Search

144 p. ill., SCIENTIFIC REPORT 14 -- 1 INTRODUCTION .14 -- 1.1 BACKGROUND 14 -- 1.1.1 Transmission 14 -- 1.1.2 Hepatitis C in Belgium 15 -- 1.1.3 Treatments 16 -- 1.2 OBJECTIVE OF THIS REPORT AND RESEARCH QUESTIONS 17 -- 2 REVIEW OF THE PUBLISHED ECONOMIC EVALUATIONS 18 2.1 INTRODUCTION .18 -- 2.2 METHODS 18 2.2.1 Inclusion and exclusion criteria .18 -- 2.2.2 Search strategy .19 2.2.3 Selection procedure 19 2.2.4 Coverage of the reviews 21 -- 2.3 CLASSIFICATION OF THE ECONOMIC EVALUATIONS 21 -- 2.3.1 Early publications based on emerging and weak evidence 21 -- 2.3.2 Pegylated interferon as an intervention 21 -- 2.3.3 Disease progression after sustained viral response 22 -- 2.3.4 Selected economic evaluations 22 -- 2.4 OVERVIEW OF THE SELECTED ECONOMIC EVALUATIONS 23 -- 2.4.1 Country and study design 23 -- 2.4.2 Perspective .23 -- 2.4.3 Time horizon and discount rate .23 -- 2.4.4 Targeted patient group 23 -- 2.4.5 Intervention and comparators 23 -- 2.4.6 Assumptions used in modelling the HCV natural history .24 2.4.7 Non-liver mortality 25 -- 2.4.8 Quality of life 25 -- 2.5 MAIN RESULTS OF THE ECONOMIC EVALUATIONS 34 -- 2.5.1 Genotype 1 34 -- 2.5.2 Genotype 2 35 -- 2.5.3 Genotype 3 35 -- 2.5.4 Genotype 4 35 -- 2.6 SENSITIVITY AND SUBGROUP ANALYSES .35 -- 2.6.1 Sensitivity analyses .35 -- 2.6.2 Subgroup analyses .35 -- 2.7 DISCUSSION 41 -- 2.7.1 Summary of the results .41 -- 2.7.2 General conclusion .42 -- 3 THE COST-EFFECTIVENESS AND BUDGET IMPACT OF TREATMENT STRATEGIES FOR HEPATITIS C IN BELGIUM 43 -- 3.1 INTRODUCTION .43 -- 3.2 METHODS 43 -- 3.2.1 Design and analytic technique 43 -- 3.2.2 Perspective .44 -- 3.2.3 Time window and discounting 44 -- 3.2.4 Target population .44 -- 3.2.5 Intervention and comparator 45 -- 3.2.6 Model structure and basic assumptions 45 -- 3.2.7 Transition probabilities 48 -- 3.2.8 Performance of non-invasive liver tests 50 -- 3.2.9 Effectiveness of antiviral treatment .52 -- 3.2.10 Disease management, diagnostic tests and treatment costs 53 -- 3.2.11 Utilities 59 -- 3.2.12 Uncertainty 63 -- 3.2.13 Validation of the model 66 -- 3.3 RESULTS 66 -- 3.3.1 Cost-effectiveness analysis.66 -- 3.3.2 Budget impact analysis .72 -- 4 DISCUSSION AND CONCLUSION 80 --  APPPENDICES 83 -- APPENDIX 1. SCENARIO ANALYSES .83 -- APPENDIX 1.1. KCE REPORTS 157 ANTIVIRAL TREATMENT - ANNUAL TRANSITION PROBABILITIES BETWEEN FIBROSIS STAGES103 83 -- APPENDIX 1.2. TABLES OF THE SCENARIO ANALYSES FOR THE COST-EFFECTIVENESS ANALYSES 86 -- REFERENCES . 137

