Pharmaceutical Product Licensing: Requirements For Europe (Ellis Horwood Books in the Biological Sciences)

Book Cover......Page 1
Half-Title......Page 2
Title......Page 6
Copyright......Page 7
Table of Contents......Page 8
1.1 INTRODUCTION......Page 36
1.2.1 Early history to the nineteenth century......Page 37
1.2.3 The early twentieth century in the USA: early regulation......Page 38
1.2.4 Thalidomide......Page 39
1.2.5 Thalidomide: the regulatory aftermath......Page 40
1.3.1 Introduction......Page 42
1.3.2 Directive 65/65/EEC: definitions and requirements......Page 43
1.3.3 Directive 75/318/EEC: the ‘norms and protocols’ Directive......Page 44
1.3.4 Directive 75/319/EEC: legal and administrative provisions......Page 45
1.3.7 Commission Communication of 6 May 1982: parallel importation of medicinal products......Page 46
1.3.9 Council Recommendations 83/571/EEC: ‘guidelines’......Page 48
1.3.11 Directive 87/21/EEC: abridged applications for ‘copy products’ and protection of innovation......Page 49
1.4 THE EUROPEAN PHARMACOPOEIA......Page 50
1.5 PUBLICATION OF THE COMMUNITY RULES FOR PRODUCT REGISTRATION IN 1989......Page 51
OPEAN MARKET IN PHARMACEUTICAL PRODUCTS .........Page 52
REFERENCES......Page 54
2.3 THE MEMBER STATES OF THE EUROPEAN ECONOMIC COMMUNITY......Page 55
2.4.2 The Council of Ministers......Page 56
2.4.3 The European Parliament......Page 57
2.4.5 The European Court of Justice (ECJ)......Page 58
2.5.1 Regulations......Page 59
2.5.3 Decisions......Page 60
2.6 THE SINGLE EUROPEAN ACT AND THE SINGLE MARKET......Page 61
2.8 THE NORDIC COUNCIL......Page 62
REFERENCE......Page 63
3.1 INTRODUCTION......Page 64
3.3 REQUIREMENTS RELATING TO THE FORMAT OF THE APPLICATION......Page 65
3.4.2 Administrative information......Page 67
3.4.3 Summary of product characteristics......Page 68
3.4.4 Expert Reports......Page 69
3.5.2 Description of analytical methods and analytical validation......Page 71
3.5.3 Part IIA: Composition......Page 73
3.5.4 Part IIB: Method of manufacture of the dosage form......Page 74
3.5.5 Part IIC: Control of starting materials......Page 75
(c)  Quality control during synthesis......Page 76
(d)  Development chemistry......Page 77
(f) Active ingredient specification......Page 78
3.5.5.3 Other ingredients......Page 79
3.5.7 Part IIE: Control tests on the finished product......Page 80
3.5.8.1 Active ingredients......Page 82
3.5.8.2 Finished product......Page 83
3.6.1 PART VA: Dosage form......Page 85
3.7 PRODUCT LABELLING......Page 86
REFERENCES......Page 88
4.1  INTRODUCTION......Page 89
4.2.2  EC guidelines......Page 91
4.3.2  EC guidelines......Page 92
4.4.2.1 Single dose toxicity......Page 93
4.5.1 EC requirements......Page 94
4.5.2 EC guidelines......Page 95
4.6.2 EC guidelines......Page 96
4.7.1 EC requirements......Page 97
4.7.2 EC guidelines......Page 98
5.2.1 National requirements for the regulation of clinical drug trials......Page 100
5.2.2 Good Clinical Practice (GCP)......Page 101
5.2.3 Clinical guidelines......Page 104
5.3.3 Part IVA: Clinical pharmacology......Page 105
5.3.5 Overall summary......Page 106
5.4 THE CLINICAL EXPERT REPORT......Page 107
5.5 CONCLUSION......Page 108
6.2.1 Directive 65/65/EEC......Page 109
6.3.1 The objectives of the new Directive......Page 110
6.3.3 Harmonisation of the rules for products which are copies of established medicinal products......Page 111
6.3.4 Harmonisation of the rules for combination products......Page 112
6.5 EVIDENCE OF THE TEN YEAR AUTHORISATION AND MARKETING......Page 113
6.6.1 The Smith Kline and French judicial review......Page 114
