Supply Chain Planning for Clinical Trials: A Practical Guide

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