Risk Management Principles for Devices and Pharmaceuticals
vi
Figure 15-1. MDR Needs to Set a High Standard of Quality and Safety............................................226
Figure 15-2. MDR Clinical Evidence Objectives Per Device Life Cycle Phase. .................................227
Figure 15-3. Valid Clinical Association................................................................................................230
Figure 15-4. Technical Performance.....................................................................................................231
Figure 15-5. Clinical Performance.......................................................................................................231
Figure 15-6. Clinical Evidence Example for Radiation Treatment Planning. ......................................232
Figure 15-7. Endpoints for Clinical Evidence......................................................................................233
Figure 15-8. MDR Requirements Related to Endpoints for Clinical Evidence...................................234
Figure 15-9. Acceptable Benefit-Risk. .................................................................................................237
Figure 18-1. Time at Risk Estimate Based on On-Treatment and Post-Treatment Period for a Patient
Receiving One Dose of Bisphosphonate Before Receiving One Dose of Prolia. .............263
Figure 19-1. PASP Clinical Decision Support Notification in the Practice Fusion EHR....................276
Figure 19-2. Screenshot of Safety Surveillance Interface in Practice Fusion EHR. .............................277
Figure 22-1. Types of Outcomes in RM Program Evaluation Research by Data Collection
Method (Quantitative Versus Qualitative) (per GVP Module XVI Revision 3)..............334
Figure 22-2. An Embedded Mixed Methods Design with Complementarity Model to Evaluate
the Effectiveness of the Risk Minimization Program for Product C. ..............................337
Figure 23-1. Key Milestones in Developing, Implementing, and Operating a REMS: Brand Drug. ....348
Figure 23-2. Key Milestones in Developing, Implementing, and Operating a REMS:
Generic Drugs..................................................................................................................349
Figure 23-3. FDA Engagement Timeline. ...........................................................................................350
Figure 23-4. FDA Engagement for ANDA REMS.............................................................................351
Figure 23-5. Services Involved in a Typical ETASU REMS................................................................352
Figure 23-6. Services Involved in a Typical ETASU REMS: Example ...............................................353
Figure 23-7. Integration of REMS with Other Launch Activities.......................................................354
Figure 23-8. REMS Assessment Categories. .......................................................................................355
Tables
Table 1-1. Timeline of US Drug Regulation Advancements..............................................................11
Table 1-2. Example Framework of FDA Risk Management Guidance and Regulations. ..................13
Table 1-3. Legacy Pharmaceutical Products Deemed to Have a REMS Following FDAAA
Implementation.................................................................................................................20
Table 1-4. Examples of Triggers for FDA Requiring a REMS...........................................................21
Table 1-5. Example of a REMS Implementation Plan. ......................................................................28
Table 1-6. FDA Benefit-Risk Framework..........................................................................................35
Table 2-1. Regulatory Reporting of ICSRs for Investigational drugs. ................................................40
Table 2-2. Foreign Safety Measures Report and Research Report......................................................41
Table 2-3. Regulatory Reporting of Postmarket Adverse Drug Reactions in Japan............................44
Table 2-4. Regulatory Reporting of Postmarket Infections in Japan...................................................45
Table 4-1. Reporting Requirements for Biologicals. ...........................................................................65
Table 6-1. Summary Elements of an ETLA.......................................................................................86
Table 6-2. Factors Affecting the Safety Margin Calculations for FIH. ..............................................92
Table 6-3. Hypothetical Risk Management Strategy for GLP-1 Agonist Biotherapeutics...................93
Table 7-1. Contents of ISO 14971:2019...........................................................................................100
Table 7-2. Hazard Analysis Table. ....................................................................................................104
Table 7-3. Risk Management File Contents.....................................................................................105
Table 7-4. Example Severity Levels. .................................................................................................107
Table 7-5. Example Probability Of Occurrence Levels.....................................................................107
Table 7-6. Risk Evaluation Matrix....................................................................................................108