24 p. ill., Les nouveaux médicaments antiviraux contre l’hépatite C sont plus efficaces et ont moins d’effets secondaires que les anciens, mais ils sont aussi très chers: environ 40.000 € par traitement. Pour le moment, ils ne sont remboursés que pour les patients qui ont des lésions avancées du foie et en cas de transplantation hépatique. La Ministre de la Santé a déjà annoncé qu’elle souhaitait élargir leur remboursement, à partir de 2017, aux patients à un stade moins avancé. Le Centre fédéral d’Expertise des soins de santé (KCE) suggère de continuer sur cette voie et d’envisager de traiter toutes les personnes porteuses du virus, étant donné que plus on traite tôt, plus les bénéfices pour la santé sont importants. Un tel élargissement du remboursement devrait toutefois se faire par paliers de manière à garder le budget de l’assurance maladie sous contrôle. Afin d’obtenir une réduction plus importante des prix et de permettre d’élargir plus rapidement le remboursement, d’autres options pourraient être envisagées, comme s’associer avec d’autres pays pour lancer un appel d’offres conjoint. PRÉFACE 1--MESSAGES CLÉS 2--SYNTHÈSE 4--1. CONTEXTE DE CE RAPPORT 5--1.1. L’HÉPATITE C 5--1.2. NOMBRE DE PERSONNES ATTEINTES PAR LE VHC EN BELGIQUE 6--1.3. LES TRAITEMENTS 6--1.4. OBJECTIFS DE CE RAPPORT 7--2. CRITÈRES D’ÉLIGIBILITÉ POUR LE TRAITEMENT 7--2.1. LA SITUATION JUSQU’À AUJOURD’HUI 7--2.2. DÉTERMINER LE STADE DE LA FIBROSE PAR DES TESTS NON INVASIFS ? 7--2.3. DÉTERMINATION DES CRITÈRES D’ÉLIGIBILITÉ 8--3. ANALYSE COÛT-EFFICACITÉ DES DIFFÉRENTES STRATÉGIES ENVISAGEABLES 9--3.1. CINQ STRATÉGIES 9--3.2. MÉTHODE 10--3.3. RÉSULTAT DES ANALYSES COÛT-EFFICACITÉ ET COÛT-UTILITÉ 12--3.4. TRAITEMENT DE L’INCERTITUDE 13--4. IMPACT BUDGÉTAIRE 16--5. VERS UNE ÉRADICATION? 21--5.1. LES USAGERS DE DROGUES INJECTABLES (UDI) 21--5.2. LES MSM (MEN HAVING SEX WITH MEN) 21--5.3. L’IMMIGRATION 21--6. CONCLUSION ET DISCUSSION: VERS UN AUTRE MODÈLE DE REMBOURSEMENT? 22--RECOMMANDATIONS 24

24 p. ill., De nieuwe antivirale middelen tegen hepatitis C zijn meer doeltreffend en hebben minder nevenwerkingen dan de oude, maar zijn ook zeer duur: ongeveer €40.000 per behandeling. Momenteel wordt deze behandeling enkel terugbetaald voor patiënten met gevorderde leverschade en bij levertransplantatie. De minister van Volksgezondheid heeft al aangekondigd dat ze de terugbetaling vanaf 2017 zal uitbreiden naar patiënten met minder gevorderde schade. Het Federaal Kenniscentrum voor de Gezondheidszorg (KCE) pleit ervoor om op de ingeslagen weg verder te gaan, met het oog op het uiteindelijk behandelen van alle besmette patiënten, want hoe eerder men behandelt, hoe groter de gezondheidswinst. Dergelijke uitbreiding van de terugbetaling moet wel stapsgewijs gebeuren, om de uitgaven van de ziekteverzekering onder controle te houden.Om een grotere prijskorting te verkrijgen en om de terugbetaling sneller te kunnen uitbreiden zouden ook andere pistes kunnen worden bewandeld, zoals het lanceren van een openbare aanbesteding, samen met andere landen VOORWOORD 1 -- KERN BOODSCHAPPEN 2 -- SYNTHESE 4 -- 1. CONTEXT VAN DIT RAPPORT 5 -- 1.1. HEPATITIS C 5 -- 1.2. AANTAL PERSONEN BESMET MET HCV IN BELGIË 6 -- 1.3. DE BEHANDELINGEN 6 -- 1.4. DOELSTELLINGEN VAN DIT RAPPORT 7 -- 2. TOELAATBAARHEIDSCRITERIA VOOR DE BEHANDELING 7 -- 2.1. DE SITUATIE TOT VANDAAG 7 -- 2.2. HET STADIUM VAN DE FIBROSE BEPALEN MET NIET-INVASIEVE TESTEN? 7 -- 2.3. BEPALING VAN DE TOELAATBAARHEIDSCRITERIA” 8 -- 3. KOSTENEFFECTIVITEIT VAN DE VERSCHILLENDE STRATEGIEËN 9 -- 3.1. VIJF STRATEGIEËN 9 -- 3.2. METHODE 10 -- 3.3. RESULTAAT VAN DE KOSTENEFFECTIVITEITS- EN KOSTENUTILITEITSANALYSES 12 -- 3.4. AANPAK VAN DE ONZEKERHEID 14 -- 4. BUDGETTAIRE IMPACT 16 -- 5. NAAR EEN UITROEIING? 21 -- 5.1. DE INTRAVENEUZE DRUGGEBRUIKERS (IDU) 21 -- 5.2. MSM (MEN HAVING SEX WITH MEN) 21 -- 5.3. IMMIGRATIE 21 -- 6. CONCLUSIE EN DISCUSSIE : NAAR EEN ANDER TERUGBETALINGSMODEL ? 22 -- AANBEVELINGEN 24

