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This publication, New Drug Approval in the European Union, provides an in-depth analysis of the rapidly maturing centralized and mutual recognition procedures. This publication also looks ahead to the development of an all-important clinical directive that will standardize clinical trial procedures throughout Europe.
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Introduction 1 Road to the European Union 3 Road to the European Medicines Evaluation Agency (EMEA) 3 The European Agency for the Evaluation of Medicinal Products 5 The Committee for Proprietary Medicinal Products (CPMP) 6 The Centralised Procedure 7 The Mutual Recognition Procedure 9 Harmonisation Efforts 10Chapter 1. The European Regulatory Bodies and Institutions 17 The Birth of the EMEA and the European Authorisation System 17 The European Agency for the Evaluation of Medicinal Products (EMEA) 18 The Management Board 20 The Committee for Proprietary Medicinal Products 22 The Permanent Secretariat 25 The European Commission 30 Tasks Performed by the EMEA 35 National Agencies 43 Austria 44 Belgium 44 Denmark 45 Finland 45 France 46 Germany 46 Greece 47 Iceland 47 Ireland 48 Italy 48 Luxembourg 49 The Netherlands 49 Norway 50 Portugal 50 Spain 51 Sweden 52 United Kingdom 52Chapter 2. Strategic Criteria for the Selection of a Registration Procedure in Europe 55 Part A Products 57 Part B Products 58 Factors Influencing the Regulatory Strategy 59 The Trademark Issue 59 Co-Licensing/co-promotional Agreement Issues 60 Data Exclusivity/Patent Issues 61 Regulatory Issues 61 The Selection of the Reference Member State for the Mutual Recognition Procedure 62 The Selection of the Rapporteur for the Centralised Procedure 64 Non Part A, Non Part B Products 64Chapter 3. The Centralised Procedure 67 The Centralised Procedure: When It Is Mandatory and When It Is Optional 69 Product (trade) names 70 The Centralised Procedure 72 Pre-Filing Stage 72 EMEA Consultation 73 Confirming a Product’s Part B Status 74 Intention-to-File Letter 75 The CPMP’s Selection of Rapporteurs 77 Filing the Centralised Application with the EMEA 81 Assessment Period I 85 Pre-approval Inspections 86 Clock Stops 88 Assessment Period II 90 Hearings 91 Accelerated Review Procedures and Conditional Approvals 93 The CPMP Opinion 95 The Appeals Process 96 The Decision-Making Process 96 European Public Assessment Report 98 Co-licensing Agreements and the Centralised Procedure 99 The CADREAC Procedures 100 Succeeding with the Centralised Procedure 102Chapter 4. The Decentralised or Mutual Recognition Procedure and the Use of the National Procedures 107 Mutual Recognition of a Marketing Application 108 Mutual Recognition Initiated by a Competent Authority (Parallel Approach) 109 Mutual Recognition Initiated by the Applicant (Serial Approach) 111 Summary of the Mutual Recognition/Decentralised Procedure 111 Selecting the Reference Member State 115 Assessment of the Application by the Reference Member State 118 Updating the Dossier for the Mutual Recognition Procedure 119 The Submission and Validation of the Application in the Concerned Member States 120 Notification to the CPMP. 123 Multiple Applications (“Clones”) 123 A Closer Analysis of the Mutual Recognition Process 124 Day 1 to 90 of the Mutual Recognition Process… 124 Applicant Responses to Concerned Member States 126 Mutual Recognition Facilitation Group Break-Out Session 127 Community Referral for Arbitration 129 Implementation of a Mutual Recognition at the National Level 131 Experience with and the Performance of the Mutual Recognition Procedure 133 The Use of the National Procedures 134 Marketing Authorisation in One Member State Only 134 Other Situations in which National Procedures Can Be Used 135Chapter 5. Community Referrals and the CPMP Arbitration Procedure 139 Referrals Under Article 10 (Mutual Recognition Procedure) 142 Referrals Under Article 11 (Divergent Decisions) 147 Referrals Under Article 12 (Community Interest) 150 Referrals Under Article 15 (Protection of Public Health and Variations) 153 The CPMP Arbitration Procedure 155Chapter 