Clinical Pharmacology: Current Topics and Case Studies

Cover......Page 1
Clinical Pharmacology:\rCurrent Topics\rand Case Studies......Page 3
ISBN 9783709101438......Page 4
Table of Contents......Page 6
LIST OF CONTRIBUTORS......Page 20
SECTION 1\rIntroduction......Page 27
CHAPTER 1 The discipline of Clinical Pharmacology......Page 29
References......Page 31
1 Historical success......Page 33
2 The dawn of a molecular era, the \"druggable genome\" and market fragmentation......Page 34
3 Innovation and stagnation......Page 36
5.2 Preclinical drug development......Page 38
5.3 Clinical drug development......Page 39
7 Confidence crisis and public opinion......Page 41
8 Conclusion......Page 42
References......Page 43
Further reading......Page 44
1 The drug regulators\' decision-making......Page 45
2 Authorizing a medicinal product in the EU......Page 46
2.1 The Centralized Authorization......Page 48
2.2 The Mutual Recognition Procedure (MRP) and the Decentralized Procedure (DCP) [8]......Page 49
3 Regulatory life-cycle management of medicinal products......Page 50
3.1 From efficacy to post-marketing relative effectiveness assessment......Page 51
3.2 Pharmacovigilance and signal detection......Page 52
3.3 Risk management plans (RMPs)......Page 53
3.4 When should a medicinal product be authorized?......Page 54
References......Page 56
1 Introduction......Page 59
2 Reimbursement principles in general......Page 60
3 Relative effectiveness - background......Page 61
4.2 Methods......Page 62
4.3 Results......Page 63
5 MEDEV - local payers vs. global payers......Page 64
6 The Pharmaceutical Forum......Page 65
7.1 Good principles......Page 67
7.2 Data for relative effectiveness assessment......Page 69
7.3 Networking......Page 70
8.2 USA - comparative effectiveness research......Page 71
9.3 Designing and performing the studies we need......Page 72
Acknowledgements......Page 73
References......Page 74
SECTION 2\rClinical Trials......Page 77
1 Development of world-wide standards in clinical research ethics......Page 79
2 Research Ethics Committees today - function and composition......Page 82
3.1 Increasing workload......Page 83
4 Compensation for committee members......Page 85
References......Page 87
2 Historic background......Page 89
2.3 The sulfanilamide disaster and the \"Food, Drug and Cosmetic Act\", 1938......Page 90
2.5 Nuremberg trial and Nuremberg Code......Page 91
3 Development of Good Clinical Practice Guidelines......Page 92
4.1 .1 European Commission - European Union (EU)......Page 93
4.2 ICH observers......Page 94
5 ICH TOPIC E6, Note of Guidance for Good Clinical Practice (CPMP/ICH/135/95) - the Principles of ICH GCP [1]......Page 95
6.2.1 Investigator\'s qualifications and agreements......Page 96
6.2.3 Medical care of trial subjects......Page 97
6.2.8 Informed consent of trial subjects......Page 98
6.2.9 Should study participants receive payment?......Page 99
6.2.11 Patient information......Page 100
6.2.12 The informed consent process......Page 101
6.2.14 Case record form (CRF)......Page 102
6.2.18 Serious adverse event......Page 103
6.2.20 Causality assessment......Page 104
6.3 Sponsor......Page 105
7.1 Is ICH-GCP just a \"bronze standard\"? [28]......Page 106
8 Summary......Page 107
2 Forms of research misconduct......Page 108
3 How common is research misconduct or fraud?......Page 109
4 Conclusion......Page 110
Acknowledgement......Page 111
References......Page 112
2 Definition phase I......Page 115
4 Preclinical development......Page 117
5 Choice of subjects, study population......Page 118
7 Route and rate of administration......Page 119
8 Clinical environment......Page 120
References......Page 124
Further reading......Page 125
2 Types of clinical trials......Page 127
2.2 Definition......Page 128
3.1 The basic idea, like most good things is very simple [2]......Page 129
3.4 Stratified randomization......Page 130
3.6 Allocation concealment......Page 131
4.1 Human behaviour is influenced by what we know or believe......Page 132
5.1 Parallel group design......Page 133
5.3 Factorial design......Page 134
7 Interim analyses......Page 135
References......Page 136
1 Introduction......Page 139
2.1 Study population......Page 141
2.2 Data sources......Page 142
2.2.1 Exposure......Page 143
2.3 Measurement issues......Page 144
2.4 Measures of association and impact......Page 145
