Fundamentals of Pharmaceutical and Biologics Regulations PDF

FUNDAMENTALS OF PHARMACEUTICAL AND BIOLOGICS REGULATIONS A GLOBAL PERSPECTIVE Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected] ...

FUNDAMENTALS OF PHARMACEUTICAL AND BIOLOGICS REGULATIONS A GLOBAL PERSPECTIVE Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  FUNDAMENTALS OF PHARMACEUTICAL AND BIOLOGICS REGULATIONS A GLOBAL PERSPECTIVE Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  Copyright ©2023 by the Regulatory Affairs Professionals Society. All rights reserved. ISBN: 978-1-947493-86-5 Every precaution is taken to ensure accuracy of content; however, the publisher cannot accept responsibility for the correctness of the information supplied. Regulatory Affairs Professionals Society (RAPS) 5635 Fishers Lane, Suite 400 Rockville, MD 20852 USA RAPS.org ii Regulatory Affairs Professionals Society (RAPS) Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  Foreword P harmaceuticals and biologics play a vital role in the treatment and prevention of disease, yet they also have the potential to produce serious adverse effects. For this reason, regulatory frameworks are essential to help ensure the safety, efficacy, and quality of medicinal products. Fundamentals of Pharmaceutical and Biologics Regulations: A Global Perspective, published by the Regulatory Affairs Professionals Society (RAPS), aims to provide a comprehensive overview of global regulatory requirements for medicinal products. This book is the latest in a long line of authoritative Fundamentals texts from RAPS. We published the first edition of RAPS Fundamentals of US Regulatory Affairs in 1999 – but so much has changed in healthcare products and their regulation since then. Drug development and marketing processes – from discovery to postapproval requirements – are now truly global. Great strides have been made in the international harmonization of regulatory requirements, but there are still scores of regulatory bodies around the world with unique processes and pathways. A regulatory professional working on a new medicinal product needs to know – or know where to find – regulations, requirements, pathways, and processes from around the world. To support them, RAPS – with the advice and guidance of our Editorial Advisory Committee – has realigned our Fundamentals content along a sector-based scheme. This book broadens the scope of Fundamentals to include more content on drug development to help inform the regulatory submission process. A similar, as-comprehensive book on the regulation of medical devices and diagnostics is slated for publication in 2024. More than 50 regulatory professionals contributed to the chapters in this book. These volunteers come from 14 countries spanning four continents and from all areas of specialty within the profession. They work for organizations across the spectrum – from large pharmaceutical corporations to small consultancies. They were ably led by editors Linda McBride, RPh, RAC-US; and Siegfried Schmitt, PhD; as well as section editors Kimberly Belsky, MS, FRAPS; Devanshi Maharaja, MSc, MTech; Daniel G. Mannix, PhD, FRAPS; Flora Siami, MPH; and Kip Vought. Together, these individuals have gathered information from health authorities around the globe so that you have a single resource that is as complete as possible to help you understand the multitude of laws, regulations, and guidances and how to apply them to the medicinal product throughout the product lifecycle. RAPS is enormously grateful for the knowledge these individuals have instilled in this new book. As the newest member of the Fundamentals family, this book relies on updated content from its predecessors and on the authors who contributed that knowledge. RAPS thanks those contributors for helping us to build this new evolution. On behalf of RAPS staff and the volunteers who created this book, I hope you find Fundamentals of Pharmaceutical and Biologics Regulations: A Global Perspective to be useful – as you support your organizations’ objectives, as you enhance your regulatory competence, and even as you prepare to sit for the Regulatory Affairs Certification-Drugs (RAC-Drugs) examination. We will continue to update and improve this book over time, and we welcome any feedback or suggestions you might have at [email protected]. Sincerely, William J. McMoil Executive Director Regulatory Affairs Professionals Society iii Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  iv Regulatory Affairs Professionals Society (RAPS) Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  Introduction T he first question we asked ourselves when the idea came up for this book was: Does the regulatory community really need it? The answer was an unequivocal “yes,” and here is why. We are both of an age at which chats with friends and family revolve around ailments and medication more often than we would like to admit. And, as healthcare industry professionals, we are often asked probing questions such as whether a vaccine really has as many side effects as the label says; why a drug costs so much; or why it has taken so long to develop an Alzheimer’s drug. Of course, this book is not written for our friends and family members, but really for the regulatory professionals who need to have the answers to such questions. So where do we find the answers? Sadly, the information is all over the place – there is an article here, a book chapter there. Some are in Chinese; some are in English; and others in yet another language. There was no single, comprehensive source for a global regulatory perspective on drugs and biologics. And that is why this book is an absolute necessity for regulatory professionals globally. Does it give you the answers to all and every- thing? That would be wishful thinking. It does, however, give you, dear reader, the single best source of authoritative regulatory information and guidance that our collaborative of more than 50 global expert authors and we, as editors, can bring you. We sincerely hope you will enjoy reading it and glean helpful bits of information that answer your questions – and maybe even those of your families and friends. And if you have a minute, do let us know your feedback. Linda McBride, RPh, RAC-US Siegfried Schmitt, PhD Partner, IAA Consulting LLC Vice President Technical, Parexel Consulting Linda McBride, RPh, RAC-Drugs, is a partner at IAA Consulting with Siegfried Schmitt, PhD, has been Vice President Technical in the Strategic extensive experience in the science of drug development in the biopharma- Compliance Consulting group of Parexel International since 2007. He has ceutical industry. Over her career of more than 30 years, she has had direct more than 30 years of experience and expertise in the global pharmaceutical experience in developing and implementing registration strategies for and medical device industries. He provides consulting services to customers pharmaceuticals and biologics in various therapeutic areas, from candidate in the healthcare industry on all aspects of regulatory compliance, particular- selection through marketing application and postapproval. McBride has ly in the design and implementation of effective and efficient quality man- significant expertise in preparing teams for successful interactions with agement systems. The services cover the entire product lifecycle, from the health authorities and for delivering approvals for marketing applications clinical to the commercial phase. Schmitt serves on several editorial advisory for pharmaceutical and biological products while striving to achieve the committees, has written or contributed to 28 books, and has published well corporate vision for success. She is a RAPS member and serves on its Edi- over a hundred articles for renowned journals, including RAPS Regulatory torial Advisory Committee and the Convergence Planning Committee. Focus. He has been a member of RAPS since 2010, serves on its Editorial Advisory Committee, and as co-chair of Euro Convergence 2023. v Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  vi Regulatory Affairs Professionals Society (RAPS) Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  Author Acknowledgments Editors Authors Monique J. Carter, MS, RAC-US, FRAPS Senior Director, Global Regulatory Sciences Linda McBride, RPh, RAC-US Kholoud Mamdouh Abdelfattah, MSc - Internal Medicine Partner Clinical Variations Unit Manager Pfizer, Inc. IAA Consulting LLC Egyptian Drug Authority Mantej (Nimi) Chhina, PhD, JD, MSc Siegfried Schmitt, PhD Bayan A. Arar, BPharm, RPh Executive Director, Head of Global R&D Vice President Technical Healthcare & Life Sciences Consultant and Regulatory Policy Parexel International BioMarin Pharmaceutical Inc. Sharry Arora, MPharm, RAC-Drugs Regulatory Affairs and Pharmacovigilance Rowena Cook, MS, RAC-Global Section Editors Manager Senior Regulatory Affairs Specialist Xeolas Pharmaceuticals Limited Twist Bioscience Kimberly Belsky, MS, FRAPS Executive Director, Regulatory Policy and Simon Authier, DVM, PhD, MSc, MBA Shuli Cui, MS, RAC-US Intelligence, AdPromo, and Regulatory Principal Director Senior Manager, Regulatory Affairs Operations Charles River Laboratories Alnylam Pharmaceuticals, Inc. Mallinckrodt Pharmaceuticals Ajay Babu Pazhayattil, DBA, MPharm Cristina Damatarca, MD, PgDip Devanshi Maharaja, MSc, MTech Partner President and Founder Manager, Regulatory Affairs Itaan Pharma Inc. SafePharm LLC The Janssen Pharmaceutical Companies of Johnson & Johnson Charlene F. Barroga, PhD, DABT Pragnesh Donga, MPharm, MBA, President & CEO RAC-Drugs Daniel G. Mannix, PhD, FRAPS Tessellux LLC Zydus Lifesciences Limited Senior Vice President, Regulatory Affairs IO Biotech Nicole Beard, PhD, MSc Robert Falcone, PhD, FRAPS Founder, Head International Regulatory Senior Regulatory Affairs Manager Flora Siami, MPH Affairs Prestige Consumer Healthcare Senior Vice President Biogecho Consulting Sarl NESTcc Stefanie Fasshauer, MBA Prashant Bhatia, MS Head of Regulatory Affairs, APAC Kip Vought Associate Director, Medical Devices and PharmaLex Partner Combination Products IAA Consulting LLC AstraZeneca Pharmaceuticals Margaret L. Fleming, PhD, MSE Senior Associate Jennifer G. Brown, PhD, RAC-US Exponent Director, Toxicology MacroGenics Anu Gaur, PhD, MBA, MSRA, RAC- Global, RAC-US Timothy A. Candy, PharmD, MS, BCPS