Additional Information
Book Details
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Contents | xi | ||
| Preface | vii | ||
| List of Abbreviations | xxi | ||
| Chapter 1 The Past | 1 | ||
| 1.1. Introduction | 1 | ||
| 1.2. The First Clinical Trial: Frederick II Hohenstaufen (1194–1250)\r | 2 | ||
| 1.3. The First Randomised Clinical Trial: James Lind (1716–1794) | 2 | ||
| 1.4. ‘Elixir’ of Sulphanilamide (1937) | 3 | ||
| 1.5. The Nuremberg Code (1947) | 4 | ||
| 1.6. The Thalidomide Disaster (1957) | 4 | ||
| 1.7. The Declaration of Helsinki (1964) | 6 | ||
| 1.8. The Tuskegee Trial (1932–1972) | 10 | ||
| 1.9. TGN 1412 — A Drug Trial Disaster in the United Kingdom (2006) | 12 | ||
| 1.10. Propatria (2008) | 13 | ||
| 1.11. BIA 10-2474 (2016) | 15 | ||
| 1.12. Monitoring Aspects | 16 | ||
| References | 16 | ||
| Chapter 2 Medicinal Products: The Development Process | 19 | ||
| 2.1. Introduction | 19 | ||
| 2.2. Stages in Drug Development | 22 | ||
| 2.3. Preclinical Development | 23 | ||
| 2.4. Clinical Development | 27 | ||
| 2.5. Monitoring Aspects | 33 | ||
| References | 33 | ||
| Chapter 3 Clinical Trials: Design Aspects | 37 | ||
| 3.1. Introduction | 37 | ||
| 3.2. Equipoise | 39 | ||
| 3.3. Studies with Different Research Objectives | 40 | ||
| 3.4. Studies with Different Methodologies | 43 | ||
| 3.5. Parallel and Crossover Designs | 46 | ||
| 3.6. Bias and Confounders | 48 | ||
| 3.7. Blinding and Randomisation | 53 | ||
| 3.8. Endpoints | 57 | ||
| 3.9. Reliability and Validity | 58 | ||
| 3.10. Sample Size and Statistical Power | 60 | ||
| 3.11. Placebo | 63 | ||
| 3.12. Monitoring Aspects | 64 | ||
| References | 65 | ||
| Chapter 4 The Rules and the Regs | 69 | ||
| 4.1. Introduction | 69 | ||
| 4.2. The International Council for Harmonisation | 70 | ||
| 4.3. European Legislation on Medicinal Products | 76 | ||
| 4.4. The European Medicines Agency | 77 | ||
| 4.5. Marketing Authorisation in the EU | 78 | ||
| 4.6. Post-Market Safety Assessments in the EU | 84 | ||
| 4.7. Clinical Trial Regulations in the EU | 88 | ||
| 4.8. Regulatory Procedures in the United States | 95 | ||
| 4.9. Monitoring Aspects | 101 | ||
| References | 102 | ||
| Chapter 5 The Ethical Pillars of Clinical Research | 109 | ||
| 5.1. Introduction: What is Ethics? | 109 | ||
| 5.2. Medical Ethics | 110 | ||
| 5.3. Informed Consent | 116 | ||
| 5.3.1. Introduction | 116 | ||
| 5.3.2. Aspects of the IC process | 117 | ||
| 5.3.3. IC information and communication | 118 | ||
| 5.3.4. The ICF | 124 | ||
| 5.3.5. IC waivers | 127 | ||
| 5.4. Privacy and Confidentiality | 128 | ||
| 5.5. Vulnerable Subjects | 135 | ||
| 5.6. Risk/Benefit Assessment | 138 | ||
| 5.7. Solid Science | 138 | ||
| 5.8. Monitoring Aspects | 139 | ||
| References | 140 | ||
| Chapter 6 The Players Part I: Ethics Committee and Data Monitoring Committee | 145 | ||
| 6.1. The Ethics Committee | 145 | ||
| 6.1.1. Introduction | 145 | ||
| 6.1.2. EC responsibilities | 147 | ||
| 6.1.3. The basis for EC considerations | 148 | ||
| 6.1.4. EC membership | 157 | ||
| 6.1.5. EC procedures | 158 | ||
| 6.1.6. Monitoring aspects | 160 | ||
