Clinical drug trials: studying the safety and efficacy of new pharmaceuticals
Saved in:
| Main Author: | |
|---|---|
| Format: | Book |
| Language: | English |
| Published: |
Bruxelles
Bruylant [u.a.]
2005
|
| Series: | Collection genevoise
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| Subjects: | |
| Online Access: | Inhaltsverzeichnis |
| Item Description: | Zugl.: Genève, Univ., Diss., 2004 |
| Physical Description: | XIX, 545 S. |
| ISBN: | 3725550220 2802721631 |
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| adam_text | Table of contents
Acknowledgments IX
Summary of contents XI
Acronyms XIII
List of Principal Laws and Regulations cited XVII
1. Introduction 1
1.1. Scope of the thesis 1
1.2. Focus of the thesis 2
1.2.1. A broad regulatory outlook 2
1.2.2. Medical literature 3
1.2.3. Economic literature 4
1.2.4. Ethics 4
1.3. Laws under analysis 4
1.4. Plan of the thesis 7
Parti 9
2. Historical overview of clinical trial regulations 9
2.1. International principles 10
2.1.1. The Nuremberg Code 10
2.1.2. The Helsinki Declaration and other texts 13
2.1.3. Three central ethical principles 16
2.1.4. Patient empowerment 17
2.1.5. A fundamental shift from a burden to a benefit 19
2.2. Historical overview of Swiss regulations on clinical trials 20
2.2.1. Successive Swiss regulations of clinical trials 20
2.2.1.1. Cantonal regulations 20
2.2.1.2. Prescriptions of the Swiss Academy of Medical Sciences 20
2.2.1.3. General federal provisions on informed consent 21
2.2.1.4. Former intercantonal regulations 22
2.2.1.5. Comprehensive federal regulations: the LPTh and the
OClin 23
2.2.2. Scandals in Switzerland: the VanTx affair 25
2.3. Historical overview of U.S. clinical trials regulations 26
2.3.1. Scandals in the United States 26
2.3.1.1. The Tuskegee study 27
2.3.1.2. Radiation studies 28
2.3.1.3. Mind control experiments 30
2.3.1.4. Recent scandals 31
2.3.2. Successive U.S. regulations of clinical trials 32
2.4. Historical overview of E.U. regulations 35
3. Definition of clinical trials 36
3.1. The three regional definitions 37
3.2. Clinical trials of therapeutic products 38
3.2.1. Is there a rationale for the OClin s product related limitations 38
3.2.2. Definition of therapeutic products 40
3.2.2.1. Pharmaceuticals 40
Table of contents
3.2.2.2. Transplants 41
3.2.2.3. Stem cell therapy 43
3.2.2.4. Narcotics 46
3.2.3. Gene therapy 47
3.2.3.1. Definition of somatic gene therapy 47
3.2.3.2. Opposition to gene therapy 48
3.2.3.3. Gene therapy and the Odin 49
3.2.3.4. Ex vivo gene therapy 50
3.2.4. The administration of a therapeutic product 50
3.2.5. Safety, efficacy and other properties 51
3.3. A living human subject 52
3.4. Research as compared to individualized health care 53
3.4.1. Systematic methods 54
3.4.2. Generalizable information 56
3.4.3. The criterion of intent 57
3.4.4. Status of the drug 59
3.4.5. Other elements to be taken into account 60
3.4.6. Specific borderline situations 61
3.4.6.1. Non interventional studies 61
3.4.6.2. Expanded access programs 62
3.4.6.2.1. The international context 62
3.4.6.2.2. The various forms of compassionate use in
the United States 63
3.4.6.2.3. The various forms of compassionate use in
Switzerland 65
3.4.6.2.4. Do compassionate access programs come
under the OClin? 66
3.4.6.3. Retrospective studies 68
3.4.6.4. Research on biological material 70
3.4.6.5. Clinical trials versus non medical activities 71
3.5. The scope of the OClin 72
3.5.1. Temporal scope of the OClin 72
3.5.2. Geographical scope of the OClin 73
3.5.3. Preemption of cantonal regulations 74
4. The economic dimension of clinical trials 76
4.1. The objectives of clinical trials 76
4.1.1. Obtaining marketing approval 76
4.1.1.1. Proving the drug s safety 77
4.1.1.1.1. Historical background 77
4.1.1.1.2. Safety tests 78
4.1.1.2. Proving efficacy 79
4.1.1.2.1. Historical background of the efficacy
requirement 79
4.1.1.2.2. The role of therapeutic indications 82
4.1.1.2.3. Required standard of substantiation 83
4.1.1.3. Proving bioequivalence 85
4.1.1.4. The marketing authorization process and its alternatives 86
4.1.2. Contributing to basic knowledge 86
4.1.3. Assisting physicians 87
4.1.4. Advertising the drug 88
4.1.4.1. Before marketing approval 88
4.1.4.2. After marketing approval 89
4.1.5. Minimizing liability 89
4.1.6. Intellectual property ( IF ) 90
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Table of contents
4.1.6.1. Getting IP rights ( IPR ) 90
4.1.6.2. Defending patent infringement claims 91
4.1.7. Obtaining reimbursement status 93
4.1.8. Getting investors interested 95
4.1.9. Getting a pharmaceutical firm interested in a biotech company 96
4.1.10. Factors in deciding to launch a clinical trial 97
4.2. Economic issues in clinical trials 99
4.2.1. Costs of clinical trials 99
4.2.1.1. Number and length of trials 99
4.2.1.2. Estimates of total costs 101
4.2.2. Risks of clinical trials 102
4.2.3. Implications of clinical trial costs 103
4.2.3.1. Consequences on the industry 103
4.2.3.2. Consequences for patients 104
4.2.3.3. Consequences on price levels 105
4.3. Regional harmonization of clinical trial requirements 106
4.3.1. International Harmonization Conference 107
4.3.1.1. The ICHE6 Guideline 108
4.3.1.2. The ICHE5 Guideline 108
4.3.1.2.1. What role do ethnicity and race play? 109
4.3.1.2.2. Bridging studies 110
4.3.2 Recognition by Swissmedic of foreign clinical trials 112