25 p. ill., FOREWORD 1 -- KEY MESSAGES 2 -- SUMMARY 4 -- 1. BACKGROUND 5 -- 1.1. HEPATITIS C 5 -- 1.2. NUMBER OF HCV-INFECTED PEOPLE IN BELGIUM 6 -- 1.3. THERAPIES 6 -- 1.4. OBJECTIVES OF THIS REPORT 6 -- 2. ELIGIBILITY CRITERIA FOR THE TREATMENT 7 -- 2.1. THE CURRENT SITUATION 7 -- 2.2. DETERMINING THE STAGE OF FIBROSIS THROUGH NON-INVASIVE TESTS? 8 -- 2.3. SETTING THE ELIGIBILITY CRITERIA 8 -- 3. COST-EFFECTIVENESS ANALYSIS OF THE VARIOUS POTENTIAL STRATEGIES 9 -- 3.1. FIVE STRATEGIES 9 -- 3.2. METHOD 10 -- 3.3. RESULT OF THE COST-EFFECTIVENESS AND COST-UTILITY ANALYSES 12 -- 3.4. TREATMENT OF THE UNCERTAINTY 14 -- 4. BUDGET IMPACT 16 -- 5. TOWARDS AN ERADICATION? 22 -- 5.1. INTRAVENOUS DRUG USERS. 22 -- 5.2. MSM (MEN WHO HAVE SEX WITH MEN) 22 -- 5.3. IMMIGRATION 22 -- 6. CONCLUSION AND DISCUSSION: TOWARDS A DIFFERENT REIMBURSEMENT MODEL? 23 -- RECOMMENDATIONS 25

p. 454-461 INTRODUCTION: Despite the lack of randomized evidence, stereotactic body radiotherapy (SBRT) is being accepted as superior to conventional radiotherapy for patients with T1-2N0 non-small-cell lung cancer in the periphery of the lung and unfit or unwilling to undergo surgery. To introduce SBRT in a system of coverage with evidence development, a correct financing had to be determined. METHODS: A time-driven activity-based costing model for radiotherapy was developed. Resource cost calculation of all radiotherapy treatments, standard and innovative, was conducted in 10 Belgian radiotherapy centers in the second half of 2012. RESULTS: The average cost of lung SBRT across the 10 centers (6221&OV0556;) is in the range of the average costs of standard fractionated 3D-conformal radiotherapy (5919&OV0556;) and intensity-modulated radiotherapy (7379&OV0556;) for lung cancer. Hypofractionated 3D-conformal radiotherapy and intensity-modulated radiotherapy schemes are less costly (3993&OV0556; respectively 4730&OV0556;). The SBRT cost increases with the number of fractions and is highly dependent of personnel and equipment use. SBRT cost varies more by centre than conventional radiotherapy cost, reflecting different technologies, stages in the learning curve and a lack of clear guidance in this field. CONCLUSIONS: Time-driven activity-based costing of radiotherapy is feasible in a multicentre setup, resulting in real-life resource costs that can form the basis for correct reimbursement schemes, supporting an early yet controlled introduction of innovative radiotherapy techniques in clinical practice.

14 p. ill. Kankerbehandelingen op maat, met geneesmiddelen die zeer doelgericht de kanker aanvallen, bieden vandaag reeds voor een aantal kankers een grote meerwaarde ten opzichte van de klassieke, ‘blinde’ chemotherapie. Voorwaarde is dat men de ‘doelwitten’ in de kankercel op een betrouwbare en efficiënte manier kan opsporen. Dit is de rol van de diagnostische testen, ‘companion diagnostics’ genoemd. Het Kankercentrum van het Wetenschappelijk Instituut Volksgezondheid (WIV) en het Federaal Kenniscentrum voor de Gezondheidszorg (KCE) onderzochten de nieuwe Next Generation Sequencing gene panel testen. Ze kunnen meerdere genen gelijktijdig onderzoeken, en dat zorgt voor een stroomversnelling bij de aanpak van kanker. Het vergoeden van de testen binnen het huidige RIZIV-budget lijkt mogelijk als ze gecentraliseerd worden uitgevoerd in gespecialiseerde laboratoria die een voldoende groot aantal testen uitvoeren. Daarnaast moet het garanderen en controleren van hun kwaliteit de grootste prioriteit krijgen. VOORWOORD 1 -- SAMENVATTING 2 -- 1. INLEIDING 3 -- 1.1. ACHTERGROND 3 -- 1.2. ONDERZOEKSVRAGEN 3 -- 1.3. ALGEMENE AANPAK 4 -- 2. NEXT GENERATION SEQUENCING PANELTESTS 4 -- 2.1. STAPPEN BIJ HET UITVOEREN VAN EEN NGS-PANELTEST 4 -- 2.2. BESCHIKBAARHEID VAN NGS-PANELS 5 -- 2.3. VOORDELEN VAN DE NGS-PANELTESTS VOOR HET LABORATORIUM 7 -- 2.4. AANDACHTSPUNTEN 7 -- 2.5. REGELGEVING, KWALITEITSBEWAKING EN EDUCATIE 8 -- 3. ECONOMISCHE ASPECTEN 9 -- 3.1. IMPACT VAN DE TESTACCURAATHEID OP DE KOSTENEFFECTIVITEIT 9 -- 3.2. FACTURATIECODES EN NGS-BEHOEFTEN VOOR BELGIË 11 -- 4. INVOERING VAN NGS-PANELTESTS 12 -- AANBEVELINGEN 13

