Oncotyrol – Center for Personalized Cancer Medicine: Methods and Applications of Health Technology Assessment and Outcomes Research

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Oncotyrol — Center for Personalized Cancer Medicine: Methods and Applications of Health Technology Assessment and Outcomes Research Oncotyrol — Center for Personalized Cancer Medicine: Methoden und angewandte Projekte in Health Technology Assessment und Versorgungsforschung Uwe Siebert 1,2,3,4,∗, Beate Jahn 1, Ursula Rochau 1,2, Petra Schnell-Inderst 1,2, Agnes Kisser 5, Theresa Hunger 1,2, Gaby Sroczynski 1,2, Nikolai Mühlberger 1,2, Wolfgang Willenbacher 6, Simon Schnaiter 7, Gottfried Endel 8, Lukas Huber 9,10, Guenther Gastl 6 , on behalf of the Oncotyrol HTA & Outcomes Research Working Groupa 1

Institute of Public Health, Medical Decision Making and Health Technology Assessment, Department of Public Health and Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics and Technology, Hall i.T., Austria ∗

a

Corresponding Author: Uwe Siebert, MD, MPH, MSc, ScD, Professor of Public Health (UMIT), Adjunct Professor of Health Policy and Management (Harvard University), Chair, Department of Public Health and Health Technology Assessment, UMIT - University for Health Sciences, Medical Informatics and Technology, Eduard Wallnoefer Center I, A-6060 Hall i.T., AUSTRIA. Tel.: +43(0)50-8648-3930; fax: +43(0)50-8648-673931. E-Mails: [email protected], [email protected] (U. Siebert). Oncotyrol HTA & Outcomes Research Working Group: Allerstorfer, Sigrid (Roche Diagnostics GmbH, Vienna, Austria), Biskupiak, Joseph (Dept. of Pharmacotherapy and Program in Personalized Health Care, University of Utah, Salt Lake City, USA), Brixner, Diana (Dept. of Pharmacotherapy and Program in Personalized Health Care, University of Utah, Salt Lake City, USA), Dietz, Birgitta (AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany), Hebborn, Ansgar (F. Hoffmann-La Roche AG, Basel, Switzerland), Höß, Victoria (Roche Austria GmbH, Vienna, Austria), Holzner, Bernhard (ESD Evaluation Software Development, Rum, Austria), Horninger, Wolfgang (Department of Urology, Innsbruck Medical University, Innsbruck, Austria), Klocker, Helmut A. (Department of Urology, Innsbruck Medical University, Innsbruck, Austria), Krahn, Murray D.(Toronto Health Economics and Technology Assessment (THETA) Collaborative, University of Toronto, Toronto General Research Institute, Toronto General Hospital, Toronto, Canada), Marth, Christian (Department of Obstetrics and Gynaecology, Innsbruck Medical University, Innsbruck, Austria), Meijer, Paulien (Merck & Co., Inc., Kenilworth, USA), Oberaigner, Wilhelm (Cancer Registry of Tyrol, TILAK GmbH, Innsbruck, Austria), Oderda, Gary M.(Dept. of Pharmacotherapy and Program in Personalized Health, University of Utah, Salt Lake City, USA), Radich, Jerald (Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA), Ramsey, Scott D. (Fred Hutchinson Cancer Research Center, Seattle, USA), Rumpold, Gerhard (ESD Evaluation Software Development, Rum, Austria), Schmidt, Stefan (Hematology and Oncology, Internal Medicine V, Medical University Innsbruck, Innsbruck, Austria), Stadler-Haebich, Christine (Roche Diagnostics GmbH, Vienna, Austria), Stenehjem, David D. (Dept. of Pharmacotherapy and Program in Personalized Health Care, University of Utah, Salt Lake City, USA),

http://dx.doi.org/10.1016/j.zefq.2015.06.012 1865-9217/

Please cite this article in press as: Siebert U, et al. Oncotyrol — Center for Personalized Cancer Medicine: Methods and Applications of Health Technology Assessment and Outcomes Research. Z. Evid. Fortbild. Qual. Gesundh. wesen (ZEFQ) (2015), http://dx.doi.org/10.1016/j.zefq.2015.06.012

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Division of Health Technology Assessment and Bioinformatics, ONCOTYROL - Center for Personalized Cancer Medicine, Innsbruck, Austria 3 Center for Health Decision Science, Department of Health Policy and Management, Harvard T.H. Chan School of Public Health, Boston, MA, USA 4 Institute for Technology Assessment and Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 5 Ludwig Boltzmann Institute for Health Technology Assessment, Vienna, Austria 6 Internal Medicine V - Haematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria 7 Cemit GmbH, Innsbruck, Austria 8 Main Association of Austrian Social Insurance Institutions, Vienna, Austria 9 Center Management, ONCOTYROL - Center for Personalized Cancer Medicine, Innsbruck, Austria 10 Division of Cell Biology, Medical University Innsbruck, Austria Submitted/eingegangen 23 March 2015; revised/überarbeitet 30 June 2015; accepted/akzeptiert 30 June 2015

KEYWORDS Personalized medicine; research cooperation; translation; health technology assessment; outcomes research; cancer

SCHLÜSSELWÖRTER Personalisierte Medizin; Forschungskooperation; Translation; Health Technology Assessment; Versorgungsforschung; Krebserkrankungen