4.3.3. Recognition of foreign clinical trials in the United States 114
4.4. Strategic weight of clinical trials, in particular in Switzerland 115
4.4.1. Strategic importance of clinical trials 115
4.4.2. Assets and drawbacks of Swiss clinical trials 116
4.5. Clinical trials in developing countries 119
4.5.1. Advantages and disadvantages of clinical trials in developing
countries 120
4.5.2. Scandals in developing countries 122
4.5.3. Reactions to scandals 124
Part II 127
5. The professional participants in a clinical trial 127
5.1. The sponsor 128
5.1.1. Legal requirement pertaining to the sponsor 128
5.1.2. Who becomes sponsor? 129
5.1.3. Number of sponsors 130
5.1.4. The sponsor s duties 131
5.2. The investigator 132
5.2.1. Investigators motivations 133
5.2.2. Sponsor s selection of investigators 134
5.2.3. Academic and commercial investigators 135
5.2.4. Number of investigators 136
5.2.5. Qualifications of the investigator 137
5.2.6. Responsibilities of the investigator 138
5.2.7. Investigators institutions 139
5.3. Conflicts of interest involving sponsors and investigators 139
5.3.1. Impartiality of the investigator 141
5.3.1.1. Tension between research and therapy 141
5.3.1.2. Independence toward the sponsor 141
5.3.2. Financial issues 142
5.3.2.1. Types of financial involvements 143
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5.3.2.2. Possible consequences 144
5.3.2.3. Disclosure of conflicts 145
5.3.2.4. Conflicts of interest in the United States 147
5.3.2.4.1. Historical background 147
5.3.2.4.2. FDA regulation on conflicts of interest 148
5.3.2.4.3. Changes in academic research institutions 151
5.3.2.5. Conflicts of interest in Switzerland 154
5.3.2.5.1. Provisions of the LPTh and the OClin 154
5.3.2.5.2. Policies of the Geneva University 156
5.3.2.5.3. SAMS policies 157
5.3.3. Conflicts of interest pertaining to confidentiality requests 158
5.3.3.1. The Olivieri case 158
5.3.3.2. Confidentiality clauses 159
5.4. Monitors 160
5.4.1. Obligation to monitor the trial 160
5.4.2. Role of the monitor 162
5.4.3. Appointment of monitors 163
5.5. Auditors 164
5.6. Contract research organizations 165
5.6.1. A growing presence 165
5.6.2. Permissible delegation 166
5.6.3. Activities commonly delegated 167
5.7. Site Management Organizations 168
5.8. Data Safety Monitoring Boards 169
5.8.1. Necessity of a DSMB 169
5.8.2. Appointment of a DSMB 170
5.8.3. Role of a DSMB 171
6. The types and characteristics of drug clinical trials 174
6.1. The different kinds of clinical trials 174
6.1.1. Phase I 175
6.1.1.1. Conditions of phase I trials 175
6.1.1.2. Objectives of a phase I trial 176
6.1.1.3. Therapeutic and nontherapeutic trials 177
6.1.1.4. Subjects recruited for a phase I trial 179
6.1.2. Phase II clinical trials 180
6.1.3. Phase III clinical trials 182
6.1.3.1. Objectives 182
6.1.3.2. Importance of phase III trials 182
6.1.3.3. Organization of phase III trials 183
6.1.4. Phase IV clinical trials 184
6.1.4.1. Phase IV trials requested by the drug agency 185
6.1.4.1.1. Reasons for phase IV studies 185
6.1.4.1.2. Characteristics of phase IV studies 186
6.1.4.1.3. Compliance with phase IV commitments 187
6.1.4.2. Phase IV trials decided by pharmaceutical companies 188
6.1.4.2.1. Objectives 188
6.1.4.2.2. Characteristics 189
6.1.4.3. Pharmacovigjlance 190
6.1.4.3.1. Purpose of pharmacovigilance 190
6.1.4.3.2. Periodic safety update reports 191
6.1.4.3.3. Adverse reactions reports 193
6.1.5. Flexibilities in the phase division 193
6.2. The key documents of a clinical trial 196
6.2.1. The protocol 196
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Table of contents
6.2.1.1. Contents of a protocol 197
6.2.1.2. Preparation of the protocol 198
6.2.1.3. Drug agencies role in the design of clinical trials 199
6.2.1.4. Changes to the protocol 200
6.2.2. The brochure 201
6.2.3. Case report forms ( CRFs ) 201
6.2.3.1. Role of CRFs 202
6.2.3.2. Completing and changing CRFs 203
6.3. The gold standard: chasing bias 203
6.3.1. Importance of randomized controlled trials 205
6.3.2. Historical aspects 207
6.3.3. Controls 208
6.3.3.1. Purpose of controls 209
6.3.3.2. The placebo effect 211
6.3.3.3. Active controls 213
6.3.3.3.1. Scientific difficulties in connection with
active controls 213
6.3.3.3.2. Sponsors preferences for placebos 214
6.3.3.3.3. Obligation to conduct comparative trials 216
6.3.3.3.4. Advantages of comparative trials 216
6.3.3.4. Washout periods 217
6.3.3.5. Hiding the control 218
6.3.3.5.1. Blinding 218
6.3.3.5.1.1. Single blinding 218
6.3.3.5.1.2. Double blinding 219
6.3.3.5.1.3. Other types of blinding 220
6.3.3.5.2. Two almost identical products 221
6.3.3.5.3. Inadvertent unblinding 222
6.3.3.5.4. Permissible unblinding 223
6.3.4. Randomization 224
6.3.5. Ethical problems related to controls and randomization 225
6.3.5.1. The notion of equipoise 226
6.3.5.1.1 Theoretical and clinical equipoise 226
6.3.5.1.2. Personal equipoise 228
6.3.5.1.3. Duration of equipoise 229
6.3.5.1.4. Consequences 230
6.3.5.2. The placebo controversy 230
6.3.5.2.1. The controversy in developed countries 231
6.3.5.2.2. The placebo controversy in developing
countries 233
6.3.5.2.3. The revised Helsinki Declaration 233
6.3.5.2.4. Consequences in developed countries 235
6.3.5.2.5. Consequences in developing countries 237
6.3.6. The study s endpoints 238
6.3.6.1. Primary and secondary endpoints 239
6.3.6.2. Tracking endpoints 240
6.3.6.3. Surrogate endpoints 240
6.3.6.4. Post hoc analysis 242
