International pharmaceutical product registration: aspects of quality, safety and efficacy
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1994
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| Schriftenreihe: | Ellis Horwood series in pharmaceutical technology
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INTERNATIONAL
PHARMACEUTICAL PRODUCT REGISTRATION
ASPECTS OF QUALITY, SAFETY AND EFFICACY
EDITORS ANTHONY C. CARTWRIGHT MEDICINES CONTROL AGENCY, DEPARTMENT OF
HEALTH, LONDON
AND BRIAN R. MATTHEWS ALCON LABORATORIES LTD., CROYDON, SURREY
ELLIS HORWOOD NEW YORK LONDON TORONTO SYDNEY TOKYO SINGAPORE
IMAGE 2
CONTENTS
PREFACE AND ACKNOWLEDGEMENTS XXX
LIST OF CONTRIBUTORS XXXVIII
PART I CHEMISTRY, PHARMACY AND MANUFACTURING
1 PHARMACEUTICAL DEVELOPMENT 3
M. J. MORRIS
1.1 INTRODUCTION 3
1.2 SCIENTIFIC PRINCIPLES 4
1.2.1 PREFORMULATION STUDIES 4
1.2.1.1 SOLUBILITY 4
1.2.1.2 PH AND PK A 5
1.2.1.3 PARTICLE SIZE 5
1.2.1.4 POLYMORPHISM AND CRYSTAL PROPERTIES 6
1.2.1.5 MOISTURE CONTENT 7
1.2.2 LIQUID DOSE FORMS 7
1.2.3 SEMI-SOLID DOSE FORMS 9
1.2.4 SOLID DOSE FORMS 10
1.2.5 CONTROLLED RELEASE PREPARATIONS 12
1.2.5.1 SOLID DOSE ORAL PREPARATIONS 13
1.2.5.2 LIQUID PREPARATIONS 14
1.2.6 OTHER DOSE FORMS 15
1.2.6.1 INJECTIONS AND IMPLANTS 15
1.2.6.2 OCULAR PREPARATIONS 16
1.2.6.3 INHALATION THERAPY 17
1.2.6.4 TRANSDERMAL SYSTEMS 18
1.3 REGULATORY REQUIREMENTS 19
1.3.1 EUROPEAN COMMUNITY REQUIREMENTS 19
1.3.2 UNITED STATES REQUIREMENTS 23
IMAGE 3
VI CONTENTS
1.3.3 JAPANESE REQUIREMENTS 25
1.3.4 REQUIREMENTS IN OTHER TERRITORIES 26
1.4 NEW DEVELOPMENTS AND CONCLUSIONS 26
1.5 REFERENCES 29
2 PACKAGING MATERIALS 32
D. A. DEAN
2.1 INTRODUCTION 32
2.2 PACKAGING MATERIALS AND THEIR PROPERTIES 36
2.2.1 INTRODUCTION 36
2.2.2 GLASS IN PACKAGING 36
2.2.3 METALS IN PACKAGING 37
2.2.4 PLASTICS IN PACKAGING 38
2.2.5 ELASTOMERIC MATERIALS (MAINLY USED FOR CLOSURES) 39
2.2.6 OTHER CONTACT MATERIALS 40
2.2.7 SUMMARY OF PACKAGING MATERIALS FOR PRIMARY PACKS . . .. 40
2.3 REGULATORY GUIDELINES 41
2.4 THE ENVIRONMENTAL CONCERNS 43
2.5 CHECKING OUT INFORMATION 44
2.6 PACKAGING MATERIAL - EVALUATION AND TESTING WITH THE PRODUCT . .. 48
2.7 PACKAGING MATERIAL - EVALUATION AND TESTING (INDEPENDENT OF PRODUCT)
52
2.7.1 TESTS AND EVALUATIONS APPLICABLE TO ANY MATERIAL 52
2.7.2 TESTS FOR SPECIFIC MATERIALS 54
2.7.3 BIOLOGICAL TESTS 55
2.7.4 TESTS FOR ELASTOMERS 55
2.7.5 MICROBIOLOGICAL TESTS 55
2.8 THE EVALUATION OF THE ROLE OF THE PACK IN THE ADMINISTRATION OF THE
PRODUCT 56
2.9 THE EVALUATION OF CLOSURES AND CLOSURE SYSTEMS 58
2.10 CONCLUSIONS 59
2.11 APPENDICES A2.1-A2.7 61
2.12 REFERENCES 75
3 MANUFACTURING 79
I. K. SYKES
3.1 INTRODUCTION 79
3.2 EC REQUIREMENTS FOR MANUFACTURING INFORMATION ON DRUG PRODUCTS . .
81 3.2.1 MANUFACTURING FORMULA 81
3.2.1.1 STARTING MATERIALS 81
3.2.1.2 BATCH SIZE 82
3.2.1.3 BATCH HOMOGENEITY 82
3.2.1.4 CONTINUOUS MANUFACTURE 82
3.2.2 THE MANUFACTURING PROCESS 83
IMAGE 4
CONTENTS VII
3.2.2.1 PRODUCTION FLOW CHART 83
3.2.2.2 PROCESS DESCRIPTION 83
3.2.2.3 IN-PROCESS CONTROLS 84
3.2.2.4 REWORKING 84
3.2.2.5 STERILISATION PROCESSES 87
3.2.2.6 PHARMACEUTICAL ASSEMBLY 90
3.2.3 VALIDATION OF THE MANUFACTURING PROCESS 90
3.2.3.1 TYPES OF PROCESS VALIDATION 91
3.2.4 VALIDATION OF THE MANUFACTURING EQUIPMENT 93
3.2.4.1 INSTALLATION QUALIFICATION (IQ) 93
3.2.4.2 OPERATIONAL QUALIFICATION (OQ) 93
3.2.4.3 PERFORMANCE QUALIFICATION (PQ) 93
3.2.5 VALIDATION OF PROCEDURES 94
3.2.6 DOCUMENTATION OF VALIDATION 94
3.2.6.1 VALIDATION PROTOCOL 94
3.2.6.2 VALIDATION REPORT 95
3.2.6.3 PROCESS VALIDATION DOCUMENTATION 95
3.2.7 ROLE OF THE PHARMACEUTICAL EXPERT 97
3.2.7.1 METHOD OF MANUFACTURE 97
3.2.7.2 PROCESS VALIDATION 97
3.2.7.3 SITE OF MANUFACTURE 98
3.2.8 INSPECTION 98
3.3 FDA REQUIREMENTS FOR MANUFACTURING INFORMATION ON DRUG PRODUCTS . 99
3.3.1 FORMAT AND CONTENT OF CHEMISTRY, MANUFACTURING AND CONTROL SECTION
OF AN NDA 100
3.3.1.1 DRUG SUBSTANCE 100
3.3.1.2 DRUG PRODUCT 100
3.3.1.3 ENVIRONMENTAL ASSESSMENT 102
3.3.2 SUMMARY TO AN NDA 103
3.3.3 INSPECTIONS 104
3.3.4 POST-LICENSING DATA 106
3.4 BIOLOGICAL AND BIOTECHNOLOGY-DERIVED PRODUCTS IN THE EC 107
3.4.1 SITE OF MANUFACTURE 109
3.4.2 MANUFACTURING PROCESS 109
3.4.2.1 PROCESS FLOW CHART 109
3.4.2.2 STARTING MATERIALS 109
3.4.2.3 SEED LOT SYSTEM IK)
3.4.2.4 PRE-CULTURE 110
3.4.2.5 FERMENTATION I LL
3.4.2.6 HARVEST 113
3.4.2.7 PURIFICATION 113
3.4.2.8 PRIMARY PHARMACEUTICAL OPERATIONS 116
3.4.2.9 ASEPTIC FILLING 117
3.4.2.10 LYOPHILISATION 117
3.4.2.11 PACKAGING AND LABELLING 118
IMAGE 5
VIII CONTENTS
3.4.2.12 FINISHED PRODUCT STORAGE 118
3.5 THE FDA PERSPECTIVE ON BIOLOGICAL AND BIOTECHNOLOGY-DERIVED PRODUCTS
118
3.5.1 THE ESTABLISHMENT LICENCE APPLICATION 118
3.5.2 THE PRODUCT LICENCE APPLICATION 124
3.5.3 INSPECTION 125
3.6 REFERENCES 126
4 ACTIVE INGREDIENTS 129