Summary Background: The Oncotyrol — Center for Personalized Cancer Medicine is an international and interdisciplinary alliance combining research and commercial competencies to accelerate the development, evaluation and translation of personalized healthcare strategies in cancer. The philosophy of Oncotyrol is to collaborate with relevant stakeholders and advance knowledge ‘‘from bench to bedside to population and back’’. Oncotyrol is funded through the COMET Excellence Program by the Austrian government via the national Austrian Research Promotion Agency (FFG). This article focuses on the role of health technology assessment (HTA) and outcomes research in personalized cancer medicine in the context of Oncotyrol. Methods: Oncotyrol, which currently comprises approximately 20 individual projects, has four research areas: Area 1: Biomarker and Drug Target Identification; Area 2: Assay Development and Drug Screening; Area 3: Innovative Therapies; Area 4: Health Technology Assessment and Bioinformatics. Area 4 translates the results from Areas 1 to 3 to populations and society and reports them back to Area 3 to inform clinical studies and guidelines, and to Areas 1 and 2 to guide further research and development. Results: In a series of international expert workshops, the Oncotyrol International Expert Task Force for Personalized Cancer Medicine developed the Methodological Framework for Early Health Technology Assessment and Decision Modeling in Cancer and practical guidelines in this field. Further projects included applications in the fields of sequential treatment of patients with chronic myeloid leukemia (CML), benefit-harm and cost-effectiveness evaluation of prostate cancer screening, effectiveness and cost-effectiveness of multiple cervical cancer screening strategies, and benefits and cost-effectiveness of genomic test-based treatment strategies in breast cancer. Conclusion: An interdisciplinary setting as generated in Oncotyrol provides unique opportunities such as systematically coordinating lab and bench research, product development, clinical studies and decision science/HTA and transparent joint planning of research and development with a partnership of researchers, manufacturers and health policy decision makers. However, generating a joint research and legal framework with numerous partners from different sectors can be challenging, particularly in the starting period of such an endeavor. The journey to translational personalized medicine through multidisciplinary collaborations may still be long and difficult, but it is evident that it must be continued to turn vision into reality.

Zusammenfassung Hintergrund: Das Oncotyrol — Center for Personalized Cancer Medicine ist eine internationale und interdisziplinäre Allianz, welche wissenschaftliche und kommerzielle Kompetenzen vereint, um die Entwicklung, die Evaluation und die Translation der personalisierten Krebsmedizin voranzubringen. Die Philosophie von Oncotyrol zielt auf eine Zusammenarbeit mit den relevanten Stakeholdern ab und auf den Transfer von Wissen ‘‘from bench to bedside and back’’. Oncotyrol wird von der österreichischen Regierung via die Österreichische Forschungsförderungsgesellschaft (FFG) im Rahmen des COMET Excellence Programms gefördert. Dieser Artikel beschreibt im Kontext von Oncotyrol die Rolle von Health Technology Assessment (HTA) und Versorgungsforschung in der personalisierten Krebsmedizin.

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Methoden: Oncotyrol umfasst derzeit ca. 20 einzelne Projekte, die in vier Forschungs-Areas eingebettet sind: Area 1: Biomarker and Drug Target Identification; Area 2: Assay Development and Drug Screening; Area 3: Innovative Therapies; Area 4: Health Technology Assessment and Bioinformatics. Area 4 stellt die Ergebnisse aus den Areas 1 und 3 in den Kontext von Populationen und der Gesellschaft und berichtet zurück an Area 3 um klinische Studien und Leitlinien zu unterstützen, und an die Areas 1 und 2 um auf die zukünftige Forschung und Entwicklung Einfluss zu nehmen. Ergebnisse: In einer Reihe von internationalen Experten Workshops entwickelte die Oncotyrol International Expert Task Force for Personalized Cancer Medicine das methodische ,,Framework für frühe Health Technology Assessments und entscheidungsanalytische Modellierungen bei Krebserkrankungen‘‘ und praktische Guidelines in diesem Feld. Weitere Projekte befassen sich mit Anwendungen im Bereich der sequenziellen Behandlungen von Patienten mit chronischer myeloische Leukämie (CML), Nutzen-Schaden-Abwägungen und Kosteneffektivitätsanalysen beim Prostatakrebsscreening, der Effektivität und Kosteneffektivität multipler Früherkennungsmethoden des Zervixkarzinoms, oder dem Nutzen und der Kosteneffektivität von auf genomischen Tests basierenden Behandlungsstrategien bei Frauen mit Brustkrebs. Schlussfolgerungen: Ein wie in Oncotyrol konzipiertes interdisziplinäres Setting bietet einzigartige Möglichkeiten wie die systematische Koordination zwischen Laborforschung, Produktentwicklung, klinischen Studien sowie Entscheidungswissenschaften und HTA. Oncotyrol fördert in einer Partnerschaft mit Forschern, Herstellern und politischen Entscheidungsträgern eine transparente gemeinsame Planung von Forschung und Entwicklung. Allerdings stellt die Durchführung gemeinsamer Forschungsprojekte und das aufwändige rechtliche Rahmenwerk die zahlreichen Partner aus verschiedenen Gesundheitsbereichen auch vor große Herausforderungen, insb. in der Startphase eines solchen Zentrums. Der Weg zur translationalen personalisierten Medizin durch multidisziplinäre Kollaborationen mag noch lang und schwierig sein, jedoch ist es evident, dass dieser Weg weiter beschritten werden muss, um die Visionen Wirklichkeit werden zu lassen.