6.3.7. Control of eligibility criteria 243
6.3.8. Dropouts 245
6.3.9. Duration of the trial 246
6.3.10. Statistics 246
6.3.10.1. Sample size 247
6.3.10.2. Underpowered studies 248
Table of contents
6.3.10.3. The p value and confidence interval 249
6.3.10.4. Causation 250
6.3.10.5. Presentation of results 250
6.3.11. Quality assurance 252
6.4. Manufacturing controls and labeling 253
Part III 257
7. Approval of clinical trials 257
7.1. Approval of clinical trials by ethics committees 258
7.1.1. Organization of Swiss RECs 258
7.1.1.1. Historical perspective 259
7.1.1.2. Role of the canton under the LPTh 259
7.1.1.2.1. Cantonal appointment of RECs 259
7.1.1.2.2. Further cantonal responsibilities 261
7.1.1.2.3. Difficulties with the cantonal organization 262
7.1.1.3. Composition of RECs 263
7.1.1.3.1. Qualifications of REC members 263
7.1.1.3.2. Female REC members 266
7.1.1.3.3. Non represented groups 267
7.1.1.3.4. Accountability 268
7.1.1.3.5. Knowledge of local conditions 268
7.1.1.4. Independence of RECs 270
7.1.1.4.1. The legal requirements 270
7.1.1.4.2. What independence for institutional RECs? 271
7.1.1.4.3. Conflicts of interest within RECs 273
7.1.1.5. External assistance 275
7.1.2. RECs decision taking process 276
7.1.2.1. Choice of REC 276
7.1.2.2. Multicentric review 277
7.1.2.3. The investigator s application 279
7.1.2.4. Information gathering process by the REC 282
7.1.2.5. Assessment criteria 283
7.1.2.5.1. Scientific validity 284
7.1.2.5.2. Relevance 284
7.1.2.5.3. Assessment of risks 285
7.1.2.5.4. Assessment of benefits 286
7.1.2.5.5. The balancing of risks and benefits 287
7.1.2.5.6. Appropriate information given to subjects 288
7.1.2.5.7. Financial relationship between the sponsor
and the investigator 289
7.1.2.5.8. Review of recruitment procedures 290
7.1.2.5.9. Review of publication policies 292
7.1.2.6. The vote 293
7.1.2.7. The form of the decision 295
7.1.3. Information about the operation of RECs 296
7.1.3.1. In Switzerland 296
7.1.3.2. In other countries 297
7.1.3.3. Limits of the RECs assessment 299
7.1.4. Proposals for improving RECs 300
7.1.4.1. Continuing education 300
7.1.4.2. Longer deadlines 300
7.1.4.3. Funding RECs properly 301
7.1.4.4. Private RECs? 301
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7.1.4.5. Public RECs 303
7.1.5. Supervision of ethics committees 305
7.1.5.1. Cantonal oversight in Switzerland 305
7.1.5.1.1 Sovereignty of each canton 305
7.1.5.1.2. Problems with cantonal oversight 306
7.1.5.2. A new role for Swissmedic 307
7.1.5.3. Oversight by the sponsor 308
7.2. Drug agency s approval of clinical trials 309
7.2.1. The clearance process 309
7.2.1.1. In Switzerland 309
7.2.1.2. In the United States 310
7.2.2. Contents of the application 311
7.2.3. Assessment of the application 313
7.2.3.1. In Switzerland 313
7.2.3.2. In the United States 314
7.2.4. The authorization process 315
7.2.4.1. Products involved 315
7.2.4.2. The application and the authorization process 316
7.2.5. The opportunities for appeal 317
8. Research subjects 318
8.1. Recruitment of subjects 318
8.1.1. Practical and economic issues 318
8.1.2. Factors affecting recruitment 320
8.1.2.1. Patient pool 320
8.1.2.2. Existence of alternative treatments 321
8.1.2.3. Eligibility criteria 322
8.1.2.4. Lack of information about the trial 324
8.1.2.5. Design of the trial 325
8.1.2.6. Cost issues 326
8.1.3. Recruitment strategies 326
8.1.4. Recruitment incentives for investigators 328
8.1.5. Self recruitment 329
8.1.6. Fairness in recruitment 330
8.1.7. Research subjects registers 332
8.2. Legal qualification of the relationship 333
8.2.1. Contract between the investigator and the research subject 333
8.2.2. Contract between the sponsor and the research subject? 334
8.3. The informed consent process 335
8.3.1. Brief historical overview 336
8.3.2. Information provided 338
8.3.2.1. Research versus treatment 342
8.3.2.2. Risk disclosure 344
8.3.2.3. Benefit disclosure 346
8.3.2.4. Information about available alternatives 348
8.3.2.5. Information about conflicts of interest 349
8.3.2.6. Information about costs 351
8.3.2.7. Information about future research 352
8.3.2.8. Information about subjects rights 353
8.3.3. Consent as a process 353
8.3.3.1. The main steps of the process 353
8.3.3.2. Right to think it over 355
8.3.3.3. Written consent forms 356
8.3.3.3.1. Purpose
Table of contents
8.3.3.3.3. Frequent problems with consent forms 359
8.3.3.4. Testing comprehension 360
8.3.3.5. Patient advocates and witnesses 361
8.3.3.6. The role of the primary care physician 362
8.3.3.7. Right to ask questions 363
8.3.3.8. Group consent 364
8.3.3.9. Rights to refuse enrollment 366
8.3.3.10. Right to withdraw from the trial 367
8.3.3.11. Renewal of consent 369
8.4. Enrollment of incapable subjects 370
8.4.1. Two main categories 371
8.4.1.1. Article 55 LPTh: research on incompetent subjects 372
8.4.1.2. Article 56: emergency research 375
8.4.1.3. Classification difficulties 375
8.4.2. Special medical and ethical considerations 377
8.4.2.1. Special considerations in pediatric trials 377
8.4.2.2. Special considerations in emergency trials 381
8.4.3. Subsidiarity 383
8.4.4. Substitute to consent 384
8.4.4.1. Proxy consent for incompetent subjects 384
8.4.4.2. Proxy consent in emergency research 388
8.4.4.3. Consultation in emergency research 389
8.4.4.4. Assent 391
8.4.4.5. Signs of refusal 393
8.4.4.6. Recovered or newly acquired capacity 395