2.5.1 Bias......Page 147
2.5.2 Confounding......Page 148
3 Overview of study design types......Page 149
3.1 Descriptive studies......Page 150
3.2 Analytical study designs......Page 151
3.2.2 Cohort study - principles and practical example......Page 152
3.2.3 Case-control study - principles and a practical example......Page 155
3.2.3.1 The cases......Page 156
3.2.3.2 The controls and the source population......Page 157
3.2.3.4 Handling potential confounders......Page 158
3.2.3.5 Analysis and results......Page 159
3.2.4 Case-crossover studies......Page 160
3.3 Meta-analysis of observational studies......Page 161
References......Page 163
Further reading......Page 167
CHAPTER 10 Pharmacokinetics I: PK-PD approaches - antibiotic drug development......Page 169
1 PK-PD approach......Page 170
2 Microdialysis for measuring free drug concentrations......Page 173
3 MD calibration methods......Page 174
5 Microdialysis and PK-PD......Page 176
6 Kill curves......Page 177
7 Experimental settings of in vitro models......Page 178
References......Page 180
1 Origins of 14C-labelled tracers......Page 183
3 Accelerator Mass Spectrometry......Page 185
3.1 The emergence of microdosing......Page 186
3.2 Application of microdosing......Page 187
4 Pharmacokinetic linearity......Page 188
5 Microdosing and metabolism......Page 190
References......Page 191
2 Measures of the disease frequency......Page 193
2.1 Prevalence......Page 194
2.2 Incidence......Page 195
3 Relationship between prevalence, incidence and mortality......Page 196
4 Survival analysis......Page 197
5 Censured data......Page 198
8 Epidemiologic study designs......Page 199
9.2 Variables......Page 200
10.1 Hypothesis testing and the p value......Page 201
10.2 Post hoc analysis or \"fishing for results\"......Page 202
10.4 Correlation analysis......Page 203
10.5.3 Dose-response relationship......Page 204
10.5.7 Specificity......Page 205
References......Page 206
CHAPTER 13 Placebo effects and placebo control in clinical trials......Page 207
1 The recent debate about research ethics in placebo controlled trials (peTs)......Page 208
2 Placebo VS. active control......Page 209
4 Placebo controlled trial: ethical or not?......Page 210
5 Criteria for justification of placebo......Page 212
References......Page 215
SECTION 3\rTools in Clinical Pharmacology......Page 217
1 Introduction......Page 219
2 Positron emission tomography (PET)......Page 221
4 Optical imaging......Page 224
5 Magnetic resonance imaging (MRI)......Page 225
7 Ultrasound imaging......Page 226
References......Page 227
CHAPTER 15 Current concepts of pharmacogenetics, pharmacogenomics, and the \"druggable\" genome......Page 231
1 Genetic variation in the human genome: biological basis of pharmacogenetics......Page 232
2 The promise of pharmacogenetics, pharmacogenomics, and genomic medicine......Page 233
3 Genetic variants affecting pharmacokinetics......Page 236
4 Pharmacogenetic testing for optimizing drug dose......Page 237
5 Pharmacogenetic testing to prevent adverse drug reactions......Page 238
6 Genetics of pharmacodynamics......Page 240
7 The predictive power of pharmacogenomics......Page 241
8 The \"druggable\" genome......Page 243
9 Challenges that lie ahead......Page 244
References......Page 246
1 Introduction......Page 251
2 Why do molecular targeting drugs fail in current clinical drug development?......Page 253
3 Biomarker in clinical drug development......Page 255
4 How biomarkers may improve clinical drug development......Page 257
5 Biomarker as surrogate endpoints......Page 260
6 Outlook......Page 262
References1.......Page 264
1 Introduction......Page 267
2 Molecular tools for drug target identification......Page 268
2.1 At the nucleotide level......Page 269
2.2 At the protein level......Page 273
3 Molecular tools for target validation......Page 275
3.1 Target (over)expression......Page 276
3.2 Target downregulation......Page 277
3.3 Conditional target regulation......Page 280
4 Molecular tools for monitoring pharmacodynamics in translational studies......Page 281
References......Page 286
SECTION 4\rTopics in Clinical Pharmacology......Page 287
1 Introduction......Page 289
2 Thalidomide - a disaster as starting point for the methodical assessment of drug safety......Page 291
3 During drug development only frequent ADRs can be detected......Page 292
