officer – Advisory and Administration Units EB2  –  Executive Board 2 (General Office for Drugs; General Office for Foods, General Office for Biologics) EB 3 – Executive Board 3 (General Office for Toxicology; General Office Medical Devices; General Office Tobacco Products; Office for Cosmetics and Sanitizing; General Office for Health Services)

assessment. Finally, in the clinical development phase of gene therapy products, it is essential to evaluate the environmental biosafety of the component identified as a genetically modified organism: this task is performed by the National

EB 4 – Executive Board 4 (General Office for Inspection; Office for Official Laboratories) EB 5  –  Executive Board 5 (General Office for Product Monitoring; General Office for Ports, Airports and Borders; Office for Pharmacovigilance) CAT – Technical Committee for Advanced Therapy RENETA  –  Anvisa Network of Specialists in Advanced Therapy (https://www.reneta.org.br/) GGBIO – General Office of Biologics GSTCO –  Office for Blood, Tissues, Cells, Organs and ATMP

Technical Commission on Biosafety (in Portuguese, Comissão Técnica Nacional de Biossegurança – CTNBio) [33]. A clinical trial dossier for Anvisa should be composed of the following documents:

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• Clinical development plan for the investigational ATMP, containing information on the clinical development project of the product. • Specific protocol of the clinical trial to be performed in Brazil. • Investigator’s brochure containing basic information on the preclinical and clinical data of the product. • Documents proving the production process quality. The general flow of document submission to Anvisa stipulates analysis deadlines for the Agency by type and technical complexity of the dossier: 180  days for the Clinical Advanced Therapy Product Development Dossier (in Portuguese, DDCTA) and 30  days for the Simplified Clinical Advanced Therapy Product Development Dossier (in Portuguese, DSCTA). Those time frames consider Anvisa’s complete evaluation process: (i) first analysis of the dossier with the Agency’s requests and recommendations; (ii) reassessments of responses and requirements; (iii) discussion meetings with the sponsor; (iv) scientific evaluation by CAT/RENETA, when necessary; and v) official approval publication procedures. Currently, the first analysis by Anvisa takes around 60 days, and the maximum approval/ nonapproval period is about 100 days. Therefore, the definition of deadlines for the evaluative and decision process at Anvisa and the responses and adaptations of the sponsor is a crucial component of a transparent and predictable regulatory process [35]. For the initiation of the clinical trials, it is essential that robust and specific preclinical research data with the investigational product, preferentially performed in a setting of Good Laboratory Practice (GLP) [36], are provided. For the regulatory analysis, the sponsor needs to demonstrate how the preclinical studies and respective results were performed and obtained, including the pharmacology and toxicology studies, in vitro or in vivo, preferentially in relevant animal models. Such studies should generate data verifying that the product is reasonably safe for initial tests on humans. In addition, the preclinical data should be adequate in supporting the pro-

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posed clinical trial with recommendations for the safe dose, scaling scheme, and administration route [37]. Previous use of the product in patients, when existent, even in emergency use situations, can be incorporated in the dossiers to corroborate the preclinical data. Regarding gene therapies, specific questions should be studied in the preclinical phase, for example, proof of concept studies, product biodistribution, level and persistence of genetic expression, alteration in germinative lineage, and others. The toxicology studies should also consider the risk of the used vectors and their potential for insertional mutagenesis [27]. The basic structure of clinical development of a therapeutic product is generally divided into three phases, with each supplying subsidies and support for the next stage, with robust data which corroborates the positive balance between benefit-­risk [37]. One of the critical phases for the regulator is when the ATMP is used for the first time in human beings, which denotes higher risks due to the uncertainties and limitations of the preclinical data in predicting safety and efficacy. The principal focus in a phase I study is monitoring product safety in a specific population of few patients. However, it must be noted that the safety evaluation of a product remains being investigated during the whole development. These studies should be to determine human metabolic and pharmacologic actions, obtaining sufficient information on the pharmacokinetics, associated adverse events, and dosage schemes [38]. The innovative characteristics of ATMP related to pharmaceutical biotechnology and the indications for rare conditions without therapeutic alternatives have challenged the researchers in the proposition of trial designs with combined phases, for example, phase I/II, phase II/III, and additional trials in phase III following the approval. For many ATMP, phase I trials are conducted for safety evaluation (the primary objective of this type of study), frequently combined with an early efficacy evaluation (considered secondary objectives). Another possible design combines the dose escalation phase with the initial efficacy evaluation by means of the patient cohort expansion, receiving

7  Advanced Therapy Products in Brazil: Regulatory Aspects

the dose considered safe in the scaling stage, permitting that efficacy data on patients in phase I be grouped with the efficacy data of patients in phase II, resulting, therefore, in a phase I/II study design. Small populations of patients, especially in rare diseases, also allow researchers to propose innovative trial projects, with the involvement of Anvisa from the start of the process, including new or surrogate endpoints, single-arm trials, and the use of data on the natural history of the disease as the comparative group. Randomized clinical trials are considered to supply more reliable evidence upon evaluating a new intervention’s safety and efficacy and obtaining regulatory approvals [38, 39]. Nevertheless, it will not always be possible to rigorously follow the randomized clinical trials rules, principally for rare diseases that have few to no effective treatment options available, making important the consideration of other measures which can aid in improving the strength of scientific evidence applied to the ATMP. Anvisa has been discussing strategies for using complementary data from the literature to support decisions and concerns about prospecting safety, in addition to natural history studies that help in evaluating the results of efficacy proposals. In the case of advanced therapies, the information on the production process and the release criteria are also necessary to adequately correlate the literature results used with the exclusive product characteristics [39]. Valid scientific principles should be applied in all ATMP development phases related to safety, active components, raw materials, starting materials, and production process quality control. In the case of ex vivo gene therapy products, for example CAR-T cells, a dossier should be drawn up for Anvisa evaluation, with the description of the cell source, clinical and laboratory screening of donors, collection and processing methods, culture conditions and procedure for the cell genetic modification procedure. Extensive safety trials and modified cell characterization must include information on the cellular identity and viability, cell subpopulation percentages, transduction efficiency, genetic expression persistence, transgene integrity, genetic stability during the in vitro proliferation,

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number of copies of the transgene per transduced cell and presence of replication competent virus, as well as the sterility [40]. Care must also be taken when dealing with autologous products so that adequate labeling and tracking systems can be used. An initial stage in developing a GTP is the construction of the vector responsible for delivering the gene of interest to the target cell. This vector must be tested and rigorously characterized. The regulatory documentation on the vector construction should include the description of the vector components, their source and derivation, restriction and cloning site, regulatory elements, and others, as well as their production and purification method, identity, quality, purity, and potency [40]. It is important to highlight that Brazil has explicit legislation that prohibits genetic modification in human germ cell, human zygote, and human embryo [41]. From the initial developmental phases onward, the analytical trials qualification should be established to permit collection of reliable data and development of acceptance criteria that are adequate for the quality control of raw materials and starting materials. Other fundamental points in the clinical trial information process are the qualifications of researchers who supervise the experimental product’s administration and detect and manage adverse events. Moreover, attention must be given to the standardization of the product preparation processes prior to its administration and the training of all professionals involved [33]. When Anvisa receives insufficient or unclear information in the documentation, which impedes the understanding and the adequate evaluation of risks and potential benefits, appropriate regulatory questions are made. The sponsor must correct the identified deficiencies or provide supplementary information to pursue the regulatory analysis. Critical situations can lead to the nonapproval of the clinical trial, for example, if it is detected that patients or participants in the research will be exposed to risks and significant harm. Following the consent by Anvisa, pending other Brazilian legal requirements, the clinical trial can be initiated, according to Good Clinical Practice (GCP) [42] rules. Annually, the sponsor must forward monitoring reports to the Agency,

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including adverse events and partial summaries of the results obtained. It is furthermore highlighted that severe adverse events that are life-­ threatening and deaths must be timely reported to the Agency, the maximum deadline being 7 (seven) days from the date of occurrence of the case. The remaining serious adverse events should be reported within 15 (fifteen) days [33]. During the evaluation process by Anvisa on certain ATMP, a case-by-case approach may be applied to guarantee that national requisites and international recommendations be appropriately attended to. An investigational ATMP can be used out of a clinical trial before its approval by means of specific programs, such as expanded access (group of patients), compassionate use (specific patient), and poststudy supply, with the previous approval and supervision by Anvisa [43]. The exceptions applied to an out of clinical trial investigational ATMP, as per the Anvisa Resolution 38/2013, are shown in Table 7.2. Table 7.2  Principal concepts of access programs to investigational products in Brazil Type of access Compassionate Use

Expanded Access

Poststudy use

Description Use of a promising new product, yet without registration at Anvisa, but in any phase of clinical development, destined for a specific patient with a severely debilitating disease, which threatens his or her life in the absence of a satisfactory therapeutic alternative Use of a new promising product, yet without registration at Anvisa, or registered but not commercially available in the country, which is in a phase III study in development or concluded, destined to a group of patients with seriously debilitating diseases or in imminent risk of death and without a satisfactory therapeutic alternative Gratuitous use of the developed product, applicable in cases of study termination or when the patient participation in the study has been finalized

Source: Anvisa Resolution 38/2013 [43]

7.3.2 ATMP Marketing authorization An ATMP can only be authorized for market if the benefit-risk profile is positive, the benefits being related to the principal favorable effects of primary and secondary clinical outcomes. The risks describe the incidence, gravity, duration, reversibility, and dose-response relation of unfavorable effects and adverse events of the product. Clinical study limitations related to sample size and representation of the target patient population must be adequately discussed and will be taken into consideration in the decision-making process [27]. Brazilian regulations establish that proof of product safety and quality requires specific tests to assess identity, potency, sterility, purity, qualification and quantification of impurities, presence of mycoplasmas, endotoxins, adventitious viruses, in accordance with the main international guidelines [27]. The product identity is demonstrated through specific identification tests and its distinction from any other substance. In turn, the potency tests should indicate the specific capacity of the product for reaching a determined result. Another critical aspect, ATMP purity, can be defined as the capacity to detect foreign elements or materials present following the production processes. The purity testing of a gene therapy product, for example, involves tests for detection of viral capsid residual proteins, host cell residual DNA, RNA, competent replication virus, undesirable nucleotide sequences, solvents, cryopreservation media or auxiliary products of production and purification, such as cytokines, antibodies, antibiotic residues, culture media, sera, and others. To complete the product characterization, a dossier should be presented on the stability tests program, for each type of product, for example, the product of advanced cellular therapy and ex vivo GTP, including the cell number and cellular viability, sterility, and potency tests [44–46]. A brief description of the essential documents that must be presented to Anvisa for ATMP marketing authorization is shown in Table 7.3.