8.4.4.7. Advance consent 395
8.4.5. Level of benefits and risks 397
8.4.5.1. Defining direct and indirect benefits 397
8.4.5.2. The rule and the exception 398
8.4.5.3. How must benefits be assessed? 399
8.4.5.4. Level of risks 400
8.4.6. Additional requirements 402
8.4.6.1. Additional requirements under Article 55 LPTh? 402
8.4.6.2. Additional requirements for emergency trials 403
8.4.6.3. Public feedback in the United States 404
8.4.6.4. Community information in U.S. emergency research 404
8.4.7. Other exceptions to informed consent under U.S. law 406
8.5. Enrollment of vulnerable subjects 407
8.5.1. Prisoners 408
8.5.2. Women 410
8.5.2.1. Pregnant women 412
8.5.2.2. Research on ex utero embryos 415
8.5.2.3. Pregnancy registries 416
8.5.3. Terminally ill patients 417
8.5.4. Seniors 418
8.5.5. Indigent people 420
8.5.6. Foreigners 421
8.5.7. Minorities 422
8.5.8. Subjects in developing countries 423
8.6. Other rights of research subjects 425
8.6.1. Right to receive proper health care 425
8.6.2. Follow up 426
8.6.2.1. Debriefing 426
8.6.2.2. Right to follow up information and care 428
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8.6.2.3. Right to continued supply of the experimental product? 429
8.6.3. Confidentiality and privacy 432
8.6.3.1. Under the LPTh and the OClin 433
8.6.3.1.1. The LPTh and the OClin 433
8.6.3.1.2. ICH Guideline 433
8.6.3.1.3. Information to be provided 434
8.6.3.2. Article 321 and 321bi» CP 436
8.6.3.2.1. Applicability 436
8.6.3.2.2. Exception to Article 321bis 437
8.6.3.3. Under the law on data protection 438
8.6.3.3.1. Right to access the file 439
8.6.3.3.2. Right to restrict access 440
8.6.3.3.3. Right to correct mistakes 440
8.6.4. Payments to and by subjects 441
8.6.4.1. Payments to subjects 441
8.6.4.1.1. Admissibility 441
8.6.4.1.2. Review by ethics committees 442
8.6.4.1.3. Amounts offered 443
8.6.4.2. Payments by subjects 444
8.6.4.2.1. Payment for the experimental product 444
8.6.4.2.2. Payments for other health care costs 445
8.6.4.2.3. Insurance coverage 446
8.6.5. Liability and compensation for damages 448
8.6.5.1. General principles of liability under Swiss law 449
8.6.5.1.1. The investigator s liability 450
8.6.5.1.2. The sponsor s liability under general legal
principles 451
8.6.5.1.3. Other liable parties 452
8.6.5.2. The OClin system of liability and insurance coverage 452
8.6.5.2.1. Scope of liability under the OClin 454
8.6.5.2.2. Sponsor s insurance coverage 456
8.6.5.3. Review by ethics committees 458
8.6.5.4. Situation in the United States 459
8.6.6. Waivers 460
8.6.6.1. Waivers of rights 460
8.6.6.2. Biological material 460
8.6.6.2.1. The Moore case 461
8.6.6.2.2. Biological material ownership under Swiss
law 463
8.6.6.2.3. Gratuity in research 465
8.7. Obligations of research subjects? 466
8.7.1. Obligation to follow directions 466
8.7.2. Subjects confidentiality obligations? 467
9. Supervision of clinical trials 468
9.1. Reporting obligations 468
9.1.1. Changes to the clinical trial 468
9.1.1.1. Objectives of notification 469
9.1.1.2. Essential changes 470
9.1.1.2.1. Scope of the changes 470
9.1.1.2.2. REC review 471
9.1.1.3. Minor changes 472
9.1.2. Reporting obligations for adverse events 473
9.1.2.1. Adverse events and adverse reactions 474
Table of contents
9.1.2.1.2. Foreseeability 476
9.1.2.1.3. Severity 477
9.1.2.1.4. Form of the report 477
9.1.2.2. New facts threatening subjects safety 478
9.1.2.3. Death of a subject 479
9.1.2.4. Deadly harm 480
9.1.2.5. Serious and unexpected adverse reactions 480
9.1.2.6. The complete file of adverse events 482
9.1.2.7. Reporting obligations of the sponsor to the investigator 483
9.1.2.8. Database of adverse reactions 484
9.1.2.9 Events that do not require reporting 484
9.2. Oversight by the authorities 485
9.2.1. Oversight by RECs 485
9.2.1.1. Extent of the post approval role of RECs under Swiss
law 485
9.2.1.2. IRBs continuing review in the United States 486
9.2.1.3. Specific powers of RECs 487
9.2.2. Supervision by the drug agency 489
9.2.2.1. Trial suspensions 489
9.2.2.1.1. New information 489
9.2.2.1.2. Objective reasons 489
9.2.2.2. Remedial plans 492
9.2.2.3. Inspections in Switzerland 493
9.2.2.4. Disqualification of data 494
9.2.2.5. Inspections in the United States 495
9.2.2.6. Criminal inquiries 496
9.2.2.7. Appeals 496
9.2.3. Supervision of a clinical trial by the investigator s institution 497
9.2.4. Supervision of a clinical trial by the canton 497
9.2.5. Supervision by foreign agencies 498
9.2.6. Supervision by other entities 498
9.3. Frequent shortcomings of clinical trials 499
10. End of clinical trials 502
10.1. Common reasons for ending a clinical trial 502
10.1.1. Normal termination 502
10.1.2. Early termination 502
10.2. Notifying authorities 505
10.3. Preparing the study report 505
10.4. Publication and publicity 507
10.4.1. Publication by the investigator or the sponsor 507
10.4.1.1. Publishing both good and bad 507
10.4.1.2. Publishing without delays 511
10.4.1.3. Providing supporting documents 511
10.4.1.4. Not publishing unethical studies 512
10.4.1.5. The Consort Guidelines 513
10.4.2. Information available from drug agencies 514
10.4.2.1. In Switzerland 514
10.4.2.2. In the United States 515
10.4.2.2.1. Information while the trial is underway 515
10.4.2.2.2. Information when the drug is under review 516
10.4.2.2.3. Information once development effort is
abandoned 516
10.4.2.3. In the European Union 517
