Clinical trials are a critical part of the pharmaceutical development process. These trials cannot proceed without timely and regular receipt of the drugs being tested, which can prove a challenge for drug manufacturers who have not yet established the structures required to produce quality-controlled specimens of the drug at scale. Managing supply chains of pre-production drugs for clinical trials is therefore an essential component of drug development.
Supply Chain Planning for Clinical Trials offers a practical introduction to this process for researchers and industry professionals. Beginning with the basics of clinical trial supply chain management, it proceeds step by step through all aspects of demand and supply planning for clinical trials. The result is a thorough overview that also offers practical examples of how to plan supply for clinical trials.
Supply Chain Planning for Clinical Trials readers will also find: - Tools for minimizing risk and expense by optimizing the relationship between supply and demand - Detailed discussion of topics including quality and regulatory considerations and the business processes that support clinical trial supply chain management - Spreadsheet-based models to illustrate key concepts, adaptable to the readers’ specific scenarios
Supply Chain Planning for Clinical Trails is ideal for pharmaceutical industry professionals involved in clinical trial supply planning, as well as academics and researchers interested in the pharmaceutical industry and its logistics.
Table of Contents
Preface xiii
Acknowledgments xvii
1 Supply Chain Management 1
1.1 Supply Chain Management 1
1.2 Plan 3
1.3 Source 6
1.4 Make 8
1.5 Deliver/Return 11
1.6 Data, Analytics, and Metrics 12
1.7 The People-Process-Technology Framework 16
1.8 Key Takeaways 16
Notes 17
2 Introduction to Clinical Trials 19
2.1 Introduction to Clinical Trials 19
2.2 A Conversation About Clinical Trials 19
2.3 Intrinsic Elements of a Clinical Trial 23
2.4 Extrinsic Elements of a Clinical Trial 26
2.5 Preclinical Drug Development 27
2.6 The Clinical Development Plan 28
2.7 Phase I Clinical Trials 29
2.8 Clinical Pharmacology Trials 30
2.9 Phase II and III Clinical Trials 31
2.10 Adaptive Trials 32
2.11 Master Protocol Designs - Platform, Basket, and Umbrella Trials 32
2.12 Decentralized Clinical Trials 33
2.13 Post-marketing Clinical Trials 34
2.14 Clinical Trial Stakeholder Summary 34
2.15 Trends in Clinical Trial Design and Conduct 36
2.16 Key Takeaways 37
Notes 38
3 Introduction to the Clinical Trial Supply Chain 39
3.1 Introduction to the Clinical Trial Supply Chain 39
3.2 Drug Modalities 40
3.3 Starting Materials and Drug Substance 43
3.4 Drug Product 44
3.5 Analytical Development and Characterization 45
3.6 Manufacturing Process Development 48
3.7 Packaging 49
3.8 Labeling 51
3.9 Distribution 53
3.10 Clinical Trial Supply Chain Summary 54
3.11 CMC Development and Manufacturing Strategy 55
3.12 CMC Stakeholder Summary 57
3.13 Trends in Clinical Manufacturing and Supply Chain Management 61
3.14 Key Takeaways 62
Notes 63
4 Quality Considerations 65
4.1 What Is Quality? 65
4.2 Good Manufacturing Practice: An Overview 67
4.3 Source: Supplier Identification and Qualification 70
4.4 Make: Batch Records, Sampling, Batch Release, Deviations, and Disposition 71
4.5 Deliver: Good Distribution Practice, Temperature Excursions, Returns, and Recalls 73
4.6 Plan: Planning Inputs and Change Management 75
4.7 Preapproval Inspection 77
4.8 The Qualified Person 78
4.9 Key Takeaways 80
Notes 81
5 Regulatory Considerations 83
5.1 Introduction to Regulatory Applications 83
5.2 Regulatory Application Content and the CTD 84
5.3 Health Authority Interactions 87
5.4 The Clinical Trial Regulation in the European Union 87
5.5 Application Authoring, Submission, and Approval 88
5.6 Amendments 90
5.7 Commitments and Restrictions 92
5.8 Regulatory Status Tracking 93
5.9 Batch and IMP Lifecycle Management 94
5.10 Process Version Management 97
5.11 Key Takeaways 100
Notes 101
6 RTSM and Its Role in the Clinical Supply Chain 103
6.1 Randomization and Trial Supply Management 103
6.2 RTSM Scope and Functionality 104
6.3 The Kit Identifier 106
6.4 IMP Supply Strategies 107
6.5 IMP Expiry Management Settings 114
6.6 Transactions, Alerts, and Drug Accountability 115
6.7 Reports and Their Link to Demand and Supply Planning 118