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Table 7.3  Main documents in the ATMP approval dossier in Brazil and examples of information to be discussed ATMP Registration dossier

Documents Nonclinical studies report

General topics to be discussed Proof of intended therapeutic effect (proof of concept), of safe and effective dose, of route and administration frequency safety, of interaction with tissues (potential secondary effects), of viability, lifespan, distribution, persistence, metabolism, excretion, toxicity (product, impurity, and excipients), immunogenicity, tumorigenic potential, criteria used in selecting in vitro and in vivo species and relevant animal models and others Clinical studies Studies on clinical safety, biodistribution and grafting, lifespan, ectopic report graft, oncogenetic transformation, cellular lineage stability, additional studies on excretion and genomic sequencing alteration, clinical efficacy for the proposed indication, administration and intended dosage scheme, detected adverse events and statistical support data Quality report Starting materials, raw materials, and excipients used, necessary materials for the production of vectors and genetic manipulation of cells, genetic sequencing analysis, virulence attenuation and description of tropisms, information on selection and collection of human material, information on the active component and final product, analytical methodologies employed, description and flows of the production stages, reports on critical stages validation, validation reports on analytical methods, traceability mechanisms, transportation validation, stability studies, and storage procedures Report on the approval analysis issued by the competent authorities, when applicable cGMP for the manufacturer of active component and final product Proposals for use orientation to health professionals and patients (product information) Description of primary and secondary packaging The risk-management plan (RMP) is a mandatory document to be presented to Anvisa for the marketing authorization of the ATMP that will be used in the Brazilian population Strategies for long-term monitoring Mechanisms for distribution, logistics, and export/import, when applicable

Source: Anvisa Resolution 505/2021 [27]

Approval for ordinary ATMP marketing authorization is conceded when the information on quality is adequate, and the data proving the efficacy and safety are unequivocal, statistically significant, and based on complete clinical trials [27]. In the Brazilian legislation, the category of priority product was also established, with an accelerated evaluation process encompassing ATMP destined for the treatment of rare and neglected diseases, for severe and debilitating conditions in which there is no available therapeutic alternative, and for public health emergencies. In this category, Anvisa evaluation period was reduced from 365 to 120 days. The central idea of regulatory accelerated process was to guarantee that patients in specific situations could benefit from new treatments. ATMP that address a new therapeutic indication in the pediatric population can also be included in this priority category.

Priority analysis is also granted to the ATMP for which clinical trials (phases 1 and 2) are carried out in Brazil. In all situations, the applicant for accelerated analysis should present in the dossier adequate justifications for inclusion in these categories [27]. Additionally, it is recommendable that an initial presubmission dialog between the company and the Agency is initiated. Finally, it is essential to highlight that the accelerated process has the same quality requirements as a standard marketing authorization. It requires a robust production process that is reproducible, validated, and carried out in a facility with cGMP [46]. Exceptionally, ATMP approval is conceded under exceptional conditions, which requires further confirmation of long-term clinical efficacy [27]. For this conditional approval, the ATMP must fulfill a clinical necessity without current treatment or clearly offer a therapeutic advantage

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over available therapies. Additionally, it should be analyzed if the product proposes to treat a severe or rare and debilitating condition, or in situations of risk of death or in public health emergencies. The exception occurs when the benefit of immediate availability supersedes the product risks and the fact that additional data on its long-term clinical efficacy are still needed [27]. Evidence obtained utilizing a surrogate clinical outcome, such as a biomarker, rather than a direct therapeutic measurement, can be accepted for the registration under certain conditions, as long as the surrogate outcome can be adequately validated. In some cases, additional trials will be necessary, with real clinical outcomes that can be ongoing or planned to be performed, whose results may be presented on defined dates in terms of commitments established between authorization holder and the Agency. It is also necessary to evaluate if the company has the conditions and planning to supply data and information annually to Anvisa during the time established for monitoring. ATMP marketing authorization types applied in Brazil are shown in Table 7.4. For example, from 2020 to 2022, Anvisa approved five gene therapy products [47] for the treatment of rare diseases and hematological malignancies, granted under conditions with obligations and terms of commitment that will extend over a long time, requiring annual monitoring by the Agency. The list of ATMP authorized for market in Brazil is shown in Table 7.5. Despite the type of registration conceded and the agreed monitoring conditions, any significant alteration of the data submitted to Anvisa should be notified and, on determined occasions, be previously approved by the Agency prior to implementation. This update with the Agency is of fundamental importance to dynamically follow the product’s lifecycle while ensuring regulatory control. For example, following the ATMP marketing authorization approval, studies may be necessary to supply continuous evidence of the positive risk-benefit equilibrium, along with data on real use in patients. These post approval studies are continuous product development strategies, which include clinical studies for a new indication, expansion of the target population, comparability

Table 7.4  ATMP marketing authorization types applied in Brazil Marketing authorization types Deadlines Ordinary 365 days Priority 120 days (accelerated review)

With Conditions

120 days (accelerated review)

Specifics conditions Non-priority conditions Rare diseases, or neglected, emerging, or re-emerging disease Public health emergencies, or serious conditions There is no therapeutic alternative available in Brazil Have a new therapeutic indication or expanded use for the pediatric population Having conducted clinical trials phase 1 or 2 in Brazilian national territory The benefit-risk balance of the preliminary clinical evidence indicates that the ATMP is safe and has the potential efficacy to address unmet medical needs in severe conditions or in rare debilitating diseases or in life-­ threatening situations, or in public health emergencies

Source: Anvisa Resolution 505/2021 [27]

of the product following production changes, validation of surrogate clinical outcomes, demonstration of the superiority to other treatments, etc. Brazilian regulations [27] define the possibility of exceptional clinical use of an ATMP not approved by Anvisa under medical responsibility, with a specific prescription for a given patient. This regulatory resource was instituted in Brazil for exceptional situations in which a product, not under clinical development, may be used as an emergency procedure for a patient at risk of death for treatment of diseases without therapeutic alternatives available in the Country. This type of experimental product cannot be commercialized, and its clinical use is based on the prescribing doctor’s

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Table 7.5  ATMP marketing authorization in Brazil since 2018 Approved products Luxturna® (voretigene neparvovec)

MA types Priority. With conditions

Zolgensma® (onasemnogene abeparvovec)

Priority. With conditions

Kymriah® (tisagenlecleucel)

Priority. With conditions

Carvykti® (ciltacabtagene autoleuce)

Priority. With conditions

Yescarta® (axicabtagene ciloleucel)

Priority. With conditions

Indications Treatment of adult and pediatric patients with sufficient viable retinal cells, with vision loss due to inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations Treatment of pediatric patients under 2 years of age with 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the SMN1 gene and a clinical diagnosis of SMA Type 1, or patients with 5q SMA with a bi-allelic mutation in the SMN1 gene and up to 3 copies of the SMN2 gene Treatment of pediatric and young adult patients up to and including 25 years of age with B cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse posttransplant or in second or later relapse and adult patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) after two or more lines of systemic therapy Treatment of adult patients with relapsed and refractory multiple myeloma, who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progression on the last therapy Treatment of adult patients with diffuse large B cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL) that relapses within 12 months from completion of, or is refractory to, first-line chemoimmunotherapy, and adult patients with relapsed or refractory (r/r) DLBCL and primary mediastinal large B cell lymphoma (PMBCL), after two or more lines of systemic therapy, and adult patients with r/r follicular lymphoma (FL) after three or more lines of systemic therapy

Year approval 2020

2020

2022

2022

2022

Source: Anvisa [47]

scientific rationale and previous clinical experience. In addition to the individual control performed by the responsible professional, it is

fundamental that the product is produced under the GMP conditions in all production operations of the active ingredient and the final product.

130

7.3.3 GMP Certification for ATMP Other requisites, which should be defined entirely, are critical quality attributes and the cGMP issued by Anvisa to produce the active ingredient and the final ATMP [27]. Anvisa’s cGMP is mandatory for the marketing authorization of ATMP in Brazil [27]. cGMP is required to produce the active ingredient (drug substance) and the finished product (drug product). A GMP certificate is not required for manufacturing and testing sites of starting materials for ATMP. However, the site must comply with GMP principles. The quality of the starting material is assessed in the context of the assessment of a marketing authorization/clinical trial application. In addition, starting materials and raw materials are qualified by the company (supplier qualification) [27]. In the certification process, Anvisa uses the general GMP requirements of biological medicines [48, 49] and Good Practices in Cells [50] to carry out inspections in related factories, as well as requirements established by the PIC/s guides. In addition, depending on the risk assessment, Anvisa may use official documents (recent inspection reports, certificates) issued by other authorities that are part of the PIC/s [27]. The main GMP requirements include detailed records, written standardized operating procedures, quality and analytical trials control program, qualification of suppliers and equipment, process validation, personnel qualification, and training program, certification of installations and environmental monitoring [28, 46]. The stability studies on intermediate and finished products should be appropriate for the definition of the validity deadline and proposed filling system [28, 46]. Total adhesion to GMP, required in the marketing authorization process, provides quality and safety in the process, and permits a reproducible and consistent performance of commercial product lots. A manufacturer must describe any change in the product, independent of occurring before or following the marketing authorization approval. The difference in the manufacturing process must be evaluated, and the resulting product must be compared to the existing product

J. B. S. Junior et al.

to guarantee that the change has not altered safety, purity, potency, or integrity of the therapeutic product or any other quality characteristics compromising its clinical performance. Comparability studies can be based on a combination of in vitro or in vivo studies, pharmacokinetics or pharmacodynamics evaluation, toxicity in animals, clinical tests, and others, depending on the process alteration. Product comparability must be demonstrated through comparative analyses of lots of products manufactured according to the prior and new procedures. In these cases, Anvisa evaluates and determines, considering the results presented, if the comparability data are sufficient or if additional studies will be needed. Examples of changes requiring a comparability study include production site alteration or critical alterations in the production flow, changes in the cell or virus banks, vector modification, cell culture alterations, isolation or purification, and changes in the storage container or product formulation, among others [28].