Introduction The Oncotyrol — Center for Personalized Cancer Medicine [1] is an international and interdisciplinary alliance combining research and commercial competencies to accelerate the development, evaluation and translation of personalized health care strategies in cancer. Oncotyrol consists of an international partnership between scientific institutions and industry, and is located in Innsbruck, Tyrol, Austria. Currently, the Oncotyrol Consortium involves over 40 partners, including more than 10 national and international scientific institutions, as well as more than 30 companies. Oncotyrol is funded through the COMET Excellence Program by the Austrian government via the national Austrian Research Promotion Agency (FFG). [2]

Motivation and Research Proposal The Oncotyrol Center is the result of a continuous strategic development of the institutions from the university campus in Tyrol collaborating in the field of cancer research. In 2006 and 2007, the local oncological research community recognized that several of their scientific projects had matured and had expanded beyond the realm of basic research. However, these projects still lacked capacity to be adopted into clinical practice or industry markets. In order to strengthen translational research opportunities, a formal cross-collaboration, based on the existing projects of the COMET competence program (‘K program’) and with initiatives and programs of other health and life sciences institutions and departments at the campus Tyrol

was made. Concurrently, the field of oncology as a whole was increasingly more focused on approaches to personalized healthcare. This shift spawned the idea to position Oncotyrol as an incubating structure for applied and personalized cancer medicine research. The motivation was to establish an international consortium to close the gap between basic research, clinical research, and population research, on one hand, and the commercial development of translational approaches and healthcare solutions on the other hand. This task involves the collaboration of academic research groups, clinics, and commercial enterprises. Since Oncotyrol’s formation in 2008, it has established itself as a research- and business-oriented center, as well as a company that has recently reached the market with its first products and services. In this context, Oncotyrol acts as a for profit organization by claiming and exploiting shares of the assets generated within the projects and exclusively reinvesting the revenues into new research efforts. After assessing the opportunity to apply for a K1 Center (details in funding and budget section), health and life sciences researchers of the campus Tyrol were invited to submit research and translation project proposals. The management structure established for the K-projects (details in funding and budget section; KMT and KIT) was centralized into the project management company Cemit GmbH, which was subsequently responsible for the administrative management of the Oncotyrol Center.

Vision, Mission and Goals In a recent publication, Schleidgen and colleagues described the term ‘personalized medicine’ (PM) in detail and

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developed a definition based on a systematic literature review on definitions of ‘personalized medicine’. The resulting definition is: ‘‘PM seeks to improve stratification and timing of health care by utilizing biological information and biomarkers on the level of molecular disease pathways, genetics, proteomics as well as metabolomics’’. [3] The term ‘personalized medicine’ is often used to refer to genomic medicine, which is ‘‘the use of information from genomes and their derivatives (RNA, proteins and metabolites) to guide medical decision-making’’. [2] Although there is no doubt that genomic technologies are central to the promise of personalized medicine, [4] the Oncotyrol International Expert Task Force for Personalized Cancer Medicine used a broader definition: besides genomic information, the individual characteristics can include ‘‘any property of the patient including age, severity of disease, risk measurements, course of the disease, former treatments, and patient preferences’’. [5] Particularly patient preferences seem to be an important aspect to include because patients often interpret personalized medicine as emphasis on tailoring health care to their individual preferences. Incorporating patient preferences implies patient-shared decision processes and has additional methodological consequences for the assessment of personalized technologies. Preferences are not merely another naturally given patient characteristic, such as age or biomarker status; preferences are value judgments. However, a formal and quantitative integration of such judgments is currently not included in traditional HTA standards. In economic evaluation, average preferences — for example, for specific health states differing in health-related quality of life — are usually included in cost-utility analyses, and the heterogeneity of individual preferences is not considered in most HTA reports. The vision stated by Oncotyrol includes a future, in which personalized cancer medicine becomes reality, with cancer patients treated based on personalized factors such as clinical and sociodemographic patient characteristics, molecular characteristics of the individual tumor, environmental information, as well as individual patient preferences. In order for this vision to become reality, scientific knowledge must be translated into healthcare solutions and medical products. Oncotyrol positions itself to bridge the gap between basic and applied research, and commercial development, in order to bring the benefits of scientific progress to the patient in a timely, safe, effective and efficient manner. Oncotyrol’s mission [1] includes commitments to: • translating the research results of the academic partners into applied healthcare solutions, • fulfilling the needs of clinicians and patients in the routine day-to-day work of prevention, diagnosis and treatment, • amending the product pipeline of industrial partners in a timely and efficient way, and • using public funding in a responsible way to maximize the benefit for patients and to advance capacity building at the life science location Tyrol. The overarching goal of the Oncotyrol research program is to (1) accelerate the development and evaluation of personalized healthcare solutions for the prevention, diagnosis and therapy of cancer, (2) to develop and provide tools and IT solutions in order to foster the translation of

applied research results into routine practice, and (3) to impact healthcare decisions by informing clinical guideline development and guiding reimbursement decisions, with the ultimate goal of improving the health of individuals, populations and society as a whole.