B. R. MATTHEWS
4.1 INTRODUCTION: PURPOSE OF THIS CHAPTER 129
4.2 BACKGROUND 130
4.2.1 WHAT IS CONTROLLED UNDER THE PHARMACEUTICAL REGULATIONS? . . 130
4.2.2 HOW MUCH INFORMATION IS NEEDED? 131
4.3 DATA REQUIREMENTS: NEW DRUGS 133
4.3.1 APPROPRIATE, AVAILABLE AND ACCEPTABLE PHARMACOPOEIAL
SPECIFICATIONS 133
4.3.2 SUITABILITY OF AVAILABLE DATA FOR SUBMISSION 133
4.3.3 SUBMISSION OF ALL RELEVANT DATA 134
4.3.4 ANALYTICAL VALIDATION 134
4.3.5 ANALYTICAL METHOD DESCRIPTION 135
4.3.6 REFERENCE MATERIALS: SAMPLES 135
4.3.7 NOMENCLATURE OF ACTIVE INGREDIENTS 135
4.3.8 INCLUSION OF DATA: IN THE SUBMISSION OR IN A DRUG MASTER FILE? 136
4.4 DATA TO BE SUBMITTED 137
4.4.1 DESCRIPTION 137
4.4.2 PHYSICAL AND CHEMICAL CHARACTERISTICS 137
4.4.3 NOMENCLATURE 137
4.4.4 MANUFACTURER 137
4.4.5 MANUFACTURING OR SYNTHETIC PROCESS, PURIFICATION, AND IN- PROCESS
CONTROLS 137
4.4.5.1 SYNTHESIS 137
4.4.5.2 PURIFICATION AND FINAL DRYING 139
4.4.5.3 OTHER STAGES 139
4.4.5.4 IN-PROCESS AND INTERMEDIATE CONTROLS 140
4.4.5.5 PROCESS VALIDATION DATA 140
4.4.6 DEVELOPMENT CHEMISTRY AND PROOF OF STRUCTURE 141
4.4.7 SPECIFICATION FOR THE ACTIVE INGREDIENT 141
4.4.8 ANALYTICAL METHODS 143
4.4.9 ANALYTICAL VALIDATION 143
4.4.10 STABILITY DATA 143
4.4.11 REFERENCE MATERIALS (REFERENCE STANDARDS) 145
4.5 REFERENCES 145
IMAGE 6
CONTENTS IX
4.5.1 UNITED STATES 145
4.5.2 JAPAN 146
4.5.3 EUROPEAN COMMUNITY 146
4.5.4 ICH PROPOSALS 147
5 EXCIPIENTS 148
P. K. WOTTON, G. WADE AND R. C. MORETON
5.1 INTRODUCTION 148
5.2 DEFINITION AND ROLE OF EXCIPIENTS 148
5.2.1 DEFINITIONS 148
5.2.2 EXCIPIENTS IN RELATION TO EFFICACY 149
5.2.3 SAFETY OF EXCIPIENTS 150
5.3 REGULATORY AND RELATED TEXTS 151
5.3.1 INTERNATIONAL ASPECTS OF EXCIPIENT APPROVAL 152
5.3.1.1 UNITED STATES 152
5.3.1.2 EUROPE 152
5.3.1.3 NEW EXCIPIENTS 154
5.3.1.4 ESTABLISHED (NON-PHARMACOPOEIAL) EXCIPIENTS . .. 155 5.3.2 THE
ISO 9000-SERIES OF QUALITY SYSTEMS STANDARDS 155
5.3.3 INTERNATIONAL ASPECTS: HARMONISATION 156
5.4 EXCIPIENT PERFORMANCE 158
5.4.1 INTRODUCTION 158
5.4.2 PHARMACOPOEIAL TESTS 159
5.4.3 EXTRA-PHARMACOPOEIAL TESTING 159
5.4.4 PERFORMANCE SPECIFICATIONS 160
5.4.5 EQUIVALENCE OF EXCIPIENT LOTS FROM TWO OR MORE SUPPLIERS . . 161
5.4.5.1 QUALITY 162
5.4.5.2 PERFORMANCE 162
5.4.5.3 DISSOLUTION/BIOAVAILABILITY 163
5.4.5.4 STABILITY REQUIREMENTS 163
5.4.5.5 REGULATORY CONSIDERATIONS 163
5.4.5.6 COSTS 163
5.4.6 EXAMPLES 163
5.4.6.1 SODIUM STARCH GLYCOLLATE 164
5.4.6.2 CETOSTEARYL ALCOHOL 164
5.4.6.3 LACTOSE 164
5.4.6.4 MAGNESIUM STEARATE 165
5.4.6.5 HYDROXYPROPYL METHYLCELLULOSE (HYPROMELLOSE) . . 165 5.5 WHAT
REALLY CONCERNS THE REGULATORY AUTHORITIES? 166
5.5.1 ESTABLISHED, TRADITIONAL OR NON-CRITICAL EXCIPIENTS 167 5.5.2
TRADITIONAL, CRITICAL EXCIPIENTS 167
5.5.3 NEW EXCIPIENTS 168
5.5.4 NEW, CRITICAL EXCIPIENTS 168
5.6 REFERENCES 169
IMAGE 7
X CONTENTS
6 CONTROL TESTS ON THE FINISHED PRODUCT 172
A. ARTIGES, M.-H. LOULERGUE AND J.-P. REYNIER
6.1 INTRODUCTION 172
6.2 EUROPEAN REQUIREMENTS 174
6.2.1 HARMONISATION OF NATIONAL REGULATIONS 174
6.2.2 REQUIREMENTS CONCERNING CONTROL TESTS ON THE FINISHED PRODUCT 175
6.2.3 HOW TO CONSTITUTE THE DOSSIER 176
6.2.3.1 ADMINISTRATIVE ENVIRONMENT AND REGULATIONS . . . 176 6.2.3.2
SCIENTIFIC RESEARCH AND DEVELOPMENT QUALITY . . . 179 6.2.3.3 THE
TRANSITION TO PRODUCTION AND CONFORMITY QUALITY 188
6.3 JAPANESE AND UNITED STATES (FDA) REQUIREMENTS 191
6.3.1 SPECIFIC JAPANESE REQUIREMENTS 192
6.3.1.1 ADMINISTRATIVE ORGANISATION AND GENERAL CONSIDERATIONS 192
6.3.1.2 PRESENTATION OF THE DATA 192
6.3.1.3 RELATIONSHIP WITH THE JAPANESE PHARMACOPOEIA (JP) 194
6.3.1.4 RELATIONSHIP WITH GMP 195
6.3.1.5 DOCUMENT SUMMARY ( GAIYO ) 195
6.3.2 UNITED STATES REQUIREMENTS - FOOD AND DRUG ADMINISTRATION (FDA)
196
6.3.2.1 ADMINISTRATIVE ORGANISATION AND GENERAL CONSIDERATIONS 196
6.3.2.2 PRESENTATION OF THE DATA 196
6.3.2.3 DRUG MASTER FILES (DMFS) 199
6.3.2.4 RELATIONSHIP WITH THE USP 199
6.3.2.5 VERIFICATION BY THE FDA OF THE METHODS FOR CONTROL TESTING OF
THE FINISHED PRODUCT 199
6.4 CONCLUSIONS 201
6.5 REFERENCES 201
6.5.1 EUROPEAN REFERENCES 201
6.5.2 JAPANESE REFERENCES 202
6.5.3 UNITED STATES REFERENCES 203
APPENDIX A6.1 203
EUROPEAN PHARMACOPOEIA: DOSAGE FORMS AND TECHNOLOGICAL TESTS 203
DOSAGE FORMS (GENERAL MONOGRAPHS) 203
DOSAGE FORM MONOGRAPHS UNDER ELABORATION 204
TECHNOLOGICAL TEXTS 204
TECHNOLOGICAL TEXTS UNDER ELABORATION 204
APPENDIX A6.2 204
JAPANESE PHARMACOPOEIA: DOSAGE FORM GENERAL MONOGRAPHS . . . 204
IMAGE 8
CONTENTS XI
7 STABILITY DATA 206
A. C. CARTWRIGHT
7.1 INTRODUCTION 206
7.1.1 THE PURPOSE OF STABILITY TESTING OF MEDICINAL PRODUCTS IN THEIR
FINAL PACKAGING 206
7.1.2 THE PURPOSE OF STABILITY TESTING OF ACTIVE SUBSTANCES . . .. 207
7.1.3 THE DEVELOPMENT OF STABILITY TESTING REQUIREMENTS 207
7.2 SCIENTIFIC AND TECHNICAL BACKGROUND TO THE DESIGN OF STABILITY
