Composing Policy Interventions for Antibiotic Development Christopher Okhravi Composing Policy Interventions for Antibiotic Development Dissertation presented at Uppsala University to be publicly examined in Lecture Hall 2, Ekonomikum, Kyrkogårdsgatan 10A, Uppsala, Tuesday, 29 September 2020 at 13:15 for the degree of Doctor of Philosophy. The examination will be conducted in English. Faculty examiner: Jonathan Michie, Professor of Innovation and Knowledge Exchange at the University of Oxford, Director of the University's Department for Continuing Education. Abstract Okhravi, C. 2020. Composing Policy Interventions for Antibiotic Development. 173 pp. Uppsala: Uppsala University. ISBN 978-91-506-2838-8. Antibiotic resistance is eroding the efficacy of the drugs we have and, unless future science dictates otherwise, bacteria will eventually become resistant to whatever new antibiotics we discover. We must therefore plan for a continuous stream of innovation. Unfortunately, pharmaceutical firms have left the scene to pursue more profitable areas. While the free market may eventually give rise to a solution, the question is how much destruction we are willing to accept on the way, and whether it eventually will be too late. A plethora of policy interventions, aimed at stimulating antibiotic research and development, have been suggested, and simulation modelers have begun estimating their effects. Suggested interventions range from prizes, grants, and competitions to regulatory fast-tracking and non-profit development. No unified picture of what to do has emerged. From the perspective of policy-makers, the need does not seem to be for more but for better information. This thesis suggests that to truly compare policy interventions, aimed at stimulating antibiotic development, we should draw on simulation model alignment techniques. To support such an endeavor this thesis presents the seeds of a compositional language capable of formally expressing policy interventions as offers that can be actualized into contracts. The language is not merely theoretical but implementable and usable within actual simulation models. The language is not only derived from previous research on compositional contracts in functional languages and the resources- events-agents ontology, but also the author's unique position as a participant in DRIVE-AB, which comprised 16 public and 7 private partners from 12 countries, and finally six separately published simulation experiments that are all based on work by the author. A constructive proof is provided to establish the utility of the solution in terms of its capacity to capture important facets of important policy interventions. Keywords: evidence-based policy, simulation, antibiotics, ontology, composition, alignment, docking, contracts, REA, research and development, design science research, domain-specific language Christopher Okhravi, Department of Informatics and Media, Kyrkogårdsg. 10, Uppsala University, SE-751 20 Uppsala, Sweden. © Christopher Okhravi 2020 ISBN 978-91-506-2838-8 urn:nbn:se:uu:diva-417037 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-417037) By making things as similar as possible their differences emerge. Acknowledgements My sincerest gratitude is extended to the following few individuals who in various ways have supported me at critical junctures on this journey. Steve McKeever Simone Callegari Enrico Baraldi Francesco Ciabuschi Carl Anderson Kronlid Olof Lindahl Jenny Eriksson Lundström Martin Stojanov Görkem Paçacı Madelen Hermelin Mattias Nordlindh Anneli Edman Owen Eriksson Many names are left unmentioned to emphasize the weight of my gratitude extended to the above. I am convinced that you who remain unmentioned already know that you truly are valued as a colleague or friend. Finally, I wish to express my heartfelt gratitude to my significant other and my parents for their love, strength, and unending support. Funding Part of this work has received support from the Innovative Medicines Initia- tive Joint Undertaking under grant agreement n◦115618, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind con- tribution. Disclosure The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Contents 1 Introduction .................................................................................................. 9 1.1 Problem ........................................................................................... 11 1.2 Research question .......................................................................... 15 1.3 Contributions .................................................................................. 18 1.4 Context ............................................................................................ 20 1.5 Related simulation work ................................................................ 21 1.6 Overview ......................................................................................... 24 2 Background ................................................................................................ 26 2.1 Antibiotic resistance ....................................................................... 26 2.2 Development of antibiotics ............................................................ 27 2.3 Economics of antibiotics ............................................................... 30 2.4 Policy interventions for antibiotics ............................................... 33 2.5 Evidence-based policy ................................................................... 34 2.6 Docking and alignment .................................................................. 37 2.7 Domain specific languages ............................................................ 40 3 Theory ........................................................................................................ 42 3.1 Agent-based modeling ................................................................... 42 3.2 Resources, events, and agents ....................................................... 47 3.3 Compositional financial contracts ................................................. 58 4 Methodology .............................................................................................. 72 4.1 Paradigm ......................................................................................... 72 4.2 Research strategy ........................................................................... 72 4.3 Research output .............................................................................. 73 4.4 Evaluation ....................................................................................... 75 4.5 Delimitations .................................................................................. 76 5 Experiments ............................................................................................... 78 5.1 Summary of experiments ............................................................... 78 5.2 Detailed case ................................................................................... 80 6 Objectives of a solution ............................................................................. 92 6.1 Compositionality ............................................................................ 93 6.2 Actualizability ................................................................................ 93 6.3 Prospectability ................................................................................ 95 6.4 Atomicity ........................................................................................ 97 6.5 Transferability ................................................................................ 99 6.6 Transformability ............................................................................. 99 6.7 Optionality .................................................................................... 100 6.8 Parallel conjunctivity ................................................................... 101 6.9 Sequential conjunctivity .............................................................. 102 6.10 Conditionality ............................................................................... 104 6.11 Scalability ..................................................................................... 106 6.12 Causality ....................................................................................... 108 6.13 Finality .......................................................................................... 109 6.14 Cyclicity ........................................................................................ 110 6.15 Reducibility .................................................................................. 111 7 Solution space .......................................................................................... 113 7.1 Behavers ....................................................................................... 113 7.2 State .............................................................................................. 116 7.3 Execution ...................................................................................... 117 8 Proposal .................................................................................................... 121 8.1 Contracts ......................................................................................