6.6.2 Essential similarity and the active ingredient......Page 115
6.6.4 Essential similarity and the clinical indications......Page 116
6.8 CHEMISTRY AND PHARMACY OF ABRIDGED APPLICATIONS......Page 117
6.8.1 Composition/container/development pharmaceutics......Page 118
6.8.5 Control tests on the finished product......Page 119
6.10 CLINICAL DATA......Page 120
6.11 BIOAVAILABILITY AND BIOEQUIVALENCE DATA......Page 121
6.11.1 Verifiability of bioavailability and bioequivalence studies......Page 122
REFERENCES......Page 123
7.1 INTRODUCTION......Page 124
7.2.2 In the European Community......Page 125
7.2.3 Comparison with United States Food and Drug Administration DMFs......Page 126
7.3.1 Introduction......Page 127
7.3.2 Data requirements......Page 128
7.3.3 Experience with DMFs in the United Kingdom......Page 129
7.4.2 The European drug master file procedure......Page 130
REFERENCES......Page 132
8.1 INTRODUCTION......Page 133
8.2.1.2 The Medicines (Radioactive Substances) Order 1978......Page 134
8.2.2 Relevant European Pharmacopoeia definitions......Page 135
8.3.1 Introduction......Page 136
8.3.4 Pharmaceutical data requirements......Page 137
8.3.4.2 Development pharmaceutics......Page 138
8.3.4.5 Other constituents......Page 139
8.3.4.7 Stability data......Page 140
8.4.1 Introduction......Page 141
8.4.2.1 Introduction......Page 142
(d) Method of preparation......Page 143
(f) Control tests on the finlshed product......Page 144
(h) Stability testing......Page 145
(c) Mutagenic potential......Page 146
8.4.2.4 Clinical data requirements......Page 147
8.4.3.2 Directive 89/343/EEC specific requirements......Page 148
8.4.3.3 European Pharmacopoeia requirements......Page 149
8.4.3.4 Instruction leaflet......Page 150
9.1 INTRODUCTION......Page 151
9.2.2 The present EC market for medical devices......Page 152
9.2.3 Control of medical devices in the Member States of the EC......Page 153
9.3  IDEAL CHARACTERISTICS FOR A NEW SYSTEM OF CONTROLS FOR MEDICAL DEVICES......Page 156
9.4.1 The role of CEN and CENELEC......Page 157
9.4.2 The consultative processes in the EC in the development of a Directive......Page 159
89/336/EEC .........Page 161
9.5.5 Article 5: Role of harmonised standards......Page 163
9.5.7 Article 7: Removal of products from the market......Page 164
9.5.11 Article 11: Appointment and withdrawal of notifled bodies......Page 165
9.5.16 Article 16: Effective dates......Page 166
9.5.18.3 Requirements regarding design and construction......Page 167
9.5.19 Annex 2: Declaration of conformity (full quality system)......Page 169
9.5.20 Annex 3: EC type-examination procedure......Page 170
to type .........Page 172
9.5.23  Annex 6: Custom-made devices and devices intended for clinical investigations......Page 173
9.5.25 Annex 8: Minimum criteria for inspection bodies to be notifled......Page 174
9.6.2 Definitions......Page 175
9.6.4 Classification of medical devices......Page 177
9.6.5 Provisions which differ from the active implantable medical devices Directive......Page 178
9.6.6 Provisions in common with the active implantable medical devices Directive......Page 179
9.6.7.1 General requirements......Page 180
9.6.7.2 Design and construction......Page 181
9.6.9 Statement concerning devices intended for special purposes......Page 183
(a) Non-invasive devices coming into contact with intact skin......Page 184
(d) Surgically invasive devices......Page 185
9.6.11 Clinical evaluation......Page 186
9.7 COMMENTS ON THE MEDICAL DEVICE DIRECTIVES......Page 187
10.1 INTRODUCTION......Page 191
