IMPACT of INDUSTRY TRANSFORMATION on the LIFECYCLE of PHARMACEUTICAL PRODUCTS: a Science and Risk Based Perspective

IMPACT OF INDUSTRY TRANSFORMATION ON THE LIFECYCLE OF PHARMACEUTICAL PRODUCTS: A Science and Risk Based Perspective NADER SHAFIEI A thesis submitted in partial fulfilment of the requirements of Liverpool John Moores University for the degree of Doctor of Philosophy School of Pharmacy and Biomolecular Sciences April 2013 Dedication I dedicate this thesis: to my wife Amanda for her support, patience and devotion without whom none of this would be possible; to my children David and Amelia; to my parents for always encouraging me to strive for new heights. And To the memory of our grandparents who left fingerprints of grace on our lives; they shall not be forgotten! ii Table of Contents ACKNOWLEDGEMENTS ........................................................................... VII AUTHOR’S DECLARATION ...................................................................... VII COPYRIGHT CONSIDERATIONS ............................................................... VII ABSTRACT…………………… ..................................................................... VIII LIST OF FIGURES .................................................................................... IX LIST OF TABLES ...................................................................................... X LIST OF ACRONYMS AND ABBREVIATIONS .............................................. XII DEFINITIONS………………… ..................................................................... XIII STRUCTURE OF THIS THESIS ..................................................................... 1 PREFACE………..………… ............................................................................ 3 CHAPTER 1: INTRODUCTION ................................................................... 5 1.1 DEVELOPMENT OF THE PHARMACEUTICAL INDUSTRY ...................... 5 1.1.1 Early days of pharmacy (ancient times to 1100 AD) .................................................. 5 1.1.2 Pharmacy in the medieval times (1100 – 1617 AD) ................................................... 6 1.1.3 Pharmacy in early modern times (1617 – 1841 AD) .................................................. 7 1.1.4 Role of bacteriology, physiology and pharmacology .................................................. 8 1.1.5 The emergence of pharmaceutical industry (1860 – 1930) ........................................ 9 1.1.6 The modern pharmaceutical industry ....................................................................... 12 1.2 PHARMACEUTICAL REGULATORY ENVIRONMENT ............................. 12 1.2.1 Regulatory environment in the EU ........................................................................... 13 1.2.2 Regulatory environment in the US ........................................................................... 15 1.2.3 World Health Organization (WHO) ........................................................................... 17 1.2.4 The historical events driving the need for regulations .............................................. 17 1.2.5 Pharmaceutical regulations and quality ................................................................... 17 1.3 CURRENT CHALLANGES IN THE PHARMACEUTICAL INDUSTRY ... 19 1.3.1 Ongoing industry transformation .............................................................................. 19 1.3.2 The regulators reaction ............................................................................................ 20 1.3.3 The industry reaction ............................................................................................... 21 1.3.4 The role of the pharmaceutical quality ..................................................................... 21 1.3.5 Rationale for the research and importance to the Pharmaceutical Industry ............. 22 1.4 AIMS AND OBJECTIVES OF THIS THESIS ............................................... 24 1.4.1 Research Objectives ............................................................................................... 24 1.4.2 Overview of the methods used to accomplish the research objectives .................... 25 CHAPTER 2: CHARACTERISATION OF THE PHARMACEUTICAL REGULATORY ENVIRONMENT .................................................................. 26 2.1 INTRODUCTION ................................................................................................. 26 2.2 LITERATURE SEARCH AND REVIEW ......................................................... 26 2.2.1 Purpose and inclusion criteria (Step1) ........................................................ 27 2.2.2 Databases and search phrases (Step 2) .................................................... 27 2.2.3 Selection of primary articles (Step 3) .......................................................... 31 2.2.4 Qualitative reviews of the primary articles (Step 4)................................ 31 2.2.5 Identification of important regulatory events (Step 5) ............................ 32 2.2.6 Identification of regulatory trends with respect to key factors driving pharmaceutical regulations (Step 6) ............................................................ 32 2.3 RESULTS AND DISCUSSION......................................................................... 32 2.3.1 Rationale relating to method selection ....................................................... 33 2.3.2 Public health protection ................................................................................... 34 2.3.3 Public health promotion and advancement ................................................ 35 2.3.4 Crisis management ............................................................................................ 36 2.3.5 Harmonization ..................................................................................................... 37 2.3.6 Fostering innovation ......................................................................................... 38 2.3.7 Modernization ..................................................................................................... 39 2.3.8 Discussion............................................................................................................ 40 2.3.9 Summary of the salient points ....................................................................... 42 iii CHAPTER 3: IDENTIFICATION AND RANKING OF TRIGGERS IMPACTING THE INDUSTRY TRANSFORMATION: A SYSTEMATIC REVIEW OF THE LITERATURE…………………..…. ................................................................. 43 3.1 INTRODUCTION ................................................................................................. 43 3.2 METHOD ............................................................................................................... 44 3.2.1 Selection of primary articles (Step 1) .......................................................... 45 3.2.2 Review of the primary articles (Step 2) ...................................................... 47 3.2.3 Selection of derived articles (Step 3) .......................................................... 47 3.2.4 Testing for article diversity (Step 4) ............................................................ 47 3.2.5 Search for transformation triggers in all articles (Step 5) .................... 48 3.2.6 Ranking of transformation triggers (Step 6) .............................................. 49 3.3 RESULTS AND DISCUSSION......................................................................... 51 3.3.1 Results for article search and article diversity testing ........................... 51 3.3.2 Results of the literature review ..................................................................... 52 3.4 CONCLUSIONS .................................................................................................. 58 CHAPTER 4: ESTABLISHMENT OF OPERATIONAL EVIDENCE IN SUPPORT OF THE TRANSFORMATION TRIGGERS: A SYSTEMATIC ANALYSIS OF THE OPERATIONAL EVIDENCE ........................................................................ 59 4.1 INTRODUCTION ................................................................................................. 59 4.2 METHOD ............................................................................................................... 59 4.2.1 Description of the product related databases ........................................... 59 4.2.2 Operational data collection and analysis ................................................... 60 4.2.2.1 Trigger 1 - Healthcare Management Focused ................................... 61 4.2.2.2 Trigger 2 - Fully Integrated Pharma Network .................................... 61 4.2.2.3 Trigger 3 – Personalised Medicine ....................................................... 62 4.2.2.4 Trigger 4 – Virtual R&D ............................................................................ 62 4.2.2.5 Trigger 5 – Translational Research ...................................................... 63 4.2.2.6 Trigger 6 – Adaptive Trials ..................................................................... 63 4.2.2.7 Trigger 7 – Regulatory Harmonisation ................................................. 63 4.2.2.8 Trigger 8 – Science and Risk Based Regulations ............................ 64 4.2.2.9 Trigger 9 – Progressive/Live Licensing ............................................... 64 4.2.2.10 Trigger 10 – Regulatory Enforcement.............................................. 64 4.2.2.11 Trigger 11 – Biotechnology ................................................................. 65 4.2.2.12 Trigger 12 – Nanomedicine ................................................................

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