Scientific Research Program Oncotyrol is a translational research center for personalized cancer medicine. The public-private partnership within the Oncotyrol Consortium is based on the Austrian COMET Program funded by FFG. Oncotyrol is subdivided into two divisions, delineated by the funding source. The publicly funded portion is positioned in Oncotyrol Division1, while Division 2 of Oncotyrol comprises the independent business division used for commercialization, contract research, scientific services, and COMET-independent publicly funded projects. Division 1 focuses on translational research and is divided into four ‘Scientific Areas’, which currently comprise approximately 20 individual projects, -

Area 1: Biomarker and Drug Target Identification Area 2: Assay Development and Drug Screening Area 3: Innovative Therapies Area 4: Health Technology Assessment and Bioinformatics

Figure 1 depicts the four Scientific Areas of Oncotyrol following the philosophy ‘‘From bench to bedside to population and back’’. While Areas 1 and 2 predominately concentrate on bench research, Area 3 focuses on bringing these results to the patients’ bedside, and finally, Area 4 translates these results to populations and society. The research generated in Area 4 applying population sciences such as outcomes research and HTA as well as bioinformatics are reported back to Area 3, and subsequently used to guide additional research in Areas 1 and 2. For example, if an innovative diagnostic test is developed in Area 2, the characteristics of this test (e.g., test performance in terms of a receiver operating characteristic (ROC) curve) can help: to identify the optimal test threshold for a test to be considered positive, to determine a price for the test that is considered cost effective in a society, and, in some cases, to demonstrate at an early development stage that the test is not accurate enough to achieve market success, and therefore, should either be improved or abandoned in the research and development pipeline.

Management and Funding Partners of the Consortium Oncotyrol connects academic, clinical and industrial partners in order to enhance medical progress and bring benefits to the patient in the most effective and efficient way possible. More than 10 national and international scientific, and 30 national and international company partners are joined in 20 research projects. Scientific partners range from the Medical University of Innsbruck (MUI) and UMIT — University for Health Sciences, Medical Informatics and Technology to health policy decision making

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Four Scientific Areas of Oncotyrol.

institutions such as the Main Association of Austrian Social Security Institutions (Hauptverband der Österreichischen Sozialversicherungsträger, HBV) and the Tyrolean Sickness Fund (TGKK). Partners also include international research institutions as well as company partners, including small and medium enterprises in Tyrol and the Tyrolean Hospital Association (Tiroler Landeskrankenanstalten GmbH, TILAK), as well as large pharmaceutical manufacturing companies operating internationally (see Supplementary Web Appendix).

Governance Structure The governance structure of Oncotyrol consists of different bodies: the board of shareholders, the international strategy board (ISB), the Chief Executive Officer (CEO), the Chief Scientific Officer (CSO), and the general management provided as a Core Facility by Cemit GmbH (see Figure 2). The Oncotyrol Area Board is formed by the center management, representatives of the funding bodies, as well as the area leaders.

Legal Framework In Division 1, there is a legal framework for both the overall Oncotyrol consortium agreement and the individual Oncotyrol project agreements. In Division 2, contracts can be directly negotiated between Oncotyrol and the partner(s) with the respective flexibility. Oncotyrol is a GmbH (ltd) with a for profit status. However, according to the Center’s statutes, all profits are reinvested into research.

Funding and Budget Oncotyrol is a K1-Center funded within the Austrian COMET Excellence Program. During the program period, Oncotyrol was/is funded by the Austrian Federal Ministry for Transport Innovation and Technology (BMVIT) and the Federal Ministry of Economics and Labor/the Federal Ministry of Economy, Family and Youth (BMWA/BMWFJ) via the Austrian Research Promotion Agency (FFG) and the province of Tyrol via the Tyrolean Future Foundation/Standortagentur Tirol (SAT).

The COMET program is subdivided into three program lines, K-projects (currently 24 projects), K1-centers (currently 16 centers) and K2-centres (currently 5 centers), differentiated mainly by volume, with the K2-centers being the largest ones. The program is not limited by topics, with centers covering different research areas from life science to tribology. The total budget of Oncotyrol between 2008 and 2016 is approximately 40 million Euros (i.e., ≈4.5 million Euros per year). The budget entails 45% industrial partner contributions and 55% public funding (including 5% academic partner contributions). The basic runtime for K1-centres like Oncotyrol is seven years with a detailed written and oral evaluation including a strategy update and project portfolio adoptions resulting in a stop or go decision after four years (2012) and the possibility of one additional ‘‘phasingout’’ year after another evaluation. Continued evaluation is performed by biannual reporting.