| 6.2. The Data Monitoring Committee | 161 | ||
| 6.2.1. Introduction | 161 | ||
| 6.2.2. DMC responsibilities | 163 | ||
| 6.2.3. The basis for DMC considerations | 165 | ||
| 6.2.4. DMC membership | 166 | ||
| 6.2.5. DMC procedures | 166 | ||
| 6.2.6. Monitoring aspects | 167 | ||
| References | 167 | ||
| Chapter 7 The Players Part II: The Sponsor and the Clinical Research Organisation | 171 | ||
| 7.1. The Sponsor | 171 | ||
| 7.1.1. Introduction | 171 | ||
| 7.1.2. Providing the method | 172 | ||
| 7.1.3. Providing medical information and expertise | 173 | ||
| 7.1.4. Providing the investigational material | 173 | ||
| 7.1.5. Providing the means to facilitate trial conduct | 174 | ||
| 7.1.6. Providing the management of the study and the data | 174 | ||
| 7.1.7. Providing the monitoring for the study | 175 | ||
| 7.1.8. Providing the money | 175 | ||
| 7.1.9. Trial quality | 176 | ||
| 7.1.10. Delegation of tasks | 177 | ||
| 7.2. The Contract Research Organisation | 177 | ||
| 7.3. Monitoring Aspects | 179 | ||
| References | 180 | ||
| Chapter 8 The Players Part III: The Investigator, the Sub-Investigator and the Clinical Research Coordinator | 183 | ||
| 8.1. The Investigator | 183 | ||
| 8.1.1. Introduction | 183 | ||
| 8.1.2. Investigator responsibilities | 185 | ||
| 8.1.3. Investigator qualifications | 192 | ||
| 8.1.4. Investigator identification, selection and evaluation | 192 | ||
| 8.1.5. Monitoring aspects | 195 | ||
| 8.2. Investigator Initiated Trials | 196 | ||
| 8.2.1. Introduction | 196 | ||
| 8.2.2. Monitoring aspects | 198 | ||
| 8.3. The Sub-Investigator | 199 | ||
| 8.4. The Study Nurse or CRC | 201 | ||
| 8.4.1. Introduction | 201 | ||
| 8.4.2. CRC responsibilities | 202 | ||
| 8.4.3. Monitoring aspects | 204 | ||
| References | 204 | ||
| Chapter 9 The Players Part IV: The Pharmacy and the Clinical Laboratory | 207 | ||
| 9.1. The Pharmacy | 207 | ||
| 9.1.1. Introduction | 207 | ||
| 9.1.2. Investigational medicinal products | 208 | ||
| 9.1.3. Product documentation | 211 | ||
| 9.1.4. Product quality | 214 | ||
| 9.1.5. Product manufacture | 215 | ||
| 9.1.6. Product handling | 218 | ||
| 9.1.7. Monitoring aspects | 223 | ||
| 9.2. The Clinical Laboratory | 224 | ||
| 9.2.1. Introduction | 224 | ||
| 9.2.2. Sample collection and processing | 227 | ||
| 9.2.3. Monitoring aspects | 228 | ||
| References | 229 | ||
| Chapter 10 The Players Part V: The Subject or Patient | 233 | ||
| 10.1. Introduction | 233 | ||
| 10.2. Subject Identification | 234 | ||
| 10.3. Subject Selection | 236 | ||
| 10.4. Subject Recruitment | 239 | ||
| 10.5. Subject Retention | 245 | ||
| 10.6. Subject Compliance | 249 | ||
| 10.7. Perfect and Not-So-Perfect Patient Populations | 254 | ||
| 10.8. Monitoring Aspects | 255 | ||
| References | 257 | ||
| Chapter 11 Safety Assessment and Monitoring | 261 | ||
| 11.1. Introduction | 261 | ||
| 11.2. Adverse Events | 264 | ||
| 11.3. Adverse Drug Reactions | 265 | ||
| 11.4. Unexpected Adverse Drug Reactions | 267 | ||
| 11.5. Serious Adverse Events | 268 | ||
| 11.6. Suspected Unexpected Serious Adverse Reactions | 271 | ||
