xii Regulatory Affairs Professionals Society (RAPS)
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
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