128 p. ill. SCIENTIFIC REPORT .9 -- 1 INTRODUCTION 9 -- 1.1 BACKGROUND 9 -- 1.2 RESEARCH QUESTIONS .13 -- 1.3 GENERAL APPROACH 14 -- 1.4 EVALUATION OF DIAGNOSTIC TESTS 14 -- 2 TOWARDS NEXT GENERATION SEQUENCING PANEL TESTS IN ONCOLOGY .16 -- 2.1 MOLECULAR DIAGNOSTICS USED IN ONCOLOGY 16 -- 2.2 NEXT GENERATION SEQUENCING, THE TECHNOLOGY 18 -- 2.3 INTRODUCTION TO NEXT GENERATION SEQUENCING PANEL TESTS .20 -- 2.3.1 The sequencing revolution 20 -- 2.3.2 Importance of targeted sequencing for exploratory clinical research in oncology 22 -- 2.3.3 New technologies, more options, new challenges 26 -- 2.4 COMPOSITION OF THE NGS PANELS .26 -- 2.4.1 NGS panels for solid tumours 27 -- 2.4.2 NGS panels for hemato-oncology 28 -- 2.4.3 Other considerations for NGS panel selection 28 -- 3 REGULATORY ASPECTS, QUALITY ASSURANCE AND EDUCATIONAL NEEDS 29 -- 3.1 NEED FOR INFORMED CONSENT AND PRE-TEST COUNSELLING 29 -- 3.2 REGULATORY CONTEXT OF MOLECULAR TESTS FOR SOMATIC MUTATIONS 29 -- 3.2.1 Regulations for diagnostic laboratories in Belgium .29 -- 3.2.2 Regulations for in-house methods and in-vitro diagnostics 30 -- 3.3 EXTERNAL QUALITY ASSURANCE OF MOLECULAR TESTS FOR SOMATIC MUTATIONS 32 -- 3.3.1 EQA schemes for Haematological and Solid Tumours.32 -- 3.3.2 Performance of the participating (Belgian) laboratories 33 -- 3.4 QUALITY ASSURANCE OF NGS PANEL TESTS FOR SOMATIC MUTATIONS 37 -- 3.4.1 General considerations and the importance of quality 37 -- 3.4.2 Quality assurance for the wet and dry lab part of NGS 39 -- 3.5 REPORTING OF NGS DATA 44 -- 3.6 NEEDS FOR EDUCATION AND A MULTIDISCIPLINARY EXPERT COMMITTEES.50 -- 4 IMPACT OF TEST ACCURACY ON INCREMENTAL COST-EFFECTIVENESS RATIOS 52 -- 4.1 INTRODUCTION AND SCOPE 52 -- 4.2 METHODOLOGY 52 -- 4.2.1 Search strategy .52 -- 4.2.2 Selection procedure 53 -- 4.2.3 Selection criteria53 -- 4.3 RESULTS 53 -- 4.4 ILLUSTRATIVE EXAMPLES FOR BELGIUM 54 -- 4.4.1 Data sources 54 -- 4.4.2 Results and discussion .55 -- 4.4.3 The relevance of test specificity when applied to NGS panels .59 -- 5 FINANCING OF COMPANION DIAGNOSTICS AND TARGETED THERAPY .61 -- 5.1 THE DISCONNECTION BETWEEN PHARMACEUTICALS AND COMPANION DIAGNOSTIC 61 -- 5.1.1 The need for a companion diagnostic conflicts with traditional drug development .61 -- 5.1.2 Disconnection between reimbursement of companion diagnostics and drugs in Belgium .62 -- 5.2 BILLING CODES FOR MOLECULAR DIAGNOSTICS IN ONCOLOGY IN BELGIUM 63 -- 5.2.1 Evolution of billing codes, overall expenditures and testing volumes 64 -- 5.2.2 Current issues with billing codes 65 -- 5.3 MOLECULAR TESTS BILLED BY TYPE OF TUMOUR DIAGNOSED IN BELGIUM (2010-2011) .68 -- 5.3.1 Aims and methods of analysis by tumour type .68 -- 5.3.2 Selection of tumour types.68 -- 5.3.3 IMA/AIM data .68 -- 5.3.4 Results 69 -- 5.4 CURRENT COST OF NGS PANEL TESTS 73 -- 6 OPTIONS FOR INTRODUCING NGS PANEL TESTS IN THE BELGIAN HEALTHCARE 76 -- APPENDICES 79 -- APPENDIX 1. GLOSSARY 79 -- APPENDIX 2. COMPOSITION OF NGS PANELS 91 -- APPENDIX 3. SEARCH STRATEGIES - IMPACT OF TEST ACCURACY ON ICERS 110 -- APPENDIX 3.1. PUBMED 110 -- APPENDIX 3.2. EMBASE 110 -- APPENDIX 3.3. ECONLIT 111 -- APPENDIX 3.4. CRD NHS DATABASES 112 -- APPENDIX 4. MOLECULAR TESTS BY PATHOLOGY, WITH BILLING CODES 113 -- APPENDIX 5. SELECTED NOMENCLATURE CODES 119 -- REFERENCES 123