STUDIES . 209 7.2.1 FACTORS INFLUENCING THE DESIGN OF STABILITY STUDIES
209
7.2.2 STABILITY TESTING OF PRODUCTS FOR DISTRIBUTION IN THE TROPICS . .
209 7.2.3 CLASSIFICATION OF CLIMATIC ZONES AND CHOICE OF TESTING
CONDITIONS 209
7.2.4 KINETICS OF CHEMICAL DEGRADATION REACTIONS IN PHARMACEUTICAL
PRODUCTS 212
7.2.5 CHEMICAL STABILITY OF SOLIDS 213
7.2.6 TOXICITY OF CHEMICAL DEGRADATION PRODUCTS 213
7.2.7 PHYSICAL STABILITY 214
7.2.8 INFLUENCE OF PACKAGING ON PRODUCT STABILITY 215
7.2.9 REDUCED TESTING DESIGNS FOR STABILITY STUDIES 216
7.2.9.1 BRACKETING 216
7.2.9.2 MATRIXING (FRACTIONAL FACTORIAL DESIGN) 217
7.2.10 STAGES OF DEVELOPMENT AND MARKETING OF PRODUCTS AND THE NEED FOR
STABILITY TESTING 217
7.3 REGULATORY REQUIREMENTS FOR STABILITY TESTING IN THE UNITED STATES,
EUROPEAN COMMUNITY AND JAPAN 218
7.3.1 TESTING OF NEW ACTIVE SUBSTANCES (NASS) AND OTHER PRODUCTS -
CURRENT GUIDELINES 218
7.3.1.1 ACCOMPANYING DATA NEEDED WHEN STABILITY DATA ARE SUBMITTED 219
7.3.2 TESTING OF BULK ACTIVE DRUG SUBSTANCES 220
7.3.2.1 NEW ACTIVE SUBSTANCES (NASS - SUBSTANCES NOT PREVIOUSLY
AUTHORISED) 220
7.3.2.2 STABILITY TESTING OF EXISTING (APPROVED) ACTIVE SUBSTANCES 222
7.3.3 TESTING OF DOSAGE FORMS IN THEIR FINAL PACKAGING 222
7.3.3.1 NAS PRODUCTS 222
7.3.3.2 EXISTING ACTIVE SUBSTANCE PRODUCTS (ABRIDGED/ ABBREVIATED
PRODUCTS) 226
7.3.4 SUBMISSION OF ADDITIONAL DATA DURING THE APPROVAL PROCESS . . 227
7.3.5 STABILITY STUDIES ON REVISED PRODUCTS 22K
7.3.6 ROUTINE FOLLOW-UP TESTING OF PRODUCTION BATCHES OF FINISHED
PRODUCT IN ITS FINAL PACKAGING, AND GMP TESTING 229
7.3.7 EXTENSION OF SHELF LIFE AFTER AUTHORISATION OF THE PRODUCT . . .
230
IMAGE 9
XII CONTENTS
7.4 INTERNATIONAL HARMONISATION 230
7.4.1 NEW ACTIVE DRUG SUBSTANCE TESTING 232
7.4.1.1 STRESS TESTING OF THE DRUG SUBSTANCE 232
7.4.1.2 SYSTEMATIC TESTING OF THE DRUG SUBSTANCE TO ESTIMATE THE RE-TEST
PERIOD AND RECOMMENDED STORAGE CONDITIONS 232
7.4.2 NEW ACTIVE SUBSTANCE PRODUCT TESTING 234
7.4.3 OTHER CATEGORIES OF PRODUCTS 237
7.4.3.1 NEW DOSAGE FORMS 237
7.4.3.2 GENERIC PRODUCTS 238
7.4.3.3 BIOLOGICAL AND BIOTECHNOLOGICAL PRODUCTS 239
7.4.4 LIGHT STABILITY TESTING OF PRODUCTS 239
7.5 CONCLUSIONS 242
7.6 REFERENCES 242
8 ANALYTICAL VALIDATION 246
G. P. R. CARR AND J. C. WAHLICH (SECTION 8.1) R. J. N. TANNER (SECTION
8.2) 8.1 PRODUCT AND ACTIVE INGREDIENT RELATED VALIDATION 246
8.1.1 INTRODUCTION 246
8.1.2 REQUIREMENTS OF REGULATORY AUTHORITIES 247
8.1.2.1 UNITED KINGDOM AUTHORITY (MEDICINES CONTROL AGENCY) 247
8.1.2.2 UNITED STATES AUTHORITY (FOOD AND DRUG ADMINISTRATION) 247
8.1.2.3 EUROPEAN COMMUNITY (EC) 247
8.1.2.4 UNITED STATES PHARMACOPEIA 250
8.1.2.5 JAPANESE AUTHORITY (MINISTRY OF HEALTH AND WELFARE, MHW) 251
8.1.2.6 CANADIAN AUTHORITY (HEALTH PROTECTION BRANCH, HPB) 251
8.1.2.7 AUSTRALIAN AUTHORITY (THERAPEUTIC GOODS AUTHORITY, TGA) 252
8.1.2.8 INTERNATIONAL CONFERENCE ON HARMONISATION (ICH) . 252 8.1.2.9
CONCLUSIONS 252
8.1.3 PARAMETERS TO BE VALIDATED FOR DIFFERENT TEST METHODS . . .. 253
8.1.3.1 VALIDATION PARAMETERS 253
8.1.3.2 SELECTION OF PARAMETERS FOR DIFFERENT ANALYTICAL METHODS 253
8.1.4 DETERMINATIONS OF VALIDATION PARAMETERS 254
8.1.4.1 INTRODUCTION 254
8.1.4.2 ACCURACY 255
8.1.4.2.1 DEFINITION OF ACCURACY 255
8.1.4.2.2 DETERMINATION OF ACCURACY 255
8.1.4.3 PRECISION 259
IMAGE 10
CONTENTS XIII
8.1.4.3.1 DEFINITION OF PRECISION 259
8.1.4.3.2 DETERMINATION OF PRECISION 259
8.1.4.4 LINEARITY 261
8.1.4.4.1 DEFINITION OF LINEARITY 261
8.1.4.4.2 DETERMINATION OF LINEARITY 261
8.1.4.5 LIMIT OF DETECTION (LOD) AND LIMIT OF QUANTITATION (LOQ) 264
8.1.4.5.1 DEFINITIONS OF LOD AND LOQ 264
8.1.4.5.2 DETERMINATIONS OF LOD AND LOQ . . . 264 8.1.4.6 SELECTIVITY
AND SPECIFICITY 266
8.1.4.6.1 DEFINITION OF TERMS 266
8.1.4.6.2 DETERMINATION OF SELECTIVITY 267
8.1.4.6 3 DETERMINATION OF SPECIFICITY 270
8.1.4.7 ANALYTE AND SYSTEM STABILITY AND OTHER PHENOMENA 270 8.1.4.7.1
REQUIREMENTS 270
8.1.4.7.2 POTENTIAL CAUSES OF INSTABILITY AND OTHER ANALYTE INFLUENCES
271
8.1.4.7.3 DETERMINATION AND CONTROL 271
8.1.4.8 ROBUSTNESS 272
8.1.4.8.1 DEFINITION 272
8.1.4.8.2 DETERMINATION OF ROBUSTNESS 273
8.1.5 REVALIDATION 276
8.1.6 SYSTEM SUITABILITY TESTS (SSTS) 277
8.1.6.1 DEFINITION 277
8.1.6.2 TRADITIONAL APPROACHES TO SSTS 279
8.1.6.3 INDIVIDUAL SSTS 279
8.1.6.3.1 ROBUSTNESS 279
8.1.6.3.2 ACCURACY 279
8.1.6.3.3 PRECISION 280
8.1.6.3.4 SELECTIVITY 281
8.1.6.3.5 ANALYTE AND SYSTEM STABILITY 281
8.1.6.3.6 LINEARITY 281
8.1.6.3.7 LIMIT OF QUANTITATION AND DETECTION 282
8.1.6.3.8 TAILING FACTOR 282
8.1.6.3.9 COLUMN EFFICIENCY 282
8.1.6.3.10 RETENTION TIME 283
8.1.7 CONCLUSIONS 283
8.1.8 REFERENCES 283
12 PHARMACOKINETIC AND TOXICOKINETIC METHODS VALIDATION 286 8.2.1
INTRODUCTION 286
8.2.1.1 THE THREE PHASES OF THE DEVELOPMENT AND APPLICATION OF AN ASSAY
