International Medical Device Clinical Investigations: A Practical Approach

Contents......Page 6
Preface......Page 20
1: European Regulatory Environment......Page 23
Regulatory Aspects......Page 24
Good Clinical Practices GCPs......Page 35
Privacy/Data Protection......Page 52
2: The U.S. Clinical Investigation Requirements Under the IDE......Page 62
General......Page 63
IDE Process......Page 64
Summary/Comparison......Page 68
Section I: Why undertake Clinical Trials?......Page 72
2. Design in Clinical Trials......Page 73
Clinical Study......Page 74
Clinical Evaluation in the Development of a Device......Page 75
Designs for Clinical Trials......Page 77
How Is the Process of Study Design Organised and Controlled?......Page 78
Design Characteristics......Page 80
References......Page 85
3. Managing Multi-Dimensional Clinical Projects......Page 86
Managerial Skills of the Co-ordinator......Page 87
Organisation of a Multi-Dimensional Clinical Research Project......Page 89
Tools and Tips......Page 91
Communication Within a Multi-Dimensional Clinical Research Project......Page 97
Develop and/or Use Your Own Intuition......Page 98
Listening......Page 101
Phase I: Enthusiasm Phase......Page 103
Phase IV: Initiation of Blame......Page 104
Phase VI: Rewards......Page 105
Project Team Members......Page 106
Time Planning and Scheduling in Clinical Research......Page 107
Summary......Page 108
Section II: Strategy and Project Planning......Page 111
Introduction......Page 112
Risk and Hazards......Page 113
Risk Management......Page 116
Classification......Page 117
Comparative Classification Requirements......Page 122
Conclusion......Page 124
5. Clinical Strategy Development......Page 126
Strategy Steps......Page 127
Costs and Company Sizes......Page 129
Communication Kinks......Page 131
Global Strategy......Page 132
Conclusion......Page 133
6. Clinical Trial Project Plan......Page 134
Planning Phase......Page 135
Preparation Phase......Page 137
Work Breakdown Structure......Page 144
First Project Team Meeting......Page 167
Operations Manual......Page 171
7. Quality Assurance for Good Clinical Practices......Page 179
Requirements/Criteria......Page 180
Establish a Project Team or Steering Group......Page 182
Determine HOW Clinical Investigations Are Handled Within the Company......Page 183
Organisation of the Documentation......Page 184
Quality System Examination......Page 185
Traceability of Documentation......Page 186
Body Layout House Style......Page 187
Conclusion/Summary......Page 188
Appendix A: Sample Procedure......Page 189
Appendix B: Characteristics of Procedures......Page 194
Section III: How to Prepare a Clinical Trial......Page 204
8. Protocol Development......Page 205
Pre-Investigation Information......Page 206
What Should be Included in a Protocol?......Page 207
References......Page 218
9. The Clinical Investigator's Brochure......Page 220
Which Format Is Preferred?......Page 221
Table of Contents......Page 223
Technical Information......Page 224
In-Vitro/Ex-Vivo Performance Testing......Page 225
Clinical Experience......Page 226
Patient Insurance......Page 227
Compliance to Good Clinical Practice......Page 229
How to Design the Brochure......Page 231
Influence of Study Parameters......Page 233
Nature of the Device......Page 234
How to Estimate the Necessary Budget......Page 235
Negotiation with the Investigators......Page 238
Case Study......Page 239
Conclusion......Page 240
The Rationale of an Investigator Contract......Page 241
Payment Cheques......Page 242
Particulars of the Agreement......Page 243
Contents of the Contract......Page 247
The Agreement......Page 248
When to Discuss the Contract During the Preparation Phase......Page 254
12. Informed Consent......Page 255
Historical Background......Page 256
Legal Aspect......Page 257
Local Aspects of Consent......Page 258
Basic Elements of Informed Consent......Page 260
Additional Elements of Informed Consent......Page 261
Guidelines for the Informed Consent of Trial Subjects......Page 262
The Process of Obtaining Informed Consent......Page 266
Specific Cases......Page 267
Conclusion......Page 268
13. The Design of Case Report Forms......Page 270
Who Is Involved in the Design?......Page 271
The Development Process......Page 273
Design Issues......Page 275
What Should a Set of CRFs for an Individual Study Look Like?......Page 278
Standardisation......Page 279
Advantages to the Data Entry Clerk......Page 281
References......Page 282
The Aim of Clinical Investigations......Page 283
Notification to Competent Authorities......Page 285
Conditions of Clinical Investigations......Page 286
Section 13.3h of Annex I......Page 287
Labelling Section 13 of Annex I......Page 288
Labelling Standards......Page 290
Instructions for Use......Page 293
Language Considerations......Page 296
Multi- Lingual or Country- Specific Labels......Page 298
Conclusion......Page 300
Definition of Labelling......Page 301
United States Labelling Requirements......Page 302
Quality System Requirements......Page 303
Actual Labelling Requirements......Page 304
Translations......Page 307
What Goes Where......Page 308
15. Ethics Committee Approval......Page 316
Composition, Functions, and Operations......Page 317
Operations of the EC/IRB......Page 319
Special Situations......Page 320
Procedures of the EC or IRB......Page 321
