CURRENT EXPERIENCE WITH PIP APPROVALS Wissenschaftliche Prüfungsarbeit zur Erlangung des Titels „Master of Drug Regulatory Affairs“ der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vorgelegt von Viktoria Behse aus Münster Bonn 2010 Disclaimer While every reasonable precaution has been taken in the preparation of this document, the author does not assume responsibility for errors or omissions. The information contained in this document is believed to be accurate. However, no guarantee is provided. Use this information at your own risk. Betreuer und 1. Referent: Frau Dr. Ingrid Klingmann Zweiter Referent: Frau Dr. Birka Lehmann Wissenschafltliche Prüfungsarbeit von Viktoria Behse Page 3 Current experience with PIP approvals 16 May 2010 TABLE OF CONTENTS TABLE OF CONTENTS........................................................................................................ 3 LIST OF TABLES .................................................................................................................. 5 LIST OF FIGURES ................................................................................................................ 5 LIST OF ABBREVIATIONS................................................................................................. 6 1 INTRODUCTION...................................................................................................... 7 2 OBJECTIVE............................................................................................................... 8 3 BACKGROUND INFORMATION.......................................................................... 8 3.1 THE PAEDIATRIC REGULATION................................................................... 8 3.2 THE PAEDIATRIC COMMITTEE................................................................... 10 3.3 PAEDIATRIC DISEASES AND NEEDS ......................................................... 11 3.4 PAEDIATRIC POPULATION .......................................................................... 12 3.5 PAEDIATRIC INVESTIGATION PLAN ......................................................... 14 3.5.1 Paediatric Investigation Plan....................................................................... 14 3.5.2 Waiver......................................................................................................... 14 3.5.3 Deferral ....................................................................................................... 15 3.5.4 Elements of the PIP application.................................................................. 15 3.5.5 Procedure for the application and assessment ............................................ 15 4 CURRENT STATUS................................................................................................ 18 4.1 PDCO – PUBLISHED DATA ........................................................................... 18 4.2 EMA – PUBLISHED DATA ............................................................................. 20 5 ANALYSIS AND DISCUSSION............................................................................. 21 5.1 LENGTH OF TIME ........................................................................................... 21 5.1.1 Period: submission to start of procedure..................................................... 21 5.1.2 Period: PDCO opinion to EMA decision.................................................... 22 5.1.3 Period: Start of procedure to EMA decision............................................... 23 5.1.4 Period: EMA decision to publication.......................................................... 24 5.2 INFORMATION ON THE MEDICINAL PRODUCT...................................... 25 5.2.1 Therapeutic area, condition and active substance....................................... 25 5.2.2 Route of administration and pharmaceutical form...................................... 27 5.3 PIP AND PIP MODIFICATIONS ..................................................................... 28 Wissenschafltliche Prüfungsarbeit von Viktoria Behse Page 4 Current experience with PIP approvals 16 May 2010 5.3.1 Date of completion...................................................................................... 28 5.3.2 Deferral ....................................................................................................... 29 5.3.3 Measures ..................................................................................................... 29 5.4 WAIVER ............................................................................................................ 29 5.5 STUDIES............................................................................................................ 30 5.5.1 Clinical studies............................................................................................ 32 5.5.2 Preclinical studies ....................................................................................... 34 5.5.3 Quality studies ............................................................................................ 35 6 PUBLIC INDUSTRY EXPERIENCES.................................................................. 35 6.1 ADVICE............................................................................................................. 35 6.2 PREPARATION OF PIP/WAIVER SUBMISSIONS ....................................... 36 6.2.1 Timing......................................................................................................... 36 6.3 VALIDATION ................................................................................................... 37 6.3.1 Preclinical information ............................................................................... 37 6.3.2 Clinical information.................................................................................... 37 6.3.3 Quality information..................................................................................... 39 6.4 EVALUATION .................................................................................................. 39 6.4.1 Waiver......................................................................................................... 39 6.4.2 PIP /Waiver assessment procedure ............................................................. 40 6.4.3 Modification of PIP .................................................................................... 40 6.5 COMPLIANCE CHECK.................................................................................... 41 6.6 CONCLUSION .................................................................................................. 41 7 STRATEGIES FOR PIP APPLICATIONS .......................................................... 41 8 SUMMARY AND OUTLOOK ............................................................................... 43 LIST OF REFERENCES ..................................................................................................... 45 LIST OF APPENDICES....................................................................................................... 50 APPENDIX 1: NUMBERING OF DOCUMENTS RELATING PAEDIATRIC PROCEDURES ........................................................................................................ 51 APPENDIX 2: INTEGRATED OPINIONS AND DECISIONS ON PIP/WAIVER APPLICATIONS...................................................................................................... 52 APPENDIX 3: DATA ON THERAPEUTIC AREAS AND THEIR CONDITIONS AND ACTIVE SUBSTANCES ............................................................................... 68 APPENDIX 4: ASPECTS TO CONSIDER BY THE PREPARATION OF THE PIP APPLICATION ................................................................................................ 78 Wissenschafltliche Prüfungsarbeit von Viktoria Behse Page 5 Current experience with PIP approvals 16 May 2010 LIST OF TABLES Table 1 Types of applications and relating Articles ......................................................... 8 Table 2 Characterisation and categorisation of the paediatric population ...................... 13 Table 3 Description of the phases of the PIP/waiver/modification application procedure ........................................................................................................... 17 Table 4 Top 5: Rapporteur or Peer-Reviewer and the corresponding percentage number of procedures (period: 08/2007 to 12/2009) ......................................... 20 Table 5 Overview on analysed decisions including subgroups ...................................... 21 Table 6 Attended time between submission and start of procedure ............................... 22 Table 7 Attended time between PDCO opinion and EMA decision............................... 23 Table 8 Attended time between PDCO opinion and EMA decision; re-examination procedure ........................................................................................................... 23 Table 9 Duration in days between final decision and publication .................................. 25 Table 10 Overview on therapeutic areas and their number of different conditions and active substances......................................................................................... 26 Table 11 Given routes of administrations and their pharmaceutical forms ...................... 27 Table 12 Overview on studies (N=753)............................................................................ 31 Table 13 Maximum number of studies and their frequency of occurrence .....................