286
8.2.1.2 DEFINITION OF THE TERMS: STANDARD AND SAMPLE . . . 287
IMAGE 11
XIV CONTENTS
8.2.1.3 REGULATORY REQUIREMENTS 287
8.2.2 ASSAY DEVELOPMENT 287
8.2.2.1 A STRUCTURED APPROACH TO ASSAY VALIDATION . . .. 287
8.2.2.2 SELECTION OF A SUITABLE MATRIX 287
8.2.2.3 EXTERNAL AND INTERNAL STANDARDS 287
8.2.3 ASSAY VALIDATION 288
8.2.3.1 DOCUMENTATION OF AN ASSAY PROCEDURE 288
8.2.3.2 CALIBRATION STANDARDS 288
8.2.3.3 LIMIT OF QUANTIFICATION 290
8.2.3.4 ACCURACY AND PRECISION 291
8.2.3.5 LINEARITY 292
8.2.3.6 SELECTIVITY 292
8.2.3.7 STABILITY 294
8.2.3.8 RECOVERY 295
8.2.3.9 ASSAY REPRODUCIBILITY 296
8.2.3.10 ADDITIONAL VALIDATION FOR SAMPLES IN DIFFERENT MATRICES, OR
FROM DIFFERENT SPECIES 296
8.2.3.11 LIMITED RE-VALIDATION FOR NEW STAFF AND OF LAPSED ASSAYS 297
8.2.3.12 BATCH SIZE 297
8.2.3.13 ADDITIONAL VALIDATION ISSUES FOR IMMUNOASSAYS . . 297 8.2.3.14
THE VALIDATION REPORT 299
8.2.4 STUDY MONITORING 300
8.2.4.1 INTRODUCTION 300
8.2.4.2 CALIBRATION STANDARDS 300
8.2.4.3 QUALITY CONTROL SAMPLES 301
8.2.4.4 RE-ANALYSIS OF STUDY SAMPLES 302
8.2.4.5 THE BIOANALYTICAL APPENDIX 303
8.2.5 CONCLUSIONS 303
8.2.6 ACKNOWLEDGEMENTS 304
8.2.7 REFERENCES 304
9 BIOPHARMACEUTICS 307
I. J. MCGILVERAY
9.1 INTRODUCTION 307
9.2 BIOPHARMACEUTICS INFORMATION TO BE DOCUMENTED 310
9.2.1 FACTORS AFFECTING DISSOLUTION AND/OR DRUG ABSORPTION . . .. 310
9.2.1.1 PHYSICOCHEMICAL CHARACTERISTICS OF THE ACTIVE DRUG SUBSTANCE 311
9.2.1.2 FACTORS RELATED TO FORMULATION 314
9.2.1.3 DOSAGE (GALENICAL) FORM 316
9.2.1.4 MANUFACTURING PROCESS 319
9.2.1.5 STABILITY AND STORAGE (STABILITY OF ACTIVE SUBSTANCE AND DOSAGE
FORM) 320
IMAGE 12
CONTENTS XV
9.2.1.6 DISSOLUTION TESTS AND PROCEDURES 320
9.2.1.7 REGULATORY CONCLUSIONS ON PHYSICOCHEMICAL FACTORS 321
9.2.2 DISSOLUTION STANDARDS 324
9.2.3 PHYSIOLOGICAL FACTORS AFFECTING BIOAVAILABILITY 327
9.2.3.1 PERMEABILITY AND PK A 328
9.2.3.2 GI TRANSIT/MOTILITY 328
9.2.3.3 SITE-SPECIFIC ABSORPTION OR NARROW ABSORPTION WINDOW 328
9.2.3.4 PREABSORPTIVE METABOLISM 328
9.2.3.5 HEPATIC METABOLISM 329
9.2.3.6 BILIARY EXCRETION 329
9.2.3.7 RENAL EXCRETION 329
9.2.3.8 PROTEIN AND TISSUE BINDING 329
9.2.3.9 REGULATORY CONCLUSIONS ON PHYSIOLOGICAL FACTORS . . 330 9.3
PHARMACOKINETICS AND BIOAVAILABILITY 330
9.3.1 PRECLINICAL ASPECTS OF BIOAVAILABILITY 330
9.3.2 CLINICAL PHARMACOLOGY AND BIOAVAILABILITY 330
9.3.3 ABSOLUTE AND COMPARATIVE BIOAVAILABILITY 332
9.3.4 BIOAVAILABILITY AND SCALE-UP FROM DEVELOPMENT TO PRODUCTION 332
9.4 BIOEQUIVALENCE 335
9.4.1 DEFINITIONS 335
9.4.2 EVIDENCE TO ESTABLISH BIOEQUIVALENCE 336
9.4.3 WAIVERS FROM BIOEQUIVALENCE REQUIREMENTS 337
9.4.4 BASIS FOR DEMONSTRATING BIOEQUIVALENCE 338
9.4.5 STUDY DESIGN, SUBJECTS, ENVIRONMENT 339
9.4.6 ANALYTE FOR BIOEQUIVALENCE 340
9.4.6.1 USE OF METABOLITE IN BIOAVAILABILITY/BIO- EQUIVALENCE 340
9.4.6.2 URINARY ELIMINATION IN BIOEQUIVALENCE 342
9.4.7 PRESENTATION OF BIOAVAILABILITY AND BIOEQUIVALENCE DATA . . . 342
9.4.8 METRICS OF BIOEQUIVALENCE 343
9.4.9 STATISTICAL ANALYSIS 345
9.5 MODIFIED RELEASE BIOAVAILABILITY/BIOEQUIVALENCE 347
9.5.1 GUIDANCE ON QUALITY 348
9.5.2 PHARMACOKINETIC AND CLINICAL EVALUATION OF MODIFIED RELEASE DOSAGE
FORMS 350
9.5.3 FOOD EFFECT INVESTIGATIONS WITH MODIFIED RELEASE PRODUCTS . . 352
9.6 CONCLUSIONS 354
9.7 ACKNOWLEDGEMENTS 354
9.8 REFERENCES 354
A.9.1 APPENDIX 361
IMAGE 13
XVI CONTENTS
10 RADIOPHARMACEUTICALS 364
B. R. MATTHEWS
10.1 INTRODUCTION 364
10.2 CONTROL OF RADIOPHARMACEUTICALS IN THE EUROPEAN COMMUNITY . . . 365
10.2.1 INTRODUCTION 365
10.2.2 THE IMPLEMENTATION OF DIRECTIVE 89/343/EEC AND OTHER RELEVANT
LEGISLATION 366
10.2.3 EXPERT REPORTS 368
10.2.4 APPLICATION OF ARTICLE 4 OF DIRECTIVE 65/65/EEC . . .. 369
10.2.5 DATA REQUIREMENTS 370
10.2.5.1 INTRODUCTION 370
10.2.5.2 DATA REQUIREMENTS 370
10.2.6 SUMMARY OF PRODUCT CHARACTERISTICS 385
10.2.7 LABELLING REQUIREMENTS 385
10.2.8 INSTRUCTION LEAFLET 386
10.2.9 MANUFACTURE 387
10.3 CONTROL OF RADIOPHARMACEUTICALS IN THE UNITED STATES 388
10.3.1 INTRODUCTION 388
10.3.2 THE APPLICATION FOR APPROVAL FOR MARKETING 389
10.3.2.1 THE APPLICATION FORM 390
10.3.2.2 THE INDEX 390
10.3.2.3 THE SUMMARY 390
10.3.2.4 TECHNICAL SECTIONS 390
10.3.2.5 ENVIRONMENTAL IMPACT STATEMENT 402
10.3.2.6 LABELLING 403
10.4 CONTROL OF RADIOPHARMACEUTICALS IN JAPAN 403
10.4.1 INTRODUCTION 403
10.4.2 DATA REQUIREMENTS 404
10.4.2.1 GENERAL; AND CHEMISTRY AND PHARMACEUTICAL DATA 404
10.4.2.2 PRECLINICAL DATA 405
10.4.2.3 CLINICAL STUDIES 407
10.5 REFERENCES 407
PART II PRECLINICAL TOXICOLOGY AND PHARMACOLOGY
11 PRECLINICAL TESTING STRATEGY 411
R. BASS AND P. GIINZEL
11.1 INTRODUCTION 411
11.2 PRECLINICAL REQUIREMENTS CURRENTLY IN USE 412
11.3 GENERAL CO-ORDINATION BETWEEN PRECLINICAL AND CLINICAL STUDIES . .
413 11.4 GENERAL CONCEPT OF DEVELOPING PRECLINICAL TESTING STRATEGIES .