President Principal Consultant, Regulatory Affairs SYNERGY Global Regulatory Affairs Opus Regulatory, Inc. Consultancy, Inc. vii Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  Amrita Ghosh, RAC-US Hongbo Pan, MBA Kathrin Schalper, PhD, RAC-CAN, Senior CRC and Regulatory Lead GRA Head of China and China R&D site RAC-Devices, RAC-EU, RAC-US Stanford University, Nuclear Medicine lead (Shanghai and Beijing) Principal Consultant, Regulatory Affairs CSL Senita Consulting, LLC Ruchi Gupta, MS Regulatory Program Director Viktória Pásztor, MS Payal Shah, MS, RAC-US Senior Regulatory Affairs Associate Alan M Hoberman, PhD, DABT, ATS Parexel Hungary Kurt M. Stahl Executive Director, Global Developmental, Senior Toxicologist Reproductive and Juvenile Toxicology Komalkumar Patel, MS MacroGenics, Inc. Charles River Laboratories Associate Director, Pharmaceutical Development, Beat U. Steffen, MSc, MBA, FRAPS Nidhi Kotecha, PhD, MPharm, Experic Founder & CEO RAC-Drugs confinis Senior Manager, Quality Assurance Grzegorz Podrygajlo, PhD Gates Biomanufacturing Facility Director, Global Manufacturing Support, Jesshanie Tabaniag, RPh Global Regulatory Affairs, CMC International Regulatory Manager Ching Li, PhD CSL Roche Products Limited - UK Senior Manager Biotest Pharma GmbH Azzurra Raviza, MS Blaine Van Leuven, MS, RAC-Global Senior Director, Global Regulatory Affairs Executive Director, Regulatory and Yingying Liu, MS Pfizer Inc. Strategic Development - CMC Associate Director Caidya CSL Zaida Recinos-Vasquez, MS Global Regulatory CMC Strategist Tyler Vandivort, PhD, DABT, RAC-Drugs Anne Marie Woodland, MS, RAC-EU, Pfizer Inc. Director of Regulatory Affairs and RAC-US Operations Senior Vice President, Regulatory Affairs Brian M Roche, PhD, DABT, DSP Amplicore Pharma Beam Therapeutics Executive Director, Global Safety Pharmacology Christinne V. Villanueva, MS Danini Marin, MSc Charles River Laboratories Manager, Regulatory Affairs Regulatory Affairs Consultant Aura Biosciences, Inc Darlene (Dar) Rosario, MBA, RAC-US Amanda M.G. McEwen, MRes Principal Consultant RA, QA, Combination Chauneen Leah Wood, MS, RAC-US Vice President, Clinical Development Products, Biotechnology Director, Regulatory Affairs Salubris Biotherapeutics, Inc. Velocity Consulting Inc Verathon, Inc. Katelyn J. Mulligan, MS Barbara A. Rusin, MS Nikolaos Zacharias, MSc Senior Submission Manager Owner/Independent GxP Consultant Senior CMC RA project manager Bristol Myers Squibb Phoenix Select Regulatory Consulting, LLC Marjorie E. Zettler, PhD, MPH Parvarsha Nafees, PharmD Leonor Pessanha Saldanha, PharmD, MS Executive Director of Clinical Science Senior Associate Manager Regulatory Principal Regulatory Affairs Specialist Regor Pharmaceuticals, Inc. Affairs PPD Martin Dow Limited Yuwei Zhang, MD, PhD, MBA, MPH Jennifer K. Saxe, PhD RWD Analytics Director Kingman Ng, PhD Global Lead, Environmental Safety & Parexel Executive Director, Global Regulatory Sustainability Affairs CM&C Johnson & Johnson Consumer Health Eli Lilly and Company viii Regulatory Affairs Professionals Society (RAPS) Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  Table of Contents Section I: General Information Chapter 1: Healthcare Landscape and Drug Development.............................................................................................................................. 1 Ruchi Gupta, MS Chapter 2: The Drug Development Continuum, Preclinical to Market Access................................................................................................. 5 Darlene Rosario, MBA, RAC-US; Pragnesh Donga, MPharm, MBA, RAC-Drugs; Kathrin Schalper, PhD, RAC-US, RAC-EU, RAC-Canada, RAC-Devices Chapter 3: International Harmonization via ICH, WHO, and other Global Initiatives................................................................................. 19 Anu Gaur, PhD, MBA, MSRA, RAC-US, RAC-Global Section II: Nonclinical Studies Chapter 4: Principles of Good Laboratory Practice and Nonclinical Development........................................................................................ 29 Kurt Stahl, BS; Jennifer G. Brown, PhD, RAC-US Chapter 5: Safety Pharmacology Studies........................................................................................................................................................ 37 Charlene F. Barroga PhD, DABT; Brian M. Roche, PhD, DSP, DABT; Simon Authier, DVM, PhD, MSc, MBA Chapter 6: Pharmacokinetic and Toxicokinetic Studies.................................................................................................................................. 53 Tyler Vandivort, PhD, RAC-Drugs, DABT Chapter 7: Genotoxicity Studies..................................................................................................................................................................... 63 Tyler Vandivort, PhD, RAC-Drugs, DABT Chapter 8: Carcinogenicity Studies................................................................................................................................................................. 73 Tyler Vandivort, PhD, RAC-Drugs, DABT Chapter 9: Developmental and Reproductive Toxicity Assessments............................................................................................................... 85 Charlene F. Barroga, PhD, DABT; Alan M. Hoberman, PhD, DABT, ATS Chapter 10: Regulatory Environmental Risk Assessment of Human Pharmaceuticals................................................................................... 99 Margaret L. Fleming, PhD; Jennifer K. Saxe, PhD Section III: Chemistry, Manufacturing, and Controls Chapter 11: The Global Regulatory Process for the Registration of Active Substances................................................................................ 111 Darlene Rosario, MBA, RAC-US; Yuwei Zhang, MD, PhD, MPH, MBA; Robert Falcone, PhD, FRAPS, FTOPRA Chapter 12: Coordinating Drug Supply for Clinical and Nonclinical Development.................................................................................... 125 Ajay Babu Pazhayattil, DBA, MPharm; Payal Shah, MS, RAC-US Chapter 13: Pharmaceutical Development Studies and Manufacturing Experience..................................................................................... 141 Komalkumar Patel, MS; Nikolaos Zacharias, MSc; Kingman Ng, PhD; Beat U. Steffen, MSc, MBA, FRAPS; Nicole Beard, PhD, MSc Chapter 14: Analytical Development – Testing and Stability....................................................................................................................... 159 Blaine Van Leuven, MS, RAC-Global; Nidhi Kotecha, MPharm, PhD, RAC-Drugs ix Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  Section IV: Clinical Trials Chapter 15: Conducting Clinical Trials: Drug Application Types, Data Requirements and Obtaining Marketing Approval...................... 167 Sharry Arora, MPharm, RAC-Drugs; Viktória Pásztor, MS; Bayan A. Arar, BPharm, RPh Chapter 16: Phases of Development (1,2,3,4)............................................................................................................................................... 177 Rowena Cook, MS, RAC-Global; Amanda McEwen, MRes; Shuli Cui, MS, RAC-US; Stefanie Fasshauer, MBA Chapter 17: Enhancing Diversity in Clinical Trials...................................................................................................................................... 215 Monique Carter, MS, RAC, FRAPS; Zaida Recinos-Vasquez, MSPS, MSRAQA; Leonor Pessanha Saldanha, PhD, MSc Chapter 18: Health Authority Interactions................................................................................................................................................... 231 Chauneen Leah Wood, MS, RAC-US; Azzurra Ravizza, MS Chapter 19: Pediatrics................................................................................................................................................................................... 255 Linda McBride, RPh, RAC-US Chapter 20: Regional-Specific Studies.......................................................................................................................................................... 271 Mantej (Nimi) Chhina, PhD, JD, MSc; Marjorie Zettler, PhD, MPH Section V: Marketing Authorization Chapter 21: Framework for Benefit-Risk Assessment.................................................................................................................................. 283 Cristina Damatarca, MD, PgDip Chapter 22: eCTD and Digital Applications................................................................................................................................................ 295 Amrita Ghosh, RAC-US; Danini Marin, MSc; Katelyn Mulligan, MS Chapter 23: Expedited Approval Pathways................................................................................................................................................... 305 Yingying Liu, MS; Kathrin Schalper, PhD, RAC-CAN, RAC-Devices, RAC-EU, RAC-US; Ching Li, PhD; Christinne V. Villanueva, MS; Hongbo Pan, MBA; Grzegorz Podrygajlo, PhD Chapter 24: Dossier Requirements................................................................................................................................................................ 353 Jesshanie Tabaniag, RPh; Kholoud Mamdouh Abdelfattah, MSc; Stefanie Fasshauer, MBA; Danini Marin, MSc; and Prashant Bhatia, MSc Section VI: Postmarketing Authorization Chapter 25: Postauthorization Commitments.............................................................................................................................................. 395 Linda McBride, RPh, RAC-US Chapter 26: Transfers and Renewals............................................................................................................................................................. 405 Linda McBride, RPh, RAC-US Chapter 27: Product Extensions, Variations, and Supplements..................................................................................................................... 425 Linda McBride, RPh, RAC-US Chapter 28: Compliance............................................................................................................................................................................... 