7.3.4 General Aspects of Pharmacovigilance Pharmacovigilance is related to identification, evaluation and prevention of adverse effects or any problems related to the use of medications commercialized in the Brazilian market, including adverse events stemming from quality deviations, therapeutic ineffectiveness, medication errors, use of medicines for indications not approved in the registration, unauthorized use, intoxication, and medication interactions, among others [51, 52]. Pharmacovigilance processes and postuse monitoring mechanisms should be applied to the ATMP approved by Anvisa. Therefore, RMP is an indispensable requisite in the dossier [27, 52] which should address elements involving the safety profile specification and identification of potential risks to be managed or studied in the postregistration period. In addition, ATMP RMP should also address the specific risks associated, for example, with donors of starting material, with surgical or

7  Advanced Therapy Products in Brazil: Regulatory Aspects

administration procedures, with the risks involved inadvertent germline transmission of gene transfer vectors, and others.

7.4 Perspectives Anvisa has the fundamental mission of promoting efficient regulation to fulfill the innovations in ATMP, allowing patients access to new, effective, safe, and high-quality products. It is also in the Agency’s role to supply the necessary information to patients and health-care professionals with transparency and clarity based on regulatory science and approved product information, thus decreasing the asymmetries. The regulatory evaluation is based on robust scientific data and constant analysis of the risk-benefit profile, ensuring the safety of the patients but also permitting the development of innovative products. Strategies to improve understanding of the regulatory aspects for ATMP include Anvisa participation in scientific forums, sector discussions and dialogues with researchers and patients, with the perspective of developing the best regulatory practices and providing the development of quality, safe and effective innovative products focused on a positive impact on the quality of life of Brazilian patients.

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132 junto a Anvisa (2016). Parecer Cons. n°12/2016/ PF-ANVISA/PGF/AGU. 31 mar. 18. MacGregor C., Petersen A., Munsie M. (2015). Stem Cell Tourism: Selling Hope Through Unproven Stem Cell Treatments  – Lessons from the X-Cell Center Controversy. The University of Edinburgh. https://www.eurostemcell.org/stem-­c ell-­t ourism-­ selling-­hope-­through-­unproven-­stem-­cell-­treatments-­ lessons-­x-­cell-­center. Accessed 23 dec 2022. 19. Turner L., Knoepfler P. (2016). Selling stem cells in the USA.  Cell Stem Cell:154–7. doi:https://doi. org/10.1016/j.stem.2016.06.007. Accessed 23 dec 2022. 20. Sipp D., Caulfield T., Kaye J., Barfoot J., Blackburn C., Chan S. et al. (2017). Marketing of unproven stem cell-based interventions: A call to action. Science translational medicine, 9(397). doi:https://doi. org/10.1126/scitranslmed.aag0426. Accessed 23 dec 2022. 21. Lysaght T., Lipworth W., Hendl T., Kerridge I., Lee T.L., Munsi M.,et  al (2017). The deadly business of an unregulated global stem cell industry. J Med Ethics:744-6. doi:https://doi.org/10.1136/medethics-­ 2016-­104046. Accessed 23 dec 2022. 22. United States (US), Food and Drug Administration. FDA Warns About Stem Cell Therapies. Some Patients may be Vulnerable to Stem Cell Treatments that are Illegal and Potentially Harmful. https://www. fda.gov/consumers/consumer-­u pdates/fda-­warns-­ about-­stem-­cell-­therapies. Accessed 23 dec 2022. 23. European Union, European Medicines Agency. EMA Warns Against Using Unproven Cell-Based Therapies. EMA/CAT/94295/2020 Committee for Advanced Therapies. https://www.ema.europa. eu/en/documents/public-­s tatement/ema-­w arns-­ against-­using-­unproven-­cell-­based-­therapies_en.pdf. Accessed 23 dec 2022. 24. Brasil, Agência Nacional de Vigilância Sanitaria. Relatório Seminário Nacional sobre Regulação de Terapias Celulares. https://www.gov.br/anvisa/ ptbr/centraisdeconteudo/publicacoes/sangue-­ teci-­d os-­c elulas-­e -­o rgaos/outras-­p ublicacoes/ relatorio-­s eminario-­n acional-­r egulacao-­e m-­ terapias-­celulares-­2012.pdf. Accessed 23 dec 2022. 25. Brasil, Agência Nacional de Vigilância Sanitaria. RDC 214/2018. Dispõe sobre as Boas Práticas em Células Humanas para Uso Terapêutico e pesquisa clínica, e dá outras providências. https:// bvsms.saude.gov.br/bvs/saudelegis/anvisa/2018/ rdc0214_07_02_2018.pdf. Accessed 24 dec 2023. 26. Brasil, Lei Federal. Lei 9782/1999. Define o Sistema Nacional de Vigilância Sanitaria, cria a Agência Nacional de Vigilância Sanitaria. http://www.planalto.gov.br/ccivil_03/leis/l9782.htm27. Accessed 23 dec 2022. 27. Brasil, Agência Nacional de Vigilância Sanitaria. RDC 505/2021. Dispõe sobre o registro de produto de terapias avançadas. https://www.in.gov.br/en/ web/dou/-­/ resolu-­c ao-­r dc-­n -­5 05-­d e-­2 7-­d e-­m aio-­ de-­2021-­323002775. Accessed 23 dec 2022.

J. B. S. Junior et al. 28. Pharmaceutical Inspection Co-operation Scheme (PIC/s). Guide To Good Manufacturing Practice for Medicinal Products. Annex 2A Manufacture of Advanced Therapy Medicinal Products for Human Use. https://picscheme.org/en/ publications?tri=gmp#zone. Accessed 23 dec 2022. 29. Galvez P., Clares B., Hmadcha A., Ruiz A., Soria B. (2013). Development of a cell-based medicinal product: regulatory structures in the European Union. Br Med Bull:85–105. doi:https://doi.org/10.1093/bmb/ lds036. Accessed 23 dec 2022. 30. Committee for Advanced Therapies (CAT), CAT Scientific Secretariat, Schneider C.  K., Salmikangas P., Jilma B., Flamion B., Todorova L. R. et al. (2010). Challenges with advanced therapy medicinal products and how to meet them. Nature reviews. Drug discovery, 9(3), 195–201. doi:https://doi.org/10.1038/ nrd3052. Accessed 23 dec 2022. 31. European Union, European Medicines Agency. Reflection Paper on Classification of Advanced Therapy Medicinal Products. Committee for Advanced Therapies (CAT). https://www.ema.europa. eu/en/documents/scientific-­g uideline/reflection-­ paper-­c lassification-­a dvanced-­t herapy-­m edicinal-­ product-­s_en-­0.pdf. Accessed 23 dec 2022. 32. United States (US), Food and Drug Administration. Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products. https://www.fda.gov/files/ vaccines%2C%20-­b lood%20%26%20biologics/ published/Design-­a nd-­A nalysis-­o f-­S hedding-­ Studies-­for-­Virus-­or-­Bacteria-­Based-­Gene-­Therapy-­ and-­Oncolytic-­Products−Guidance-­for-­Industry.pdf. Accessed 23 dec 2022. 33. Brasil, Agência Nacional de Vigilância Sanitaria. RDC 506/2021. Dispõe sobre as regras para a realização de ensaios clínicos com produto de terapias avançadas investigacional no Brasil, e dá outras providências. https://www.in.gov.br/en/ web/dou/-­/resolucao-­rdc-­n-­506-­de-­27-­de-­maio-­de-­ 2021-­323008725. Accessed 23 dec 2022. 34. Brasil, Lei Federal. Lei 6360/76. Dispõe sobre a Vigilância Sanitária a que ficam sujeitos os Medicamentos, as Drogas, os Insumos Farmacêuticos e Correlatos, Cosméticos, Saneantes e Outros Produtos. http://www.planalto.gov.br/ccivil_03/leis/ l6360.htm. Accessed 23 dec 2022. 35. Kirk J.L. (2017). EU Clinical Trials Regulation: The Application Process. International Society for Pharmaceutical Engineering  – ISPE. https://ispe. org/pharmaceutical-­engineering/march-­april-­2017/ eu-­c linical-­t rials-­r egulation-­a pplication-­p rocess#. Accessed 23 dec 2022. 36. UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (2001). Handbook: good laboratory practice (GLP) / UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases. World Health Organization. https://apps.who.int/iris/handle/10665/66894.Accessed 23 dec 2022.