| 11.7. Pharmacovigilance | 276 | ||
| 11.8. Development and Periodic Safety Update Reports | 279 | ||
| 11.9. Monitoring Aspects | 281 | ||
| References | 283 | ||
| Chapter 12 The Visits | 287 | ||
| 12.1. Introduction | 287 | ||
| 12.2. The Pre-Study Visit | 288 | ||
| 12.3. The Investigator Meeting | 289 | ||
| 12.4. The Site Initiation Visit | 292 | ||
| 12.5. The (Routine) Monitoring Visits | 296 | ||
| 12.6. The Study Close Out Visit | 306 | ||
| 12.7. The Audits | 312 | ||
| 12.8. The Inspections | 320 | ||
| 12.9. Monitoring Aspects | 327 | ||
| References | 328 | ||
| Chapter 13 The Essential Documents Part I: Before Study Start | 333 | ||
| 13.1. Introduction: Essential Documents | 333 | ||
| 13.2. The Investigator’s Brochure | 337 | ||
| 13.3. The Study Protocol | 340 | ||
| 13.4. Information Given to Trial Subjects | 343 | ||
| 13.5. Financial and Contractual Aspects of the Trial | 344 | ||
| 13.6. Insurance Statement | 346 | ||
| 13.7. EC Favourable Opinion Statement | 346 | ||
| 13.8. EC Composition | 348 | ||
| 13.9. Clinical Trial Authorisation Statement | 348 | ||
| 13.10. CVs of Investigator and Sub-Investigators | 348 | ||
| 13.11. Medical and Laboratory Tests and Normal Ranges | 351 | ||
| 13.12. Certifications and Accreditations | 352 | ||
| 13.13. Label Examples | 353 | ||
| 13.14. Product Handling and Shipping Instructions | 354 | ||
| 13.15. Certificates of Analysis | 355 | ||
| 13.16. Decoding (Un-Blinding) Instructions | 357 | ||
| 13.17. Master Randomisation List | 358 | ||
| 13.18. Pre-trial Monitoring Report | 359 | ||
| 13.19. Trial Initiation (Monitoring) Report/Letter | 359 | ||
| 13.20. Standard Operating Procedures | 360 | ||
| 13.21. Trial Master File | 361 | ||
| 13.22. Investigator Site File | 363 | ||
| 13.23. Monitoring Aspects | 365 | ||
| References | 366 | ||
| Chapter 14 The Essential Documents Part II: During Trial Conduct | 369 | ||
| 14.1. Introduction | 369 | ||
| 14.2. Amendments, Revisions, Updates and Modifications | 372 | ||
| 14.3. EC Favourable Opinions on Updates | 376 | ||
| 14.4. Competent Authority Approvals on Updates | 376 | ||
| 14.5. CVs of Any New Investigators and Sub-Investigators | 377 | ||
| 14.6. Monitoring Visit Reports and Follow-Up Letters | 378 | ||
| 14.7. Communication Logs | 381 | ||
| 14.8. Signed Informed Consent Forms | 381 | ||
| 14.9. Source Documents | 382 | ||
| 14.10. Case Report Forms | 384 | ||
| 14.11. Safety Information; SAE and SUSAR Notifications | 388 | ||
| 14.12. ‘Dear Health Care Professional’ Communications | 388 | ||
| 14.13. Subject Screening and Enrolment Logs | 389 | ||
| 14.14. Drug Accountability Logs | 389 | ||
| 14.15. Shipping Records and Certificates of Analysis | 391 | ||
| 14.16. Records of Retained Body Specimens | 392 | ||
| 14.17. Monitoring Aspects | 393 | ||
| References | 393 | ||
| Chapter 15 The Essential Documents Part III: After Completion or Termination of the Trial | 395 | ||
| 15.1. Introduction | 395 | ||
| 15.2. Drug Accountability and Drug Destruction Documentation | 396 | ||
| 15.3. Completed Subject Identification Code List | 398 | ||