447 Siegfried Schmitt, PhD; Barbara Rusin, MS; Anne Marie Woodland, MS, RAC-EU, RAC-US Chapter 29: Recalls....................................................................................................................................................................................... 463 Siegfried Schmitt, PhD x Regulatory Affairs Professionals Society (RAPS) Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  Chapter 30: Postmarket Surveillance............................................................................................................................................................. 467 Linda McBride, RPh, RAC-US Chapter 31: Advertising and Promotion....................................................................................................................................................... 481 Timothy A. Candy, PharmD, MS, BCPS Chapter 32: Market Access: Reimbursement and Pricing............................................................................................................................. 499 Anu Gaur, PhD, MBA, MSRA, RAC-US, RAC-Global; Parvarsha Nafees, PharmD Appendices Regulations and Guidelines Across Chapters – Comparative Matrix........................................................................................................... 543 Abbreviations and Acronyms........................................................................................................................................................................ 577 Glossary of Terms.......................................................................................................................................................................................... 605 Index............................................................................................................................................................................................................. 627 Case Studies Case Study 5-1................................................................................................................................................................................................ 47 Case Study 5-2................................................................................................................................................................................................ 47 Case Study 6-1................................................................................................................................................................................................ 59 Case Study 9-1................................................................................................................................................................................................ 95 Case Study 16-1............................................................................................................................................................................................ 203 Case Study 16-2............................................................................................................................................................................................ 204 Case Study 17-1............................................................................................................................................................................................ 225 Case Study 20-1............................................................................................................................................................................................ 271 Case Study 20-2............................................................................................................................................................................................ 272 Case Study 20-3............................................................................................................................................................................................ 275 Case Study 20-4............................................................................................................................................................................................ 276 Case Study 20-5............................................................................................................................................................................................ 277 Case Study 20-6............................................................................................................................................................................................ 278 Case Study 23-1............................................................................................................................................................................................ 346 Case Study 31-1............................................................................................................................................................................................ 492 Figures Figure 2-1. The Medicinal Product Development Continuum.......................................................................................................................... 5 Figure 2-2. Traditional de novo product development process vs. product repurposing.................................................................................... 7 Figure 2-3. Phase Transition Duration from Phase 1 through NDA/BLA Authorization............................................................................... 8 Figure 2-4. Phases of Clinical Research.......................................................................................................................................................... 11 Figure 2-5. CTD Triangle............................................................................................................................................................................... 14 Figure 2-6. Communicating value to healthcare stakeholders......................................................................................................................... 15 Figure 2-7. Relationship between Pricing, Reimbursement, and Market Access............................................................................................. 16 Figure 3-1. ICH Process of Harmonization.................................................................................................................................................... 22 Figure 4-1. Final Study Report Items............................................................................................................................................................. 32 Figure 4-2. Nonclinical Safety Evaluation Goals............................................................................................................................................ 33 Figure 5-1. Continuum of Safety Pharmacology Assessments from Acute to Chronic Toxicity Studies........................................................ 45 Figure 6-1. Drug Exposure Parameters Derived from PK Data...................................................................................................................... 54 Figure 8-1. Genotoxic versus Nongenotoxic Dose-Response Curves.............................................................................................................. 74 xi Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  Figure 8-2. ICH S1B(R1) Schema for Determining the Added Value of a 2-Year Carcinogenicity Study..................................................... 80 Figure 9-1. Stages of the Reproduction and Development Cycle (A to F) as described in ICH S5(R3)........................................................ 85 Figure 9-2. Scheme for Fertility and Early Embryonic Development Studies, Embryo-fetal Development Studies, and Combined Studies..................................................................................................................................................................................... 87 Figure 9-3. Scheme for Pre- and Postnatal Development Studies and Enhanced Studies.............................................................................. 87 Figure 9-4. Scheme for Enhanced Pre- and Postnatal Development Studies in Rabbit for Vaccines............................................................. 94 Figure 9-5. Scheme to Determine if Standard Models for Hazard Assessment of Developmental Toxicity can be used for Molecules that produce Anti-Drug Antibodies (ADA)..................................................................................................................................................... 95 Figure 10-1. FDA Categorical Exclusion for Drug Approval – Small Molecules......................................................................................... 101 Figure 10-2. FDA Studies Required for Drug Approval............................................................................................................................... 102 Figure 10-3. EU ERA Process for Drug Approval........................................................................................................................................ 103 Figure 10-4. FDA Categorical Exclusion for Drug Approval – Biologics..................................................................................................... 106 Figure 11-1. Top 10 Pharmaceutical Markets............................................................................................................................................... 111 Figure 11-2. Percent of Global Pharmaceutical Sales by Economic Blocks.................................................................................................. 111 Figure 11-3. Brazil API Background Regulations......................................................................................................................................... 119 Figure 11-4. China API Registration Procedure........................................................................................................................................... 120 Figure 11-5. Japan API Process Review........................................................................................................................................................ 