7  Advanced Therapy Products in Brazil: Regulatory Aspects 37. Hulley S.B., Cummings S.R., Brower W.S. (2015). Delineando a Pesquisa Clínica. 4th ed. Porto Alegre: Artmed. 384 p. 38. Downing, N.  S., Aminawung J.  A., Shah N.  D., Krumholz H.  M., Ross J.  S. (2014). Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005–2012. JAMA, 311(4), 368–377. doi:https://doi.org/10.1001/jama.2013.282034. Accessed 23 dec 2022. 39. Djurisic, S., Rath A., Gaber S., Garattini S., Bertele V. et al. (2017). Barriers to the conduct of randomized clinical trials within all disease areas. Trials, 18(1), 360. doi:https://doi.org/10.1186/s13063-­017-­2099-­9. Accessed 23 dec 2022. 40. European Union, European Medicines Agency. Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells. EMA/CAT/GTWP/671639/2008 Rev. 1. https://www.ema.europa.eu/en/documents/ scientific-­guideline/guideline-­quality-­non-­clinical-­ clinical-­a spects-­m edicinal-­p roducts-­c ontaining-­ genetically-­modified_en-­0.pdf. Accessed 23 dec 2022. 41. Brasil, Lei Federal. Lei 11.105/2005. Estabelece normas de segurança e mecanismos de fiscalização de atividades que envolvam organismos geneticamente modificados – OGM e seus derivados, e outras. https:// www.planalto.gov.br/ccivil_03/_ato2004-­2006/2005/ lei/l11105.htm. Accessed 23 dec 2022. 42. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Guideline for good clinical practice E6(R2). Anvisa Portuguese version, 2019. https://www.gov. br/anvisa/pt-­br/centraisdeconteudo/publicacoes/medicamentos/publicacoes-­sobre-­medicamentos/guia-­de-­ boas-­praticas-­clinicas-­ich-­e6-­r2/view Accessed 20 jan 2023. 43. Brasil, Agência Nacional de Vigilância Sanitaria. RDC 38/2013. Aprova o regulamento para os programas de acesso expandido, uso compassivo e fornecimento de medicamento pós-estudo. http://antigo. anvisa.gov.br/documents/10181/3795687/%281%2 9RDC_38_2013_COMP.pdf/40d3904e-­5e15-­4ca4-­ a8bc-­a9e507a97ada. Accessed 23 dec 2022. 44. United States (US), Food and Drug Administration. Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up. https://www.fda.gov/regulatory-­information/search-­ TaggedEndTaggedPfda-­g uidance-­d ocuments/

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testing-­retroviral-­vector-­based-­human-­gene-­therapy-­ products-­replication-­competent-­retro-­virus-­during. Accessed 23 dec 2022. 45. European Union, European Medicines Agency. Quality, Non-Clinical and Clinical Aspects of Medicinal Products Containing Genetically Modified Cells. https://www.ema.europa.eu/en/quality-­ non-­c linical-­c linical-­a spects-­m edicinal-­p roducts-­ containing-­genetically-­modified-­cells. Accessed 23 dec 2022. 46. European Union, European Medicines Agency. Good Manufacturing Practice (GMP)Guidelines, Part IV− GMP Requirements for Advanced Therapy Medicinal Products. https://www.ema.europa.eu/en/news/new-­ guidelines-­good-­manufacturing-­practices-­advanced-­ therapies. Accessed 23 dec 2022. 47. Brasil, Agência Nacional de Vigilância Sanitaria. Produtos Registrados. https://www.gov.br/anvisa/ pt-­br/assuntos/sangue/terapias-­avancadas/produtos-­ registrados. Accessed 23 dec 2022. 48. Brasil, Agência Nacional de Vigilância Sanitaria. RDC 658/2022. Dispõe sobre as Diretrizes Gerais de Boas Práticas de Fabricação de Medicamentos. https://in.gov.br/en/web/dou/-­/resolucao-­rdc-­n-­658-­ de-­30-­de-­marco-­de-­2022-­389846242. Accessed 23 dec 2022. 49. Brasil, Agência Nacional de Vigilância Sanitaria. IN 36/2019. Dispõe sobre as Boas Práticas de Fabricação complementares a Insumos e Medicamentos Biológicos. https://www.in.gov.br/en/web/dou/-­/ instrucao-­n ormativa-­i n-­n -­3 6-­d e-­2 1-­d e-­a gosto-­d e-­ 2019-­211913888. Accessed 23 dec 2022. 50. Brasil, Agência Nacional de Vigilância Sanitaria. RDC 508/2021. Dispõe sobre as Boas Práticas em Células Humanas para Uso Terapêutico e pesquisa clínica, e dá outras providências. https://www.in.gov. br/en/web/dou/-­/resolucao-­rdc-­n-­508-­de-­27-­de-­maio-­ de-­2021-­323013606 Accessed 23 dec 2022. 51. Brasil, Agência Nacional de Vigilância Sanitaria. Farmacovigilância. http://antigo.anvisa.gov.br/en_ US/farmacovigilancia. Accessed 23 dec 2022. 52. European Union. European Medicines Agency. Guideline on Safety and Efficacy Follow-Up and Risk Management of Advanced Therapy Medicinal Products. Committee for Medicinal Products for Human Use (CHMP). https://www.ema.europa.eu/ en/documents/scientific-­guideline/draft-­guideline-­ safety-­effi-­cacy-­follow-­risk-­management-­advanced-­ therapy-­m edicinal-­p roducts-­r evision_en.pdf. Accessed 23 dec 2022. Accessed 23 dec 2022.

8

Regulation of Clinical Research for Cellular and Gene Therapy Products in India Varsha Dalal, Hem Lata, Gitika Kharkwal, and Geeta Jotwani

Abstract

The understanding of disease biology and advances in cellular and molecular biology platforms have ushered in a new era of cell and gene based therapeutic products. The US-FDA refers to this category of products as Cellular and Gene Therapy Products (CGTPs), while the European Medicines Agency, Europe, refers to them as Advanced Therapy Medicinal Products (ATMPs). The research and development (R&D) and final commercialization of these products have thus picked up pace, especially in the last decade. This emerging scenario necessitates framing regulations and guidelines that take into consideration the unique biological nature of these products. Regulators and government agencies of different countries across the globe have come up with regulations and guidance documents to guide, monitor, and regulate the research and development in this field. India, given its powerful resources of skilled scientific manpower and infrastructure, is also con-

tributing to development of these innovative therapeutic products. Keeping in line with the international counterparts, the Indian regulators and government agencies have developed regulations and guidelines for stakeholders. This chapter summarizes the regulatory landscape for research and development of CGTP in India. It provides an overview of the government agencies and committees overseeing this field and their roles that a stakeholder working in this field needs to have knowledge of. Furthermore, the chapter outlines the salient features of rules, regulations, and guidelines relevant to CGTP, the approval process, the current approved products in Indian market, and finally, the challenges and way forward for CGTP in India. Keywords

India · Stem cells · Cell therapy · Gene therapy · Regulations · Guidelines

Abbreviations V. Dalal · H. Lata · G. Jotwani (*) Division of Basic Medical Sciences, Indian Council of Medical Research Hqrs, New Delhi, India e-mail: [email protected]

AE ATMP

G. Kharkwal Biological Sciences Division, Indian Council of Medical Research – National Institute of Occupational Health, Ahmedabad, Gujarat, India

CAR CDSCO

Adverse Events Advanced Therapy Medicinal Products Chimeric Antigen Receptor Central Drugs Standard Control Organization

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 M. C. Galli (ed.), Regulatory Aspects of Gene Therapy and Cell Therapy Products, Advances in Experimental Medicine and Biology 1430, https://doi.org/10.1007/978-3-031-34567-8_8

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CGTP

Cellular and Gene Therapy Products CLA Central Licensing Authority CQA Critical quality attributes CTP Cellular Therapy Products CTRI Clinical Trial Registry of India DBT Department of Biotechnology DCA Drugs and Cosmetics Act DCC Drug Consultative Committee DCGI Drug Controller General of India DGHS Directorate General of Health Services DHR Department of Health Research DSMB Data Safety Monitoring Board DTAB Drug Technical Advisory Board EC Ethics Committees EPA Environment (Protection) Act ESC Embryonic Stem Cells GE Genetically Engineered GEAC Genetic Engineering Appraisal Committee GLP Good Laboratory Practice GMP Good Manufacturing Practice GSR General Statutory Rules GT Gene Therapy GTAEC Gene Therapy Advisory and Evaluation Committee GTP Gene Therapy Product HSCT Hematopoietic Stem Cell Transplantation IBSC Institutional Biosafety Committee ICMR Indian Council of Medical Research IC-SCR Institutional Committee for Stem Cell Research ICTRP International Clinical Trials Registry Platform IEC Institutional Ethics Committee IND Investigational New Drug iPSCs Induced Pluripotent Stem Cells MA Market Authorization MAA Market Authorization Approval MoEF & CC Ministry of Environment, Forest and Climate Change MoHFW Ministry of Health and Family Welfare

NAC-SCRT National Apex Committee for Stem Cell Research andTherapy NDCTR New Drugs and Clinical Trials Rules NGHCT National Guidelines for Hematological Cell Transplantation NGSCR National Guidelines for Stem Cell Research PRP Platelet-Rich Plasma QA Quality Assurance QC Quality Control R&D Research and Development RCGM Review Committee on Genetic Manipulation RDAC Recombinant DNA Advisory Committee rDNA Recombinant DNA SEC Subject Expert Committees UCB Umbilical cord blood

8.1 Introduction The cell and gene therapy products refer to a wide variety of complex biological products ranging from stem cells for repair and regeneration to nucleic acid entities and gene-editing tools for gene modification [1–4]. It is these drugs that fall under the umbrella of Advanced Therapy Medicinal Products (ATMPs). The European legislation defines ATMP as gene and cell therapy and tissue engineered medicinal products. However, no such terms have been coined for these drugs in India. Therefore, henceforth in this chapter, the term Cellular and Gene Therapy Products (CGTPs) will be used. Basic and clinical research and development in CGTP is growing at a fast pace across the globe. India too has witnessed remarkable progress in the field in the last few decades, keeping in view the large number of genetic disorders and rare diseases and unmet medical needs. The extraordinary scientific advances have demonstrated the potential of regenerative therapies in transforming the health of the nation by providing a therapeutic option for diseases that were previously considered