. . 414 11.5 GENERAL CONCEPT OF DEVELOPING INDIVIDUAL TESTING STRATEGIES
. . .. 415
IMAGE 14
CONTENTS XVII
11.5.1 TAKING INTO ACCOUNT THE MAIN CHARACTERISTICS OF ENVISAGED
CLINICAL STUDIES 415
11.5.2 AREAS OF POSSIBLE HUMAN RISK TO BE CLARIFIED EXPERIMENTALLY 416
11.5.3 MANDATORY PRINCIPLES AND STANDARDS 416
11.5.4 TECHNICAL DETAILS OF THE EXPERIMENTS TO BE PERFORMED . . 416
11.6 THE USE OF FLOW-CHARTS FOR THE DEVELOPMENT OF PRECLINICAL TESTING
STRATEGIES 416
11.6.1 THE PRINCIPLE OF THE FLOW-CHARTS 418
11.6.2 TEST AREAS AND AVAILABLE FLOW-CHARTS 420
11.6.2.1 SINGLE-DOSE TOXICITY 423
11.6.2.2 TOXICITY BY REPEATED ADMINISTRATION 423
11.6.2.3 TOXICITY TO REPRODUCTION 424
11.6.2.4 GENOTOXIC POTENTIAL 427
11.6.2.5 TUMORIGENIC POTENTIAL 427
11.7 CONCLUSIONS 428
11.8 REFERENCES 428
12 SINGLE-DOSE AND REPEAT-DOSE TOXICITY 430
J. C. TOPHAM
12.1 INTRODUCTION 430
12.2 SINGLE-DOSE TOXICITY STUDIES 431
12.2.1 REGULATORY CONSIDERATIONS 431
12.2.2 OUTLINE PROTOCOL FOR A SINGLE-DOSE TOXICITY STUDY . . .. 431
12.2.3 FEATURES OF SINGLE-DOSE TOXICITY STUDY 432
12.2.3.1 OBJECTIVES 432
12.2.3.2 SPECIES 433
12.2.3.3 SEX AND NUMBER OF ANIMALS 433
12.2.3.4 ROUTE OF ADMINISTRATION 434
12.2.3.5 DOSE LEVELS, VEHICLE AND DOSE VOLUMES . . .. 434
12.2.3.6 OBSERVATIONS 435
12.2.3.7 DATA EVALUATION AND PRESENTATION 435
12.2.4 THE FUTURE 436
12.3 REPEAT-DOSE TOXICITY STUDIES 437
12.3.1 OBJECTIVES 437
12.3.2 DURATION OF REPEAT-DOSE STUDIES 440
12.3.3 OUTLINE PROTOCOL FOR REPEAT-DOSE TOXICITY STUDIES . . .. 443
12.3.3.1 SPECIES 443
12.3.3.2 ROUTE OF ADMINISTRATION 444
12.3.3.3 DURATION, DOSE-FREQUENCY AND DRUG WITHDRAWAL PERIODS 445
12.3.3.4 NUMBER OF ANIMALS AND GROUPS 445
12.3.3.5 DOSE SELECTION 446
12.3.3.6 PHARMACOKINETIC MONITORING AND TOXICOKINETICS 446 12.3.3.7
OBSERVATIONS 448
IMAGE 15
XVIII CONTENTS
12.3.4 DATA EVALUATION 450
12.3.4.1 STUDY DESIGN AND STATISTICAL CONSIDERATIONS . . 450 12.3.4.2
CONTROL DATA 451
12.3.4.3 DRUG SUBSTANCE 452
12.3.4.4 EFFECT DEFINITION 452
12.3.5 OVERALL ASSESSMENT OF SINGLE- AND REPEAT-DOSE TOXICITY STUDIES
454
12.3.6 THE FUTURE 455
12.4 ACKNOWLEDGEMENTS 455
12.5 REFERENCES 455
13 REPRODUCTIVE TOXICOLOGY 458
B. ULBRICH, A. K. PALMER AND R. BASS
13.1 AIM OF STUDIES 458
13.2 APPROACH TO TESTING 458
13.3 DESIGNING STUDIES 460
13.3.1 SELECTION OF SPECIES 460
13.3.2 SELECTION OF DOSAGES 461
13.3.3 ROUTE AND FREQUENCY OF ADMINISTRATION 461
13.3.4 KINETICS 462
13.3.5 USE (AND MISUSE) OF PRELIMINARY STUDIES 462
13.3.6 GROUP SIZES 467
13.3.7 OBSERVATIONS 467
13.4 STUDY OPTIONS 467
13.4.1 MALE AND FEMALE FERTILITY AND EARLY EMBRYONIC DEVELOPMENT 468
13.4.1.1 TREATMENT PERIODS 469
13.4.1.2 MATING 469
13.4.2 EFFECTS ON PREGNANCY, CONCEPTUS AND OFFSPRING 469
13.4.2.1 POSTNATAL EVALUATION 469
13.4.2.2 PRENATAL EVALUATION 471
13.4.2.3 SPECIAL STUDIES (DIRECT TREATMENT OF OFFSPRING) . . 471 13.5
DATA ANALYSIS 471
13.6 DATA PRESENTATION 472
13.7 INTERPRETATION - EXTRAPOLATION 473
13.8 REFERENCES 473
14 MUTAGENICITY 474
D. G. GATEHOUSE
14.1 INTRODUCTION 474
14.2 SCIENTIFIC BACKGROUND TO FIELD OF GENOTOXICITY 475
14.2.1 MUTATION 475
14.2.2 MECHANISMS OF MUTAGENESIS 475
14.2.2.1 EVENTS AT GENE LEVEL (POINT MUTATIONS) . . .. 476
14.2.2.2 EVENTS AT INDIVIDUAL CHROMOSOME LEVEL . . . 476
IMAGE 16
CONTENTS XIX
14.2.2.3 EVENTS AT LEVEL OF THE COMPLETE GENOME . . 477
14.2.3 RELEVANCE OF MUTAGENICITY RESULTS TO HUMAN HAZARD . 477
14.2.3.1 GERM CELL MUTATIONS 477
14.2.3.2 SOMATIC CELL MUTATION AND CANCER 478
14.2.3.3 OTHER POSSIBLE DELETERIOUS EFFECTS OF SOMATIC MUTATIONS 479
14.3 REGULATORY REQUIREMENTS 479
14.3.1 OVERVIEW 4GO
14.3.2 EC REQUIREMENTS 488
14.3.3 JAPANESE REQUIREMENTS 491
14.3.4 UK GUIDELINES 492
14.4.5 CANADIAN GUIDELINES 495
14.4 IN VITRO METABOLIC ACTIVATION AND THE ROLE OF IN VIVO ASSAYS . . ..
497
14.5 TIMING OF PRECLINICAL GENOTOXICITY TESTS IN RELATION TO PHASE I
CLINICAL STUDIES 499
14.6 TEST SYSTEMS (PROTOCOL VARIATIONS) 500
14.6.1 IN VITRO TESTS FOR GENE MUTATION IN BACTERIA 500
14.6.2 IN VITRO TESTS FOR CHROMOSOME DAMAGE IN MAMMALIAN CELLS . 508
14.6.3 IN VITRO TESTS FOR GENE MUTATION IN MAMMALIAN CELLS . .. 515
14.6.4 IN VIVO TESTS FOR CHROMOSOME DAMAGE IN RODENTS . . .. 517
