Fundamentals of Pharmaceutical and Biologic Regulations: A Global Perspective
x Regulatory Affairs Professionals Society
Figures
Figure 1-1. The Medicinal Product Development Continuum .......................................................................................................................4
Figure 1-2. Traditional de Novo Product Development Process Versus Product Repurposing .......................................................................5
Figure 1-3. Phase Transition Duration From Phase 1 Through NDA/BLA Authorization ...........................................................................6
Figure 1-4. Phases of Clinical Research .........................................................................................................................................................10
Figure 1-5. CTD Triangle .............................................................................................................................................................................12
Figure 1-6. Communicating Value to Healthcare Stakeholders .....................................................................................................................14
Figure 1-7. Relationship Between Pricing, Reimbursement, and Market Access ..........................................................................................14
Figure 2-1. ICH Process of Harmonization ...................................................................................................................................................21
Figure 4-1. Continuum of Safety Pharmacology Assessments From Acute to Chronic Toxicity Studies .....................................................45
Figure 5-1. Drug Exposure Parameters Derived From PK Data ...................................................................................................................54
Figure 6-1. Phase-Appropriate Nonclinical Development Plan From Acute Studies Through Chronic Toxicity Studies ...........................67
Figure 8-1. Decision Tree for Follow-Up Testing with an Ames-Positive Drug (Active Ingredient) ...........................................................91
Figure 9-1. Genotoxic Versus Nongenotoxic Dose-Response Curves ...........................................................................................................96
Figure 9-2. ICH S1B(R1) Schema for Determining the Added Value of a 2-Year Carcinogenicity Study ................................................103
Figure 10-1. Stages of the Reproduction and Development Cycle (A to F) as Described in ICH S5(R3) ..................................................108
Figure 10-2. Scheme for Fertility and Early Embryonic Development Studies, Embryofetal Development Studies, and Combined
Studies ..................................................................................................................................................................................................108
Figure 10-3. Scheme for Pre- and Postnatal Development Studies and Enhanced Studies .........................................................................109
Figure 10-4. Scheme for Enhanced Pre- and Postnatal Development Studies in Rabbits for Vaccines2 ....................................................116
Figure 10-5. Scheme to Determine If Standard Models for Hazard Assessment of Developmental Toxicity Can Be Used for
Molecules That Produce Anti-Drug Antibodies ..................................................................................................................................117
Figure 11-1. FDA Categorical Exclusion for Drug Approval – Small Molecules ........................................................................................122
Figure 11-2. FDA Studies Required for Drug Approval ..............................................................................................................................123
Figure 11-3. EU ERA Process for Drug Approval ......................................................................................................................................125
Figure 11-4. FDA Categorical Exclusion for Drug Approval – Biologics ...................................................................................................129
Figure 12-1. Percentage of World Pharmaceutical Market by Economic Bloc ............................................................................................138
Figure 12-2. Brazil’s API Background Regulations...................................................................................................................................... 145
Figure 12-3. China’s API Registration Procedure........................................................................................................................................ 147
Figure 12-4. Japan’s API Process Review .....................................................................................................................................................148
Figure 14-1. Clinical Supply......................................................................................................................................................................... 165
Figure 14-2. Routine Challenges in Clinical Supply ....................................................................................................................................167
Figure 14-3. US-Marketed Products API Supply ........................................................................................................................................167
Figure 14-4. Example Sample Kit Label and Bottle Label ..........................................................................................................................169
Figure 15-1. Product Requirements .............................................................................................................................................................174
Figure 15-2. Factors Impacting Product Requirements – Ishikawa (Fishbone) ...........................................................................................174
Figure 15-3. QbD Elements Flow Chart .....................................................................................................................................................175
Figure 15-4. Possible Leachables From a Plastic Bottle ...............................................................................................................................185
Figure 15-5. Overview of Different Combination Product Categories ........................................................................................................192
Figure 16-1. Analytical Method Lifecycle ....................................................................................................................................................202
Figure 18-1. Clinical Trial Lifecycle ............................................................................................................................................................231
Figure 18-2. Russian Approval Process ........................................................................................................................................................243
Figure 19-1. Contributing Factors of Clinical Trial Underrepresentation ...................................................................................................258
Figure 19-2. Demographic Diversity of Global Clinical Trials Participation for New Drugs Approved by the FDA ................................258
Figure 19-3a. Distribution of Clinical Trial Participants: US Compared to the Rest of World ..................................................................259
Figure 19-3b. Global Distribution of Clinical Trial Participants by Country Versus US ............................................................................259
Figure 19-4. Clinical Trial Sex, Race, Age, and Ethnicity Distribution in the US ......................................................................................260
Figure 19-5. Percentage of Trials With Participant Levels Above Census ..................................................................................................261
Figure 19-6. Representation in Pfizer Trials Versus US Census Level ........................................................................................................261
Figure 19-7. OMB Minimum of Race and Ethnicity Categories ................................................................................................................263
Figure 19-8. Intrinsic and Extrinsic Ethnic Factors .....................................................................................................................................268
Figure 20-1. CHMP Scientific Advice Process ............................................................................................................................................282
Figure 22-1. Requests for Local Clinical Data and Different Therapeutic Areas ........................................................................................314