Background: Economic evaluations of companion diagnostics often fail to include the impact that tests have on the overall economic value of test–drug combinations. Methods: To illustrate the importance of test accuracy on the cost–effectiveness of companion diagnostics by means of examples. Data were extracted from the literature. Results: The accuracy of a test and in particularly its specificity, is often more influential on the overall cost–effectiveness results than the price of the test. Specificity becomes more crucial when prevalence of the biomarker is low. Multiple, simultaneous testing faces specific challenges regarding its overall specificity. Conclusion: This article opens a discussion on some fundamental points linked to economic evaluations of test–therapy combinations.

14 p. ill. Les nouveaux traitements ‘sur mesure’ du cancer, qui ciblent des étapes très précises du processus tumoral, présentent certains avantages par rapport à la chimiothérapie classique et ‘aveugle’. Mais il y a une condition préalable : identifier les patients chez qui ils seront efficaces. C’est le rôle des tests appelés ‘diagnostics compagnons’. Le Centre du Cancer de l’Institut scientifique de Santé publique (ISP) et le Centre Fédéral d’Expertise des Soins de santé (KCE) ont examiné les panels de tests dits de Next Generation Sequencing, qui analysent plusieurs gènes à la fois, permettant une accélération dans la prise en charge des cancers. Si ces tests sont effectués dans un laboratoire central spécialisé qui en réalise un nombre suffisant, le remboursement de ces tests semble possible dans le budget actuel de l’INAMI. Mais la garantie et le contrôle de leur qualité reste la grande priorité. PRÉFACE 1 -- RÉSUMÉ 2 -- 1. INTRODUCTION 3 -- 1.1. CONTEXTE 3 -- 1.2. QUESTIONS DE RECHERCHE 3 -- 1.3. APPROCHE GENERALE 3 -- 2. PANELS DE GENES PAR NGS 4 -- 2.1. PHASES D’EXÉCUTION DES TESTS DE PANELS DE GÈNES PAR NGS 4 -- 2.2. DISPONIBILITE DES PANELS NGS 5 -- 2.3. AVANTAGES DES TESTS DE PANEL DE GENES PAR NGS POUR LE LABORATOIRE 7 -- 2.4. POINTS D‘ATTENTION 7 -- 2.5. REGLEMENTATIONS, ASSURANCE QUALITE ET FORMATION 8 -- 3. ASPECTS ÉCONOMIQUES 8 -- 3.1. IMPACT DE LA PRECISION DU TEST SUR LE RAPPORT COUT-EFFICACITE 9 -- 3.2. CODES DE FACTURATION ET BESOINS SNG POUR LA BELGIQUE 11 -- 4. INTRODUIRE DES TESTS DE PANEL DE GENES PAR NGS 12 -- RECOMMANDATIONS 13

p. 21 Modelling of NIPT Figure 3 presents an overview of the current screening strategy in Belgium. In Figure 4, the current first trimester biochemistry screening and second trimester screening is replaced by NIPT at week 12. In the next part of this supplementary file, we present and explain the three models in detail (current screening, NIPT 2nd line and NIPT 1st line) with inclusion of the number of pregnant women and T21 pregnancies at different moments in the model.