121 Figure 12-1. Clinical Supply......................................................................................................................................................................... 129 Figure 12-2. Routine Challenges in Clinical Supply..................................................................................................................................... 132 Figure 12-3. US Marketed Products API Supply.......................................................................................................................................... 133 Figure 12-4. Cold Chain Lifecycle................................................................................................................................................................ 133 Figure 12-5. An Example Sample Kit Label and Bottle Label..................................................................................................................... 135 Figure 13-1. Product requirements................................................................................................................................................................ 142 Figure 13-2. Factors impacting product requirements – Ishikawa (fishbone) diagram.................................................................................. 142 Figure 13-3. QbD Elements Flow Chart...................................................................................................................................................... 143 Figure 13-4. Possible Leachables from a Plastic Bottle................................................................................................................................. 150 Figure 14-1. Analytical Method Life Cycle and Links to Product Development......................................................................................... 160 Figure 16-1. Clinical Trial Lifecycle.............................................................................................................................................................. 179 Figure 16-2. Russian Approval Process......................................................................................................................................................... 191 Figure 16-3. Primary Hyperoxaluria Integrated Clinical/Regulatory Development Plan: Phase 1/2 to Start of Phase 2/3.......................... 204 Figure 16-4. OPTIC Study Design.............................................................................................................................................................. 208 Figure 17-1. Contributing Factors of Clinical Trial Underrepresentation..................................................................................................... 215 Figure 17-2. Demographic Diversity of Global Clinical Trials Participation for New Drugs Approved by the FDA.................................. 216 Figure 17-3a. Distribution of Clinical Trial Participants – US Compared to the Rest of World.................................................................. 217 Figure 17-3b. Global Distribution of Clinical Trial Participants by Country vs US..................................................................................... 217 Figure 17-4. Clinical Trial Sex, Race, Age, and Ethnicity Distribution in the US........................................................................................ 218 Figure 17-5. Percentage of Trials with Participant Levels Above Census..................................................................................................... 218 Figure 17-6. Representation in Pfizer Trials vs. US Census Level................................................................................................................. 219 Figure 17-7. OMB Minimum of Race and Ethnicity Categories................................................................................................................. 221 Figure 17-8. Intrinsic and Extrinsic Ethnic Factors...................................................................................................................................... 224 Figure 18-1. CHMP SA Process................................................................................................................................................................... 238 Figure 18-2. Parallel Scientific Advice (FDA-EMA).................................................................................................................................... 240 Figure 18-3. NICE Standard Scientific Advice Process................................................................................................................................ 247 Figure 18-4. NICE MHRA Scientific Advice Process................................................................................................................................. 248 Figure 18-5. NICE CADTH Scientific Advice Process............................................................................................................................... 248 Figure 18-6. NICE HTA-EMA Scientific Advice process........................................................................................................................... 249 Figure 20-1. Requests for Local Clinical Data and Different Therapeutic Areas.......................................................................................... 272 Figure 20-2. Representative Schematic of Potential Approaches to Conducting Regional-Specific Studies................................................ 273 Figure 20-3. Clinical Development Strategies Employing Local vs. MRCT Strategies (Adapted from ICH E17)..................................... 274 Figure 21-1. Continuous Benefit-Risk Assessment for Defining and Maintaining the Safety Profile of Drugs Through the Development Lifecycle............................................................................................................................................................................ 284 Figure 21-2. BRAT Six-Step Process............................................................................................................................................................ 288 Figure 21-3. EMA Eight-Step PrOACT-URL............................................................................................................................................ 289 Figure 21-4. FDA’s Benefit-Risk Framework for New Drug Review............................................................................................................ 290 Figure 22-1. History of Regulatory Submission Tools.................................................................................................................................. 295 xii Regulatory Affairs Professionals Society (RAPS) Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  Figure 23-1. Outcome of PRIME Eligibility Requests by Therapeutic Area................................................................................................ 311 Figure 23-2. Expedited Pathways in Different Development Stages in China.............................................................................................. 321 Figure 23-3. Standard Marketing Authorization Application Procedures and Expedited Pathways............................................................ 321 Figure 23-4. General Timeframe of SAKIGAKE........................................................................................................................................ 327 Figure 23-5. SAKIGAKE Designation Procedure........................................................................................................................................ 328 Figure 23-6. Standard Review, Conditional Early Pathway, Priority Review and Orphan Drugs in Japan................................................... 328 Figure 23-7. Conditional Early Pathway Procedures in Japan....................................................................................................................... 329 Figure 24-1. ASEAN CTD.......................................................................................................................................................................... 367 Figure 28-1. How Good Practices Align with the Product Lifecycle............................................................................................................ 447 Figure 28-2. China Drug Regulatory Legislative System............................................................................................................................. 455 Figure 28-3. China Drug Regulatory Landscape.......................................................................................................................................... 456 Figure 29-1. Recall of Clinical Trial Supplies Process Flow.......................................................................................................................... 465 Figure 31-1. Example of a Reminder Ad...................................................................................................................................................... 484 Figure 31-2. Ad for a Boxed Warning Drug................................................................................................................................................. 484 Figure 31-3. General Timeline View of Pre-submission Requirements for Subpart E/H Products............................................................. 485 Figure 31-4. Issuance of Enforcement Action Letters Over Time (1997–2022).......................................................................................... 489 Figure 32-1. Factors Influencing Medicinal Product Pricing........................................................................................................................ 500 Figure 32-2. Timeline of US “HTA Like’ Bodies.......................................................................................................................................... 503 Figure 32-3. Overview of the Canada Public System Reimbursement Decision Pathway............................................................................ 506 Figure 32-4. Process Map for France............................................................................................................................................................ 