8  Regulation of Clinical Research for Cellular and Gene Therapy Products in India

incurable. The journey of research to translation has indeed been very tough, and India finally has 11 ongoing gene therapy clinical trials and 5 cell-­ based products with market authorization and many more in the pipeline. The advancement in innovative technologies like CGTP brought about a dilemma on the regulatory framework, which traditionally defines and caters to the regulation of pharmaceutical drug molecules. The regulators across the globe have been facing two-fold challenges, first of defining the framework to regulate CGTP [5] and second of curtailing commercial use of cell-based products especially stem cell–based therapies whose safety and efficacy have not been established yet [6–8]. The policies and regulations governing CGTP are as varied and complex as the products themselves, trying to achieve a delicate balance of establishing standards of safety and efficacy for the CGTP, without losing the economic edge in the internationally competitive health industry [9]. Various government agencies have contributed to provide an engendering environment to achieve this balance. The Indian regulator, Central Drugs Standard Control Organization (CDSCO) under the Directorate General of Health Services (DGHS), Ministry of Health and Family Welfare (MoHFW), Government of India, is responsible for implementing the Drugs and Cosmetics Act, 1940, and its amendments. Under the Drugs and Cosmetics Act, CDSCO headed by the Drug Controller General of India (DCGI) is responsible for approval of drugs, conduct of clinical trials, laying down the standards for drugs, control over the quality of imported drugs in the country, and coordination of the activities of State Drug Control Organizations by providing expert advice with a view of bringing about the uniformity in the enforcement of the Drugs and Cosmetics Act, 1940, and the New Drugs and Clinical Trials Rules (NDCTR) 2019 [10]. These rules are also responsible for overseeing market authorization and import-export of the advanced therapeutic products including CGTP. The DCGI is advised by the Drug Technical Advisory Board (DTAB) and the Drug Consultative Committee (DCC).

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The research on genetically engineered (GE) organisms or cells under Environment (Protection) Act 1986 is also regulated by the Review Committee on Genetic Manipulation (RCGM) under the Department of Biotechnology (DBT) [11]. In addition, Indian Council of Medical Research (ICMR), a century old apex body in India for the formulation, coordination, and promotion of biomedical research, has contributed to the field of CGTP through its guidelines [12, 13]. All the agencies have played a proactive role in providing scientific and regulatory advice to all stakeholders including researchers and manufacturers. They have evolved with time to frame guidelines, policy documents, and regulations to cater to the ever-growing needs of CGTP research and development (Fig. 8.1). This chapter gives a brief overview of the CGTP ecosystem including the regulatory agencies and committees, and the approval processes in India.

8.2 Regulatory Framework for CGTP The NDCTR 2019 [10] under the Drugs and Cosmetics Act 1940 and rules 1945 governs new drugs, investigational new drugs for human use, clinical trials, bioequivalence studies, bioavailability studies, and Ethics Committees. The rule was amended to New Drugs and Clinical Trials (Amendment) Rules, 2022, wherein in rule 2, subrule (1), clause (w), subclause (v), “cell or stem cell derived product” replaced “stem cell derived product” [14]. Besides this rule, all activities related to GE organisms or cells and non-GE hazardous microorganisms and products thereof are regulated as per the “Rules for the Manufacture, Use, Import, Export and Storage of Hazardous Microorganisms/Genetically Engineered Organisms or Cells 1989 (known as ‘Rules, 1989’)” [15], notified by the Ministry of Environment, Forest and Climate Change (MoEF&CC), Government of India, under the Environment (Protection) Act, 1986 (EPA 1986). Since these rules cover GE organisms and cells, therefore gene therapy products need to comply with the provisions of those rules. As umbilical

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Fig. 8.1  Major government agencies involved in overseeing the clinical research and development of CGTP in India

cord blood (UCB) is a rich source of hematopoietic and mesenchymal stem cells, the pertinent regulations to the former also deserve a mention when one discusses CGTP. UCB banks are permitted only under license and monitoring by the CDSCO. They are expected to follow the Drugs and Cosmetics (3rd Amendment) Rules, Gazette Notification No. GSR 899(E) dated 27/12/2011 [14] for collection, processing, testing, storage, banking, and release of stored units. In addition to regulations, the research and development of stem cell–based therapeutic products is guided by National Guidelines for Stem Cell Research (NGSCR)-2017 [16], while the National Guidelines on Gene Therapy Product Development and Clinical Trials 2019 [17] is the guidance document for stakeholders interested in

developing gene therapy (GT) products. Both these guidelines give a comprehensive frame of ethical, scientific, and regulatory requirements to help the scientists, clinicians, and industry involved in developing CGTP and executing their clinical trials. The proven or established versus unproven or experimental cell therapies have always been a grey area across the globe, leading to lacunae that often is misused for commercial benefits [18]. Thus, in addition to the above two guidelines, ICMR released The National Guidelines for Hematological Cell Transplantation-2021 (NGHCT) [19] and Evidence Based Status of Stem Cell Therapy for Human Diseases-2021 [20], so as to bring clarity to all stakeholders on proven versus unproven cell therapies. The biomedical, social, and behav-

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ioral science research involving human participants, their biological material, and data is to be conducted according to the National Ethical Guidelines for Biomedical and Health Research Involving Human Participants 2017 [21]. All the acts, rules, and guidelines are on public domain and accessible through the websites of the concerned government agencies.

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product, gene therapeutic product, or xenografts, intended to be used as drug.” According to these rules, the latter two categories shall always be deemed to be “new drugs.” Latest amendments in the rules have extended the scope of new drugs to include cell- or stem cell–derived products [14]. However, these rules do not throw light on what constitutes cell-derived or gene therapeutic products. These rules also delineate the requirement of two different Ethics Committees (ECs) for 8.2.1 New Drugs and Clinical Trials conducting biomedical and health research and Rules 2019 clinical trials. Furthermore, they give the provision of deemed approvals when a drug is discovThe Union Ministry for Health and Family ered in India, or research and development of the Welfare notified the NDCTR in March 2019 [10] drug are being done in India and also the drug is under the aegis of Drugs and Cosmetics Act proposed to be manufactured and marketed in 1940, with an aim to simplify the procedure of India, the application for permission to conduct clinical trials and promote clinical research in clinical trials in respect of such drugs shall be India. As per these rules, The Drugs Controller dealt by the CLA within 30 working days of India (DCGI) appointed by the Central receipt of such application, and if the applicant Government in the Ministry of Health and Family does not receive any communication during this Welfare is the Central Licensing Authority (CLA) period, the permission to conduct the clinical trial for the purposes of these rules. The parent act, shall be deemed to have been granted by the The Drugs & Cosmetics Act, 1940 and rules 1945 CLA. The rules also lay down a new conditional have entrusted various responsibilities to central approval pathway for orphan-designated mediand state regulators for regulation of drugs and cines for rare diseases, and for new innovative cosmetics. It envisages uniform implementation medicines that have already been approved and of the provisions of the Act & Rules made there licensed by regulators in other countries. Local under for ensuring the safety, rights, and well-­ clinical trials may not be required if being of the patients by regulating the drugs and cosmetics. • The new drug is approved and marketed in countries such as USA and Europe and if no 8.2.1.1 Salient Features major unexpected serious adverse events have These rules redefine the categories of new drugs been reported. [10] to include “any active pharmaceutical ingre- • There is no probability or evidence, based on dient or phytopharmaceutical drug, which has not existing knowledge, of difference in Indian been used in the country to any significant population of the enzymes or gene involved in extent,” “a drug approved by the CLA for certain the metabolism of the new drug or any factor claims and proposed to be marketed with modiaffecting pharmacokinetics and pharmacodyfied or new claims,” “a fixed dose combination of namics, safety, and efficacy of the new drug. two or more drugs, approved separately for cer- • There is a commitment to conduct Phase IV tain claims and proposed to be combined for the clinical trial to establish safety and effectivefirst time in a fixed ratio,” “a modified or susness of such new drug. tained release form of a drug or novel drug delivery system of any drug approved by the CLA,” or All these conditions may be relaxed if the “a vaccine, recombinant Deoxyribonucleic Acid drug is indicated in life-threatening or serious (r-DNA) derived product, living modified organ- diseases or diseases of special relevance to Indian ism, monoclonal antibody, stem cell–derived health scenario or for a condition, which is unmet

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need in India such as extensive drug-resistant tuberculosis, hepatitis C, H1N1 influenza, dengue, malaria, and human immunodeficiency virus. With regards to posttrial access, the rules mention that “posttrial access” shall be provided by the sponsor of clinical trial to the trial subject free of cost if there is no alternative therapy available and the new drug under trial has been proven to be beneficial or if the patient consents to use the new drug after the trial without any liability of the sponsor.

8.2.2 Drugs and Cosmetics (3rd Amendment) Rules, Gazette Notification No. GSR 899(E), Dated 27/12/2011 This notification issued by DCGI/CDSCO outlines the conditions for licensing of UCB banks for collection, storage, and other activities related to the storage of cord blood units. This notification defines UCB as the whole blood including hematopoietic progenitor cells collected from placental or UCB vessels after the cord has been clamped [22].

8.2.2.1 Salient Features For the purpose of UCB collection, the agreement is to be signed with the parents and cord blood bank, the collection centers must be under the supervision of qualified registered medical practitioner, and information on changes in technical staff is to be reported to the CLA; licensee shall inform authority in writing in event of any change within the constitution of the firm operational under the license. The basic infrastructure needed for UCB storage, along with details on the requirement for processing, testing, and storage areas for UCB stem cells, as well as disposal of the infectious material and waste, health, clothing, and safety of the concerned personnel, is included. The details of appropriate/specific protocol to be followed for the collection, transportation, and storage of processed UCB cell component, along with the personnel structure of cord blood bank, quality assurance (QA), and quality control (QC),

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that is, competent technical staff meeting the basic eligibility, are included. The details of maternal blood and UCB sample screening tests and the storage temperatures of UCB and reference samples are mentioned.