10.5. Record keeping 519
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11. Conclusion 521
Glossary 523
List of court cases cited 527
Short Bibliography 531
Index 533
Table of contents 535
|
| adam_txt |
Table of contents
Acknowledgments IX
Summary of contents XI
Acronyms XIII
List of Principal Laws and Regulations cited XVII
1. Introduction 1
1.1. Scope of the thesis 1
1.2. Focus of the thesis 2
1.2.1. A broad regulatory outlook 2
1.2.2. Medical literature 3
1.2.3. Economic literature 4
1.2.4. Ethics 4
1.3. Laws under analysis 4
1.4. Plan of the thesis 7
Parti 9
2. Historical overview of clinical trial regulations 9
2.1. International principles 10
2.1.1. The Nuremberg Code 10
2.1.2. The Helsinki Declaration and other texts 13
2.1.3. Three central ethical principles 16
2.1.4. Patient empowerment 17
2.1.5. A fundamental shift from a burden to a benefit 19
2.2. Historical overview of Swiss regulations on clinical trials 20
2.2.1. Successive Swiss regulations of clinical trials 20
2.2.1.1. Cantonal regulations 20
2.2.1.2. Prescriptions of the Swiss Academy of Medical Sciences 20
2.2.1.3. General federal provisions on informed consent 21
2.2.1.4. Former intercantonal regulations 22
2.2.1.5. Comprehensive federal regulations: the LPTh and the
OClin 23
2.2.2. Scandals in Switzerland: the VanTx affair 25
2.3. Historical overview of U.S. clinical trials regulations 26
2.3.1. Scandals in the United States 26
2.3.1.1. The Tuskegee study 27
2.3.1.2. Radiation studies 28
2.3.1.3. Mind control experiments 30
2.3.1.4. Recent scandals 31
2.3.2. Successive U.S. regulations of clinical trials 32
2.4. Historical overview of E.U. regulations 35
3. Definition of clinical trials 36
3.1. The three regional definitions 37
3.2. Clinical trials of therapeutic products 38
3.2.1. Is there a rationale for the OClin's product related limitations 38
3.2.2. Definition of "therapeutic products" 40
3.2.2.1. Pharmaceuticals 40
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3.2.2.2. Transplants 41
3.2.2.3. Stem cell therapy 43
3.2.2.4. Narcotics 46
3.2.3. Gene therapy 47
3.2.3.1. Definition of somatic gene therapy 47
3.2.3.2. Opposition to gene therapy 48
3.2.3.3. Gene therapy and the Odin 49
3.2.3.4. Ex vivo gene therapy 50
3.2.4. The administration of a therapeutic product 50
3.2.5. Safety, efficacy and other properties 51
3.3. A living human subject 52
3.4. Research as compared to individualized health care 53
3.4.1. Systematic methods 54
3.4.2. Generalizable information 56
3.4.3. The criterion of intent 57
3.4.4. Status of the drug 59
3.4.5. Other elements to be taken into account 60
3.4.6. Specific borderline situations 61
3.4.6.1. Non interventional studies 61
3.4.6.2. Expanded access programs 62
3.4.6.2.1. The international context 62
3.4.6.2.2. The various forms of compassionate use in
the United States 63
3.4.6.2.3. The various forms of compassionate use in
Switzerland 65
3.4.6.2.4. Do compassionate access programs come
under the OClin? 66
3.4.6.3. Retrospective studies 68
3.4.6.4. Research on biological material 70
3.4.6.5. Clinical trials versus non medical activities 71
3.5. The scope of the OClin 72
3.5.1. Temporal scope of the OClin 72
3.5.2. Geographical scope of the OClin 73
3.5.3. Preemption of cantonal regulations 74
4. The economic dimension of clinical trials 76
4.1. The objectives of clinical trials 76
4.1.1. Obtaining marketing approval 76
4.1.1.1. Proving the drug's safety 77
4.1.1.1.1. Historical background 77
4.1.1.1.2. Safety tests 78
4.1.1.2. Proving efficacy 79
4.1.1.2.1. Historical background of the efficacy
requirement 79
4.1.1.2.2. The role of therapeutic indications 82
4.1.1.2.3. Required standard of substantiation 83
4.1.1.3. Proving bioequivalence 85
4.1.1.4. The marketing authorization process and its alternatives 86
4.1.2. Contributing to basic knowledge 86
4.1.3. Assisting physicians 87
4.1.4. Advertising the drug 88
4.1.4.1. Before marketing approval 88
4.1.4.2. After marketing approval 89
4.1.5. Minimizing liability 89
4.1.6. Intellectual property ("IF') 90
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4.1.6.1. Getting IP rights ("IPR") 90
4.1.6.2. Defending patent infringement claims 91
4.1.7. Obtaining reimbursement status 93
4.1.8. Getting investors interested 95
4.1.9. Getting a pharmaceutical firm interested in a biotech company 96
4.1.10. Factors in deciding to launch a clinical trial 97
4.2. Economic issues in clinical trials 99
4.2.1. Costs of clinical trials 99
4.2.1.1. Number and length of trials 99
4.2.1.2. Estimates of total costs 101
4.2.2. Risks of clinical trials 102
4.2.3. Implications of clinical trial costs 103
4.2.3.1. Consequences on the industry 103
4.2.3.2. Consequences for patients 104
4.2.3.3. Consequences on price levels 105
4.3. Regional harmonization of clinical trial requirements 106
4.3.1. International Harmonization Conference 107
4.3.1.1. The ICHE6 Guideline 108
4.3.1.2. The ICHE5 Guideline 108
4.3.1.2.1. What role do ethnicity and race play? 109
4.3.1.2.2. Bridging studies 110
4.3.2 Recognition by Swissmedic of foreign clinical trials 112
4.3.3. Recognition of foreign clinical trials in the United States 114
4.4. Strategic weight of clinical trials, in particular in Switzerland 115
4.4.1. Strategic importance of clinical trials 115
4.4.2. Assets and drawbacks of Swiss clinical trials 116
4.5. Clinical trials in developing countries 119
4.5.1. Advantages and disadvantages of clinical trials in developing