p. 1-10 The first- and second-trimester screening for trisomy 21 (T21) are reimbursed for all pregnant women in Belgium. Using a cut-off risk of 1:300 for T21, about 5% of all pregnant women are referred for definitive prenatal diagnosis using an invasive test, at a sensitivity of (only) 72.5%. The sensitivity and specificity of the non-invasive prenatal test (NIPT) are over 99% but come at a cost of €460 (£373) per test. The objective is to estimate the consequences of introducing NIPT for the detection of T21. METHODS: A cost-consequences analysis was performed presenting the impact on benefits, harms and costs. Context-specific real-world information was available to set up a model reflecting the current screening situation in Belgium. This model was used to construct the second and first line NIPT screening scenarios applying information from the literature on NIPT's test accuracy. RESULTS: Introducing NIPT in the first or second line reduces harm by decreasing the number of procedure-related miscarriages after invasive testing. In contrast with NIPT in the second line, offering NIPT in the first line additionally will miss fewer cases of T21 due to less false-negative test results. The introduction of NIPT in the second line results in cost savings, which is not true for NIPT at the current price in the first line. If NIPT is offered to all pregnant women, the price should be lowered to about €150 to keep the screening cost per T21 diagnosis constant. CONCLUSIONS: In Belgium, the introduction and reimbursement of NIPT as a second line triage test significantly reduces procedure-related miscarriages without increasing the short-term screening costs. Offering and reimbursing NIPT in the first line to all pregnant women is preferred in the long term, as it would, in addition, miss fewer cases of T21. However, taking into account the government's limited resources for universal reimbursement, the price of NIPT should first be lowered substantially before this can be realised.

e4710

GLOSSARY 2 -- 1 BACKGROUND AND OBJECTIVES 3 -- 1.1 NATURAL HISTORY AND EPIDEMIOLOGY 3 -- 1.2 TREATMENT 4 -- 1.3 OBJECTIVES AND CONTENT OF THE TWO REPORTS 5 -- 2 METHODS 7 -- 2.1 TARGET POPULATION 7 -- 2.2 MODEL STRUCTURE AND BASIC ASSUMPTIONS 7 -- 2.3 TRANSITION PROBABILITIES 9 -- 2.4 DISEASE MANAGEMENT AND TREATMENT COSTS 12 -- 2.5 UTILITIES 13 -- 2.6 ANTIVIRAL TREATMENT 14 -- 3 RESULTS 16 -- 3.1 MODEL VALIDATION: NATURAL EVOLUTION OF DISEASE WITHIN EUROPEAN -- COHORTS 17 -- 3.2 HEALTH OUTCOMES 18 -- 3.2.1 Life-years gained in the three cohorts 18 -- 3.2.2 Undiscounted life-years gained in DC and HCC 19 -- 3.2.3 Mean tenofovir treatment duration in CHB e+ vs e- cohorts 20 -- 3.3 BASE-CASE COST-UTILITY ANALYSES 20 -- 3.3.1 Overview of the results for the three base-case cohorts 20 -- 3.3.2 CHBe+ non-cirrhotic Europeans 21 -- 3.3.3 CHBe- non-cirrhotic Europeans 23 -- 3.3.4 Patient with compensated liver cirrhosis 25 -- 3.4 SCENARIO AND PROBABILISTIC SENSITIVITY ANALYSES 27 -- 3.4.1 Probabilistic sensitivity analysis 27 -- 3.4.2 ICERs in function of the time horizon 30 -- 3.4.3 Asian cohorts 31 -- 3.4.4 Variations in the discount rates 32 -- 3.5 BUDGET IMPACT 33 -- 4 DISCUSSION AND CONCLUSIONS 34 -- 5 APPENDICES 37 -- 5.1 NATURAL PROGRESSION TO LIVER CIRRHOSIS IN 278 CHRONIC HEPATITIS B -- PATIENTS OF EUROPEAN ORIGIN, THE IMPORTANCE OF AGE AND ELEVATED ALT . 37 -- 5.1.1 Introduction 37 -- 5.1.2 Aim 37 -- 5.1.3 Methods 37 -- 5.1.4 Results 38 -- 5.1.5 Discussion and Conclusion 39 -- 5.2 COMPARISON OF PUBLISHED QUALITY OF LIFE DATA 40 -- 5.2.1 Aims 40 -- 5.2.2 Methods 41 -- 5.2.3 Results 43 -- 5.3 DISEASE MANAGEMENT COSTS 46 -- 5.3.1 Data sources 48 -- 5.3.2 Primary inclusion counts 52 -- 5.3.3 Exclusions and sub grouping for cost study 53 -- 5.3.4 Extrapolations for partial lump sum remunerations 59 -- 5.3.5 Results 66 -- 5.3.6 Discussion 72 -- 6 REFERENCES 74