10.2.3 Requirements in the UK......Page 192
(a) Microbiological studies......Page 193
10.2.3.3 Experimental and biological studies......Page 194
10.2.3.5 Product literature......Page 195
10.3.2.1 Chemical and pharmaceutical documentation......Page 196
10.3.2.3 Studies in humans......Page 197
11.1 INTRODUCTION......Page 199
ions) .........Page 200
 on the authorisation .........Page 201
11.2.5 To ensure that all marketing authorisation applications have had critical review......Page 202
global application .........Page 203
11.3.1.4 Legal requirements as to qualification of Experts......Page 204
11.4.1 The pharmaceutical Expert......Page 205
11.4.2 The pharmaco-toxicological Expert......Page 206
dged applications) .........Page 207
11.5.1 Single versus multiple Experts......Page 208
11.5.3 The ‘foreign’ Expert versus national Expert......Page 209
11.7 LINKS BETWEEN THE THREE EXPERTS......Page 210
11.8 THE DUTIES OF THE EXPERTS......Page 211
dure of Directive 87/22/EEC) .........Page 212
11.9 THE PHARMACEUTICAL EXPERT REPORT: STRUCTURE, FORMAT, AND CONTENT......Page 213
11.9.1 Structure of the pharmaceutical Expert Report......Page 214
11.9.3 Evaluation section of the pharmaceutical Expert Report......Page 215
11.10.1 Structure of the pharmacotoxicological Expert Report......Page 219
11.10.3 Conclusions of the pharmacotoxicological Expert Report......Page 220
11.11.2 Contents of the clinical Expert Report......Page 221
11.11.3 Conclusions of the clinical Expert Report......Page 222
11.12.3 Cross-referral marketing authorisation applications......Page 223
REFERENCES......Page 224
12.1 INTRODUCTION......Page 225
12.2.2 Structure of the dossier......Page 227
12.2.3 The clinical Expert Report......Page 229
12.2.4 Overall summary......Page 230
12.2.5 Clinical pharmacology......Page 231
12.2.6 Reports of individual clinical trials......Page 232
12.3.1 Introduction......Page 234
12.3.2.1 Deficiencies relating to the drug substance......Page 235
12.3.2.2 Deficiencies relating to the finished product......Page 237
12.3.2.3 Points of general applicability......Page 240
12.3.3 Deficiencies in applications referred to CPMP......Page 241
12.3.4.3 Applications considered by the CSM......Page 242
12.4.1 Introduction......Page 246
12.4.3 Pharmacokinetics......Page 247
12.4.5 Reproduction studies......Page 248
12.4.7 Carcinogenicity......Page 249
REFERENCES......Page 250
13.1.2 The chairmanship and vice-chairmanship of the CPMP......Page 251
13.1.3 The current role of the CPMP......Page 252
13.1.5 The CPMP working parties......Page 253
13.2 THE PHARMACEUTICAL COMMITTEE......Page 256
13.3 THE COMMITTEE FOR THE ADAPTATION TO TECHNICAL PROGRESS......Page 257
14.1 INTRODUCTION......Page 259
14.2 THE FORMER CPMP PROCEDURE......Page 260
14.3 THE NEW RULES OF THE MULTISTATE PROCEDURE......Page 261
14.4 WHAT AUTHORISATIONS CAN BE USED IN THE MULTISTATE PROCEDURE?......Page 262
14.6 SUITABILITY OF PRODUCTS FOR THE MULTISTATE PROCEDURE......Page 263
14.7 SECOND APPLICANT (ABRIDGED) PRODUCTS......Page 264
14.8 CHANGES TO THE ORIGINAL AUTHORISATION (‘VARIATIONS’)......Page 265
14.10 THE MULTISTATE PROCEDURE AND TIMING......Page 266
14.11 THE ROLE OF THE RAPPORTEUR AND CO-RAPPORTEUR......Page 270
14.13 LABELS AND LEAFLETS......Page 271
14.16 THE FORMAT AND LANGUAGE OF MULTISTATE APPLICATIONS......Page 272
14.17 HEARINGS......Page 273
14.19 ANALYSIS OF MULTISTATE APPLICATIONS (1986 TO 1989)......Page 274
REFERENCE......Page 276
15.2 PROTECTION OF INNOVATION......Page 277
15.3 EARLY EVALUATION OF THE PROCEDURE......Page 278