8.2.3 Rules for the Manufacture, Use, Import, Export, and Storage of Hazardous Microorganisms/Genetically Engineered Organisms or Cells 1989 (Known as “Rules, 1989”) These rules are applicable to manufacture, import, and storage of micro-organisms and gene-technological products. They shall apply to GE organisms, micro-organisms, and cells and correspondingly to any substances and products and food stuffs, etc., of which such cells, organisms, or tissues hereof form part. They also apply to the cells generated by the utilization of such other gene-technologies and to substances and products of which such organisms and cells form part [22].

8.2.3.1 Salient Features These rules define the regulatory, approval, and advisory role of different committees, such as Institutional Biosafety Committee (IBSC), Review Committee on Genetic Manipulation (RCGM), Genetic Engineering Appraisal Committee (GEAC), and Recombinant DNA Advisory Committee in India. They also define the manufacturing, production, import, and export of GE organisms/hazardous organisms and their products.

8.2.4 National Guidelines for Stem Cell Research In 2007, ICMR and DBT jointly issued the National Guidelines for Stem Cell Research and Therapy that were subsequently revised in 2013 and 2017 with omission of the word “therapy” (NGSCR). The NGSCR-2017 [16] reiterated that clinical use of stem cell other than hematopoietic

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stem cell transplantation (HSCT) is investigational, and thus, any such use of stem cells in patients must only be done within the purview of an approved and monitored clinical trial. The trials need to be done with intent of advancing science and medicine, and not offering it as therapy. The guidelines thus emphasize that clinical use of stem cells outside an approved clinical trial is unethical and shall be considered as malpractice. The NGSCR laid down the scientific, ethical, regulatory, and social norms to tackle the challenges in the field of stem cell research. However, since these guidelines lacked statutory backing, many scholars concluded that the way forward would be to give them legislative weight. The guidelines are applicable to all stakeholders including individual researchers, organizations, sponsors, oversight/regulatory committees, and all others associated with both basic and clinical researches involving any kind of human stem cells and their derivatives. The guidelines do not apply to research using nonhuman stem cells and their derivatives. Further, these do not apply to use of hematopoietic stem cells for treatment of various hematological, immunological, and metabolic disorders, since these have already been established as a standard of medical care. Platelet-­rich plasma (PRP) and autologous chondrocyte/osteocytes implantation does not fall under the purview of these guidelines as they are categorized as other cell-based applications and not stem cell transplantation. The guidelines reiterate that the general principles of ethics for biomedical research involving human participants shall also be applicable. In addition, the guidelines specify unique provisions for stem cells, because of their inherent property for unlimited proliferation, differentiation to cells of the germ layers, oncogenic potential, unrecognized toxicities, and possible involvement in preimplantation stages of human development. However, these guidelines do not mention tissue engineered products or organoids, although these are stem cell–derived products.

8.2.4.1 Salient Features For all institutes (basic and clinical) involved in stem cell research activities, it is mandatory to constitute an Institutional Committee for Stem

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Cell Research (IC-SCR) to review and monitor the stem cell research activities (basic and clinical) and same needs to be registered with National Apex Committee for Stem Cell Research (NAC-­ SCRT) (see Sect. 8.3.1.2). Institutional Ethics Committee (IEC) needs to be registered with CDSCO. Stem Cell Clinical trials can be undertaken only by the entities having registered IC-SCR and IEC and only at Good Manufacturing Practice (GMP) and Good Laboratory Practice (GLP) certified facilities. Video consent as per the CDSCO guidelines for audiovisual recording dated January 9, 2014 is mandatory. Donor Screening for Communicable Diseases should be performed in National Accreditation Board for Testing and Calibration Laboratories/College of American Pathologists accredited laboratory. Levels of manipulations are described: (i) minimal manipulations if cell processing period is within 72  h and clinical applications same to be approved by CDSCO, IC-SCR, and IEC; (ii) substantial manipulations to be approved by CDSCO after IC-SCR and IEC clearances; (iii) major manipulations to be approved by CDSCO after clearances from NAC-SCRT through IC-SCR and IEC.  Clinical applications of minimally manipulated cells for homologous use in unapproved indications and for nonhomologous use in any indication will require approval from IC-SCR, IEC, and CDSCO. Categories of research are described: (i) establishment of new human embryonic stem cells (ESC) lines from spare embryos or induced pluripotent stem cells (iPSC) lines, ii) derivation of line by creation of human preimplantation embryos by In vitro fertilization (IVF), Intracytoplasmic Sperm Injection (ICSI), Somatic Cell Nuclear Transfer (SCNT), and research involving human germline gene therapy and reproductive cloning falls under permissible, restrictive or prohibited categories respectively. In vitro studies under “permissible” category require prior approval of IEC and IC-SCR, except studies involving established human stem cell lines registered with the IC-SCR. In vitro studies on preimplantation human embryos must be carried within 14 days of fertilization or formation of primitive streak, whichever is earlier.

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Preclinical testing needs to be approved by IEC (humans), Institutional Animal Ethics Committee (small animals), and Committee for the Purpose of Control and Supervision of Experiments on Animals (large/nonhuman primates). All stem cell and derivatives testing must include safety, biodistribution, immune rejection studies, single and repeat dose toxicity studies, tumorigenicity, genotoxicity, developmental toxicity studies, and biodistribution studies. Clinical studies/trials need clearances from IC-SCR, IEC, and CDSCO and must be registered with Clinical Trials Registry of India (CTRI). Follow-up period of minimum 2  years is mandatory. Establishing a Data Safety Monitoring Board (DSMB) is mandatory for each study. All adverse events must be reported to IEC, CDSCO, and NAC-SCRT through IC-SCR.  Trial records must be maintained for a minimum of 15 years. Only CDSCO-­ licensed institutions are permitted for UCB, commercial banking of all other biological materials is not permitted. Import of stem cell lines of overseas origin for clinical trials requires clearance from the CDSCO.  Export of indigenously developed cell lines requires IEC and IC-SCR clearances and same needs to be submitted along with the material transfer agreement during the review of such research proposals.

8.2.5 The National Guidelines on Gene Therapy Product Development and Clinical Trials 2019 These guidelines broadly specify the ethical, scientific, regulatory procedures and requirements to be followed for developing and conducting clinical trials on GTP in India [17]. It throws light on the development of safe and effective GTP, addressing product quality characterization of the components and processes involved till the development of final product, the preclinical evaluation of the product, and the clinical study design to establish GTP safety and efficacy in the target indication including long-term followup. These guidelines also delineate the regulatory processes in place for approval of clinical trials of GTP.

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8.2.5.1 Salient Features GTP is defined as any entity, which includes a nucleic acid component being delivered by various means for therapeutic benefit to patients. The term GTP is applicable to entities that are used for, but not limited to, gene augmentation, gene editing, gene silencing, and synthetic or chimeric gene augmentation. The guidelines clearly define the drugs and products that come under the umbrella of GTP and hence under their purview. These include recombinant viral and non-viral vectors, oncolytic viruses, shRNA/siRNA, ex vivo genetically modified cells like Chimeric Antigen Receptor (CAR)-T cells, iPSC, DNA vaccines and more. The guidelines cover all areas of GTP production, preclinical testing and clinical administration as well as longterm follow-­ up, providing the mechanism for review and oversight for all GTP development for human applications. The guidelines cover all considerations for Chemistry, Manufacturing and Control, QA, Product Attributes for GTP, including personnel training and infrastructure requirements. Responsibilities of investigators/institution/sponsors/Ethics Committees are also described. Requirements for preclinical evaluations of investigational strategies/GTP are also clearly outlined in the document. All GTP development activities will be steered by Gene Therapy Advisory and Evaluation Committee (GTAEC) with the secretariat at ICMR, which shall be notified by DHR. The guidelines detail all the requirements for enrolling patients in GTP human trials, their risk and safety assessments and trial designs which must be approved by the GTAEC, RCGM and CDSCO prior to patient administration. These national guidelines apply to all stakeholders in the field of gene therapy including researchers, clinicians, oversight/regulatory committees, industry, patient support groups and any others involved in GTP development or their application in humans.

8.2.6 National Ethical Guidelines for Biomedical and Health Research Involving Human Participants 2017 Clinical trials on human participants involving stem cell and GT must safeguard human rights,

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safety, dignity, and fundamental freedom of the A critical review of the comments and level I and participant. This includes processes related to level II evidence provided by medical experts and obtaining human tissues/cells for research, diag- their professional societies or any member of the nosis and clinical trials. It is important that the public and the scientific literature was done by fundamental tenets of beneficence, non-­the expert group to draft guidelines and statemalfeasance, justice, and autonomy are adhered ments for evidence-based use of stem cell to. Research and clinical trials with stem cell and therapy. GTP must be conducted under specific requirements and guidelines described in this document. 8.2.8.1 Salient Features These guidelines reiterate that institutes need to The statements cover ten individual diseases or follow NGSCR-2017 while conducting research groups of diseases or conditions. They are divided with stem cell. into two sections: the first is addressed to the public and patients using layman terms, while the second is addressed to doctors, scientists, and 8.2.7 National Guidelines allied healthcare professionals providing major for Hematological Cell research studies in the scientific literature, scienTransplantation 2021 tific level of evidence and summarised recommendation. These guidelines [19] deal with HSCT, including immune-lymphoid, myeloid and genetic disorders, which is the only known therapeutic use of 8.3 Regulatory Pathways stem cells globally. and Committees

8.2.7.1 Salient Features The NGHCT-2021 contains an updated list of approved indications using stem cells as standard of care, both in adults and pediatric patients, which is adapted from European Bone Marrow Transplant Guidelines 2019 [23]. There are over seventeen chapters, highlighting the significance of HLA typing, handling, processing, and preservation of stem cells and follow-up of patients after transplantation. It lays down a template, which can help transplantation centers/physicians to formulate their own protocols and policies to conduct HSCT.  Each transplantation center is expected to write their own procedures, wherever applicable, using the guidelines as a template.