countries 120
4.5.2. Scandals in developing countries 122
4.5.3. Reactions to scandals 124
Part II 127
5. The professional participants in a clinical trial 127
5.1. The sponsor 128
5.1.1. Legal requirement pertaining to the sponsor 128
5.1.2. Who becomes sponsor? 129
5.1.3. Number of sponsors 130
5.1.4. The sponsor's duties 131
5.2. The investigator 132
5.2.1. Investigators' motivations 133
5.2.2. Sponsor's selection of investigators 134
5.2.3. Academic and commercial investigators 135
5.2.4. Number of investigators 136
5.2.5. Qualifications of the investigator 137
5.2.6. Responsibilities of the investigator 138
5.2.7. Investigators' institutions 139
5.3. Conflicts of interest involving sponsors and investigators 139
5.3.1. Impartiality of the investigator 141
5.3.1.1. Tension between research and therapy 141
5.3.1.2. Independence toward the sponsor 141
5.3.2. Financial issues 142
5.3.2.1. Types of financial involvements 143
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5.3.2.2. Possible consequences 144
5.3.2.3. Disclosure of conflicts 145
5.3.2.4. Conflicts of interest in the United States 147
5.3.2.4.1. Historical background 147
5.3.2.4.2. FDA regulation on conflicts of interest 148
5.3.2.4.3. Changes in academic research institutions 151
5.3.2.5. Conflicts of interest in Switzerland 154
5.3.2.5.1. Provisions of the LPTh and the OClin 154
5.3.2.5.2. Policies of the Geneva University 156
5.3.2.5.3. SAMS policies 157
5.3.3. Conflicts of interest pertaining to confidentiality requests 158
5.3.3.1. The Olivieri case 158
5.3.3.2. Confidentiality clauses 159
5.4. Monitors 160
5.4.1. Obligation to monitor the trial 160
5.4.2. Role of the monitor 162
5.4.3. Appointment of monitors 163
5.5. Auditors 164
5.6. Contract research organizations 165
5.6.1. A growing presence 165
5.6.2. Permissible delegation 166
5.6.3. Activities commonly delegated 167
5.7. Site Management Organizations 168
5.8. Data Safety Monitoring Boards 169
5.8.1. Necessity of a DSMB 169
5.8.2. Appointment of a DSMB 170
5.8.3. Role of a DSMB 171
6. The types and characteristics of drug clinical trials 174
6.1. The different kinds of clinical trials 174
6.1.1. Phase I 175
6.1.1.1. Conditions of phase I trials 175
6.1.1.2. Objectives of a phase I trial 176
6.1.1.3. Therapeutic and nontherapeutic trials 177
6.1.1.4. Subjects recruited for a phase I trial 179
6.1.2. Phase II clinical trials 180
6.1.3. Phase III clinical trials 182
6.1.3.1. Objectives 182
6.1.3.2. Importance of phase III trials 182
6.1.3.3. Organization of phase III trials 183
6.1.4. Phase IV clinical trials 184
6.1.4.1. Phase IV trials requested by the drug agency 185
6.1.4.1.1. Reasons for phase IV studies 185
6.1.4.1.2. Characteristics of phase IV studies 186
6.1.4.1.3. Compliance with phase IV commitments 187
6.1.4.2. Phase IV trials decided by pharmaceutical companies 188
6.1.4.2.1. Objectives 188
6.1.4.2.2. Characteristics 189
6.1.4.3. Pharmacovigjlance 190
6.1.4.3.1. Purpose of pharmacovigilance 190
6.1.4.3.2. Periodic safety update reports 191
6.1.4.3.3. Adverse reactions reports 193
6.1.5. Flexibilities in the phase division 193
6.2. The key documents of a clinical trial 196
6.2.1. The protocol 196
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6.2.1.1. Contents of a protocol 197
6.2.1.2. Preparation of the protocol 198
6.2.1.3. Drug agencies'role in the design of clinical trials 199
6.2.1.4. Changes to the protocol 200
6.2.2. The brochure 201
6.2.3. Case report forms ("CRFs") 201
6.2.3.1. Role of CRFs 202
6.2.3.2. Completing and changing CRFs 203
6.3. The gold standard: chasing bias 203
6.3.1. Importance of randomized controlled trials 205
6.3.2. Historical aspects 207
6.3.3. Controls 208
6.3.3.1. Purpose of controls 209
6.3.3.2. The placebo effect 211
6.3.3.3. Active controls 213
6.3.3.3.1. Scientific difficulties in connection with
active controls 213
6.3.3.3.2. Sponsors' preferences for placebos 214
6.3.3.3.3. Obligation to conduct comparative trials 216
6.3.3.3.4. Advantages of comparative trials 216
6.3.3.4. Washout periods 217
6.3.3.5. Hiding the control 218
6.3.3.5.1. Blinding 218
6.3.3.5.1.1. Single blinding 218
6.3.3.5.1.2. Double blinding 219
6.3.3.5.1.3. Other types of blinding 220
6.3.3.5.2. Two almost identical products 221
6.3.3.5.3. Inadvertent unblinding 222
6.3.3.5.4. Permissible unblinding 223
6.3.4. Randomization 224
6.3.5. Ethical problems related to controls and randomization 225
6.3.5.1. The notion of equipoise 226
6.3.5.1.1 Theoretical and clinical equipoise 226
6.3.5.1.2. Personal equipoise 228
6.3.5.1.3. Duration of equipoise 229
6.3.5.1.4. Consequences 230
6.3.5.2. The placebo controversy 230
6.3.5.2.1. The controversy in developed countries 231
6.3.5.2.2. The placebo controversy in developing
countries 233
6.3.5.2.3. The revised Helsinki Declaration 233
6.3.5.2.4. Consequences in developed countries 235
6.3.5.2.5. Consequences in developing countries 237
6.3.6. The study's endpoints 238
6.3.6.1. Primary and secondary endpoints 239
6.3.6.2. Tracking endpoints 240
6.3.6.3. Surrogate endpoints 240
6.3.6.4. Post hoc analysis 242
6.3.7. Control of eligibility criteria 243
6.3.8. Dropouts 245
6.3.9. Duration of the trial 246
6.3.10. Statistics 246
6.3.10.1. Sample size 247
6.3.10.2. Underpowered studies 248
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6.3.10.3. The p value and confidence interval 249
6.3.10.4. Causation 250
6.3.10.5. Presentation of results 250