Public private partnerships — challenges and benefits Without doubt, in order to receive public funding it is attractive for academic and industrial partners to participate in public private partnerships. The landscape of industrial research fundamentally changed over the last years. Traditionally, an inhouse-focused approach was standard and is now replaced with an open innovation concept, where highly specialized experts of various backgrounds join forces for a rapid and efficient development of new technologies. However, a strong organizational framework is required for such collaborations, clarifying financial and intellectual contributions on one hand and the distribution of rights on assets, IPR and knowhow on the other. Keeping the balance in cost-sharing, risk-sharing and benefit-sharing is essential to maintain the attractiveness and efficiency of the system. A major challenge in the context of a public-private partnership is the maintenance of scientific independence, especially in the dissemination of results. In general, the principal investigator is responsible for contents and independent as such, while all partners have the right to block only publications that directly infringe patentability or essential business secrets. A special case in this context is

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Figure 2 Governance structure of Oncotyrol. Source: Internet (http://www.oncotyrol.at/en/about-us/organization/governance-structure).

the field of HTA, in which methods are developed that will be available for different interest groups, including reimbursement agencies, manufacturers, and public health insurances. These stakeholders are integrated within the project and the balance among stakeholders is kept. In the commercially oriented Division 2, which is administratively and by content clearly separated from the public-private partnerships in Division 1, data and results are generated neutrally whereas the further use is independent of Oncotyrol.

Health Technology Assessment: Overview and Selected Research Results In this section, general methodological remarks and selected research results will be provided for HTA methods and projects, which is positioned within Area 4. [6,7] As a limitation of this overview of Oncotyrol methods and applications, the presented results are examples rather than comprehensive summary. Detailed results will be published in separate forthcoming research reports and papers.

Health Technology Assessment The International Network of Agencies for Health Technology Assessment (INAHTA) defined health technology assessment

(HTA) as ‘‘the systematic evaluation of the properties and effects of a health technology, addressing the direct and intended effects of this technology, as well as its indirect and unintended consequences, and aimed mainly at informing decision making regarding health technologies. HTA is conducted by interdisciplinary groups that use explicit analytical frameworks drawing on a variety of methods’’. [8] HTA is a form of policy research. The short- and long-term consequences of health care technology are studied in a systematic and multidisciplinary way. HTA investigates the medical, social, ethical, and economic implications of development, diffusion, and use of health technology. [9] The Oncotyrol project ‘‘Methodological Framework for Early Health Technology Assessment and Decision Modeling in Cancer’’ was established as an international and interdisciplinary expertise platform tasked with researching methodological approaches to HTA, outcomes research, decision analysis and economic evaluation in personalized cancer medicine (PCM). In a series of international expert workshops, a framework was developed by adapting standard HTA methods to facilitate HTAs conducted within the context of personalized cancer medicine. In a consensus process, existing recommendations were amended and extended. The following topics were addressed: (1) HTA

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Oncotyrol — Center for Personalized Cancer Medicine structures and processes; (2) framing the research question and the elements population, intervention, comparator, outcome, study design; (3) methods of evidence synthesis of clinical effectiveness; (4) methods of economic evaluation (including the specific role of patient preferences); (5) ethical, legal, and social issues and their consideration in HTA; and (6) the link of HTA to decision making. The researchers from this Oncotyrol project concluded that current HTA guidelines are also largely applicable to the personalized cancer medicine. Specific points and methodological features were refined (e.g., heterogeneity, patient preferences, analytic time-horizon, decision-analytic modeling), and the first round of recommendations were published. [10] Other issues are further investigated in separate working groups: i) methods for causal evaluation of observational studies (i.e., valid estimation of causal exposure and/or intervention effects); ii) value of innovation analyses of personalized cancer medicine; iii) innovative reimbursement schemes for biomarker-based cancer drugs; iv) study designs of trials for predictive marker evaluation and targeted cancer therapies. In order to identify and characterize different types of randomized controlled trials (RCT) that can be applied to validate test-treatment strategies in phase III clinical cancer studies, the Oncotyrol researchers of this project performed a systematic review, identifying 22 methodological papers. [11] The project was conducted in collaboration with international Oncotyrol partners from UMIT, MUI, HVB, TGKK, Fred Hutchinson Cancer Research Center, University of Utah, AbbVie, Amgen, Merck, Novartis, Roche, and TILAK. Results were presented at several scientific national and international conferences and resulted in several papers. (see Annual Reports at http://www.oncotyrol.at/)

Decision-Analytic Modeling The methodological work also supports and aids four Oncotyrol decision-analytic modeling projects in the fields of cervical cancer, chronic myelogenous leukemia (CML), prostate cancer, and breast cancer. Decision analysis is a systematic, explicit and quantitative approach to decision making under uncertainty. It aids in choosing the optimal strategy after balancing medical benefits, risks and costs of different alternatives and systematically assessing the uncertainty of results. [12—14] Decision-analytic modeling is a particularly important tool for the evaluation of personalized cancer medicine. By using such models, the current benefit from innovative personalized technologies can be complemented by the long-term benefit from innovations. [15] In personalized medicine, microsimulation models are often well suited because this modeling approach can account for different patient characteristics, and can simulate a hypothetical population on a patient-level over a sufficiently long time horizon. [16] Different modelling strategies and their clinical applicability have been investigated using the case of multiple myeloma. Based on these analyses, a multiple myeloma model is currently developed to assess the comparative effectiveness of different treatment approaches in patients with multiple myeloma. [17]