6. The Development Process and Clinical Trial Authorisation Procedures for Medicinal Products 163 Clinical Trial Authorisations 163 National Clinical Trial Authorisation Requirements in the EU/EEA Today 164 Austria 166 Belgium 167 Denmark 167 Finland 168 France 169 Germany 171 Greece 173 Iceland 174 Ireland 175 Italy 178 Luxembourg 182 The Netherlands 182 Norway 183 Portugal 185 Spain 186 Sweden 187 United Kingdom 189 The European Union’s Clinical Trial Directive 191 Ethics Committee Review of Clinical Trials 192 Competent Authority Notification 193 Amendments to Study Protocol 194 Termination 194 European Clinical Trials Database… 194 Suspension 195 Manufacturing and Import 195 Labelling 195 Compliance with Good Clinical and Manufacturing Practices 195 Notification of Adverse Events 195 Obtaining Drug Development Guidance and Advice from European Regulatory Authorities 196 Obtaining Regulatory Advice from National Experts and Agencies for Drug Development 198 Scientific Advice from the EMEA/CPMP for Drug Development 199 Good Manufacturing Practice, Good Laboratory Practice, and Good Clinical Practice 202 GMP in Europe 202 GLP in Europe 203 GCP in Europe 203 Alternative Medicinal Products 203 Orphan Medicinal Products 207 Medicinal Products for Paediatric Use 212 Compassionate Use 212 Appendix I: Complete List of European Union Guidelines 217Chapter 7. The Marketing Authorisation Application 245 The Marketing Authorisation Application and the Notice to Applicants (NTA) 245 Categories of Marketing Application Files in Europe 247 Complete/Full and Independent Applications or Stand-Alone Applications 248 Abridged Applications 249 Applications for Fixed Combinations 252 Line Extension Applications and Amendments to an Existing Marketing Authorisation Requiring a New Application 253 Content Requirements for Complete and Independent Applications (Stand Alone) 255 Part I of the Application 255 Part IA 255 Part IB 259 Part IC 260 Part II-Chemical, Pharmaceutical and Biological Documentation 263 Part III-Pharmaco-toxicological Documentation 263 Part IV-Clinical Documentation 264 The Common Technical Document 264 The Dossier Check-In Procedure 267 Electronic Submissions 267Chapter 8. The Summary of Product Characteristics, Package Leaflet and Package Labelling 275 The Summary of Product Characteristics 277 The SPC for Products Reviewed Under the Centralised Procedure 279 The SPC for Products Under the Mutual Recognition Procedure 282 The European Commission’s Guideline on the SPC 283 The User Package Leaflet 284 Package Labelling 286 Advertising of Medicinal Products and the SPC 288 Classification for the Supply of Medicinal Products 288Chapter 9. Pharmacovigilance… 291 The EU Responsible Person 292 Requirements Relating to Adverse Experience Reporting in the EU 294 Regulation 2309/93/EEC 295 Directive 93/39/EEC 295 Guidelines on Adverse Experience Reporting 297 Volume 9 of the Notice to Applications-Section 1 298 The Collection, Verification, and Presentation of Adverse Event/Reaction Reports from Clinical Trials 312 Pharmacovigilance Crisis Management 315 Conclusions on Pharmacovigilance 316 Product Defects 317Chapter 10. Maintaining the License: Variations, Annual Re-assessments, and Renewals 325 The Variation Regulations 326 Variations Requiring New Applications 327 Type I Variations 329 Type II Variations 332 Urgent Safety Restrictions 337 Variations for Products Approved Under the National Procedures Without Mutual Recognition 337 Austria 338 Belgium 338 Denmark 338 Finland 338 France 338 Germany 339 Greece 340 Iceland 340 Ireland 340 Italy 340 Luxembourg 340 The Netherlands 340 Norway 341 Portugal 341 Spain 341 Sweden 342 UK 342 Changes to the Carton, Label and Package Leaflet 342 Annual Re-assessment 342 Renewals 343Chapter 11. The Future Regulatory Situation in Europe as the 21st Century Begins 349 Proposed Changes to Regulation EEC 2309/93 351 Mandatory Use of the Centralised Procedure 351 Other Changes 352 Proposed Changes to Directive 2001/83/EC 353 Variation Regulations, (EC) No 541/95, and (EC) No 542/95 355
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