A step-by-step, integrated approach for successful, FDA-approved combination drug products
Using a proven integrated approach to combination drug development, this book guides you step by step through all the preclinical, clinical, and manufacturing stages. Written from an FDA regulatory perspective, the book not only enables you to bring a successful combination drug product to market, it also sets forth the most efficient and effective path to FDA approval.
The book begins with an introductory chapter presenting definitions and basic regulatory principles of combination products. Next, it reviews manufacturing and controls, preclinical testing models, pharmacology, clinical testing, regulatory submissions, FDA reviews, and approvals. Among the key topics examined are:
* The pharmacology, safety pharmacology, and toxicology supporting human clinical trials of combination products
* Approaches to clinical trial protocol design and execution
* Chemical, physicochemical, and analytical aspects of manufacturing controls and validation that lead to stable components for combination products
* Key sponsor/FDA meetings and negotiations essential for approval and commercialization
Case studies involving such actual combination products as Mylotarg, Herceptin, and HercepTest help you better understand how to implement the author's practical guidelines. References at the end of each chapter enable you to find more information on any stage of the development, manufacturing and approval processes.
This book is ideal for researchers, regulators, academics, project managers, and executives involved in the complex process of combination product development. Not only does itoffer a comprehensive guide to the technical aspects of the field, it also integrates all ofthese technical aspects into a unified, effective approach to help ensure a successful, approved product.
Table of Contents:
Preface xi
Acknowledgments xiii
Contributors xv
1 Overview of Combination Products Development and Regulatory Review 1
Evan B. Siegel
2 Detailed Regulatory Approaches to Development, Review, and Approval 5
James Barquest
2.1 Introduction 5
2.2 General Background 6
2.2.1 Definitions 6
2.2.2 FDA Organization and Jurisdiction 7
2.2.3 Clinical Investigation and Premarket Review Requirements for Drugs, Biological Products, and Medical Devices 11
2.2.4 FDA Information Resources 15
2.3 Combination Products: Regulatory Background 16
2.3.1 Definition 16
2.3.2 Intercenter Agreements 18
2.3.3 Office of Combination Products 19
2.3.4 Primary Mode of Action 20
2.3.5 Intended Use 30
2.3.6 Strategic Regulatory Considerations 31
2.3.7 The Request for Designation (RFD) Process 34
2.3.8 User Fees 44
2.3.9 FDA Meetings: Successful Regulatory Interactions 50
2.3.10 Current Good Manufacturing Practice for Combination Products 59
2.4 Postmarketing Considerations 67
2.4.1 Adverse Event Reporting 68
2.4.1.1 Device Malfunction Reporting (21 CFR 803.3(r)(2)(ii), 21 CFR 803.20) 68
2.4.1.2 Five-Day MDR Reporting (21 CFR 803.10(c)(2)(i)) 68
2.4.1.3 Drug and Biological Product “Alert” Reporting (21 CFR 314.80(c)(1) and 600.80(c)(1)) 73
2.4.1.4 Blood-Related Deaths (21 CFR 606.170) 73
2.4.2 Other Compliance Issues 73
References 74
3 Nonclinical Recommendations for Successful Characterization and Development of Combination Drug Products 77
Duane B. Lakings
3.1 Introduction 77
3.2 Pharmacology 79
3.2.1 Pharmacology and Safety Pharmacology Recommendations for CDPs with Multiple Marketed Drugs 80
3.2.2 Pharmacology and Safety Pharmacology Recommendations for CDPs with Marketed Drugs and a Single NME 83
3.2.3 Pharmacology and Safety Pharmacology Recommendations for CDPs with More Than One NME 83
3.3 Pharmacokinetics 84
3.3.1 Pharmacokinetic and Drug Metabolism Recommendations for CDPs with Multiple Marketed Drugs 89
3.3.2 Pharmacokinetic and Drug Metabolism Recommendations for CDPs with Marketed Drugs and a Single NME 91
3.3.3 Pharmacokinetic and Drug Metabolism Recommendations for CDPs with More Than One NME 91