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Effectiveness and Cost Effectiveness of Sequential Treatment for CML The chronic myeloid leukemia (CML) project was initiated during the middle of Oncotyrol phase 1, as so-called ‘Oncostart Project’, with a small start-up budget. Subsequently, the project was joined with the Austrian CML registry. The project ‘CML Registry and CML Outcome & Policy Model’ was aimed at: (1) registration of outcome, disease management and related toxicities in an unselected CML patient cohort in the CML Registry, (2) evaluation and implementation of patient reported outcomes during long-term treatment into health care modeling, (3) implementation of model parameters of the natural course of disease, treatment effectiveness, quality of life (QoL), resource use and costs in Austria, (4) model application to evaluate the long-term effectiveness and cost-effectiveness of different sequential treatment strategies, (5) sub-group analyses based on personalized patient characteristics. After a systematic literature review on existing decisionanalytic modeling studies, [18] the Oncotyrol CML Outcome and Policy Model was developed and used for a medical decision analysis aiming at optimal clinical treatment outcome. [19] The most effective treatment strategy was nilotinib with second-line dasatinib after nilotinib failure. Additionally, economic parameters and resource use data for the Austrian health care setting were collected and entered into the model to conduct a cost-effectiveness analysis. [20] In the absence of an Austrian willingness-to pay threshold, two strategies were considered potentially cost-effective among those including a second-line tyrosine kinase inhibitor: imatinib followed by second-line nilotinib (131,100 D /QALY) and nilotinib followed by second-line dasatinib following nilotinib failure (152,400 D /QALY). [20] Additionally, the model was applied to the U.S. health care context. [21] Furthermore, the project team implemented a software tool for the electronic collection of QoL data (CHES — Computerbased Health Evaluation System) and conducted several QoL surveys at the University Hospital Innsbruck, which are currently being analyzed. The final step of the project is to adapt the model in order to analyze a more personalized approach to treatment decisions for CML patients. The project was conducted in collaboration with international Oncotyrol partners from UMIT, MUI, Fred Hutchinson Cancer Research Center, University of Utah, Novartis, Qiagen, ESD, and TILAK. Results were presented at several scientific national and international conferences and resulted in several papers.

Benefit-Harm Balance and Cost Effectiveness in Prostate Cancer Screening International collaboration led to the development of the Oncotyrol Prostate Cancer Outcome and Policy Model, a decision-analytic model designed to evaluate the benefits and harms of prostate cancer screening, explicitly accounting for harms due to overdiagnosis and overtreatment. Originally, one of the modules of the Oncotyrol simulation model, that is, the natural history and detection module, was based on the structure and calibrated parameters of

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an early version of the Erasmus MISCAN model published in 2003. [22] The Oncotyrol Center worked with new data to validate the model and subsequently found that the comparison of the model results with results from autopsy studies suggested an underestimation of latent cancer prevalence, which may cause an underestimation of overdiagnosis and thus bias the model in favor of screening. Recalibration of the Oncotyrol model to account for the higher prevalence resulted in a considerable increase in overdiagnosis and to the decline of screening sensitivity, which worsened the benefit-harm balance of prostate cancer screening. This project will provide important insights into patient-relevant outcomes and personalized benefit-harm-cost tradeoffs. The modeling study was conducted in collaboration with international Oncotyrol partners from UMIT, MUI, HBV, TGKK, Erasmus MC Rotterdam, Toronto Health Economics and Technology Assessment (THETA) Collaborative, Fred Hutchinson Cancer Research Center, Amgen, ESD, and TILAK. Results were presented at scientific conferences in Miami (SMDM) [23] and Amsterdam (ISPOR). [24] A manuscript has been accepted for publication. [23]

Effectiveness and Cost-Effectiveness of Multiple Cervical Cancer Screening Strategies A persistent infection with an oncogenic human papillomavirus (HPV) type is associated with a high risk for the development of cervical cancer and its precursors. Within the last years, several new diagnostic technologies have emerged, such as HPV testing, and innovative biomarkers. These new technologies, together with novel and more sophisticated screening and follow-up algorithms have the potential to improve both the balance of benefits and harms (i.e., patient-relevant outcomes) as well as the costeffectiveness of the cervical cancer screening program. A research team at Oncotyrol developed the Oncotyrol Cervical Cancer Screening Outcome and Policy Model, a decision-analytic Markov model with multiple screening strategies to reflect the Austrian health care context. The model can be applied in outcomes research to analyze the trade-off between benefits and harms of different screening strategies, which can vary by length of screening interval and test method (e.g., cytology alone, HPV testing alone or in combination with cytology, or with cytological triage for HPV-positive women). The authors used original unpublished and published Austrian clinical, epidemiological and resource data from tumor registries, federal statistics agency, health insurances, and the Main Association of Austrian Social Security Institutions. Test accuracy data were based on international meta-analyses and screening trials. The model allows for estimating the long-term clinical and economic consequences (benefits, harms and costs) of different screening strategies. This model will support policy makers, guideline developers, and public-health officials determine the optimal strategy by enumerating the impact it will have on health and system resources. Furthermore, it can aid in prioritizing and planning future clinical studies. The project was conducted in collaboration with international Oncotyrol partners from UMIT, MUI, HBV, TGKK, University of Utah, Roche Diagnostics, ESD, and TILAK.