6.8 Additional IMP Management Considerations 119
6.9 RTSM Supplier Selection 120
6.10 RTSM Trends and Future Capabilities 121
6.11 Key Takeaways 122
Notes 123
7 Supply Chain Planning for Clinical Trials 125
7.1 Framing the Road Ahead 125
7.2 Clinical Planning Objectives 126
7.3 Clinical Planning Activities 127
7.4 Mathematical Approaches to Clinical Planning 130
7.5 The Elements of Demand and Supply Planning for Clinical Trials 130
7.6 Clinical Demand and Supply Planning Business Processes 133
7.7 Alternative Clinical Supply Chain Scenarios 134
7.8 The Role of the Clinical Supply Chain Function 134
7.9 Getting Started 137
7.10 Key Takeaways 137
8 Finished Product Demand Planning: Basic Concepts 139
8.1 Introduction to Demand Planning for Clinical Trials 139
8.2 The What of Demand Forecasting: The Stockkeeping Unit 140
8.3 The Where of Demand Forecasting: Depot Versus Site 143
8.4 The Demand Forecast Period: Weeks Versus Months of Supply 144
8.5 The Demand Forecast Table 146
8.6 Forecasting Individual Subject Demand 146
8.7 Forecasting Enrollment 152
8.8 Overage 160
8.9 Site Stocking Demand 162
8.10 Total Demand and Next Steps 163
8.11 The Challenge of Accuracy in Clinical Trial Demand Planning 163
8.12 Key Takeaways 164
Notes 165
9 Finished Product Supply Planning: The Production Plan 167
9.1 Introduction to Supply Planning 167
9.2 Min-Max Inventory Management 168
9.3 Weeks-of-Supply 174
9.4 The Production Plan Table 175
9.5 The Impact of Future Demand on Production Order Requirements 176
9.6 Selecting Supply Planning Parameters and Their Impact on Production Order Requirements 178
9.7 From Requirements to Orders 181
9.8 The Production Plan Summary 184
9.9 Production Order Readiness 185
9.10 Key Takeaways 186
10 Finished Product Expiry Planning 189
10.1 Expiry Management and the Planning Process 189
10.2 First In First Out and Last In First Out Inventory Management 190
10.3 The Importance of Batch Visibility 191
10.4 Incorporating Expiry into the Finished Product Plan 192
10.5 Forecasting Expiry Events 196
10.6 Shelf-Life Extensions Versus Replacement Inventory 199
10.7 Strategies for Managing Expiry Limitations 201
10.8 Key Takeaways 203
11 Finished Product Supply Planning: The Distribution Plan 205
11.1 Introduction to Distribution Planning 205
11.2 Mapping the Clinical Packaging and Distribution Network 206
11.3 Connecting Regional Depots to the Central Depot 209
11.4 Demand and Supply Planning Parameters Revisited 212
11.5 Distribution Planning Strategies 213
11.6 Aggregate Finished Product Weeks-of-Supply 218
11.7 The Weeks-of-Supply Summary 220
11.8 The Distribution Plan Summary 220
11.9 Distribution Order Readiness 222
11.10 Key Takeaways 223
12 Upstream Supply Planning: Primary Packaging, Drug Product, and Drug Substance 225
12.1 Planning for Upstream Materials 225
12.2 General Approach to Demand Planning for Upstream Materials 226
12.3 General Approach to Supply Planning for Upstream Materials 230
12.4 Upstream Supply Planning Strategies 234
12.5 Small-Molecule Primary Packaging Planning 237
12.6 Small-Molecule Drug Product Planning 238
12.7 Small-Molecule Drug Substance Planning 239
12.8 Large-Molecule Drug Product Planning 241
12.9 Large-Molecule Drug Substance Planning 242
12.10 The Upstream Production Plan Summary 245
12.11 Upstream Production Order Readiness 246
12.12 Key Takeaways 247
13 Advanced Concepts in Demand and Supply Planning 249
13.1 Advanced Concepts in Demand and Supply Planning 249
13.2 Accuracy or Conservatism in Demand Planning 250
13.3 Aggregate Forecasting 252
13.4 Forecasting Subject Attrition and Subject Replacement 253
13.5 End-to-End Supply Planning Strategy 255
13.6 Demand and Supply Planning for Variable Durations of Treatment 258
13.7 Demand and Supply Planning for Dose Titrations, Reductions, and SKU Switches 259
13.8 Demand and Supply Planning for Extensions 261
13.9 Segregating Site Inventory from Depot Inventory 263
13.10 Inventory Pooling 264
13.11 Low-Case-High-Case Demand and Supply Planning 264
13.12 Deterministic Versus Stochastic Demand and Supply Planning 268
13.13 Key Takeaways 268
Notes 270
14 Clinical Supply Chain Reports, Budgets, and Metrics 271
14.1 The Importance of Communication in Supply Chain Management 271
14.2 Inventory Reporting 272
14.3 Visualizing the Production Plan 273
14.4 Visualizing the Supply Plan and Inventory Management Strategy 275