509 Figure 32-5. Process Map for Germany........................................................................................................................................................ 510 Figure 32-6. Mean Length of Time From EMA Authorisation to HTA Decision for Oncology Products................................................. 511 Figure 32-7. Overview of ERP Across Europe (2013).................................................................................................................................. 512 Figure 32-8. Types of Cost Containment Policies Adopted by Member States............................................................................................ 513 Figure 32-9. Process Map for England.......................................................................................................................................................... 514 Figure 32-10. Process Map for Scotland....................................................................................................................................................... 515 Figure 32-11. German Pricing for Medicinal Products Under AMNOG.................................................................................................... 520 Figure 32-12. Map of Australian Government HTA Processes for Market Entry and Reimbursement Processes....................................... 527 Figure 32-13. Framework for Pricing Drugs and Devices in Japan............................................................................................................... 529 Figure 32-14. Flow Diagram of HTA in South Korea.................................................................................................................................. 530 Figure 32-15. Historical MaHTAS Milestones............................................................................................................................................ 530 Tables Table 2-1. Pharmacology Studies – Overview................................................................................................................................................. 10 Table 2-2. Toxicology Studies – Overview...................................................................................................................................................... 10 Table 3-1. Current Members and Observers of the ICH Association............................................................................................................. 21 Table 3-2. Members and Observers of the International Pharmaceutical Regulators Programme.................................................................. 24 Table 5-1. Cardiac Ion Channels Assessed by In Vitro Assay in Chinese Hamster Ovary (CHO) Cells and Human Embryonic Kidney 293 (HEK293) Cells..................................................................................................................................................................... 38 Table 5-2. Cardiovascular (CV) Study Designs and Endpoints...................................................................................................................... 39 Table 5-3. Stand-Alone Cardiovascular or Combined Cardio-Respiratory Telemetry Studies – Latin Square (4x4) Study Design.............. 41 Table 5-4. Integrated Cardiovascular or Cardio-Respiratory Telemetry Endpoints in a Non-rodent, Repeat-Dose, Toxicology Study Design............................................................................................................................................................................................. 41 Table 5-5. Stand-Alone Rodent Respiratory or CNS (FOB or modified Irwin) Parallel Study Design......................................................... 42 Table 5-6. Combined Respiratory and CNS (FOB or modified Irwin) Study in Rodent Repeat Dose Toxicology Study Design................. 42 Table 5-7. Safety Pharmacology Strategies for Pharmaceuticals and Biopharmaceuticals.............................................................................. 44 Table 6-1. Parameters for Comparing Drug Exposure Across Studies............................................................................................................ 55 Table 6-2. Global Implementation of Major ICH Guidance Relevant to Pharmacokinetic and Toxicokinetic Studies................................. 56 Table 6-3. Preclinical Case Study: ZILRETTA®........................................................................................................................................... 59 Table 7-1. ICH S2(R1) Recommendations for In Vitro Genotoxicity Testing............................................................................................... 66 Table 7-2. ICH S2(R1) Recommendations for In Vivo Genotoxicity Testing................................................................................................ 68 Table 7-3. Overview of Common In Vitro and In Vivo Genotoxicity Testing Assays.................................................................................... 70 Table 8-1. Global Implementation of Major ICH Guidance on Carcinogenicity........................................................................................... 75 Table 8-2: Key Weight of Evidence Factors for Integrated Assessments of Carcinogenic Potential............................................................... 81 xiii Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  Table 9-1. DART Strategy for Pharmaceuticals and Biologics Depending on Relevant Species.................................................................... 89 Table 9-2. Embryo-fetal Development (EFD) Study Design Parameters for Rodent, Rabbit and Non-human Primate Species.................. 89 Table 9-3. Considerations for Design of a Pre- and Post-Natal Development (PPND) Toxicity Study in Rats............................................. 91 Table 9-4. Considerations for the Design of an Enhanced Pre- and Post-Natal Development Toxicity Study in Nonhuman Primates........ 92 Table 9-5. Potential Species for DART Studies (relative percentages used from a 10-year period at a contract testing facility)..................... 93 Table 10-1. Studies Required During the EU Environmental Risk Assessment Process.............................................................................. 104 Table 11-1. Global Regulatory Active Substances Filling Requirements...................................................................................................... 112 Table 11-2. Master File Classifications......................................................................................................................................................... 116 Table 11-3. Type of Fee (Active Substance Manufacturers).......................................................................................................................... 118 Table 11-4. Type of Fee (Active Substance Importers and Distributors)....................................................................................................... 118 Table 12-1: Standards and Guideline Types That Apply in Clinical Supply................................................................................................. 126 Table 12-2: Standards and Guideline Types That Apply in Non-Clinical Supply......................................................................................... 126 Table 12-3. Components of Clinical Supply Chain Strategy........................................................................................................................ 127 Table 12-4. Clinical Development Stages..................................................................................................................................................... 127 Table 12-5. FDA Regulations Relating to GCP and Clinical Trials............................................................................................................. 130 Table 12-6. Comparing Clinical and Non-Clinical Material Supply............................................................................................................ 131 Table 12-7. Factors to Consider When Selecting Excipients........................................................................................................................ 133 Table 13-1. QbD regulatory guidance comparison in major markets............................................................................................................ 144 Table 13-2. Container Content/Volume Label Claim/Extractable Volume Test Regional Comparison....................................................... 146 Table 13-3. Dosage Form Compatibility Cases............................................................................................................................................. 149 Table 13-4. Typical Packaging Suitability Considerations for Common Classes of Drug Products.............................................................. 149 Table 13-5. Modified FDA/CDER/CBER Risk-based Approach to Consideration of Leachables............................................................. 150 Table 13-6. Dissolution Specification Setting Considerations...................................................................................................................... 152 Table 13-7. Biopharmaceutics Classification System (BCS)......................................................................................................................... 153 Table 13-8. Considerations for Specific Dosage Forms................................................................................................................................. 153 Table 13-9. Applicability of Different Types of Waivers per Dosage Form................................................................................................... 154 Table 13-10. Most Common Routes of Administration: Advantages and Disadvantages............................................................................ 155 Table 13-11. Comparison of Regulatory Guidance....................................................................................................................................... 