Results were presented at several scientific national and international conferences, and used to inform clinical practice in Tyrol. [25]

Effectiveness and Cost-Effectiveness of Personalized Test-Treatment Strategies in Breast Cancer The Oncotyrol Breast Cancer Outcomes Model was developed at the Oncotyrol Center to evaluate personalized test-treatment strategies in Austria. The goal of this study was to evaluate patient-relevant outcomes and the costeffectiveness of the new 21-gene assay (ODX) used in combination with the Adjuvant! Online (AO) decision aid. The model can support personalized decisions about the use of adjuvant chemotherapy for women diagnosed with estrogen and/or progesterone receptor positive, HER-2/neu negative, and lymph node negative early-stage breast cancer. The Oncotyrol team developed a discrete event simulation model to reflect a hypothetical cohort of 50 year-old women over their lifetime. The main outcomes include life-years gained, quality-adjusted life-years (QALYs), costs and cost-effectiveness. Eight test-treatment strategies were evaluated. Based on the new ISPOR-SMDM recommendations, the model was validated in collaboration with the Toronto Health Economics and Technology Assessment Collaborative (THETA). Finally, results were compared to the Canadian analysis, which was performed by THETA. [26] Based on these analyses, using ODX in addition to AO is effective and cost-effective strategy for all women in Austria. These results have been presented at scientific conferences [27,28] and papers have been submitted for publication. The development of additional/future genetic tests will likely require additional test-treatment strategies to be considered. Our simulation model provides the flexibility to evaluate alternative combinations of tests methods that may complement each other and optimize respective treatment strategies. Members of the Oncotyrol team were invited to join a Horizon2020 grant proposal to evaluate the new spheroid diagnostic model in patients receiving first-line neoadjuvant chemotherapy for breast cancer— SpheroNINT Study. The project was conducted in collaboration with international Oncotyrol partners from UMIT, MUI, TGKK, Roche, and TILAK. Results were presented at several scientific national and international conferences.

Challenges and Successes Specific Opportunities in Oncotyrol The interdisciplinary and translational work conducted at Oncotyrol provides several unique opportunities for personalized medicine projects. Specifically, lab and bench research, product development, clinical studies and decision science/HTA are coordinated from the onset of a research project, allowing for a transparent joint planning of the research and development steps. The collaboration

Please cite this article in press as: Siebert U, et al. Oncotyrol — Center for Personalized Cancer Medicine: Methods and Applications of Health Technology Assessment and Outcomes Research. Z. Evid. Fortbild. Qual. Gesundh. wesen (ZEFQ) (2015), http://dx.doi.org/10.1016/j.zefq.2015.06.012

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Oncotyrol — Center for Personalized Cancer Medicine between academia and industry allows for early integration of scientific, reimbursement and business aspects. This setting also provides partners from academia and industry with a platform to meet and discuss with health policy decision makers under the protected umbrella of a scientific project within a scientific consortium. For example, industry and public agency partners are able to impact the definition of best research practices, as developed by Oncotyrol HTA Task Forces and Working Groups. Finally, the involvement in both methodological and applied projects allows for the navigation of the methods development in order to serve applied research and translation into practice.

Highlights Since established, Oncotyrol has made several important contributions and received several recognitions, some of which are mentioned below. Oncotyrol initiated three international and interdisciplinary Task Force Workshops that brought together international expertise to develop best practice recommendations within the context of personalized cancer medicine. [29] The Oncotyrol research team has also published several methodological milestone papers, including papers on HTA methods, [30] principles of personalized cancer medicine, [15] concepts of personalization in health economics, [10] model review and validation, [17,26,28] and cancer registry analyses, [31—36] as well as papers assessing specific health technologies, including medical and economic decision analyses for CML treatment, [18—20] benefit-harm analyses for personalized prostate cancer screening, [23,37] benefit and cost-effectiveness analysis on breast cancer test-treatment strategies. [16,27] Two members of the Oncotyrol team were invited to lead and participate in the ISPOR-SMDM Joint Modeling Good Research Practices Task Force, which are today regarded as an international standard for decision modeling. [38,39] A formal collaboration between HTAi, SMDM, and Oncotyrol was central to the development of recommendations for HTA in personalized cancer medicine. A bi-weekly continuing education program on advanced modeling for decision-analytic modelers was established in 2013 and continues to be a platform for education and communication between modelers within Oncotyrol Area 4. Such educational programs, often led by renowned international guests, are fundamental for the development and evaluation of decision-analytic cancer models. Oncotyrol facilitated formal exchanges, sabbaticals and internships for renowned international guest researchers, Oncotyrol staff and students. For example, previous international exchange institutions have included: the University of Utah, the University of Texas MD Anderson Cancer Center, Harvard T.H. Chan School of Public Health, Stanford University, THETA/Toronto, Erasmus Mundus ERAWEB. In addition, Oncotyrol staff members were able to spent time with these partner institutions as visiting scholars. Numerous HTAs, conducted by Oncotyrol researchers, have been presented at international scientific conferences and several have been internationally recognized as exceptional research. For example, a cervical cancer screening project abstract was honored as top ranked abstract at the European Society Medical Decision Making 2014, while,