6.3.11. Quality assurance 252
6.4. Manufacturing controls and labeling 253
Part III 257
7. Approval of clinical trials 257
7.1. Approval of clinical trials by ethics committees 258
7.1.1. Organization of Swiss RECs 258
7.1.1.1. Historical perspective 259
7.1.1.2. Role of the canton under the LPTh 259
7.1.1.2.1. Cantonal appointment of RECs 259
7.1.1.2.2. Further cantonal responsibilities 261
7.1.1.2.3. Difficulties with the cantonal organization 262
7.1.1.3. Composition of RECs 263
7.1.1.3.1. Qualifications of REC members 263
7.1.1.3.2. Female REC members 266
7.1.1.3.3. Non represented groups 267
7.1.1.3.4. Accountability 268
7.1.1.3.5. Knowledge of local conditions 268
7.1.1.4. Independence of RECs 270
7.1.1.4.1. The legal requirements 270
7.1.1.4.2. What independence for institutional RECs? 271
7.1.1.4.3. Conflicts of interest within RECs 273
7.1.1.5. External assistance 275
7.1.2. RECs'decision taking process 276
7.1.2.1. Choice of REC 276
7.1.2.2. Multicentric review 277
7.1.2.3. The investigator's application 279
7.1.2.4. Information gathering process by the REC 282
7.1.2.5. Assessment criteria 283
7.1.2.5.1. Scientific validity 284
7.1.2.5.2. Relevance 284
7.1.2.5.3. Assessment of risks 285
7.1.2.5.4. Assessment of benefits 286
7.1.2.5.5. The balancing of risks and benefits 287
7.1.2.5.6. Appropriate information given to subjects 288
7.1.2.5.7. Financial relationship between the sponsor
and the investigator 289
7.1.2.5.8. Review of recruitment procedures 290
7.1.2.5.9. Review of publication policies 292
7.1.2.6. The vote 293
7.1.2.7. The form of the decision 295
7.1.3. Information about the operation of RECs 296
7.1.3.1. In Switzerland 296
7.1.3.2. In other countries 297
7.1.3.3. Limits of the RECs assessment 299
7.1.4. Proposals for improving RECs 300
7.1.4.1. Continuing education 300
7.1.4.2. Longer deadlines 300
7.1.4.3. Funding RECs properly 301
7.1.4.4. "Private" RECs? 301
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7.1.4.5. Public RECs 303
7.1.5. Supervision of ethics committees 305
7.1.5.1. Cantonal oversight in Switzerland 305
7.1.5.1.1 Sovereignty of each canton 305
7.1.5.1.2. Problems with cantonal oversight 306
7.1.5.2. A new role for Swissmedic 307
7.1.5.3. Oversight by the sponsor 308
7.2. Drug agency's approval of clinical trials 309
7.2.1. The clearance process 309
7.2.1.1. In Switzerland 309
7.2.1.2. In the United States 310
7.2.2. Contents of the application 311
7.2.3. Assessment of the application 313
7.2.3.1. In Switzerland 313
7.2.3.2. In the United States 314
7.2.4. The authorization process 315
7.2.4.1. Products involved 315
7.2.4.2. The application and the authorization process 316
7.2.5. The opportunities for appeal 317
8. Research subjects 318
8.1. Recruitment of subjects 318
8.1.1. Practical and economic issues 318
8.1.2. Factors affecting recruitment 320
8.1.2.1. Patient pool 320
8.1.2.2. Existence of alternative treatments 321
8.1.2.3. Eligibility criteria 322
8.1.2.4. Lack of information about the trial 324
8.1.2.5. Design of the trial 325
8.1.2.6. Cost issues 326
8.1.3. Recruitment strategies 326
8.1.4. Recruitment incentives for investigators 328
8.1.5. "Self recruitment" 329
8.1.6. Fairness in recruitment 330
8.1.7. Research subjects registers 332
8.2. Legal qualification of the relationship 333
8.2.1. Contract between the investigator and the research subject 333
8.2.2. Contract between the sponsor and the research subject? 334
8.3. The informed consent process 335
8.3.1. Brief historical overview 336
8.3.2. Information provided 338
8.3.2.1. Research versus treatment 342
8.3.2.2. Risk disclosure 344
8.3.2.3. Benefit disclosure 346
8.3.2.4. Information about available alternatives 348
8.3.2.5. Information about conflicts of interest 349
8.3.2.6. Information about costs 351
8.3.2.7. Information about future research 352
8.3.2.8. Information about subjects' rights 353
8.3.3. Consent as a process 353
8.3.3.1. The main steps of the process 353
8.3.3.2. Right to think it over 355
8.3.3.3. Written consent forms 356
8.3.3.3.1. Purpose
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8.3.3.3.3. Frequent problems with consent forms 359
8.3.3.4. Testing comprehension 360
8.3.3.5. Patient advocates and witnesses 361
8.3.3.6. The role of the primary care physician 362
8.3.3.7. Right to ask questions 363
8.3.3.8. "Group consent" 364
8.3.3.9. Rights to refuse enrollment 366
8.3.3.10. Right to withdraw from the trial 367
8.3.3.11. Renewal of consent 369
8.4. Enrollment of incapable subjects 370
8.4.1. Two main categories 371
8.4.1.1. Article 55 LPTh: research on incompetent subjects 372
8.4.1.2. Article 56: emergency research 375
8.4.1.3. Classification difficulties 375
8.4.2. Special medical and ethical considerations 377
8.4.2.1. Special considerations in pediatric trials 377
8.4.2.2. Special considerations in emergency trials 381
8.4.3. Subsidiarity 383
8.4.4. Substitute to consent 384
8.4.4.1. Proxy consent for incompetent subjects 384
8.4.4.2. Proxy consent in emergency research 388
8.4.4.3. Consultation in emergency research 389
8.4.4.4. Assent 391
8.4.4.5. Signs of refusal 393
8.4.4.6. Recovered or newly acquired capacity 395
8.4.4.7. Advance consent 395
8.4.5. Level of benefits and risks 397
8.4.5.1. Defining direct and indirect benefits 397
8.4.5.2. The rule and the exception 398
8.4.5.3. How must benefits be assessed? 399
8.4.5.4. Level of risks 400
8.4.6. Additional requirements 402