157 Table 15-1. Key documents required for the clinical trial application submission US................................................................................... 169 Table 15-2. Changes to EU Legislation for the Conduct of Clinical Trials 2022 to 2025............................................................................ 170 Table 15-3. Key documents required for the initial clinical trial application submission in the EU.............................................................. 170 Table 15-4. Data requirement for clinical investigation stage in BRICS, APAC, and MENA countries...................................................... 171 Table 15-5. Comparison of data requirements for marketing application stage per region for BRICS, APAC and MENA countries......... 171 Table 16-1. Phase I–IV Clinical/Regulatory Terminology............................................................................................................................ 178 Table 16-2. APAC Countries and Respective Regulatory Authorities.......................................................................................................... 192 Table 16-3. Middle East/North Africa Countries and Respective Regulatory Authorities........................................................................... 197 Table 16-4. Countries of Africa and Their Respective Regulatory Authorities............................................................................................. 200 Table 16-5. Regulatory History of Iclusig®................................................................................................................................................... 205 Table 16-6. Clinical Studies Included in the Initial NDA............................................................................................................................ 206 Table 16-7. PACE Study Patient Cohorts.................................................................................................................................................... 207 Table 17-1. US Clinical Trial Participant Cross-Section Distribution by Sex, Race, and Age for Select Therapeutic Areas......................... 218 Table 17-2. Percentage of Pfizer Inc. Studies with Participation at or Above US Census Levels Across Therapy Areas............................... 220 Table 17-3. Pfizer Inc. Race and Ethnicity Diversity Plan Template............................................................................................................ 222 Table 17-4. Government of Canada Historical GBA Initiatives and Activity Timeline............................................................................... 224 Table 18-1. Formal Meetings Negotiated Under PDUFA (timelines).......................................................................................................... 233 Table 18-2. Formal Meetings Negotiated Under BsUFA (timelines)............................................................................................................ 234 Table 18-3 CADTH Scientific Advice at a Glance...................................................................................................................................... 236 Table 18-4. CADTH Scientific Advice Process............................................................................................................................................ 237 Table 18-5. Key Timelines for CADTH Scientific Advice Offerings........................................................................................................... 237 Table 18-6. Types of Questions for Scientific Advice.................................................................................................................................... 239 Table 18-7. Parallel Scientific Advice Timelines........................................................................................................................................... 240 Table 18-8. EU National Competent Authorities and Scientific Advice...................................................................................................... 241 Table 18-9. Simultaneous NCA Participating Countries.............................................................................................................................. 245 Table 18-10. NICE Advice Timelines.......................................................................................................................................................... 247 Table 18-11. PMDA Categories and Content of Consultations for New Medicinal Products..................................................................... 250 xiv Regulatory Affairs Professionals Society (RAPS) Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  Table 19-1. Comparison of Pediatric Development Regulations................................................................................................................... 267 Table 20-1. Time to Regulatory Authority and Ethics Board Approvals in an MRCT................................................................................ 278 Table 20-2. Clinical Trial Applications in North America (Canada, Mexico, US)........................................................................................ 279 Table 20-3. Clinical Trial Applications in Europe (EU, Switzerland, UK).................................................................................................... 279 Table 20-4. Clinical Trial Applications in BRICS Countries........................................................................................................................ 280 Table 20-5. Clinical Trial Applications in South America (Argentina, Colombia, Chile, Peru).................................................................... 280 Table 20-6. Clinical Trial Applications in Select Asia-Pacific (APAC) Countries........................................................................................ 281 Table 20-7. Clinical Trial Applications in Select Middle East/North Africa (MENA) Countries............................................................... 281 Table 21-1. A Brief History of the Evolving BRA Initiatives, Methods, and Procedures............................................................................. 286 Table 21-2. UMBRA Steps and Process....................................................................................................................................................... 291 Table 22-1. Advantages and Disadvantages of eCTD................................................................................................................................... 296 Table 22-2. Example of Folder Names in eCTD.......................................................................................................................................... 301 Table 22-3. Error Severity............................................................................................................................................................................. 301 Table 22-4. eCTD 4.0 Implementation Schedule as per ICH Guideline July 2022..................................................................................... 302 Table 23-1. Overview of Expedited Approval Programs in the US............................................................................................................... 307 Table 23-2. Overview of Expedited Approval Pathways in Argentina.......................................................................................................... 308 Table 23-3. Overview of Expedited Approval Pathways in Canada.............................................................................................................. 309 Table 23-4. Overview of Expedited Approval Pathways in Mexico.............................................................................................................. 310 Table 23-5. Comparison of Conditional Marketing Authorization and Marketing Authorization Under Exceptional Circumstances....... 312 Table 23-6. Overview of Accelerated Approval Pathways in EU, Switzerland, UK, and Turkey................................................................... 317 Table 23-7. Overview of Expedited Approval Pathways in Brazil................................................................................................................. 319 Table 23-8. Summary of Expedited Approval Pathways in India.................................................................................................................. 320 Table 23-9. Overview of Expedited Approval Pathways in China................................................................................................................ 322 Table 23-10. Overview of Expedited Approval Pathways in Australia.......................................................................................................... 323 Table 23-11a. Overview of Expedited Approval Pathways in Japan: SAKIGAKE, Conditional Early Pathway and Priority Review......... 324 Table 23-11b. Overview of Expedited Approval Pathways in Japan – Orphan Drug Review, Recruitment for Unapproved Drugs and Indications, and Emergency Approval..................................................................................................................................................... 325 Table 23-12. Overview of Expedited Approval Pathways in South Korea.................................................................................................... 329 Table 23-13. Overview of Expedited Approval Pathways in New Zealand................................................................................................... 330 Table 23-14. Overview of Expedited Approval Pathways in Taiwan............................................................................................................. 332 Table 23-15. Overview of ASEAN Joint Assessment Procedure.................................................................................................................. 334 Table 23-16. Overview of Approval Pathways in Brunei............................................................................................................................... 335 Table 23-17. Overview of Expedited Pathways in Cambodia....................................................................................................................... 