xiii
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
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