vi
Figure 15-1. MDR Needs to Set a High Standard of Quality and Safety............................................226
Figure 15-2. MDR Clinical Evidence Objectives Per Device Life Cycle Phase. .................................227
Figure 15-3. Valid Clinical Association................................................................................................230
Figure 15-4. Technical Performance.....................................................................................................231
Figure 15-5. Clinical Performance.......................................................................................................231
Figure 15-6. Clinical Evidence Example for Radiation Treatment Planning. ......................................232
Figure 15-7. Endpoints for Clinical Evidence......................................................................................233
Figure 15-8. MDR Requirements Related to Endpoints for Clinical Evidence...................................234
Figure 15-9. Acceptable Benefit-Risk. .................................................................................................237
Figure 18-1. Time at Risk Estimate Based on On-Treatment and Post-Treatment Period for a Patient
Receiving One Dose of Bisphosphonate Before Receiving One Dose of Prolia. .............263
Figure 19-1. PASP Clinical Decision Support Notification in the Practice Fusion EHR....................276
Figure 19-2. Screenshot of Safety Surveillance Interface in Practice Fusion EHR. .............................277
Figure 22-1. Types of Outcomes in RM Program Evaluation Research by Data Collection
Method (Quantitative Versus Qualitative) (per GVP Module XVI Revision 3)..............334
Figure 22-2. An Embedded Mixed Methods Design with Complementarity Model to Evaluate
the Effectiveness of the Risk Minimization Program for Product C. ..............................337
Figure 23-1. Key Milestones in Developing, Implementing, and Operating a REMS: Brand Drug. ....348
Figure 23-2. Key Milestones in Developing, Implementing, and Operating a REMS:
Generic Drugs..................................................................................................................349
Figure 23-3. FDA Engagement Timeline. ...........................................................................................350
Figure 23-4. FDA Engagement for ANDA REMS.............................................................................351
Figure 23-5. Services Involved in a Typical ETASU REMS................................................................352
Figure 23-6. Services Involved in a Typical ETASU REMS: Example ...............................................353
Figure 23-7. Integration of REMS with Other Launch Activities.......................................................354
Figure 23-8. REMS Assessment Categories. .......................................................................................355
Tables
Table 1-1. Timeline of US Drug Regulation Advancements..............................................................11
Table 1-2. Example Framework of FDA Risk Management Guidance and Regulations. ..................13
Table 1-3. Legacy Pharmaceutical Products Deemed to Have a REMS Following FDAAA
Implementation.................................................................................................................20
Table 1-4. Examples of Triggers for FDA Requiring a REMS...........................................................21
Table 1-5. Example of a REMS Implementation Plan. ......................................................................28
Table 1-6. FDA Benefit-Risk Framework..........................................................................................35
Table 2-1. Regulatory Reporting of ICSRs for Investigational drugs. ................................................40
Table 2-2. Foreign Safety Measures Report and Research Report......................................................41
Table 2-3. Regulatory Reporting of Postmarket Adverse Drug Reactions in Japan............................44
Table 2-4. Regulatory Reporting of Postmarket Infections in Japan...................................................45
Table 4-1. Reporting Requirements for Biologicals. ...........................................................................65
Table 6-1. Summary Elements of an ETLA.......................................................................................86
Table 6-2. Factors Affecting the Safety Margin Calculations for FIH. ..............................................92
Table 6-3. Hypothetical Risk Management Strategy for GLP-1 Agonist Biotherapeutics...................93
Table 7-1. Contents of ISO 14971:2019...........................................................................................100
Table 7-2. Hazard Analysis Table. ....................................................................................................104
Table 7-3. Risk Management File Contents.....................................................................................105
Table 7-4. Example Severity Levels. .................................................................................................107
Table 7-5. Example Probability Of Occurrence Levels.....................................................................107
Table 7-6. Risk Evaluation Matrix....................................................................................................108