14.6.4.1 MICRONUCLEUS TESTS IN RODENT BONE MARROW 517
14.6.4.2 METAPHASE ANALYSIS IN RODENT BONE MARROW . . 523 14.6.5
ADDITIONAL IN VIVO TESTS FOR GENOTOXICITY (UNSCHEDULED DNA SYNTHESIS
ASSAY IN RAT LIVER) 524
14.7 OVERVIEW OF CURRENT INTERNATIONAL INITIATIVES DESIGNED TO HARMONISE
TEST STRATEGIES/PROTOCOLS 526
14.7.1 INTERNATIONAL CONFERENCE ON HARMONISATION (ICH2) . . 527
14.7.1.1 STRATEGY ISSUES 528
14.7.1.2 TEST PERFORMANCE 531
14.7.2 INTERNATIONAL WORKSHOP ON STANDARDISATION OF PROCEDURES IN
GENETIC TOXICOLOGY 534
14.8 PRESENT DEFICIENCIES AND FUTURE DEVELOPMENTS 537
14.8.1 METABOLICALLY COMPETENT CELL LINES 537
14.8.2 TESTS FOR GENOME MUTATIONS (ANEUPLOIDY) 538
14.8.3 TRANSGENIC MOUSE MODELS FOR USE AS IN VIVO SOMATIC MUTATION
ASSAYS 540
14.8.4 SINGLE-CELL GEL ELECTROPHORESIS ASSAY (COMET ASSAY) FOR THE
EVALUATION OF POTENTIAL ORGANO-SPECIFIC EFFECTS 541
14.9 CONCLUSIONS 541
14.10 REFERENCES 542
15 ONCOGENICITY/CARCINOGENICITY 553
B. RUSHTON
15.1 INTRODUCTION 553
IMAGE 17
XX CONTENTS
15.2 GENERAL POINTS ON STUDY CONDUCT AND INTERPRETATION 554
15.3 WHEN ARE CARCINOGENICITY STUDIES NEEDED? 555
15.4 ROUTE AND METHOD OF ADMINISTRATION 556
15.5 SELECTION OF RODENT SPECIES 556
15.6 SETTING OF DOSE LEVELS 558
15.7 GROUP NUMBER AND SIZE 559
15.8 DIETARY CONSIDERATIONS 560
15.9 TIME ON STUDY 560
15.10 ORGANS TO BE EVALUATED 561
15.11 ADDITIONAL INVESTIGATIONS 562
15.12 CLINICAL TRIALS AND MARKETING TIMES 562
15.13 CLINICAL, AUTOPSY FINDINGS AND HISTOPATHOLOGICAL NOMENCLATURE . .
563 15.14 PATHOLOGY TECHNICAL ISSUES 564
15.15 STUDY DATA PRESENTATION AND INTERPRETATION 564
15.16 DISCUSSION AND CONCLUSIONS 565
15.17 REFERENCES 566
16 ANIMAL PHARMACOKINETICS AND TOXICOKINETICS 569
D. B. CAMPBELL AND R. JOCHEMSEN
16.1 INTRODUCTION 569
16.2 REGULATORY REQUIREMENTS 577
16.3 DISCOVERY 579
16.4 SPECIES COMPARISON OF BIODISPOSITION 581
16.4.1 REGULATORY REQUIREMENTS 581
16.4.2 ANALYTICAL METHODS 586
16.4.3 GENERAL CONSIDERATIONS 586
16.4.4 ABSORPTION 588
16.4.5 DISTRIBUTION 589
16.4.5.1 REGULATORY REQUIREMENTS 589
16.4.5.2 SINGLE DOSING 589
16.4.5.3 REPEATED DOSING 591
16.4.5.4 PROTEIN BINDING 592
16.4.5.5 FOETAL UPTAKE 593
16.4.5.6 MILK TRANSFER 593
16.4.6 METABOLISM 596
16.4.6.1 REGULATORY REQUIREMENTS 596
16.4.6.2 DESIGN 596
16.4.6.3 ENZYME INDUCTION/INHIBITION 597
16.4.7 ELIMINATION 598
16.4.7.1 MASS BALANCE 598
16.4.7.2 BILIARY ELIMINATION 599
16.4.8 SPECIAL ANIMAL POPULATIONS 603
16.5 TOXICOKINETICS 603
16.5.1 REGULATORY REQUIREMENTS 603
IMAGE 18
CONTENTS XXI
16.5.2 DEFINITION 607
16.5.3 STUDIES 607
16.5.4 ANALYTICAL METHODS 607
16.5.5 ANIMALS AND DOSE GROUPS 610
16.5.6 SAMPLING 610
16.5.7 EXPOSURE MEASUREMENT 611
16.5.8 DETERMINATION OF METABOLITES 612
16.5.9 COMPLICATING FACTORS IN EXPOSURE INTERPRETATION . . .. 612
16.5.10 ACUTE DOSING 614
16.5.11 REPEAT-DOSE TOXICITY 614
16.5.12 CARCINOGENICITY 615
16.5.13 GENOTOXICITY 617
16.5.14 REPRODUCTIVE AND FERTILITY STUDIES 617
16.5.15 STATISTICAL EVALUATION 619
16.5.16 GOOD LABORATORY PRACTICE 619
16.6 STEREOISOMERISM 619
16.6.1 REGULATORY REQUIREMENTS 619
16.6.2 SINGLE ENANTIOMER 622
16.6.3 RACEMATE 622
16.6.4 RACEMATE-ENANTIOMER SWITCH 624
16.7 EXPERT REPORT 624
16.8 THE FUTURE 625
16.9 CONCLUSIONS 626
16.10 ACKNOWLEDGEMENTS 627
16.11 REFERENCES 627
PART III CLINICAL
17 CLINICAL PHARMACOLOGY AND PHARMACODYNAMICS 639
A. J. WILLIAMS AND D. T. GREENWOOD
17.1 INTRODUCTION 639
17.2 THE REGULATORY POSITION 645
17.2.1 GENERAL REQUIREMENTS 645
17.2.2 SPECIFIC THERAPEUTIC AREA/DISEASE GUIDELINES 648
17.3 REFERENCES 649
18 PHARMACOKINETICS IN MAN 650
D. J. NICHOLS, P. E. COATES AND D. A. SMITH
18.1 INTRODUCTION 650
18.2 PRECLINICAL SAFETY DATA 651
18.3 PRECLINICAL METABOLISM 653
18.4 BIOANALYTICAL METHODS 654
18.5 PHARMACOKINETIC PARAMETERS 655
IMAGE 19
XXII CONTENTS
18.6 BIOAVAILABILITY AND ABSORPTION PARAMETERS 658
18.7 PHARMACOKINETIC-PHARMACODYNAMIC PARAMETERS 658
18.8 PHASE I STUDIES 659
18.9 SINGLE-DOSE TOLERATION AND PHARMACOKINETICS 660
18.10 SINGLE- AND MULTIPLE-DOSE TOLERATION AND PHARMACOKINETICS . . ..
661 18.11 DOSE PROPORTIONALITY: LINEARITY AND NON-LINEARITY WITH DOSE .