336 Table 23-18. Overview of Expedited Regulatory Pathways in Indonesia...................................................................................................... 336 Table 23-19. Orphan Drug Designation in Malaysia.................................................................................................................................... 338 Table 23-20. Expedited Regulatory Pathways in Malaysia............................................................................................................................ 338 Table 23-21. Overview of the Expedited Regulatory Pathways in Philippines............................................................................................. 340 Table 23-22. Overview of Expedited Pathways in Singapore........................................................................................................................ 341 Table 23-23. Eligible Criteria for a Drug to be Considered on the List of Rare Drugs in Vietnam............................................................. 343 Table 23-24. Overview of Expedited Approval Pathways in Saudi Arabia................................................................................................... 345 Table 24-1. Country Requirements............................................................................................................................................................... 354 Table 24-2. Regulatory Authority and Country Legal Framework............................................................................................................... 360 Table 24-3. Content and Format Requirements............................................................................................................................................ 370 Table 24-4. Country Requirements............................................................................................................................................................... 375 Table 24-5. Dossier Requirement for Collaborative and Reliance Procedures, ACCESS Consortium......................................................... 379 Table 24-6. Country-Specific Dossier Requirements Related to Selected Described Pathways.................................................................... 380 Table 24-7. Combination Product Definitions.............................................................................................................................................. 387 Table 24-8. Combination Product Definitions in Additional Regions.......................................................................................................... 390 Table 25-1. Regulatory Framework for Postauthorization Studies in Major America Regions.................................................................... 396 Table 25-2. Regulations and Guidance Documents...................................................................................................................................... 402 Table 26-1. Postapproval Regulations in Each MENA Country.................................................................................................................. 420 Table 27-1. Americas: Comparison of Regulations Across Jurisdictions....................................................................................................... 429 Table 27-2. NMRAs and Guidelines for Pharmaceuticals in African Countries.......................................................................................... 442 Table 28-1. Regulations and Guidance for GPvP Management and Reporting........................................................................................... 448 Table 28-2: PRAC Scope of Recommendations........................................................................................................................................... 453 xv Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  Table 28-3: EU Mutual Recognition Agreements........................................................................................................................................ 453 Table 30-1. MAH Reporting Requirements................................................................................................................................................. 470 Table 31-1. Common Scenarios Considered False, Lacking in Fair Balance, or Otherwise Misleading by FDA......................................... 483 Table 32-1. Drugs Eligible for CADTH’s Drug Review Processes............................................................................................................... 504 Table 32-2. Summary of CADTH’s Elements and Recommendation Categories........................................................................................ 505 Table 32-3. Latin American Country-Specific HTA Overview.................................................................................................................... 505 Table 32-4. Summary of Time From EMA Authorisation to HTA Decision and Outcome....................................................................... 507 Table 32-5. HTA and Associated Organizations in Selected EU Member States and the UK..................................................................... 511 Table 32-6. Overview of Reference Pricing and Country Baskets in Europe................................................................................................ 512 Table 32-7. Comparison of HTA in Germany, France, UK, Italy, and Spain................................................................................................ 517 Table 32-8. Summary of HTA Status in Select Asian Countries.................................................................................................................. 518 Table 32-9. Regulatory Authorities of BRIC region and their Product Categories for Controlled Pricing.................................................. 523 Table 32-10. Types of Drug Categories followed in Brazil for price fixation................................................................................................ 524 Table 32-11. Types of Regulatory Programs and Reimbursement Methods in Russia.................................................................................. 525 Table 32-12. 13 Selected Products for Japan MHLW 3-Year HTA Pilot Evaluation................................................................................... 528 Table 32-13. MaHTAS 1995–2018 Impact Overview.................................................................................................................................. 531 Table 32-14. Regulatory Authorities and Pricing Models in South Asia...................................................................................................... 532 xvi Regulatory Affairs Professionals Society (RAPS) Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  Healthcare Landscape and chapter 1 Drug Development Ruchi Gupta, MS H ealthcare always has been – and is even more so today agency collaborates with other US agencies, international regula- – a vital aspect of human life. The healthcare landscape tors, academia, trade associations, consumer groups, and others.2 continues to evolve and transform hand in hand with evolution in the medicinal product development field, now highly Role in Global Regulatory Landscape influenced by payer reform, technology, scientific advances, con- Many of the medicinal products consumed by people of leading sumer demand, and more. nations such as the US are produced in other countries. In the US, These new realities and challenges impact how medicinal FDA-regulated products are produced in over 130,000 facili- products are developed and approved. Previously, we lacked ties in more than 150 countries.3 The agency faces challenges in effective treatments for many life-threatening diseases; now, determining and confirming that its standards and requirements despite having many more treatments available, public scrutiny of have been applied in the manufacture, distribution, and storage of healthcare has intensified. Patients and their families want new medicinal products imported into the US. Given that the man- treatments sooner with accurate and understandable information ufacture of a product may involve multiple parties from different on how to use them. While this has led health authorities to countries, there are chances for the product to be improperly support innovation and advances in science and technology, it has formulated or packaged, contaminated, diverted, counterfeited, or also increased the complexity in the global regulatory landscape. adulterated. Thus, compliance and surveillance activities overseen The Food and Drug Administration (FDA) and the Euro- by regulatory bodies across the product life cycle are a critical part pean Medicines Agency (EMA) often are the regulators who first of the drug development process.4 review these innovative treatments and lead the way in bringing Inspections are a big part of such surveillance activities and efficacious and cost-effective treatments to the general and broad- depend on the stage of drug development. In situations where er population. noncompliance is identified, FDA may issue one of several types In addition, the International Council for Harmonisation of regulatory action letters, such as warning letters, administrative of Technical Requirements for Pharmaceuticals for Human Use license action letters, and license revocation to cease practices that (ICH) plays a critical role in global drug development by devel- violate regulations and promote corrective action. If warranted, oping guidelines based on scientific discussions among regulatory the FDA also has the authority to impose civil enforcement authorities and the pharmaceutical industry. ICH guidelines are up- actions, including seizure, injunction, and prosecution. dated continuously and applied by an increasing number of health FDA oversees the import and export of medicinal products authorities worldwide. The mission of ICH is to achieve greater to ensure that the FDA-regulated products comply with the harmonization worldwide and ensure that safe, effective, and requirements of the Food, Drug, and Cosmetics Act (FD&C high-quality medicines are developed, registered, and maintained