X, 77 p. ill. Depuis plusieurs années, de nouveaux médicaments sont disponibles pour traiter l'hépatite B chronique. Le coût de ce traitement s’élève à environ 5 000 euros par patient et par an. Les décideurs ont demandé au Centre fédéral d’expertise des soins de santé (KCE) d’identifier quels groupes de patients sont susceptibles de bénéficier le plus de ce traitement, et à quel prix. Le KCE conclut que le bénéfice par euro dépensé est maximal lorsque le traitement est appliqué à un stade avancé de la maladie, à savoir le stade de la cirrhose du foie. Les calculs effectués par le KCE sont basés sur une étude originale de la progression et des coûts de la maladie, menée en collaboration avec un grand nombre d’hépatologues. GLOSSARY 2 -- 1 BACKGROUND AND OBJECTIVES 3 -- 1.1 NATURAL HISTORY AND EPIDEMIOLOGY 3 -- 1.2 TREATMENT 4 -- 1.3 OBJECTIVES AND CONTENT OF THE TWO REPORTS 5 -- 2 METHODS 7 -- 2.1 TARGET POPULATION 7 -- 2.2 MODEL STRUCTURE AND BASIC ASSUMPTIONS 7 -- 2.3 TRANSITION PROBABILITIES 9 -- 2.4 DISEASE MANAGEMENT AND TREATMENT COSTS 12 -- 2.5 UTILITIES 13 -- 2.6 ANTIVIRAL TREATMENT 14 -- 3 RESULTS 16 -- 3.1 MODEL VALIDATION: NATURAL EVOLUTION OF DISEASE WITHIN EUROPEAN -- COHORTS 17 -- 3.2 HEALTH OUTCOMES 18 -- 3.2.1 Life-years gained in the three cohorts 18 -- 3.2.2 Undiscounted life-years gained in DC and HCC 19 -- 3.2.3 Mean tenofovir treatment duration in CHB e+ vs e- cohorts 20 -- 3.3 BASE-CASE COST-UTILITY ANALYSES 20 -- 3.3.1 Overview of the results for the three base-case cohorts 20 -- 3.3.2 CHBe+ non-cirrhotic Europeans 21 -- 3.3.3 CHBe- non-cirrhotic Europeans 23 -- 3.3.4 Patient with compensated liver cirrhosis 25 -- 3.4 SCENARIO AND PROBABILISTIC SENSITIVITY ANALYSES 27 -- 3.4.1 Probabilistic sensitivity analysis 27 -- 3.4.2 ICERs in function of the time horizon 30 -- 3.4.3 Asian cohorts 31 -- 3.4.4 Variations in the discount rates 32 -- 3.5 BUDGET IMPACT 33 -- 4 DISCUSSION AND CONCLUSIONS 34 -- 5 APPENDICES 37 -- 5.1 NATURAL PROGRESSION TO LIVER CIRRHOSIS IN 278 CHRONIC HEPATITIS B -- PATIENTS OF EUROPEAN ORIGIN, THE IMPORTANCE OF AGE AND ELEVATED ALT . 37 -- 5.1.1 Introduction 37 -- 5.1.2 Aim 37 -- 5.1.3 Methods 37 -- 5.1.4 Results 38 -- 5.1.5 Discussion and Conclusion 39 -- 5.2 COMPARISON OF PUBLISHED QUALITY OF LIFE DATA 40 -- 5.2.1 Aims 40 -- 5.2.2 Methods 41 -- 5.2.3 Results 43 -- 5.3 DISEASE MANAGEMENT COSTS 46 -- 5.3.1 Data sources 48 -- 5.3.2 Primary inclusion counts 52 -- 5.3.3 Exclusions and sub grouping for cost study 53 -- 5.3.4 Extrapolations for partial lump sum remunerations 59 -- 5.3.5 Results 66 -- 5.3.6 Discussion 72 -- 6 REFERENCES 74