9 a CML project abstract received the award for the Best Student Poster Presentation at the ISPOR Annual European Congress 2012. Furthermore, an award for the Best Short Course was presented to Oncotyrol staff for their course on discrete event simulation at the SMDM Biennial European Meeting 2012 in Oslo. These projects have also facilitated international collaboration. For example, the breast cancer screening project performed a full cross-model validation in collaboration with THETA, and the CML project introduced the concept of value-of-information analysis [40] to the EbM Networks in Austria and Germany. Finally, the prostate screening project established a formal collaboration with the Department of Public Health - Erasmus Medical Center Rotterdam, a world leader in prostate cancer microsimulation. Oncotyrol also had impact on national policy. For example, the Austrian methods handbook for HTA, commissioned by the Austrian Federal Ministry of Health, has been developed in collaboration with Oncotyrol researchers to be used as guidance for all HTA analysts and decision-makers. [41] UMIT researchers involved in Oncotyrol have participated in chapters on meta-analysis and decision-analytic modeling to be used in the Austrian health care context. [41] Several members of the Oncotyrol project team are currently involved in several EUnetHTA activities, which furthers HTA efforts internationally. The Oncotyrol staff are principal investigators of the Clinical Effectiveness domain of the HTA Core Model ‘Screening’ (handbook under review), they collaborate with the European HTA agencies in a common core HTA ‘Diagnostic Tests’, where they had submitted a successfully Core HTA proposal: ‘Prognostic tests for breast cancer recurrence’. The Core HTA, in cooperation with EU HTA agencies, was finished in 2012. [42]

Challenges The evolvement of Oncotyrol has also highlighted challenges. For example, a major challenge was to incorporate the philosophies and requirements of basic researchers (knowledge-driven) as well as those of the industry partners (product-driven) into a productive collaboration - on one hand in terms of content and work standards, and on the other hand, in terms of administrative and legal constraints. In addition, the collaboration framework had to meet public funding requirements. Finally, in a process of mutual agreement, this platform of interdisciplinary collaboration has been successfully established. Although Oncotyrol includes different Areas and projects, it is dependent on the access to external data, for example from clinical studies, registries, HTA agencies, clinics and other sources. Only sparse data on real world evidence are available in Austria and the use of different IT systems further complicates the situation. This requires effort and time. A particular challenge of Area 4 is the fact that important model parameters are not published and access to these data may be complicated, time consuming, and in some cases, futile. There is a time lag for the results from the four Areas in Oncotyrol. For example, it may take up to years until those products developed in bench research are clinically

Please cite this article in press as: Siebert U, et al. Oncotyrol — Center for Personalized Cancer Medicine: Methods and Applications of Health Technology Assessment and Outcomes Research. Z. Evid. Fortbild. Qual. Gesundh. wesen (ZEFQ) (2015), http://dx.doi.org/10.1016/j.zefq.2015.06.012

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10 evaluated and assessed in HTAs, and conclusions are delivered back to product developers. During this time, the research landscape may change and Oncotyrol’s strategies and research plans may need to be adjusted. Despite the size and substantial budget of Oncotyrol, additional staff and funding will be needed to successfully compete in the international environment in the long run. Several successful Oncotyrol researchers received attractive job offers from industry and HTA agencies and have left the center. This diffusion and capacity building for the market is intended, but remains a challenge for the continuity of the work in the center. Therefore, Oncotyrol must not only maintain, but increase its international visibility in order to continue to attract top leaders as well as junior and senior researchers from the global scientific community.

Final Remarks The journey towards personalized medicine has just begun. As the development of personalized health care approaches, methods to evaluate these approaches will likely continue to be optimized in the future. Oncotyrol provides a valuable contribution not only to the development of these methods but also to the understanding of the difficulties and challenges in this research and its management. The work of Oncotyrol over the last years showed that the structure of Oncotyrol can effectively and efficiently aid the development of innovations in personalized cancer medicine. Through these efforts, it has become more probable to envision a future in which personalized cancer medicine becomes reality. However, budget constraints and unexpected events are often underestimated. The journey to translational personalized medicine through multidisciplinary collaborations may still be long and difficult, but it is evident that it is one that needs to be continued.

Conflict of Interest The following authors received research support from Oncotyrol to their institutions: T. Hunger, B. Jahn, N. Mühlberger, U. Rochau, P. Schnell-Inderst, U. Siebert, G. Sroczynski. The following authors are or have been partially employed by Oncotyrol: L. Huber, U. Rochau, S. Schnaiter, U. Siebert.

Acknowledgments Financial support for this manuscript and the described projects was provided in part by the COMET Center ONCOTYROL, which is funded by the Austrian Federal Ministries BMVIT/BMWFJ (via FFG) and the Tyrolean Future Foundation / Standortagentur Tirol (SAT). The funding agreement ensured the authors’ independence in designing studies, data interpretation, writing, and publishing results. We thank Heidi Fiegl (Department of Obstetrics and Gynaecology, Innsbruck Medical University, Innsbruck, Austria), Katharina Hintringer (TGKK - Tyrolean Sickness Fund, Innsbruck, Austria), Arno Melitopulos (TGKK - Tyrolean Sickness Fund, Innsbruck, Austria), Andras Fehervary (Novartis International AG, Basel Switzerland), Klaus Pugner

U. Siebert et al. (Amgen Europe GmbH, Zug, Switzerland), Alexander Zach (F. Hoffmann-La Roche AG, Basel, Switzerland) for their contribution and advice in the Oncotyrol projects.

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.zefq. 2015.06.012.

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Please cite this article in press as: Siebert U, et al. Oncotyrol — Center for Personalized Cancer Medicine: Methods and Applications of Health Technology Assessment and Outcomes Research. Z. Evid. Fortbild. Qual. Gesundh. wesen (ZEFQ) (2015), http://dx.doi.org/10.1016/j.zefq.2015.06.012