in Act) and the regulations promulgated under these statutes.5 the most resource-efficient manner while meeting high standards.1 Imported products regulated by FDA are subject to inspection at the time of entry by the US Customs and Border Protection Food and Drug Administration (CBP). Imported products not in compliance with US regulations FDA, an agency of the US the Department of Health and are subject to detention. Moreover, FDA verifies with CPB a Human Services (HHS), is responsible for protecting the public company’s licensure for imports, may perform random sampling, health by assuring the safety, efficacy, and security of human and will issue import alerts for noncompliant products.6 A foreign drugs and biological products, as well as other products outside manufacturer must have a US license to import a biological prod- the scope of this book. FDA’s mission includes advancing public uct into the US. health by supporting innovations that make medicines safer, more FDA works closely with external organizations and foreign effective, and more affordable. The agency is tasked with providing governments to promote product safety and regulatory consisten- the public with the accurate, science-based information they need cy. Its efforts include: to use medicinal products to maintain and improve their health. developing new enforcement and regulatory tools; FDA plays a significant role in US counterterrorism efforts. The conducting more foreign inspections; 1 Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  Fundamentals of Pharmaceutical and Biologics Regulations: A Global Perspective collaborating with foreign regulators and other stakeholders; ing and simulation), pharmacovigilance, rare diseases, vaccines, and developing harmonized standards and standards convergence; veterinary medical products. (Not all of these agencies necessarily educating industry representatives about its requirements; and participate in all clusters.) increasing transparency and accountability in the supply chain FDA also is a member or participant in several international organizations, including the International Council for Harmon- Several offices within FDA address global issues. The Office of isation, Pharmaceutical Inspection Convention, Pharmaceutical Regulatory Affairs (ORA) inspects and reviews products offered Inspection Co-operation Scheme, International Medical Device for entry into the US. The agency’s product centers implement Regulators Forum, and Codex Alimentarius, which promotes the policies and outreaches that touch their product portfolios. international food standards. The Office of Global Policy and Strategy (OGPS) serves as a In addition to its own programs, FDA collaborates exten- pan-agency coordinator, information distributor, and access point sively with other HHS and federal agencies on international for multilateral organizations like the World Health Organiza- issues. Within HHS, the Office of Global Affairs (OGA) works tion. OGPS also addresses international trade of regulated prod- with FDA and other agencies on such issues as trade and health, ucts and mutual recognition agreements, facilitates information emerging infectious diseases and global health security, phar- sharing with its global counterparts, and manages FDA’s foreign maceutical pricing and reimbursement, and tobacco control offices worldwide.3 and nutrition. In their own words, “they foster critical global The Office of International Products (OIP) coordinates the relationships, coordinate international engagement across HHS FDA’s international work, which helps foster partnerships with and the U.S. government, and provide leadership and expertise counterpart foreign agencies and international organizations. OIP in global health diplomacy and policy to contribute to a safer, offices around the world focus on specific regions: Latin America healthier world.” OGA collaborates with the US Department (Costa Rica), Europe (Brussels, London), China (Beijing), and of State and serves as the US government’s liaison to the World India (New Delhi). Health Organization. International Arrangements European Medicines Agency FDA uses various tools to set up partnerships with other nations The European Medicines Evaluation Agency (EMEA) was to promote product safety, and they fall into two categories of founded in 1995. It worked across the European Union (EU) international arrangements: Cooperative Arrangements and nations to protect human and animal health by evaluating Confidentiality Commitments.7 A Confidentiality Commitment human and veterinary medicines as their primary focus. It also sets up the legal framework for the FDA to share certain kinds of provided partners and stakeholders with independent, unbiased, non-public information with international organizations and regu- science-based information on medicines.8 The name was changed lators in other countries as part of cooperative law enforcement or to European Medicines Agency (EMA) in late 2009.9 The main regulatory activities. objective for establishing EMA was to have a harmonized process A Cooperative Arrangement is a written document that de- among the regulatory bodies of different member states within the scribes the good-faith intentions of the FDA, other regulators, and EU. The agency also is responsible for products developed in the international organizations to engage in cooperative activities. specialized areas of medicines for rare diseases, herbal medicines, medicines for children, and advanced therapy medicines. Up until Parallel Scientific Advice 2020, the UK hosted EMA. Because the UK left the EU on 31 Another globalized approach shared by the EMA and the FDA January 2020, the EMA headquarters moved to Amsterdam in is establishing a mechanism for experts to concurrently engage March 2019.10 in scientific discourse with sponsors on key issues during the What is unique about EMA is the dual nature in which a development phase of new medicinal products (drugs, biologicals, medicinal product may be authorized. In the EU, all medicines vaccines, advanced therapies, nanotechnology, and pediatric drug must have a marketing authorization (MA) before they can be development). It helps the pharmaceutical industry and regulatory used by patients. There are two ways of obtaining this authoriza- agencies proactively engage early in product development. tion. Under the Centralised Procedure, EMA gives an opinion, resulting in a single MA for the whole of the EU. Under national Cluster Calls MA procedures, individual member states authorize the medi- Various health authorities, including FDA, EMA, Health Canada, cines for use in their territory.11 Most medicinal products for hu- the Japanese Pharmaceuticals and Medical Devices Agency man and veterinary use – including those derived from biotech- (PMDA), and Australian Therapeutic Goods Administration nology and other high-technology methods, human medicines (TGA), also have developed a process called ‘cluster calls’ to allow for HIV/AIDS, cancer, diabetes, or neurodegenerative diseases, for increased collaboration and discussion of important topics in and all designated orphan medicines – are to be approved by the areas such as advanced therapies (e.g., cell and tissue products), Centralised Procedure. biosimilars, blood safety, oncology-hematology products and non- EMA is governed by an independent Management Board clinical oncology products, orphan products, patient engagement, composed of 36 independent members. The board’s role is to pediatric products, pharmacogenomics, pharmacometrics (model- define EMA’s budget, develop the yearly work plan and ensure the 2 Regulatory Affairs Professionals Society (RAPS) Purchased from RAPS Library (library.raps.org) for the exclusive use of [email protected]. © 2024 RAPS Library. Please report unauthorized use to [email protected]  CHAPTER 1: Healthcare Landscape and Drug Development agency works effectively with partnering organizations.12 like EFPIA (European Federation of Pharmaceutical Industries and Association) and PhRMA (Pharmaceutical Research and EMA on the Global Regulatory Stage Manufacturers of America.18 It also has numerous working groups Like FDA, EMA acknowledges the importance and requirement with many experts working towards the process of harmonization for international collaboration. It believes this will also ensure data and creation and implementation of ICH guidelines. The process integrity to support clinical trials and manufacturing, encourages of harmonization and development of guidelines is a multi-step a global approach to authorization and supervision of medicines, process requiring consensus between regulators on the guideline and avoid unnecessary duplication of efforts. Such a collaboration topic and content to its adoption and implementation in various aims to create efficiencies by promoting the effective use of global ICH regions.19 As of March 2023, over 70 ICH guidelines have regulatory resources.13 Confidentiality arrangements or mutual been drafted on technical requirements around Safety, Quality, recognition agreements (MRAs) are critical for such bilateral Efficacy, and Multidisciplinary. Some of the major advantages/ activities and heavily used by EMA and European Commission to successes of ICH include: work closely in all international activities. Confidentiality arrange- Common Technical Document (CTD) and electronic CTD ments facilitate the exchange of confidential information between (eCTD), which brings together all Quality, Safety, and Effi- regulators. MRAs on good manufacturing practice (GMP) allow cacy information in a common, harmonized format accepted EU authorities to rely on GMP inspections performed by other by regulators in all ICH regions.20 regulators, waive batch testing of products on entry into the EU Clinical trials conducted in one ICH region can be used and share information on inspection-related information and in other ICH regions by setting the common standards on quality defects.14 science and ethics. The EU has MRAs with various countries, including Austra- Medical Dictionary for Regulatory Activities (MedDRA) is lia, Brazil, Canada, Israel, Japan, New Zealand, Switzerland, and a highly specific, standardized medical terminology used to the US. EMA also supports European Commission collaborations fac