What Is the Study Manager's Part in Optimising the Preparation Process?......Page 326
What Happens After the Study Proposal Has Been Approved by the EC/IRB?......Page 328
Appendix A. Comparison of European and U.S. GCP Requirements......Page 329
Appendix B. Checklist for EC/IRB Approval......Page 333
Introduction......Page 336
I. Basic Principles......Page 337
II. Medical Research Combined with Professional Care Clinical Research......Page 339
III. Non-Therapeutic Biomedical Research Involving Human Subjects Non-Clinical Biomedical Research......Page 340
16. Insurance and Liability......Page 341
Safety......Page 343
Types of Insurance......Page 344
Section IV: How to Monitor a Clinical Trial......Page 346
17. Selection and Training of Clinical Trial Monitors......Page 347
Regulatory Requirements......Page 348
Monitor Selection......Page 351
Training Programme......Page 352
Standard Operating Procedures......Page 358
General Training/Education......Page 359
18. How to Prepare the Clinic......Page 360
The Protocol or Clinical Investigation Plan......Page 363
Situation I......Page 364
Situation II......Page 365
Pre-Study Meeting......Page 366
Information to Other Parties in the Clinic......Page 368
Initiation Visit......Page 370
Appendix A. Pre-Study Checklist to be Used by Monitor......Page 372
Appendix B. Contents of the Investigator File......Page 375
19. Monitoring Visits......Page 377
What Is the Purpose of a Monitoring Visit?......Page 378
Why Are Monitoring Visits Necessary?......Page 379
Scheduling a Monitoring Visit......Page 380
Pre-Investigational Site Visit......Page 381
Pre-Study Training and Documentation......Page 386
The Study Initiation Visit......Page 388
Periodic Visits......Page 389
After the Monitoring Visit......Page 391
Study Close-Out Visit......Page 392
Data Checks and File Audits......Page 393
The Do's and Don'ts of Clinical Monitoring......Page 394
Do's......Page 395
Don'ts......Page 396
Appendix. Form Examples......Page 398
20. In-House Monitoring by the Clinic......Page 400
CRF Completion......Page 402
Procedure for Effective and Efficient CRF Completion......Page 404
Liaison Within the Clinic to Other Disciplines......Page 407
Study Co-ordinator as Assistant to the Investigator......Page 408
How Is Staff Motivation Maintained?......Page 411
Preparing for the Monitor Visit......Page 413
Problem Solving in Close Co-operation with the Study Monitor......Page 416
Appendix. Sample Work Instructions for the Staff......Page 417
21. Data Management......Page 425
Data Entry......Page 426
Data Validation......Page 429
When to Start Data Management......Page 430
How to Manage Data......Page 431
Data Management in Relation to Other Disciplines......Page 436
CRF Design from the Data Management Point of View......Page 438
22. Filing and Archiving......Page 442
The Active Study File......Page 443
What Essential Documents Should Be Filed?......Page 444
How to Set Up a TMF......Page 445
Retention of Records at the Investigational Site......Page 446
How to Set Up a Study File at the Investigational Site......Page 447
How to Classify the Archives......Page 448
New Technology to Store and Archive Data......Page 449
After Study Completion Archiving......Page 450
Appendix A. Investigator's Study File Checklist......Page 451
Appendix B. TMF Checklist......Page 454
Appendix C. Centre-Specific File Checklist......Page 458
Appendix D. Essential GCP Documents......Page 460
23. Adverse Event Processing During Clinical Trials......Page 482
Legislation/Requirements......Page 483
How the Adverse Event Is to Be Reported to the Sponsor......Page 486
Investigation of the Adverse Event by the Sponsor......Page 488
Processing the Investigation's Findings......Page 489
Commercialised Product......Page 491
Non-Commercialised Product......Page 492
Notification of Corrective Actions to Relevant Parties......Page 493
Follow-Up......Page 494
Closure of an Adverse Event......Page 495
Conclusion......Page 496
Appendix A. Flowchart: Adverse Event Handling of Commercialised Products......Page 498
Appendix B. Flowchart: Clinical Trial Adverse Events......Page 499
Appendix C. Sample Format for Reporting Adverse Events......Page 500
Appendix D. Root Cause Analysis of Reported Problems......Page 502
Section V: How to Analyse and Report Clinical Data......Page 503
24. Statistics......Page 504
General Items of Importance......Page 505
25. Reporting of Data......Page 508
Planning a Clinical Study Report......Page 509
The Clinical Study Team and Report Writing......Page 511
Guidelines and Procedures......Page 512
Phase I: Description of the Study......Page 514
Phase II: Presentation of Results......Page 516
Phase III: Introduction, Conclusions, and Discussion......Page 517
Phase V: Peer Review......Page 518
References......Page 519
26. How to Handle Suspected Fraud......Page 520
Types of Fraud......Page 522
Direct Proof......Page 523
Indirect Proof......Page 524
What Questions Should a Monitor Ask When Suspecting Fraud?......Page 525
What Are the Consequences of Fraud?......Page 526
How Should the Sponsor React in Case of Fraud?......Page 527
References......Page 529
Glossary......Page 531
A......Page 546
C......Page 547
D......Page 550
E......Page 551
F......Page 552
G......Page 553
I......Page 554
M......Page 556
N......Page 558
P......Page 559
Q......Page 560
S......Page 561
T......Page 563
W......Page 564