14.5 Portfolio Reports 277
14.6 Translating the Supply Plan into a Budget Forecast 279
14.7 Cost of Goods Analyses 282
14.8 Metrics 283
14.9 Dashboards 285
14.10 Key Takeaways 287
Notes 288
15 Clinical Supply Chain Planning Processes 289
15.1 The Clinical Supply Chain Planning Processes 289
15.2 Demand and Supply Plan Creation 290
15.3 Demand and Supply Planning 293
15.4 Operational Clinical Demand and Operations Planning 299
15.5 Strategic Clinical Demand and Operations Planning 303
15.6 Supply Plan Handover and Order Readiness 305
15.7 Global Supply Execution Readiness 306
15.8 Supply Network Planning 307
15.9 Three Keys to Business Process Success 309
15.10 Key Takeaways 310
16 A Week in the Life of a Clinical Planner 313
16.1 Before the Week Begins 313
16.2 Monday: Scenarios Incoming 314
16.3 Tuesday: Study Design Scenario Planning 315
16.4 Wednesday: A Lower-than-Planned Yield 318
16.5 Thursday Morning: Regulatory Restrictions 321
16.6 Thursday Afternoon and Friday: The Adaptive Trial Design 323
16.7 Friday Afternoon: Excellence in Planning 329
16.8 Key Takeaways 331
17 Comparator and Ancillary Planning 333
17.1 Comparator and Ancillary Definitions 333
17.2 Regulatory Implications for IMP and Non-IMP Comparators 334
17.3 Active IMP Comparator Considerations 336
17.4 Additional Blinded IMP Comparator Considerations 339
17.5 Non-IMP Comparator Medication Considerations 340
17.6 Ancillary Supply Considerations 340
17.7 Key Takeaways 343
Notes 344
18 Make-to-Order and Just-in-Time Supply Chains in Clinical Trials 345
18.1 Make-to-Stock and Make-to-Order Supply Chain Management 345
18.2 MTS, MTO, Lean, and JIT Supply Chain Principles 347
18.3 Inventory Pooling and Just-in-Time Manufacturing 349
18.4 Allogenic Cell Therapy Supply Chain Considerations 352
18.5 Autologous Cell Therapy Supply Chain Considerations 354
18.6 Key Takeaways 358
Notes 358
19 Direct-to-Patient Supply Chain Management 361
19.1 Introduction to Decentralized Clinical Trials 361
19.2 Direct-to-Patient Supply Chain Models 362
19.3 Direct-to-Patient Supply Chain Stakeholders and Costs 364
19.4 Direct-to-Patient Supply Chain Planning Considerations 366
19.5 The Direct-to-Patient Supply Chain Execution Process 368
19.6 Other Direct-to-Patient Supply Chain Execution Considerations 370
19.7 Parting Thoughts on the Direct-to-Patient Supply Chain 373
19.8 Key Takeaways 373
Notes 374
20 Contract Organization Management and Oversight 375
20.1 Strategic Supplier Management Within the Biopharmaceutical Industry 375
20.2 Insourcing, Make-Versus-Buy, and Outsourcing 376
20.3 Supplier Identification and Selection 378
20.4 Supplier Qualification and Contracting 381
20.5 Strategic Supplier Management 382
20.6 Clinical Supply Chain Sourcing Strategies 385
20.7 Contract Research Organization Engagement 386
20.8 Key Takeaways 388
Notes 389
21 International Logistics for Clinical Biopharmaceutical Products 391
21.1 International Logistics for Clinical Biopharmaceutical Products 391
21.2 Duties, Taxes, Valuation, and Registration 392
21.3 Logistics Stakeholders and IncoTerms 394
21.4 The International Shipping Business Process 396
21.5 Import for Export, Free Trade Zones, and Special Economic Zones 400
21.6 Key Takeaways 401
Notes 402
22 Clinical Supply Chain Planning Tools and Technology 403
22.1 Data, Technology, and Clinical Supply Chain Planning 403
22.2 Demand and Supply Planning in Spreadsheets 405
22.3 Data Governance 408
22.4 Training 410
22.5 Business Process Integration 411
22.6 Beyond Spreadsheets: Selection and Implementation Strategies for Advanced Planning Systems 412
22.7 The Future of Technology in Clinical Supply Chain Management 414
22.8 Key Takeaways 416
23 Integrating the Clinical Supply Chain into a Commercial Launch 419
23.1 Transitioning from Clinical Supply Chain Management to Global Supply Chain Management 419
23.2 Commercial Supply Chain Strategy 420
23.3 Integrating Clinical and Commercial Demand and Supply Planning 423
23.4 Sales and Operations Planning as an Integrator of Clinical and Commercial Supply Chain Management 425
23.5 Commercial Supply Chain Execution 427
23.6 The Commercial Quality Management System and Regulatory Considerations 428
23.7 The Evolution of the Global Supply Chain Organization 430
23.8 Key Takeaways 431
Notes 432
Appendix: Clinical Supply Chain Planning Data Elements and Formulas 433
Glossary 439
Index 449