| 15.4. Audit Certificates | 398 | ||
| 15.5. Final Closeout Monitoring Visit Report and COV FU Letter | 399 | ||
| 15.6. Treatment Allocation and Decoding Documentation | 400 | ||
| 15.7. Final Reports to EC and CA | 401 | ||
| 15.8. Clinical Study Report | 401 | ||
| 15.9. Monitoring Aspects | 404 | ||
| References | 404 | ||
| Chapter 16 Data Management | 407 | ||
| 16.1. Introduction | 407 | ||
| 16.2. Data Collection: Data Entry or Data Acquisition | 409 | ||
| 16.2.1. Introduction | 409 | ||
| 16.2.2. Case report forms | 409 | ||
| 16.2.3. Electronic data capture | 411 | ||
| 16.3. System and Data Validation | 413 | ||
| 16.4. Data Cleaning and Queries | 414 | ||
| 16.5. Data Analysis | 417 | ||
| 16.6. Data Retention: Filing and Archiving | 419 | ||
| 16.7. Data Reporting | 422 | ||
| 16.8. Data Publication | 423 | ||
| 16.9. Monitoring Aspects | 423 | ||
| References | 424 | ||
| Chapter 17 A Special Case: Medical Devices | 427 | ||
| 17.1. Introduction | 427 | ||
| 17.2. Classification of Medical Devices | 431 | ||
| 17.3. Product Authorisation and CE Marking | 432 | ||
| 17.4. Clinical Investigations on Medical Devices | 434 | ||
| 17.5. Safety Events on Medical Devices | 438 | ||
| 17.6. Monitoring Aspects | 439 | ||
| References | 440 | ||
| Chapter 18 Compliance | 443 | ||
| 18.1. Introduction | 443 | ||
| 18.2. Quality Management | 444 | ||
| 18.3. Non-Compliance | 446 | ||
| 18.4. Protocol Deviations, Protocol Violations and Errors | 449 | ||
| 18.5. Misconduct and Fraud | 451 | ||
| 18.6. Monitoring Aspects | 455 | ||
| References | 456 | ||
| Chapter 19 The Challenge of Monitoring | 459 | ||
| 19.1. Introduction | 459 | ||
| 19.2. Risk-Based Monitoring | 465 | ||
| 19.3. CRA Tasks and Responsibilities | 471 | ||
| 19.3.1. Introduction | 471 | ||
| 19.3.2. Source document verification | 476 | ||
| 19.3.3. Drug accountability verification and reconciliation | 477 | ||
| 19.3.4. CRF verification | 478 | ||
| 19.3.5. Site management | 479 | ||
| 19.3.6. Reporting monitoring visits | 479 | ||
| 19.4. CRA Education, Skills and Competences | 480 | ||
| 19.5. Career Paths in Clinical Research | 483 | ||
| References | 485 | ||
| Chapter 20 The Future of Clinical Trial Monitoring — Some Afterthoughts | 487 | ||
| 20.1. Incidents | 488 | ||
| 20.2. Medicinal Products Development | 488 | ||
| 20.3. Clinical Study Design | 489 | ||
| 20.4. The Rules and the Regs | 490 | ||
| 20.5. Ethical Considerations in Clinical Research | 491 | ||
| 20.6. The Ethics Committee (EC) and the Data Monitoring Committee (DMC) | 491 | ||
| 20.7. The Sponsor and the Clinical Research Organisation | 492 | ||
| 20.8. The Investigator | 492 | ||
| 20.9. The Pharmacy and the Clinical Laboratory | 493 | ||
| 20.10. The Subject or Patient | 493 | ||
| 20.11. Safety Assessment | 494 | ||
| 20.12. Visits | 494 | ||
| 20.13. Essential Documents Before Study Start, During Trial Conduct and After Trial Termination | 495 | ||
| 20.14. Data Management | 495 | ||
| 20.15. Medical Devices | 495 | ||
| 20.16. GCP Compliance | 496 | ||
| 20.17. CRA and Monitoring | 496 | ||
| References | 497 | ||
| Index | 499 |