15.5 EXEMPTION FROM THE OBLIGATORY BIOTECHNOLOGY PROCEDURE......Page 279
15.6 THE HIGH TECHNOLOGY PROCEDURE......Page 280
15.7 THE CONCERTATION TIMETABLE......Page 281
15.8 APPEALS......Page 282
15.10 CHANGES TO THE MARKETING AUTHORISATION (‘VARIATIONS’)......Page 283
15.12 EXPERIENCE WITH THE HIGH TECHNOLOGY PROCEDURE......Page 284
16.1 REGULATORY STRATEGY......Page 285
16.1.1 Regulatory strategy in national applications......Page 286
16.2.2 Choice of the rapporteur country......Page 287
16.2.6 Choice of the Experts for hearings......Page 288
16.4 REGULATORY STRATEGY IN THE MULTISTATE PROCEDURE......Page 289
16.5 OVERALL REGULATORY STRATEGY FOR THE PRODUCT......Page 290
16.6 THE PER SCHEME......Page 291
REFERENCE......Page 292
17.2 SOURCES OF INFORMATION......Page 293
17.3.1 Introductory remarks......Page 294
17.3.2 Purpose of an application......Page 295
17.3.5 Submitting the application and supporting data......Page 296
17.3.7 Validation......Page 297
17.3.8 Professional assessment......Page 299
17.3.9 Reference to advisory bodies......Page 301
17.3.11 The issue of a product licence or clinical trial certificate......Page 306
17.4.1 The scope of the scheme......Page 307
17.4.2 How the procedure works......Page 308
17.5.2 The procedures......Page 309
17.7.1 Introduction......Page 310
17.7.3 Prescription only medicines......Page 311
17.7.4 General sales list products......Page 312
17.7.6 Changing legal status......Page 313
17.7.7.1 Radiopharmaceuticals......Page 315
17.7.7.4 Contact lenses and contact lens care products......Page 316
17.7.7.5  Topical hydrocortisone creams and ointments......Page 317
17.7.8 An outline of the legal status position in the EC......Page 318
APPENDIX 1 Statutory Instruments relating to the Medicines Act......Page 319
APPENDIX 2 Medicines act leaflets (MALs)......Page 325
18.2 THE EC MEMBER STATES......Page 328
18.3 THE ORGANISATION OF THE ASSESSMENT OF MARKETING AUTHORISATION APPLICATIONS (Table 18.3)......Page 330
18.4 THE ROLE OF THE NATIONAL COMMITTEES OF INDEPENDENT EXPERTS......Page 331
18.5 THE APPEALS PROCEDURES......Page 335
OF ACTIVE INGREDIENTS, INTERMEDIATES, AND FINISHED PRODUCTS .........Page 336
18.7 THE NAMES AND ADDRESSES OF NATIONAL AUTHORITIES IN THE EC MEMBER STATES......Page 338
REFERENCE......Page 340
19.1 INTRODUCTION......Page 341
19.4 WORKING PARTIES AND THEIR MEMBERSHIP......Page 342
19.6 REVISION OF EXISTING GUIDELINE TEXTS......Page 343
REFERENCE......Page 344
20.2.1 Implementation date......Page 345
20.2.4 New categories of exemptions from the Directives......Page 346
20.2.9 Testing of samples......Page 347
20.2.12 Inspections and good manufacturing practice......Page 348
20.2.15 Notification of suspensions and revocations......Page 349
REFERENCE......Page 350
21.2 THE CONSULTATION PROCESS......Page 351
21.4 THE PROPOSALS FOR PROCEDURES AFTER 1992......Page 352
21.5.2 Centralised applications......Page 353
21.7.1 Public health......Page 354
21.8 THE EUROPEAN MEDICINES EVALUATION AGENCY (EMEA)......Page 355
21.8.2 Administrative board......Page 356
21.8.5 The Scientific Council......Page 357
21.9.1 Products eligible for the procedure......Page 358
21.9.3 Appeals in the centralised procedure......Page 359
21.10.1 Products eligible for the decentralised procedure......Page 360
21.10.2 The working of the decentralised procedure......Page 361
21.10.3 Appeals in the decentralised procedure......Page 362
21.12 THE SUPERVISORY AUTHORITY......Page 363
REFERENCE......Page 364
Appendix Abbreviations and acronyms......Page 365
Index......Page 369