x Regulatory Affairs Professionals Society
Figures
Figure 1-1. The Medicinal Product Development Continuum .......................................................................................................................4
Figure 1-2. Traditional de Novo Product Development Process Versus Product Repurposing .......................................................................5
Figure 1-3. Phase Transition Duration From Phase 1 Through NDA/BLA Authorization ...........................................................................6
Figure 1-4. Phases of Clinical Research .........................................................................................................................................................10
Figure 1-5. CTD Triangle .............................................................................................................................................................................12
Figure 1-6. Communicating Value to Healthcare Stakeholders .....................................................................................................................14
Figure 1-7. Relationship Between Pricing, Reimbursement, and Market Access ..........................................................................................14
Figure 2-1. ICH Process of Harmonization ...................................................................................................................................................21
Figure 4-1. Continuum of Safety Pharmacology Assessments From Acute to Chronic Toxicity Studies .....................................................45
Figure 5-1. Drug Exposure Parameters Derived From PK Data ...................................................................................................................54
Figure 6-1. Phase-Appropriate Nonclinical Development Plan From Acute Studies Through Chronic Toxicity Studies ...........................67
Figure 8-1. Decision Tree for Follow-Up Testing with an Ames-Positive Drug (Active Ingredient) ...........................................................91
Figure 9-1. Genotoxic Versus Nongenotoxic Dose-Response Curves ...........................................................................................................96
Figure 9-2. ICH S1B(R1) Schema for Determining the Added Value of a 2-Year Carcinogenicity Study ................................................103
Figure 10-1. Stages of the Reproduction and Development Cycle (A to F) as Described in ICH S5(R3) ..................................................108
Figure 10-2. Scheme for Fertility and Early Embryonic Development Studies, Embryofetal Development Studies, and Combined
Studies ..................................................................................................................................................................................................108
Figure 10-3. Scheme for Pre- and Postnatal Development Studies and Enhanced Studies .........................................................................109
Figure 10-4. Scheme for Enhanced Pre- and Postnatal Development Studies in Rabbits for Vaccines2 ....................................................116
Figure 10-5. Scheme to Determine If Standard Models for Hazard Assessment of Developmental Toxicity Can Be Used for
Molecules That Produce Anti-Drug Antibodies ..................................................................................................................................117
Figure 11-1. FDA Categorical Exclusion for Drug Approval – Small Molecules ........................................................................................122
Figure 11-2. FDA Studies Required for Drug Approval ..............................................................................................................................123
Figure 11-3. EU ERA Process for Drug Approval ......................................................................................................................................125
Figure 11-4. FDA Categorical Exclusion for Drug Approval – Biologics ...................................................................................................129
Figure 12-1. Percentage of World Pharmaceutical Market by Economic Bloc ............................................................................................138
Figure 12-2. Brazil’s API Background Regulations...................................................................................................................................... 145
Figure 12-3. China’s API Registration Procedure........................................................................................................................................ 147
Figure 12-4. Japan’s API Process Review .....................................................................................................................................................148
Figure 14-1. Clinical Supply......................................................................................................................................................................... 165
Figure 14-2. Routine Challenges in Clinical Supply ....................................................................................................................................167
Figure 14-3. US-Marketed Products API Supply ........................................................................................................................................167
Figure 14-4. Example Sample Kit Label and Bottle Label ..........................................................................................................................169
Figure 15-1. Product Requirements .............................................................................................................................................................174
Figure 15-2. Factors Impacting Product Requirements – Ishikawa (Fishbone) ...........................................................................................174
Figure 15-3. QbD Elements Flow Chart .....................................................................................................................................................175
Figure 15-4. Possible Leachables From a Plastic Bottle ...............................................................................................................................185
Figure 15-5. Overview of Different Combination Product Categories ........................................................................................................192
Figure 16-1. Analytical Method Lifecycle ....................................................................................................................................................202
Figure 18-1. Clinical Trial Lifecycle ............................................................................................................................................................231
Figure 18-2. Russian Approval Process ........................................................................................................................................................243
Figure 19-1. Contributing Factors of Clinical Trial Underrepresentation ...................................................................................................258
Figure 19-2. Demographic Diversity of Global Clinical Trials Participation for New Drugs Approved by the FDA ................................258
Figure 19-3a. Distribution of Clinical Trial Participants: US Compared to the Rest of World ..................................................................259
Figure 19-3b. Global Distribution of Clinical Trial Participants by Country Versus US ............................................................................259
Figure 19-4. Clinical Trial Sex, Race, Age, and Ethnicity Distribution in the US ......................................................................................260
Figure 19-5. Percentage of Trials With Participant Levels Above Census ..................................................................................................261
Figure 19-6. Representation in Pfizer Trials Versus US Census Level ........................................................................................................261
Figure 19-7. OMB Minimum of Race and Ethnicity Categories ................................................................................................................263
Figure 19-8. Intrinsic and Extrinsic Ethnic Factors .....................................................................................................................................268
Figure 20-1. CHMP Scientific Advice Process ............................................................................................................................................282
Figure 22-1. Requests for Local Clinical Data and Different Therapeutic Areas ........................................................................................314