8.2.8 Evidence Based Status of Stem Cell Therapy for Human Diseases 2021 This document [20] is another major effort from the ICMR toward creating an environment of clarity to clinicians and patients on the status of stem cell therapy as an available treatment option.

for Approval/Advisory on CGTP

There are various government agencies as well as national and institutional committees that play a role in executing safe and ethical research with new drugs.

8.3.1 National Level Committees 8.3.1.1 Subject Expert Committees In 2010, MoHFW constituted a Core Investigational New Drug (IND) Panel of Experts that was named “Cellular Biology Based Therapeutic Drug Evaluation Committee” to advice DCGI in matters pertaining to regulatory pathways leading to the approval of clinical trials and market authorization for the “therapeutic products derived from stem cell, human gene manipulation and xenotransplantation technology” [24]. In 2019, it was replaced by Subject Expert Committees (SEC), which operated with the mandate to reviews the IND for cell-biology-­ based drug products/stem-cell-derived products [27]. SEC evaluates scientific and technical matters relating to new drugs, clinical trials, and new

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medical devices and advises DCGI on the same. Accordingly, under rule 100 of the New Drugs & Clinical Trials Rules, 2019, with approval of MoHFW, groups/panels of about 550 medical experts with specialization in relevant fields have been constituted [25] similar to SEC replacing the New Drug Advisory Committees [26]. Presently, the IND for cellular biology–based drug products/stem cell–derived products are also reviewed by SEC [25, 27].

8.3.1.2 National Apex Committee for Stem Cell Research Stem cells and their derivatives/products are associated with ethical, legal, and social concerns that demand additional oversight and expertise. Hence, a separate mechanism for review was proposed in NGSCR-2017 at the National level, the NAC-SCRT, and at the institutional level, Institutional Committee for Stem Cell Research (IC-SCR). Accordingly, NAC-SCRT was ­constituted in October 2010 by DHR, MoHFW, Government of India, and has been revised and reconstituted periodically with the following main objectives: • To serve as an advisory body to promote and facilitate stem cell research in the country. • To perform a comprehensive review of the therapeutic use of stem cells and formulate policies to curb unethical practices. • To review specific controversial or ethically sensitive issues referred to the committee. The committee periodically assesses the adequacy of the NGSCR, considering advancements in the field also provides a forum for discussion of issues involved in basic and clinical research. The committee also reviews specific concerns referred to by the IC-SCR including studies falling under the “restrictive category.” Further, all unforeseen issues of public interest are referred to it from time to time. NAC-SCRT is delegated with task of guiding on issues related to stem cell research and therapy, keeping a track on stem cell research through registration of institutes working in the field across the country, aptly responding to representation received from various

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stakeholders and updating guidelines as per the developments in the field so that the nation is at par with the ethical and scientific developments in the field.

8.3.1.3 Gene Therapy Advisory and Evaluation Committee Gene Therapy Advisory and Evaluation Committee (GTAEC) was constituted and notified by the DHR, MoHFW, Government of India, as an independent body of experts representing diverse areas of biomedical research, concerned government agencies, and other stakeholders. This is a multidisciplinary and inter-ministerial/ inter-agency committee with its Secretariat at the ICMR Headquarters, New Delhi. The main objectives of the committee are • To serve as an apex advisory body to Government of India for research and development in gene therapy field in India. • To perform a comprehensive review of the pre-IND and IND applications of GTP. • To formulate policies to instill scientific and ethical practices among stakeholders. The committee provides a forum for discussion of issues involved in basic and clinical research and progress in the field. The committee reviews clinical trial applications and provides recommendations prior to approval from CDSCO, to provide input to SEC.  It is also responsible for formulation guidelines and its periodic update/amendment [28].

8.3.1.4 Review Committee on Genetic Manipulation The Review Committee on Genetic Manipulation (RCGM) functions in the DBT under the Ministry of Science and Technology to monitor the safety related aspects in respect of ongoing research projects and activities involving hazardous microorganisms, GE organisms and their products. The RCGM includes representatives of DBT, ICMR, Indian Council of Agricultural Research, Council of Scientific and Industrial Research, and other experts in their individual capacity. RCGM is mandated to bring out manu-

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als of guidelines, specifying procedure for regulatory process with respect to activities involving GE organisms in research use as well as industrial and environmental applications with a view to ensure human health and environmental safety. All ongoing research projects involving hazardous microorganisms, GE organisms or cells and products thereof shall be reviewed to ensure that adequate precautions and containment conditions are being met. RCGM lays down procedures restricting or prohibiting production, sale, importation and use of such hazardous microorganisms, GE organisms or cells as are mentioned in the Schedule of Rules, 1989 [15]. All materials belonging to risk group 3 (such as Bacillus Anthracis, Dengue, and HIV) and risk group 4 (Monkey pox, Ebola, and Zika virus) [29] require prior approval by IBSC, followed by RCGM for import, export and R&D activities.

Chap. III and the other for biomedical and health research under Chap. IV. The former is required to be registered with the CLA by applying in Form CT-01, and registration is subsequently granted in Form CT02 which is valid for a period of five years from the date of its issue, unless suspended or cancelled by the CLA. Any organization conducting biomedical and health research involving human participants is required to constitute EC to review and oversee the conduct of such research as detailed in the “National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, 2017” [21] and specified by ICMR. Such EC should be registered with DHR [30] in compliance with the sub-rule (l) of rule 17. The “National Ethics Committee Registry for Biomedical and Health Research” has been set up within the DHR to facilitate receipt and processing of applications seeking registration.

8.3.1.5 Clinical Trial Registry of India (CTRI) As per NDCTR, any clinical trial carried out in India involving human participants and interventions like drugs/surgical procedures/preventive measures must be registered at Clinical Trial Registry of India (CTRI). This is a central registry that has been hosted by the ICMR since 2007. It is a free online public record system, initiated as a voluntary activity and then made mandatory by DCGI in 2009. It is also primary register of the World Health Organization International Clinical Trials Registry Platform (ICTRP). Thus, the clinical trials registered at CTRI are freely searchable both from the ICTRP and CTRI.

8.3.2.2 Institutional Committee for Stem Cell Research All institutions involved in the stem cell research (basic as well as clinical) are required to constitute an IC-SCR as per NGSCR and register the same with NAC-SCRT.  This is a multi-­ disciplinary self-regulatory, independently functioning body at the institutional level that oversees all stem cell related research activities and/or clinical trials in compliance with the NGSCR and existing regulatory framework. Registration of IC-SCR with NAC-SCRT is mandatory. IC-SCR should ensure that the investigator/institution is not misusing the IC-SCR registration for undue publicity or commercial gains. This committee must include at least eleven (medical and nonmedical) representatives in order to function properly. IC-SCR is accountable for the management of registry of human ESC and iPSC derived or imported by individual investigators and notify the same to NAC-SCRT. IC-SCR needs to report all adverse events (AE) and annual progress report to NAC-SCRT.  It also facilitates training of investigators and other stakeholders engaged in stem cell research about current knowledge, international status, relevant guidelines and regulations through Continuing Medical Education programs, public lectures and seminars.

8.3.2 Local/Institutional Level Committees 8.3.2.1 Ethics Committee EC, also known as the Institutional Review Board in different parts of the world, should review and approve the clinical research proposal prior to initiation of any trial. The NDCTR-2019 mandates the constitution of two different EC, one for clinical trial, bioavailability and bioequivalence study under rule 7 of

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8.3.2.3 Institutional Bio-Safety Committee The Institutional Bio-Safety Committee (IBSC) is a statutory committee and operates within the premises of an organization. In the context of CGTP, the committee reviews research that encompasses genome modification including gene editing (e.g., by CRISPR-Cas9 technology) of stem cells, germ-line stem cells or gamete, and human embryos in  vitro. This committee ensures that the bio-safety guidelines and regulations are being followed within an organization for CGTP development and preclinical testing for establishing safety of such products. It reports and ­ communicates with RCGM with respect to functioning of IBSC in an organization [11]. 8.3.2.4 Data Safety Monitoring Board The Data Safety Monitoring Board (DSMB) is an independent group of experts that reviews data accumulated from all sites of an ongoing trial and monitors the patient safety and efficacy of the clinical trial. It is the responsibility of the sponsor to establish a DSMB prior to recruitment of the participants. DSMB ensures consistency and credibility, timely conclusion, identifications of protocol violation and high dropout rates, validity of results and safety of the participants. DSMB has the power to recommend or terminate a clinical trial after evaluating its risk/benefit. DSMB recommendations are indications that the checks and balances for the protection of participants and researchers involved in the clinical trial are working properly.

8.4 Approval Process for CGTP in India Interested entities/applicants intending to collect, isolate, store, and regulate the clinical trials and profitable use of CGTP are required to submit application to CDSCO through Suraksha, Gunvatta Avum Maanakta online portal [31]. As per the guidelines issued by ICMR, in addition to CDSCO approval, the following approvals are required:

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• Clinical trials using cell- or stem cell–derived products should have prior approval of IC-­ SCR (which must be registered with NAC-­ SCRT) and Institutional EC (IEC). • Clinical trials using GTP should have prior approval of RCGM as well as IEC and should have been reviewed by the GTAEC. The process of approval for a clinical trial is depicted in Fig. 8.2. CDSCO issues four types of approvals/ licenses for the CGTP starting from obtaining facility licenses; the conduct of clinical trial, manufacture, and import; and lastly, for sale, storage, and distribution, as indicated in Fig. 8.3.

8.5 Specific Considerations This section discusses specific considerations pertaining to the Chemistry, Manufacturing, and Control (CMC) and GMP requirements as well as preclinical and clinical testing models required for CGTP as described in the NGSCR-2017 [16] and National Guidelines on Gene Therapy Product Development and Clinical Trials 2019 [10]. The focus should be on safety, identity, strength, purity and quality, and the critical quality attributes (CQAs) followed by risk assessment of the CGTP. For a CGTP, potency is one of the key attribute and all the starting components go under extensive characterization during the manufacturing process. Any CGTP involves the use of cellular components, gene of interest, the vehicle or vector required to transfer gene of interest, which are employed in ex-vivo gene transfer modalities. Therefore, maintaining the quality aspects of each component till the release of final product is of utmost importance.

