Aus der Klinik und Poliklinik für Nuklearmedizin der Ludwig-Maximilians- Universität München Direktor: Prof. Dr. med. Peter Bartenstein “Innovation through Cyclotron/ and Generator-based Positron Emission Tomography (PET) - Radiopharmaceuticals: Challenges and Barriers in Receiving Market Authorisation” Dissertation zum Erwerb des Doktorgrades der Humanbiologie an der Medizinischen Fakultät der Ludwig-Maximilians-Universität zu München vorgelegt von Georg Konwalinka aus Rum in Tirol (Österreich) Jahr 2019 2 Mit Genehmigung der Medizinischen Fakultät der Universität München Berichterstatter: Prof. Dr. Peter Bartenstein Mitberichterstatter: Prof. Dr. Clemens Cyran Prof. Dr. Claus Belka Dekan: Prof. Dr. med. dent. Reinhard Hickel Tag der mündlichen Prüfung: 21.10.2019 3 Eidesstattliche Erklärung Hiermit erkläre ich, dass ich die vorliegende Arbeit eigenständig und ohne fremde Hilfe angefertigt habe. Textpassagen, die wörtlich oder dem Sinn nach auf Publikationen oder Vorträgen anderer Autoren beruhen, sind als solche kenntlich gemacht. Die Arbeit wurde bisher keiner anderen Prüfungsbehörde vorgelegt und auch noch nicht veröffentlicht. München, 06.06.2019 Georg Konwalinka 4 „All I know is that I know nothing.“ (Socrates, * ~ 469 before Chr, † 399 AD) A very special thanks to my doctoral supervisor Professor. Dr. med. Peter Bartenstein with whom I was able to work on an innovative and interesting topic. I thank him for his continuous dedicated support, which, despite his abundance of everyday tasks, had not to wait. I want to thank him for many interesting discussions, his visionary thinking and the effort to teach me complex issues. The collaboration with Prof. Bartenstein has challenged and encouraged me in my scientific and personal development. I would also like to give thanks to my colleagues from the various disciplines, who have pointed out new perspectives in the critical discussion and have encouraged me in my endeavour to write this thesis. Many thanks also to the numerous internationally recognized experts in the field nuclear medicine from university / medical research centres, practitioners from well-known clinic institutions, scientists in the various industries and also the experts of public law institutions. They offered me their free time to conduct these interviews, the basis to ultimately finish this thesis. Furthermore I want to thank Dr. Leonie Beyer who supported me with an excellent proof-reading of the scientific medical part, and Miss Egg, who has checked grammar and spelling of this extensive work several times. My special thanks to my friends and my family. They accompanied me during this journey and always supported me, in beautiful moments but also in times of doubt. 5 Table of ContentsTable of Figures 9 List of Tables ............................................................................................................................................ 10 1.1 Introduction to the Research Topic: .................................................................. 12 1.2 Statement of the Research Problem: ................................................................ 13 1.3 Statement of the Purpose of this Study ............................................................ 15 1.4 Methodology ..................................................................................................... 16 1.4.1 Quantitative Research – Focused Literature Review ......................................................... 17 1.4.2 Qualitative Research – Expert Interviews .......................................................................... 18 2 Role of Nuclear Medicine in Oncology ........................................................................................... 25 2.1 Theranostics – combining diagnostics and therapy .......................................... 26 2.2 Case 1 - Somatostatin Receptor Scintigraphy in Neuroendocrine Tumours (NETs) 27 2.2.1 Epidemiological data .......................................................................................................... 28 2.2.2 Diagnostic workup of NETs –Biochemical Markers ........................................................... 29 2.2.3 Therapy Options in the Treatment of NETs ....................................................................... 31 2.2.4 Specific Targeting via Somatostatin Analogues - Imaging ................................................. 32 2.2.5 Peptide Receptor Radionuclide Therapy (PRRT) with Somatostatin Analogues ............... 40 2.3 Case II- Radionuclide Imaging and Therapy in Prostate carcinoma ................... 47 3 Current Challenges in the Radiopharmaceutical Industry – A Case Story of DOTATATE ............... 65 3.1 The long Way to Market Authorisation ............................................................. 67 I. Economic and Market-related Challenges ......................................................................... 68 II. Research and Development Challenges ............................................................................ 69 III. Regulation and Marketing Authorisation Challenges ........................................................ 69 IV. Reimbursement and Revenue Planning Challenges .......................................................... 69 V. Different goals between the Scientific Community and Investors/Industry ..................... 69 VI. Special Manufacturing, Distribution and Handling of Radiopharmaceuticals ................... 69 3.2 Market Size and Potential .................................................................................. 71 3.2.1 The Radiopharmaceutical Market Potential and Investors Interest ................................. 72 3.3 Barriers and Challenges associated with Research and Development (R&D): .. 74 3.3.1 High Development Costs and Low Chances of Success – Conventional Drugs .................. 74 3.3.2 High Development Costs and Low Chances of Success – RP Imaging Markers ................. 76 3.4 Intellectual Property Right Issues ...................................................................... 78 3.4.1 Academic Institutions and Intellectual Property Rights .................................................... 79 3.5 Experimental RPs are not Evolving .................................................................... 81 3.5.1 Imaging Markers are not Validated ................................................................................... 83 3.6 Regulation and Marketing Authorisation .......................................................... 85 3.6.1 Challenges in the Regulatory and Safety Approval Process .............................................. 85 3.6.2 Regulatory Approval Process in Medical Imaging and Radiopharmaceuticals .................. 86 3.7 Uncertainty in Reimbursement and Revenue Planning..................................... 90 3.7.1 The challenge of rising healthcare costs ............................................................................ 90 3.7.2 Reimbursement – The Change of Systems ........................................................................ 92 3.7.3 Reimbursement of PET (PET/CT) Procedures and Imaging Biomarkers in Germany ........ 93 3.7.4 Reimbursement as an area of uncertainty ........................................................................ 95 3.8 Different Goals between Scientific Community and Investors/ Industry .......... 96 3.8.1 Different goals in Industry- and Academic Research ......................................................... 96 3.9 Limited Knowledge in the Scientific Community, outside the Nuclear Medicine Community .......................................................................................................................... 98 3.9.1 The Effect of Clinical Practice Guidelines on Nuclear Medicine Awareness ..................... 99 6 3.10 Special Manufacturing, Distribution and Handling of Radiopharmaceuticals: 100 3.10.1 Manufacturing: ................................................................................................................ 100 3.10.2 The Challenge of Distribution and Logistics .................................................................... 101 3.10.3 Handling: .......................................................................................................................... 101 4 Empirical Results:.......................................................................................................................... 103 4.1 The Role of Imaging ......................................................................................... 103 4.2 Radiopharmaceuticals ..................................................................................... 106 4.2.1 Issue with Reimbursement .............................................................................................. 108 4.2.2 Challenge with Regulations ............................................................................................. 113 4.2.3 The Issue with Market Potential ..................................................................................... 116 4.2.4 The Issue with Research and Development .................................................................... 120 4.2.5 The Issue with Intellectual Property Rights (IPR): ........................................................... 124 4.2.6 The Issue with Manufacturing, Distribution and Handling ............................................. 129 4.3 Diagnostic Radiopharmaceuticals used as Companion Diagnostics ................ 132 4.3.1 The Stakeholder´s Definitions of