New drug substances with abuse potential: Points to consider for the development and marketing - Regulatory environment in the European Union and the United States - Wissenschaftliche Prüfungsarbeit zur Erlangung des Titels „Master of Drug Regulatory Affairs“ der Mathematisch-Naturwissenschaftlichen Falkultät der Rheinischen Friedrich-Wilhems-Universität Bonn vorgelegt von Dr. Silke Jung Bonn 2006 Betreuer und 1. Referent: Dr. Winfried Kleinert, Bundesopiumstelle (BfArM) Zweiter Referent: RA Burkhard Stäter, Anwaltskanzlei Sträter To my husband - for his patience and support - Danksagung An erster Stelle möchte ich mich ganz herzlich bei Herrn Dr. Winfried Kleinert und Herrn RA Burkhard Sträter für die Betreuung und Unterstützung meiner Arbeit bedanken. Mein besonderer Dank gilt auch Herrn Dr. Joachim Heinze und Herrn Dr. Burkahrd Daldrup, die mir den Besuch des ergänzenden Studiengangs „Master of Drug Regulatory Affairs“ ermöglicht haben. Für die kritische Durchsicht meiner Arbeit und die vielen hilfreichen Anmerkungen danke ich meine Kolleginnen Dr. Gesine Bejeuhr, Dr. Kim Goldenstein, Dr. Maren Großmüller, Dr. Carol Huntington und Dr. Barbara Römer. Besonderer Dank gilt nicht zuletzt auch meiner Familie, vor allem meinem Mann Dr. Guido Thömmes, die meine Arbeit mit Liebe und Unterstützung begleitet hat. TABLE OF CONTENTS A1 Table of contents Table of contents......................................................................................................................... A1 Abbreviations.............................................................................................................................. A4 1. Introduction ............................................................................................................................1 1.1. Regulatory control of substances of abuse................................................................................................ 1 1.2. Medicinal products and substances of abuse............................................................................................ 2 1.2.1. Opioids.................................................................................................................................................. 2 1.2.2. Barbiturates and benzodiazepines (CNS depressants) .......................................................................... 3 1.2.3. Stimulants.............................................................................................................................................. 3 1.3. Market access for medicinal products containing new psychoactive substances.................................. 3 2. Issues under Examination......................................................................................................5 3. Material, Methods and Glossary...........................................................................................7 3.1. Material and Methods used........................................................................................................................ 7 3.2. Glossary ....................................................................................................................................................... 7 4. Results & Discussion ..............................................................................................................9 4.1. Additional data requirements for new psychoactive substances................................................................... 9 4.1.1. General methods used to assess the abuse liability of drugs................................................................. 9 4.1.1.1. Abuse liability assessment in animal studies................................................................................. 9 4.1.1.1.1 Pharmacological profile ............................................................................................................. 9 4.1.1.1.2 Drug discrimination testing........................................................................................................ 9 4.1.1.1.3 Self-administration testing ....................................................................................................... 10 4.1.1.1.4 Physical dependence testing.....................................................................................................10 4.1.1.1.5 Other methodologies ................................................................................................................ 10 4.1.1.2. Abuse liability assessment in human studies............................................................................... 11 4.1.2. Additional data requirements in the U.S. ............................................................................................ 12 4.1.3. Additional data requirements in the European Union......................................................................... 14 4.1.4. Role of abuse liability assessments ..................................................................................................... 16 4.1.5. Conclusions......................................................................................................................................... 17 4.2. Classification and control of psychoactive substances...........................................................................18 4.2.1.1. International regulatory framework ............................................................................................ 18 4.2.1.1.1 Scope of international provisions............................................................................................. 18 4.2.1.1.2 Classification and control according to UN Conventions ........................................................ 18 4.2.1.1.3 Traditional opioids in the international scheduling system...................................................... 20 4.2.1.1.4 Levels of control....................................................................................................................... 20 4.2.1.2. Classification and control system in the European Union........................................................... 22 4.2.1.2.1. Legal framework relating to controlled substances and preparations ..................................... 22 4.2.1.2.2. Classification of controlled substances ................................................................................... 23 4.2.1.2.3. Levels of control...................................................................................................................... 23 4.2.2. National Provisions for classification and control ..............................................................................24 4.2.2.1. Classification and control system in United States ..................................................................... 24 4.2.2.1.1 Legal framework relating to controlled substances and preparations ...................................... 24 4.2.2.1.2 Classification of controlled substances .................................................................................... 24 4.2.2.1.3 Terminology............................................................................................................................. 25 4.2.2.1.4 Levels of control....................................................................................................................... 25 4.2.2.2. Classification and control system in France................................................................................ 29 4.2.2.2.1 Legal framework relating to controlled substances and preparations ...................................... 29 4.2.2.2.2 Classification of controlled substances .................................................................................... 29 4.2.2.2.3 Levels of control....................................................................................................................... 30 4.2.2.3. Classification and control system in Germany............................................................................ 32 4.2.2.3.1 Legal framework relating to controlled substances and preparations ...................................... 32 4.2.2.3.2 Classification of controlled substances .................................................................................... 32 4.2.2.3.3 Levels of control....................................................................................................................... 33 4.2.2.4. Classification and control system in Italy ................................................................................... 35 TABLE OF CONTENTS A2 4.2.2.4.1 Legal framework relating to controlled substances and preparations ...................................... 35 4.2.2.4.2 Classification of controlled substances .................................................................................... 35 4.2.2.4.3 Levels of control....................................................................................................................... 36 4.2.2.5. Classification and control system in Spain.................................................................................. 38 4.2.2.5.1 Legal framework relating to controlled substances and preparations ...................................... 38 4.2.2.5.2 Classification of controlled substances .................................................................................... 38 4.2.2.5.3 Levels of control....................................................................................................................... 38 4.2.2.6.