8.5.1 Chemistry, Manufacturing, and Control Requirements The degree of manipulation(s) required for cell processing should be described and the physiological function of cells, development of suitable vector systems, assessment of genetic stability,

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IEC approval#

ICSCR approval

Pre-screening at CDSCO and examination by drug division

SEC and IND recommendations All documents Okay

Query Recommendation to DCGI

Approval granted by DCGI CTRI registration Initiation of clinical Trials

New Drug Registration to CDSCO

Review by DCGI If not complete License not granted

If complete License granted

Fig. 8.2  Flowchart depicting the approval process of CGTP. (# IBSC and RCGM approvals are required for GTP)

Fig. 8.3  Categories of approvals issued by CDSCO

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information about vectors sequence, map as well as their source, gene of interest, route of administration, and plasmids should be documented. The source of cells used (autologous vs. allogeneic), along with the methods used for their activation and expansion, needs to be defined. Any ex-vivo modifications need to be explained. Testing of infectious agents also needs to be documented for these cells. Manufacturing materials used in CGTP production must be obtained from a verified source, it should be of clinical grade and suitable for downstream human application. Even if not a part of the final product, details on source and safety of the reagents used should be mentioned as they are used in the manufacturing process. Any component that is intended to be a part of the final product should be listed in the ­documentation with details of concentration and source. Attention should be paid to biodegradable materials, which may have the potential for undergoing environmental changes (raised pH, temperature, humidity, specific handling, etc.) for the cells during the manufacturing process. Information on procedures used for transportation/shipment of the materials during manufacturing process of the product, including storage conditions and holding times, should be documented. The manufacturing area should be separated from the procurement area, so as to avoid the risk of cross-contamination during each step of the procedure, for example, via processing equipment or in storage containers such as liquid nitrogen tanks. Facility requirements should comply with GMP, prescribed for aseptic manufacturing as per Schedule M of Drugs and Cosmetics Act, 1940, [32] and Rules therein. Equipment and premises used for manufacturing should fulfill conditions of aseptic production. It is recommended that dedicated, product-specific, or single-use equipment be used in the production process, whenever possible. All procedures followed during CGTP production should be provided. This includes vector production, details of ex-vivo genetic modification, irradiation (if any), storage, and transportation. The shelf life of each CGTP has to be indicated along with supportive stability data and rationale for determination.

Data of periodic testing should also be provided for stored CGTP to establish its CQA. This is of paramount importance to demonstrate final product safety. It should include, but not be limited to, microbiological testing, identity and purity, viability, and potency testing.

8.5.2 GMP Requirements The CGTP manufacturing facilities should be compliant with standard requirement of GMP [16, 17, 33]. This includes two important areas: Infrastructure and Personnel as per Schedule M of Drugs and Cosmetic Act 1940 [33]. This Schedule clearly lays down the methodology, systems, and procedures, which need to be documented and maintained for inspection and reference and point out that the manufacturing premises shall be used exclusively for production of drugs and no other manufacturing activity shall be undertaken therein. Infrastructure: the facilities used to manufacture, process, package, or store CGTP should be suitably constructed to ensure proper cleaning, maintenance, and production operations. Personnel: the personnel engaged in CGTP production must have adequate training in procedures, maintaining process-related documents and qualification records. They should have appropriate training in maintaining asepsis and quality throughout the entire CGTP manufacturing process.

8.5.3 Preclinical Studies Factors that should be considered in designing a preclinical study include • Strong clinical and biological rationale, adequate feasibility assessment, and evaluation of delivery vehicles. • Suitable animal models, homologous to the clinical disease target, to demonstrate clinical benefit as well as off-target/secondary effects, if any.

8  Regulation of Clinical Research for Cellular and Gene Therapy Products in India

• Efficacy testing by assessing the pharmacokinetics and dose response and safety testing by doing biodistribution and toxicity studies.

149

Apart from having these rules and guidelines in place, clinicians, scientists, researchers as well Table 8.1  CTPs approved for market in India

8.5.4 Clinical Trials The most important step in taking such therapies to patients is through clinical trials. Therefore, when designing such trials, the natural history of disease should be taken into account, allowing patients to be enrolled by laying down suitable selection criteria considering disease severity, comorbidities, and prior therapy history. Dose escalation, risk evaluation and safety assessment, long-term follow-up, and process of withdrawal are the issues that need to be dealt with while designing first-in-human trials. All clinical trials studies require clearances from IC-SCR, IEC, and CDSCO and must be registered with CTRI. Follow-up period of minimum 2 years is mandatory. Establishing a DSMB is mandatory for each study. All AE must be reported to IEC, CDSCO, and NAC-SCRT through IC-SCR.  Trial records must be maintained for a minimum of 15 years.

Name, MA holder Stempeucel®

Trichosera®A (hair care)

Cutisera® (skin care)

Perioptisera® (under eye care)

8.6 CGTP Authorized for Market in India As per the NGHCT-2021, hematopoietic cell transplantation is recommended for hematological disorders as outlined in these guidelines. Autologous transplantation is primarily used for various hematological malignancies, some solid tumors, and autoimmune disorders. Other than HSCT for approved indications as listed in these guidelines, the use of stem cells in all other diseases is investigational and must be done within the purview of a clinical trial. Apart from use of the hematopoietic cells, Table  8.1 [34, 35] lists the Cellular Therapy Products (CTPs) approved for market in India: There is no approved GTP in India till date. On-going GTP clinical trials are listed in Table  8.2. Updated list can be accessed at the CTRI and the GTAEC website [28].

Cartigrow™Chondron

Ossgrow™

Apceden (Asia Pacific biotech)

StemOne (Stempeutics research)

CTP description and indication Ex vivo cultured adult allogenic mesenchymal stromal cells for treatment of critical limb ischemia due to Burgers’s disease. Hair serum prepared from the bioactive medium of mesenchymal stromal cells using a novel patented technology. Serum contains bioactive factors secreted from mesenchymal stromal cells, which promote firm, well-­ moisturized, and brighter skin with reduced blemishes and fine lines. An under-eye dark circle reduction serum prepared from the bio-active medium of stem cells reduces under-eye dark circles, rehydrates, and soothes the skin. Autologous cultured cartilage cells for treating articular cartilage defects. Autologous cultured osteoblast for avascular neurosis of hip. Autologous monocytes-derived dendritic cells for treatment of prostrate, ovarian, colorectal, and nonsmall cell lung carcinomas. Knee osteoarthritis.

Year of MAA 2016

2016

2016

2016

2017

2017

2017

2022

V. Dalal et al.

150 Table 8.2  List of GTP clinical trials in pipeline in India SNo. CTRI No. 1. CTRI/03/2022

Title Safety and feasibility of de-centralized CAR-T cell manufacturing and treatment of relapsed and refractory B cell acute leukemia and lymphoma Exploratory phase II a studies to evaluate efficacy of next-generation TGF-β2-­ selective antisenseoligonucleotide ISTH0036 in treatment naïve and in previously treated patients with neovascular age-related macular degeneration and diabetic macular edema with severe nonproliferative and mild proliferative diabetic retinopathy GTP for Hemophilia A with a high expression Factor VlII transgene in autologous Hematopoietic stem cells (CD68-ET3-LV-CD34+)

2.

CTRI/2022/04/041823

3.

CTRI/2022/03/041304

4.

CTRI/2022/03/041162

Phase 2 study to determine safety and efficacy of IMN- 003 a cell therapy in patients with relapsed and refractory CD19 -positive B cell malignancies

5.

CTRI/2022/03/041060

6.

CTRI/2021/05/033348

Safety, tolerability, and efficacy of 2′-o-methyl phosphorothioate anti sense oligoribonucleotides for the treatment of confirmed Duchenne muscular dystrophy of Indian pediatric patients: phase1 open-labeled study First-in-human pilot feasibility study of indigenously developed novel humanized CD19- directed CAR-1 modified T-cells in the therapy of relapsed/ refractory B-cell acute lymphoblastic leukemia

7.

CTRI/2021/04/032727

A pilot study of indigenously manufactured HCAR19 (second generation anti-CD19-41BBCD3ζ chimeric antigen receptor T-cell therapy) in adult patients with relapsed/ refractory diffuse large B-cell lymphoma

Centre Department of Haematology, Christian Medical and Hospital Vellore – 632004. Department clinical trials, Roomno.01, 2ndfloor, 6, Arista @ Eight Corporate House, Near Satyam House, Behind Rajpath Club, Bodakdev, Ahmadabad – 380054, Gujarat Centre for stem cell research, A unit of InStem, Christian Medical College Campus, Bagayam, Vellore, Tamil Nadu – 632002 Narayana Health Mazumdar Shaw Medical Centre Narayana Health City, # 258/A, Bommasandra industrial area Hosur road, Bengaluru 11 Dr. Biresh Guha street. Park Circus Kolkata WEST BENGAL 700017 Tata memorial Centre, Mumbai and advance Centre for treatment, research and education in cancer (ACTREC), Kharghar, Navi Mumbai, Mumbai – 400012 Tata Memorial Centre, Mumbai and Advance Centre for treatment, Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai, Mumbai – 400012

Date of permission 01/09/2021

12/04/2022

23/03/2022

16/03/2022

14/03/2022

04/05/2021

12/04/2021

(continued)

8  Regulation of Clinical Research for Cellular and Gene Therapy Products in India

151

Table 8.2 (continued) SNo. CTRI No. 8. CTRI/2021/11/03/7956

9.

CTRI/2020/08/027334

10.

CTRI/2021/04/032498

11.

CTRI/2019/09/021329

Title A randomized, sham-controlled, double-blind study to evaluate the efficacy and safety of intrathecal (IT) OAV101 in patients with later-onset Type2 spinal muscular atrophy (SMA), ≥ 2 to