4 ADR reporting and worldwide pharmacovigilance......Page 293
5 Spontaneous reporting systems......Page 294
7 Recent and future developments in pharmacovigilance......Page 298
8 Conclusions......Page 300
References......Page 303
3 Categories of interaction......Page 307
4 Factors promoting interactions and their clinical relevance......Page 308
5.1 ADME - interactions based on drug absorption......Page 310
6 ADME - interactions based on drug distribution......Page 312
6.1 ADME - interactions based on drug metabolism......Page 318
6.2 Examples for clinically relevant interactions based on CYP3A4......Page 321
7 Management of potential drug interactions......Page 323
References......Page 330
1 Introduction......Page 335
2 A need for alternatives to traditional chemicals......Page 336
3 Specifics of the development process of biologicals......Page 337
4 Protein therapeutics (PTs)......Page 340
5 Vaccines (group III PTs)......Page 342
6 Antisense approaches and aptamers......Page 343
Acknowledgement......Page 345
References......Page 346
1 Introduction......Page 349
3.1 Patient integration......Page 351
3.2 Characterization......Page 352
5.1 Vector manufacture......Page 353
6 Combined ATMPs......Page 354
7 Involvement of CAT in ATMP development......Page 355
References......Page 359
1 The current concept......Page 361
2 A history of dose individualization......Page 362
3 Pharmacogenetics and biomarkers......Page 364
4 The unmet need - improving the benefit-risk ration and effectiveness of drugs......Page 365
5 Improving the benefit/risk profile by biomarker tests......Page 366
References......Page 369
1 Generics......Page 371
1.1 Regulatory background......Page 372
1.2 Patent protection, data protection and marketing protection for new products......Page 373
1.3 Salts, esters......Page 374
1.4 Bioequivalence......Page 375
1.5.1 Narrow therapeutic index drugs (NTIDs)......Page 378
1.5.4 tmax......Page 379
1.5.7 Bioequivalence of intravenous products? complex parenterals......Page 380
2.1 Complexity......Page 382
2.2 Biosimilars: General issues......Page 383
3.1 Sophisticated nonsense?......Page 384
3.2 Rationale for the development of chi rally pure drugs......Page 385
3.3 Pharmacodynamic and kinetic differences between enantiomers......Page 386
3.4 Recent regulatory experience of the Chiral Switch: a word of caution......Page 387
4.1 Background......Page 388
4.2 What are \"me-too\" drugs?......Page 389
4.4 Is First-in-class also best-in-class?......Page 390
4.5 Are incentives for drugs that are \"first in class\" or hurdles for \"me-too\" drugs called for?......Page 391
4.7 Is there a \"class effect\"?......Page 392
References......Page 393
2 What are orphan drugs?......Page 395
4 The Committee on Orphan Medicinal Products (COMP)......Page 396
6 What are the criteria for orphan designation?......Page 397
8 What data are necessary at the time of Orphan Drug designation?......Page 399
8.2 Negative opinions......Page 400
8.3.1 Subsetting/valid condition......Page 401
8.3.2 Significant benefit......Page 402
9 Confirmation of orphan status at the time of marketing authorization......Page 403
10 Challenging marketing exclusivity for orphan medicinal products......Page 404
11.1 Designated orphan medicines......Page 405
11.2 Marketing authorizations for orphan medicines......Page 406
12 Discussion......Page 407
References......Page 411
1 Expanding scope of gender and sex differences......Page 413
3.1 Physiologic variability......Page 414
3.3 Pharmacodynamic - sex differences......Page 415
3.5 Adverse drug reactions......Page 416
3.6.1 History......Page 417
5 Pregnancy......Page 418
6 From sex differences to individual differences: where the science is taking us......Page 419
References......Page 425
1 Children as therapeutic orphans......Page 429
2.1 Ethical and legal aspects......Page 430
2.4 Lack of research infrastructures and paediatric research networks......Page 431
3.1 Paediatric initiatives in the USA......Page 432
3.2.1 Requirements and rewards......Page 433
3.2.3 Paediatri c Committee......Page 434
4.1 Paediatric indications......Page 435
4.3 luvenile animal studies......Page 436
4.4 Clinical Pharmacology studies in children......Page 437
4.5 Clinical efficacy and safety studies......Page 438
References......Page 442
Further reading......Page 444
ABOUT THE AUTHORS......Page 445
KEYWORD INDEX......Page 453