8.4.6.1. Additional requirements under Article 55 LPTh? 402
8.4.6.2. Additional requirements for emergency trials 403
8.4.6.3. Public feedback in the United States 404
8.4.6.4. Community information in U.S. emergency research 404
8.4.7. Other exceptions to informed consent under U.S. law 406
8.5. Enrollment of "vulnerable" subjects 407
8.5.1. Prisoners 408
8.5.2. Women 410
8.5.2.1. Pregnant women 412
8.5.2.2. Research on ex utero embryos 415
8.5.2.3. Pregnancy registries 416
8.5.3. Terminally ill patients 417
8.5.4. Seniors 418
8.5.5. Indigent people 420
8.5.6. Foreigners 421
8.5.7. Minorities 422
8.5.8. Subjects in developing countries 423
8.6. Other rights of research subjects 425
8.6.1. Right to receive proper health care 425
8.6.2. Follow up 426
8.6.2.1. Debriefing 426
8.6.2.2. Right to follow up information and care 428
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8.6.2.3. Right to continued supply of the experimental product? 429
8.6.3. Confidentiality and privacy 432
8.6.3.1. Under the LPTh and the OClin 433
8.6.3.1.1. The LPTh and the OClin 433
8.6.3.1.2. ICH Guideline 433
8.6.3.1.3. Information to be provided 434
8.6.3.2. Article 321 and 321bi» CP 436
8.6.3.2.1. Applicability 436
8.6.3.2.2. Exception to Article 321bis 437
8.6.3.3. Under the law on data protection 438
8.6.3.3.1. Right to access the file 439
8.6.3.3.2. Right to restrict access 440
8.6.3.3.3. Right to correct mistakes 440
8.6.4. Payments to and by subjects 441
8.6.4.1. Payments to subjects 441
8.6.4.1.1. Admissibility 441
8.6.4.1.2. Review by ethics committees 442
8.6.4.1.3. Amounts offered 443
8.6.4.2. Payments by subjects 444
8.6.4.2.1. Payment for the experimental product 444
8.6.4.2.2. Payments for other health care costs 445
8.6.4.2.3. Insurance coverage 446
8.6.5. Liability and compensation for damages 448
8.6.5.1. General principles of liability under Swiss law 449
8.6.5.1.1. The investigator's liability 450
8.6.5.1.2. The sponsor's liability under general legal
principles 451
8.6.5.1.3. Other liable parties 452
8.6.5.2. The OClin system of liability and insurance coverage 452
8.6.5.2.1. Scope of liability under the OClin 454
8.6.5.2.2. Sponsor's insurance coverage 456
8.6.5.3. Review by ethics committees 458
8.6.5.4. Situation in the United States 459
8.6.6. Waivers 460
8.6.6.1. Waivers of rights 460
8.6.6.2. Biological material 460
8.6.6.2.1. The Moore case 461
8.6.6.2.2. Biological material ownership under Swiss
law 463
8.6.6.2.3. Gratuity in research 465
8.7. Obligations of research subjects? 466
8.7.1. Obligation to follow directions 466
8.7.2. Subjects' confidentiality obligations? 467
9. Supervision of clinical trials 468
9.1. Reporting obligations 468
9.1.1. Changes to the clinical trial 468
9.1.1.1. Objectives of notification 469
9.1.1.2. Essential changes 470
9.1.1.2.1. Scope of the changes 470
9.1.1.2.2. REC review 471
9.1.1.3. Minor changes 472
9.1.2. Reporting obligations for adverse events 473
9.1.2.1. Adverse events and adverse reactions 474
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9.1.2.1.2. Foreseeability 476
9.1.2.1.3. Severity 477
9.1.2.1.4. Form of the report 477
9.1.2.2. New facts threatening subjects' safety 478
9.1.2.3. Death of a subject 479
9.1.2.4. Deadly harm 480
9.1.2.5. Serious and unexpected adverse reactions 480
9.1.2.6. The complete file of adverse events 482
9.1.2.7. Reporting obligations of the sponsor to the investigator 483
9.1.2.8. Database of adverse reactions 484
9.1.2.9 Events that do not require reporting 484
9.2. Oversight by the authorities 485
9.2.1. Oversight by RECs 485
9.2.1.1. Extent of the post approval role of RECs under Swiss
law 485
9.2.1.2. IRBs'continuing review in the United States 486
9.2.1.3. Specific powers of RECs 487
9.2.2. Supervision by the drug agency 489
9.2.2.1. Trial suspensions 489
9.2.2.1.1. New information 489
9.2.2.1.2. Objective reasons 489
9.2.2.2. Remedial plans 492
9.2.2.3. Inspections in Switzerland 493
9.2.2.4. Disqualification of data 494
9.2.2.5. Inspections in the United States 495
9.2.2.6. Criminal inquiries 496
9.2.2.7. Appeals 496
9.2.3. Supervision of a clinical trial by the investigator's institution 497
9.2.4. Supervision of a clinical trial by the canton 497
9.2.5. Supervision by foreign agencies 498
9.2.6. Supervision by other entities 498
9.3. Frequent shortcomings of clinical trials 499
10. End of clinical trials 502
10.1. Common reasons for ending a clinical trial 502
10.1.1. Normal termination 502
10.1.2. Early termination 502
10.2. Notifying authorities 505
10.3. Preparing the study report 505
10.4. Publication and publicity 507
10.4.1. Publication by the investigator or the sponsor 507
10.4.1.1. Publishing both good and bad 507
10.4.1.2. Publishing without delays 511
10.4.1.3. Providing supporting documents 511
10.4.1.4. Not publishing unethical studies 512
10.4.1.5. The Consort Guidelines 513
10.4.2. Information available from drug agencies 514
10.4.2.1. In Switzerland 514
10.4.2.2. In the United States 515
10.4.2.2.1. Information while the trial is underway 515
10.4.2.2.2. Information when the drug is under review 516
10.4.2.2.3. Information once development effort is
abandoned 516
10.4.2.3. In the European Union 517
10.5. Record keeping 519
44
f'
Table of contents
11. Conclusion 521
Glossary 523
List of court cases cited 527
Short Bibliography 531
Index 533
Table of contents 535 |
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