. .. 662 18.12 BIOAVAILABILITY AND BIOEQUIVALENCE 662
18.12.1 FIRST BIOAVAILABILITY STUDY 663
18.12.2 FOOD EFFECTS ON BIOAVAILABILITY 663
18.12.3 BIOAVAILABILITY OF COMMERCIAL DOSAGE FORM 664
18.12.4 ALTERNATIVE ORAL FORMULATIONS 664
18.12.5 ALTERNATIVE ROUTES OF ADMINISTRATION 665
18.13 METABOLISM 665
18.14 RADIOLABEL BIOTRANSFORMATION STUDY 666
18.15 PHARMACOKINETICS IN SPECIAL POPULATIONS AND SITUATIONS 667
18.15.1 DRUG INTERACTION STUDIES 667
18.15.2 PHARMACOKINETICS IN THE ELDERLY 668
18.15.3 PHARMACOKINETICS IN RENAL INSUFFICIENCY 668
18.15.4 PHARMACOKINETICS IN HEPATIC INSUFFICIENCY 669
18.16 CHIRAL DRUGS 669
18.17 POPULATION PHARMACOKINETICS AND PHARMACODYNAMICS 670
18.17.1 PHASE I 672
18.17.2 PHASE HA 672
18.17.3 PHASE LIB 672
18.17.4 PHASE III 672
18.18 INTEGRATION: PHARMACOKINETICS AND PHARMACODYNAMICS 672 18.19
CONCLUSIONS 674
18.20 REFERENCES 675
19 ETHNIC, GENETIC AND ENVIRONMENTAL FACTORS 678
L. P. BALANT AND O. PELKONEN
19.1 INTRODUCTION 678
19.1.1 PHARMACOGENETICS 678
19.1.2 ENVIRONMENTAL FACTORS 679
19.1.3 INTER-ETHNIC DIFFERENCES IN DRUG BEHAVIOUR AND ACTION . . 680
19.1.4 SCOPE OF THE CHAPTER 680
19.2 BASIC CONCEPTS AND DEFINITIONS 681
19.2.1 PHARMACOGENETICS 681
19.2.2 ENVIRONMENTAL FACTORS 682
19.2.3 INTER-ETHNIC FACTORS AND PHARMACO-ANTHROPOLOGY . . .. 682
19.2.3.1 INTER-ETHNIC DIFFERENCES IN DRUG BEHAVIOUR AND ACTION 682
19.2.3.2 PHARMACO-ANTHROPOLOGY 683
19.2.4 PHARMACOKINETICS AND PHARMACODYNAMICS 684
IMAGE 20
CONTENTS XXIII
19.3 GENETIC FACTORS 684
19.3.1 GENETIC POLYMORPHISM OF N-ACETYLATION 685
19.3.1.1 HISTORICAL AND MECHANISTIC CONSIDERATIONS . . 685 19.3.1.2
CLINICAL RELEVANCE 685
19.3.2 GENETIC POLYMORPHISM OF DEBRISOQUINE/SPARTEINE OXIDATION 686
19.3.2.1 HISTORICAL AND MECHANISTIC CONSIDERATIONS . . 686 19.3.2.2
CLINICAL RELEVANCE 686
19.3.3 GENETIC POLYMORPHISM OF MEPHENYTOIN OXIDATION . . .. 687 19.3.3.1
HISTORICAL AND MECHANISTIC CONSIDERATIONS . . 687 19.3.3.2 CLINICAL
RELEVANCE 687
19.3.4 OTHER POLYMORPHISMS 687
19.3.5 PHARMACOKINETIC CONSEQUENCES 688
19.3.6 REGULATORY CONSIDERATIONS FOR GENETIC POLYMORPHISMS . . 689 19.4
ENVIRONMENTAL FACTORS AND ENZYMATIC SYSTEMS 690
19.4.1 RELEVANT ENVIRONMENTAL FACTORS 690
19.4.1.1 CIGARETTE SMOKING 690
19.4.1.2 ALCOHOL DRINKING 691
19.4.1.3 CONCOMITANT DRUG THERAPY 691
19.4.1.4 OCCUPATIONAL CHEMICALS 691
19.4.1.5 OTHER FACTORS 692
19.4.2 ENZYMATIC SYSTEMS IN HUMANS 692
19.4.2.1 P 450 ENZYMES 692
19.4.2.2 CONJUGATIVE ENZYMES 695
19.5 INTER-ETHNIC AND GEOGRAPHICAL FACTORS 695
19.5.1 KNOWN GENETIC POLYMORPHISMS 696
19.5.1.1 N-ACETYLATION 696
19.5.1.2 DEBRISOQUINE/SPARTEINE OXIDATION 696
19.5.1.3 MEPHENYTOIN OXIDATION 697
19.5.2 NUTRITION 697
19.5.2.1 ALCOHOL DEHYDROGENASE 698
19.5.2.2 ALDEHYDE DEHYDROGENASE 698
19.5.3 PHYSICAL AND CHEMICAL ENVIRONMENT 699
19.5.4 PHARMACODYNAMIC ASPECTS 699
19.6 CLINICAL STUDY DESIGN AND INTERPRETATION 700
19.6.1 PHARMACOKINETIC/PHARMACODYNAMIC INTEGRATION 700 19.6.1.1 CONCEPTS
AND AIMS OF PK/PD INTEGRATION . . . 700 19.6.1.2 INTER-ETHNIC
DIFFERENCES IN DRUG BEHAVIOUR AND ACTION AND PK/PD INTEGRATION 701
19.6.2 PRECLINICAL STUDIES 701
19.6.2.1 CHOICE OF ANIMAL SPECIES IN TOXICOLOGY . . . 703 19.6.2.2
ANIMAL MODELS FOR ENVIRONMENTAL FACTORS . . 703 19.6.3 PHASE I STUDIES
705
19.6.3.1 OBJECTIVES AND METHODOLOGY 705
19.6.3.2 INVESTIGATIONAL PHARMACOKINETICS 706
IMAGE 21
XXIV CONTENTS
19.6.3.3 BIOAVAILABILITY INVESTIGATIONS 706
19.6.3.4 BIOEQUIVALENCE STUDIES 707
19.6.3.5 INVESTIGATIONAL PHARMACODYNAMICS 707
19.6.3.6 STUDIES IN HEALTHY VOLUNTEERS FOR THE DETECTION OF INTER-ETHNIC
DIFFERENCES IN PHARMACOKINETICS 707
19.6.4 PHASE II STUDIES 708
19.6.5 PHASE IE STUDIES 708
19.6.5.1 METHODOLOGICAL ASPECTS IN THE CONTEXT OF THE IDENTIFICATION OF
SOURCES OF VARIABILITY IN RESPONSE AND/OR BEHAVIOUR 708
19.6.5.2 STUDIES IN PATIENTS IN THE CONTEXT OF WORLD-WIDE MARKETING 709
19.6.6 PHASE IV STUDIES 710
19.6.6.1 OBJECTIVES AND METHODOLOGY 710
19.6.6.2 PHASE IV STUDIES IN THE CONTEXT OF TRANSCULTURAL DRUG LICENSING
710
19.6.7 GENOTYPING, PHENOTYPING AND PROBE DRUGS 710
19.6.7.1 GENOTYPING FOR POLYMORPHISMS 710
19.6.7.2 THE CONCEPT OF PROBE DRUGS 711
19.6.7.3 PROBE DRUGS FOR GENETIC POLYMORPHISMS . . . 712 19.6.7.4 PROBE
DRUGS FOR ENVIRONMENTAL FACTORS . . .. 715
19.6.7.5 COCKTAIL APPROACH 718
19.6.7.6 PRACTICAL CONSIDERATIONS FOR HUMAN STUDIES . . 719 19.7
REGULATORY CONSIDERATIONS FOR TRANSCULTURAL REGISTRATION 720
19.8 PROPOSAL FOR A STRATEGY TO DISCOVER AND DEFINE SOURCES OF
VARIABILITY FROM GENETIC AND/OR ENVIRONMENTAL ORIGIN 721
19.9 CONCLUSIONS 721
19.10 ACKNOWLEDGEMENTS 722
19.11 REFERENCES 722
20 GOOD CLINICAL PRACTICE 737
M. E. ALLEN
20.1 INTRODUCTION 737
20.2 THE BASICS OF GOOD CLINICAL PRACTICE 738
20.3 DEVELOPMENT OF GOOD CLINICAL PRACTICE IN THE UNITED STATES . . .
739 20.3.1 PATIENTS RIGHTS 739
20.3.2 SCIENTIFIC MISCONDUCT AND FRAUD 741
20.3.3 SUBSTANTIVE AND SUPPORTIVE DATA 742
20.4 DEVELOPMENT OF GOOD CLINICAL PRACTICE OUTSIDE THE UNITED STATES 743
20.5 DIFFERENCES IN APPROACH TO GOOD CLINICAL PRACTICE 744
20.6 LEGAL STATUS OF GOOD CLINICAL PRACTICE 745
20.6.1 THE UNITED STATES 745
20.6.2 EUROPEAN COMMUNITY 745
IMAGE 22
CONTENTS XXV
20.6.3 JAPAN 746
20.7 GOOD CLINICAL PRACTICE GUIDELINES AND REGULATIONS COMPARED . . .
747 20.7.1 ETHICS COMMITTEES AND INSTITUTIONAL REVIEW BOARDS . . 747
20.7.1.1 THE UNITED STATES 747
20.7.1.2 EUROPEAN COMMUNITY 748
20.7.1.3 JAPAN 749
20.7.2 INFORMED CONSENT 750
20.7.2.1 THE UNITED STATES 750
20.7.2.2 EUROPEAN COMMUNITY 751
20.7.2.3 JAPAN 751
20.7.3 OBLIGATIONS OF INVESTIGATORS 751
20.7.3.1 THE UNITED STATES 752
20.7.3.2 EUROPEAN COMMUNITY 752
20.7.3.3 JAPAN 753
20.7.4 OBLIGATIONS OF SPONSORS AND MONITORS 755
20.7.4.1 THE UNITED STATES 755
20.7.4.2 EUROPEAN COMMUNITY 756
20.7.4.3 JAPAN 758
20.7.5 ARCHIVING OF DATA 758
20.7.5.1 THE UNITED STATES 758
20.7.5.2 EUROPEAN COMMUNITY 759
20.7.5.3 JAPAN 759
20.7.6 AUDIT OF SPONSORS AND AUTHORITIES 759
20.7.6.1 THE UNITED STATES 759
20.7.6.2 EUROPEAN COMMUNITY 760
20.7.6.3 JAPAN 761
20.8 HARMONISATION OF GOOD CLINICAL PRACTICES 761
20.9 GOOD CLINICAL PRACTICE LEGISLATION AND GUIDELINES 762
20.9.1 THE UNITED STATES 762
20.9.1.1 REGULATIONS 762
20.9.1.2 GUIDELINE 762
20.9.1.3 COMPLIANCE PROGRAM GUIDANCE MANUALS . . 762 20.9.1.4 GUIDANCE
762
20.9.2 EUROPEAN COMMUNITY 763
20.9.2.1 GUIDELINE 763
20.9.2.2 OTHER LEGAL AND TECHNICAL REQUIREMENTS . . .. 763 20.9.3 JAPAN
76 ^
20.9.3.1 LEGAL REQUIREMENTS H3
20.9.3.2 GUIDELINE 763
20.10 ACKNOWLEDGEMENT 764
20.11 REFERENCES 7M
IMAGE 23
XXVI CONTENTS
21 CLINICAL TRIALS - GENERAL ASPECTS OF DESIGN AND INTERPRETATION 765
J. DAHLSTROM, C. R. GRIFFETT AND C. M. PERKINS
21.1 INTRODUCTION 765
21.2 ASPECTS OF DESIGN OF CLINICAL TRIALS 766
21.2.1 EXPERIMENTAL DESIGN ON THE BASIS OF DISEASE TYPE . . .. 766
21.2.2 TYPES OF CLINICAL TRIAL 768
21.2.2.1 DEFINITION 768
21.2.2.2 PHASE I 769
21.2.2.3 PHASE II 769
21.2.2.4 PHASE HI 769
21.2.2.5 PHASE IV 769
