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Regulatory Requirements for the Clinical Development of New Therapies for the Treatment of Alzheimer's Disease

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Regulatory Requirements for the Clinical Development of New Therapies for the Treatment of Alzheimer's Disease Regulatory Requirements for the Clinical Development of New Therapies for the Treatment of Alzheimer’s Disease Wissenschaftliche Prüfungsarbeit Zur Erlangung des Titels “Master of Drug Regulatory Affairs” der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vorgelegt von Dr. Susanne Vambrie aus Heide Holstein Bonn 2009 Betreuerin und erste Referentin: Frau Dr. Ingrid Klingmann Zweiter Referent: Herr Dr. Mohamed Baccouche We shall not cease from exploration And the end of all our exploring Will be to arrive where we started And to know the place for the first time. T.S. Eliot ACKNOWLEDGEMENTS I would very much like to thank Dr. Ingrid Klingmann and Dr. Mohamed Baccouche for accepting to supervise my Master Thesis on top of their daily work and obligations towards the customers of their own CROs. Additionally, I am very grateful to my friend and former colleague Anita Crampton who volunteered to read my thesis and did not hold back with her critical comments. She always encouraged me and gave me a lot of mental and emotional support which enabled me to continue writing this thesis. Finally, I am deeply indebted to my three children. Despite the fact that I mention them last in the series of my thanks, they were actually the most important persons during the time of my Master studies and they are the most important persons in my life. Despite their young age they put up with me during the periods of exhaustion and frustration. They were never tired to push me to get my work done as quickly as possible so that I could join their much more important little projects of constructing a new railway station from Lego building blocks or baking Christmas biscuits with them. They are by now perfect counsellors and without their smiles, their love and their demands I would not have survived the past 18 months without loosing my sanity. DRA-Master-Thesis TABLE OF CONTENTS List of Abbreviations ................................................................................................... 7 1 Introduction........................................................................................................ 10 1.1 Aim of this Thesis........................................................................................ 10 1.2 Historical Background ................................................................................. 10 1.3 Current Understanding of the Pathology of Alzheimer’s Disease................ 11 1.3.1 Beta Amyloid....................................................................................... 11 1.3.2 Neurofibrillary Tangles ........................................................................ 12 1.3.3 Inflammation........................................................................................ 12 2 Current Treatment ............................................................................................. 13 2.1 Acetylcholine Esterase Inhibitors ................................................................ 13 2.2 NMDA Receptor Antagonists ...................................................................... 14 3 New Treatment Approaches in Development .................................................... 15 3.1 Actual Pipeline Overview............................................................................. 15 3.2 Rationale for the Various Mechanisms Examined for the Treatment of Alzheimer’s Disease.................................................................................... 17 3.2.1 Amyloid Synthesis Inhibitors ............................................................... 17 3.2.2 Amyloid Aggregation Inhibitors............................................................ 18 3.2.3 Chelating Agents................................................................................. 18 3.2.4 Nicotinic Acetylcholine Receptor Agonists .......................................... 18 3.2.5 Muscarinic Receptor Modulators......................................................... 19 3.2.6 5-HT (Serotonin) Receptor Modulators ............................................... 19 3.2.7 Ion Channel Modulators ...................................................................... 19 3.2.8 Phosphodiesterase (PDE) 4 Inhibitors ................................................ 20 3.2.9 Vaccines.............................................................................................. 20 4 Regulatory Requirements for the Clinical Development of Medicinal Products for the Treatment of Alzheimer’s Disease.............................................................. 21 4.1 EMEA.......................................................................................................... 21 4.1.1 CPMP/EWP/553/95 – Guideline on Medicinal Products in the Treatment of Alzheimer’s Disease........................................................................ 21 4.1.2 The Revised Guidance on Medicinal Products in the Treatment of Alzheimer’s Disease............................................................................ 23 4.1.3 Paediatric Investigation Plan (PIP) Waiver.......................................... 27 4.1.4 Geriatric Requirements ....................................................................... 28 4.2 FDA............................................................................................................. 29 4.2.1 Availability of Guidelines ..................................................................... 29 4.2.2 Paediatric Assessment Waiver............................................................ 31 4.2.3 Geriatric Requirements ....................................................................... 32 4.3 Comparison of the Guidance provided by the EMEA and the FDA ............. 32 5 Requirements Fulfilled for Approval by Already Marketed Alzheimer’s Therapies ......................................................................................................................... 33 5.1 Acetylcholine Esterase (AChE) inhibitors.................................................... 33 5.1.1 Europe ................................................................................................ 33 5.1.2 USA..................................................................................................... 37 5.1.3 Conclusion .......................................................................................... 39 5.2 NMDA Receptor antagonist......................................................................... 39 5.2.1 Europe ................................................................................................ 39 5.2.2 USA..................................................................................................... 43 Dr. Susanne Vambrie Bonn 2009 5 DRA-Master-Thesis 5.2.3 Conclusion .......................................................................................... 45 6 Outlook on New Therapies in Development for Alzheimer’s Disease................ 46 6.1 Tramiprosate (Alzhemed)............................................................................ 46 6.2 Tarenflurbil (Flurizan®) ................................................................................ 47 6.3 Conclusion .................................................................................................. 48 7 Idealised Clinical Development Plan for a Disease-Modifying Anti-Alzheimer Therapy ............................................................................................................ 49 8 Summary and Conclusion ................................................................................. 52 9 References ........................................................................................................ 54 10 Annex ................................................................................................................ 58 10.1 Pipeline Analysis ......................................................................................... 58 10.2 CPMP/EWP/553/95 (Revision 1) – Note for Guidance on Medicinal Products in the Treatment of Alzheimer’s Disease..................................................... 59 10.3 Guidelines for the Clinical Evaluation of Antidementia Drugs...................... 60 Dr. Susanne Vambrie Bonn 2009 6 DRA-Master-Thesis LIST OF ABBREVIATIONS AD Alzheimer’s Disease AChE Acetylcholine Esterase ADAS-cog Alzheimer’s Disease Assessment Scale-cognitive subscale ADCS-ADL Alzheimer's Disease Cooperative Study Unit - Activities of Daily Living Inventory ADCS-CGI-C Alzheimer's Disease Cooperative Study Unit – Clinician’s Global Impression of Change ADL Activities of Daily Living ADRDA Alzheimer's Disease and Related Disorders Association ADRQL Alzheimer’s Disease-Related Quality of Life Aph-1 Anterior pharynx-defective 1 APOE Apolipoprotein E APP Amyloid Precursor Protein BACE Beta-Site Amyloid precursor protein-Cleaving Enzyme BEHAVE-AD Behavioural Pathology in Alzheimer’s Disease Rating Scale BGP Behavioural Rating Scale in Geriatric Patients b.i.d. bis in die (Latin), twice daily BRSD Behavioural Rating Scale for Dementia cAMP cyclic Adenosine Monophosphate CAS Caregiver Activity Survey CDK5 Cyclin-Dependent-Kinase 5 CDR Clinical Dementia Rating Scale CDR-SB Clinical Dementia Rating Scale-Sum of Boxes CFR Code of Federal Regulations CGI-C Clinical Global Impression of Change CGI-S Clinical Global Impression-Severity scale CHMP Committee for Medicinal Products for Human Use CIBIC-plus Clinician’s Interview Based Impression of Change CNS Central Nervous System CPMP Committee for Proprietary
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