3.4 Toxicology 92
3.4.1 Toxicology Recommendations for CDPs with Multiple Marketed Drugs 98
3.4.2 Toxicology Recommendations for CDPs with Marketed Drugs and a Single NME 102
3.4.3 Toxicology Recommendations for CDPs with More Than One NME 104
3.5 Conclusions 108
References 109
4 Clinical Pharmacology and Clinical Development of Combination Products 113
Chaline Brown
4.1 Introduction 113
4.2 Postapproval Clinical Safety Reporting 115
4.3 Clinical Development of Drug–Delivery System Combination Products 116
4.3.1 Advantages of a New Delivery Device Drug Product 117
4.3.1.1 Streamlined Regulatory Process Possible 117
4.3.1.2 Improvement in Efficacy over Previously Approved Delivery Routes 117
4.3.1.3 Noninjection Bioavailability for Peptides and Proteins 118
4.3.2 Considerations for a Combination Product with a Novel Delivery Route 119
4.3.2.1 Impact of Infusion Pumps on Pharmacodynamic Effects 119
4.3.2.2 Route-Dependent Pharmaceutical Metabolic Profile 119
4.3.2.3 Inherent Delivery Site Sensitivity 119
4.3.2.4 Addressing Concerns Regarding the Safety of Excipients in Novel Routes of Delivery 120
4.3.2.5 Addressing Concerns of Possible Immune System Reactions During Development 120
4.3.2.6 Addressing Effects Specific to Human Physiology During Development 120
4.3.2.7 Addressing Formulation Changes During Clinical Development 121
4.3.3 Case Study: Exubera® (Pfizer’s inhaled insulin, approved January 2006) 121
4.4 Clinical Development of Drug–Active Device Combination Products 127
4.4.1 Case Study: The Drug-Eluting Stent (DES) 128
4.4.2 Changing Scene for New DES Products 132
4.5 Clinical Development of Co-Packaged Combination Products 134
4.5.1 Co-Packaged Drug and Biologic Case Study: Interferon and Ribavirin for the Treatment of Hepatitis C 135
4.6 Clinical Development of Drug–In Vitro Diagnostic Combination Products 140
4.6.1 Retrospective Changes in Drug Labeling to Incorporate Genetic Tests 143
4.6.2 Prospective Co-Development of Drugs and In Vitro Diagnostics 144
4.6.3 Issues Surrounding Biomarker Development 146
4.6.4 Clinical Trial Design Issues in Drug–In Vitro Diagnostic Co-Development 147
4.6.5 FDA Guidance 149
4.6.6 Case Study: Herceptin® and HercepTest® 150
4.7 Clinical Development of Drug–Biologic Combination Products 153
4.7.1 Case Study 1: Mylotarg® (Monoclonal Antibody Linked to a Cytotoxic Drug) 154
4.7.2 Case Study 2: Bexxar® (Monoclonal Antibody Linked to a Radioisotope) 157
4.8 Clinical Development of Drug–Drug Combinations 160
4.8.1 General Considerations for FDC Efficacy Studies 162
4.8.2 Case Study: CombinatoRx, with Combination Therapy as a Business Model 163
4.9 Conclusion 165
References 165
5 Regulatory Strategy Considerations for Chemistry, Manufacturing, and Controls: An Integrated Approach 171
Patrick L. DeVillier
5.1 Introduction 171
5.2 Office of Combination Products (OCP) and Request for Designation (RFD) 172
5.3 Extent of Regulatory Oversight 173
5.4 Investigational Device Exemption and Investigational New Drug Exemption 174
5.5 Regulatory Compliant Product Development 175
5.6 Chemistry, Manufacturing, and Controls Review Requirements 177
5.7 Drug Component Requirements 178
5.8 Device Component Requirements 179
5.9 Sterilization Considerations 179
5.10 Stability Considerations 180
5.11 Bench Testing and Early Development Considerations 180
5.12 CDP Regulatory Cross-Mapping Guidance and Recommendations 181
5.13 Conclusions 200
References 200
List of Abbreviations 201
Index 205
About the Author :
Evan B. Siegel, PhD, is President and CEO of Ground Zero Pharmaceuticals, Inc., and an Adjunct Professor at the University of Queensland in Australia. Dr. Siegel has held positions as a Toxicology Reviewer at the U.S. Food and Drug Administration and Supervising Toxicologist in the California Department of Health Services. He has also served in regulatory affairs and executive positions in CROs, the pharmaceutical industry, and trade associations. In addition, Dr. Siegel was an editor of Regulatory Affairs Focus from 1999 to 2001.