21.2.3 CONTROLLED/UNCONTROLLED TRIAL DESIGN 770
21.2.3.1 CONTROLLED TRIALS 770
21.2.3.2 UNCONTROLLED TRIALS 770
21.2.4 PARALLEL GROUP OR CROSS-OVER DESIGN? 770
21.3 SPECIFIC FEATURES OF CLINICAL TRIAL DESIGN AND INTERPRETATION . .
.. 771
21.3.1 THE PROTOCOL 771
21.3.2 OBJECTIVES OF THE TRIAL 772
21.3.3 STUDY SIZE 772
21.3.3.1 STATISTICAL CONSIDERATIONS 773
21.3.4 PATIENT SELECTION 774
21.3.5 RANDOMISATION 775
21.3.6 BLINDING 776
21.3.7 DRUG DOSAGE 776
21.3.8 DURATION OF STUDY 777
21.4 CLINICAL TRIAL INTERPRETATION 777
21.4.1 OUTCOME MEASURES 777
21.4.2 INTERIM MONITORING 778
21.4.3 CONCOMITANT MEDICATION 779
21.4.4 PATIENT COMPLIANCE 779
21.4.5 WITHDRAWALS 779
21.4.6 MULTINATIONAL CLINICAL TRIALS 780
21.5 THE IMPACT OF GOOD CLINICAL PRACTICE ON CLINICAL TRIAL DESIGN AND
INTERPRETATION 780
21.5.1 DESIGNING A CLINICAL TRIAL IN ACCORD WITH GCP 781
21.5.2 ETHICAL COMMITTEES/INSTITUTIONAL REVIEW BOARDS . . .. 781
21.5.3 INFORMED CONSENT 781
21.5.4 STANDARD OPERATING PROCEDURES/QUALITY ASSURANCE . .. 782
21.6 FUTURE DIRECTIONS 783
21.7 REFERENCES 784
21.8 GUIDELINES I 785
21.9 GUIDELINES II 786
IMAGE 24
CONTENTS XXVII
22 STATISTICAL ANALYSIS OF CLINICAL DATA 787
R. T. O NEILL
22.1 INTRODUCTION 787
22.2 STATISTICAL PRINCIPLES 788
22.2.1 THE CURRENT STATUS OF PUBLISHED DOCUMENTS DESCRIBING STATISTICAL
PRINCIPLES IN MEDICAL AND PHARMACEUTICAL RESEARCH 788
22.2.1.1 UNITED STATES 789
22.2.1.2 NORDIC COUNTRIES 790
22.2.1.3 EUROPEAN COMMUNITY 791
22.2.1.4 JAPAN 791
22.2.2 OTHER RELEVANT PUBLISHED LITERATURE 792
22.3 SOME ANALYSIS ISSUES 793
22.3.1 RANDOMISATION: ASSESSING WHETHER THE GOAL WAS ACHIEVED 794 22.3.2
STATISTICAL ADJUSTMENTS FOR CO-VARIATES 795
22.3.3 SUBGROUP ANALYSIS, PATIENT SUBSETS AND VARIATION IN THERAPEUTIC
EFFICACY OR SAFETY 796
22.3.3.1 WHEN ARE THE SUBGROUPS DETERMINED? . . .. 799
22.3.4 INTENT TO TREAT ANALYSIS OF CLINICAL TRIALS WITH RESPECT TO
PROTOCOL VIOLATIONS AND MISSING DATA 799
22.3.4.1 THE PURPOSE OF A TRIAL: PHASE II AND PHASE III TRIALS 800
22.3.4.2 SOME FDA GUIDANCE AS STATED IN THE GUIDELINES . 800 22.3.4.3
OPERATIONAL QUESTIONS 801
22.3.5 COMPLIANCE AND ADHERENCE TO DRUG ASSIGNMENT IN CLINICAL TRIALS
801
22.3.6 STATISTICAL ANALYSIS OF LONGITUDINALLY COLLECTED DATA, PATIENT
DROPOUTS, AND DIFFERENTIAL PATIENT FOLLOW-UP AND EXPOSURE 802
22.3.7 SEQUENTIAL AND GROUP SEQUENTIAL CLINICAL TRIALS: INTERIM ANALYSIS
AND UNPLANNED ANALYSES OF ACCRUING DATA . . .. 804 22.3.8 CROSS-OVER
DESIGNS AND THEIR ANALYSIS 807
22.3.9 MULTICENTRE STUDIES 809
22.3.9.1 INTERPRETING THE VARIABILITY IN TREATMENT EFFECTS AMONG CENTRES
810
22.3.9.2 METHODS OF ANALYSIS HI 1
22.3.9.3 MULTINATIONAL MULTICENTRE STUDIES 811
22.3.10 ACTIVE CONTROL TRIALS: CLAIMING TREATMENT EFFECTS ARE EQUIVALENT
TO THOSE OF ANOTHER EFFECTIVE AGENT 812
22.3.11 THE ANALYSIS OF DOSE-RESPONSE: DOSE^RANGING STUDIES . . 814
22.3.12 FACTORIAL DESIGNS 815
22.3.13 FIXED DOSE COMBINATION DRUG DESIGNS 816
22.3.13.1 SHOULD A PLACEBO GROUP BE INCLUDED IN THE FIXED COMBINATION
TRIAL? 817
IMAGE 25
XXVIII CONTENTS
22.3.14 META-ANALYSIS AND SYSTEMATIC OVERVIEWS OF CLINICAL STUDIES IN
LICENCE APPLICATIONS 817
22.3.15 THE STATISTICAL ANALYSIS OF SAFETY OUTCOMES IN CLINICAL STUDIES
819
22.4 SUMMARY AND CONCLUDING REMARKS 820
22.5 REFERENCES 821
PART IV BIOLOGICAL PRODUCTS AND BIOTECHNOLOGY
23 CLINICAL ASPECTS OF RECOMBINANT DNA PRODUCTS 833
F. ROTBLAT
23.1 INTRODUCTION 833
23.2 PHARMACODYNAMICS 833
23.3 PHARMACOKINETICS 834
23.4 EFFICACY 835
23.5 REPLACEMENT PROTEINS 835
23.6 PHARMACOLOGICAL OVERDOSES 836
23.7 CYTOKINES AND INTERFERONS 836
23.8 PRODUCTS FOR THE FUTURE 837
23.9 TAILORING THE INDICATION 837
23.10 SAFETY 837
23.11 SAFETY ANALYSIS 837
23.12 PROBLEMS SPECIFIC TO RECOMBINANT PRODUCTS 838
23.12.1 SECONDARY PHARMACOLOGY 838
23.12.2 ANTIBODIES 838
23.12.3 TRANSMISSION OF VIRAL INFECTION 838
23.12.4 RESIDUAL DNA 838
23.12.5 CONTAMINANTS FROM THE MANUFACTURING PROCESSES . . .. 839 23.12.6
CHANGES IN STRUCTURE 839
23.13 CONCLUSIONS 839
23.14 REFERENCES 839
24 PRECLINICAL PHARMACOLOGICAL AND TOXICOLOGICAL REQUIREMENTS FOR
BIOLOGICAL AND BIOTECHNOLOGICAL PRODUCTS 840
R. M. LEE
24.1 INTRODUCTION 840
24.2 TOXICOLOGY 841
24.2.1 SINGLE-DOSE TOXICITY 841
24.2.2 REPEATED-DOSE TOXICITY 842
24.2.3 REPRODUCTION TOXICITY 843
24.2.4 MUTAGENIC POTENTIAL 845
24.2.5 CARCINOGENIC POTENTIAL 846
24.2.6 LOCAL TOLERANCE 846
24.3 PHARMACOLOGY 846
IMAGE 26
CONTENTS XXIX
24.3.1 PHARMACOLOGY (I): RELATED TO THE DESIRED ACTION 846
24.3.2 PHARMACOLOGY (II): NOT RELATED TO THE DESIRED ACTION . . . 846
24.4 PHARMACOKINETICS AND BIOTRANSFORMATION 847
24.5 REFERENCES 847
24.5.1 GENERAL 848
24.5.2 SPECIFIC GUIDANCE 848
ANNEX 1 - LIST OF THE PRINCIPAL ABBREVIATIONS AND ACRONYMS USED IN THE
TEXT 849
ANNEX 2 - INFORMATION SOURCES ON LEGAL AND TECHNICAL REQUIREMENTS FOR
REGISTRATION OF MEDICINAL PRODUCTS IN THE EC, JAPAN AND THE UNITED
STATES 856
INDEX 872
|
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| spelling | International pharmaceutical product registration aspects of quality, safety and efficacy eds. Anthony C. Cartwright ... New York <<[u.a.]>> Horwood 1994 XXXX, 928 S. txt rdacontent n rdamedia nc rdacarrier Ellis Horwood series in pharmaceutical technology Pharmazeutische Technologie (DE-588)4045699-7 gnd rswk-swf Arzneimittelsicherheit (DE-588)4143182-0 gnd rswk-swf Arzneimittelsicherheit (DE-588)4143182-0 s DE-188 Pharmazeutische Technologie (DE-588)4045699-7 s Cartwright, A. C. 1940- (DE-588)1190389924 edt GBV Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=021720988&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
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| subject_GND | (DE-588)4045699-7 (DE-588)4143182-0 |
| title | International pharmaceutical product registration aspects of quality, safety and efficacy |
| title_auth | International pharmaceutical product registration aspects of quality, safety and efficacy |
| title_exact_search | International pharmaceutical product registration aspects of quality, safety and efficacy |
| title_full | International pharmaceutical product registration aspects of quality, safety and efficacy eds. Anthony C. Cartwright ... |
| title_fullStr | International pharmaceutical product registration aspects of quality, safety and efficacy eds. Anthony C. Cartwright ... |
| title_full_unstemmed | International pharmaceutical product registration aspects of quality, safety and efficacy eds. Anthony C. Cartwright ... |
| title_short | International pharmaceutical product registration |
| title_sort | international pharmaceutical product registration aspects of quality safety and efficacy |
| title_sub | aspects of quality, safety and efficacy |
| topic | Pharmazeutische Technologie (DE-588)4045699-7 gnd Arzneimittelsicherheit (DE-588)4143182-0 gnd |
| topic_facet | Pharmazeutische Technologie Arzneimittelsicherheit |
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