X, 77 p. ill. Sinds enkele jaren zijn nieuwe geneesmiddelen beschikbaar voor de behandeling van chronische hepatitis B. De kostprijs van deze behandeling bedraagt zowat 5000 euro per patiënt per jaar. De beleidsmakers vroegen aan het Federaal Kenniscentrum voor de Gezondheidszorg (KCE) na te gaan welke groepen patiënten het meest baat kunnen hebben bij deze behandeling, en tegen welke prijs. Het KCE concludeerde dat het behandelen van een meer gevorderd ziektestadium, in dit geval levercirrose, gepaard gaat met de hoogste gezondheidswinst per gespendeerde euro. De berekeningen door het KCE zijn gebaseerd op een origineel onderzoek naar het ziekteverloop en de ziektekosten in samenwerking met een groot aantal leverspecialisten. GLOSSARY 2 -- 1 BACKGROUND AND OBJECTIVES 3 -- 1.1 NATURAL HISTORY AND EPIDEMIOLOGY 3 -- 1.2 TREATMENT 4 -- 1.3 OBJECTIVES AND CONTENT OF THE TWO REPORTS 5 -- 2 METHODS 7 -- 2.1 TARGET POPULATION 7 -- 2.2 MODEL STRUCTURE AND BASIC ASSUMPTIONS 7 -- 2.3 TRANSITION PROBABILITIES 9 -- 2.4 DISEASE MANAGEMENT AND TREATMENT COSTS 12 -- 2.5 UTILITIES 13 -- 2.6 ANTIVIRAL TREATMENT 14 -- 3 RESULTS 16 -- 3.1 MODEL VALIDATION: NATURAL EVOLUTION OF DISEASE WITHIN EUROPEAN -- COHORTS 17 -- 3.2 HEALTH OUTCOMES 18 -- 3.2.1 Life-years gained in the three cohorts 18 -- 3.2.2 Undiscounted life-years gained in DC and HCC 19 -- 3.2.3 Mean tenofovir treatment duration in CHB e+ vs e- cohorts 20 -- 3.3 BASE-CASE COST-UTILITY ANALYSES 20 -- 3.3.1 Overview of the results for the three base-case cohorts 20 -- 3.3.2 CHBe+ non-cirrhotic Europeans 21 -- 3.3.3 CHBe- non-cirrhotic Europeans 23 -- 3.3.4 Patient with compensated liver cirrhosis 25 -- 3.4 SCENARIO AND PROBABILISTIC SENSITIVITY ANALYSES 27 -- 3.4.1 Probabilistic sensitivity analysis 27 -- 3.4.2 ICERs in function of the time horizon 30 -- 3.4.3 Asian cohorts 31 -- 3.4.4 Variations in the discount rates 32 -- 3.5 BUDGET IMPACT 33 -- 4 DISCUSSION AND CONCLUSIONS 34 -- 5 APPENDICES 37 -- 5.1 NATURAL PROGRESSION TO LIVER CIRRHOSIS IN 278 CHRONIC HEPATITIS B -- PATIENTS OF EUROPEAN ORIGIN, THE IMPORTANCE OF AGE AND ELEVATED ALT . 37 -- 5.1.1 Introduction 37 -- 5.1.2 Aim 37 -- 5.1.3 Methods 37 -- 5.1.4 Results 38 -- 5.1.5 Discussion and Conclusion 39 -- 5.2 COMPARISON OF PUBLISHED QUALITY OF LIFE DATA 40 -- 5.2.1 Aims 40 -- 5.2.2 Methods 41 -- 5.2.3 Results 43 -- 5.3 DISEASE MANAGEMENT COSTS 46 -- 5.3.1 Data sources 48 -- 5.3.2 Primary inclusion counts 52 -- 5.3.3 Exclusions and sub grouping for cost study 53 -- 5.3.4 Extrapolations for partial lump sum remunerations 59 -- 5.3.5 Results 66 -- 5.3.6 Discussion 72 -- 6 REFERENCES 74

VIII, 111 p. ill. Het Federaal Kenniscentrum voor de Gezondheidszorg (KCE) onderzocht in samenwerking met een aantal specialisten van leverziekten de evolutie en de behandelingsmogelijkheden van chronische hepatitis B. De laatste jaren zijn nieuwe virusremmers op de markt gekomen die sinds kort ook worden terugbetaald. Deze dienen dikwijls levenslang te worden ingenomen. Het doel van de behandeling is het vermijden van ernstige verwikkelingen van de infectie op langere termijn, zoals levercirrose en leverkanker. De werkzaamheid en veiligheid van deze geneesmiddelen zijn gekend op korte termijn, maar nog niet bij langdurige inname. In afwachting van deze gegevens blijft het voorlopig moeilijk om in te schatten of de kostprijs opweegt tegen de nog te behalen gezondheidswinst. 1 AIMS AND METHODS 5 -- 1.1 AIMS 5 -- 1.2 METHODS 5 -- 1.3 OVERVIEW OF THE REPORT, PART 1 AND PART 2 5 -- 2 NATURAL HISTORY AND EPIDEMIOLOGY 6 -- 2.1 HEPATITIS B: TRANSITION AND NATURAL EVOLUTION 6 -- 2.1.1 Introduction 6 -- 2.1.2 Natural history of infections with the HBV 6 -- 2.1.3 Methods 8 -- 2.1.4 Results 9 -- 2.2 HBV IN BELGIUM AND SURROUNDING COUNTRIES 12 -- 2.2.1 Introduction and search strategy 12 -- 2.2.2 Epidemiology for Belgium, France, Germany and The Netherlands 12 -- 2.2.3 General Conclusion 16 -- 3 TREATMENT 17 -- 3.1 INDICATIONS FOR TREATMENT 17 -- 3.1.1 Treatment goals 17 -- 3.1.2 Definition of response 17 -- 3.1.3 Treatment options 18 -- 3.1.4 Interferon and pegylated interferon 18 -- 3.1.5 Nucleos(t)ide analogues in HBeAg-positive patients 20 -- 3.1.6 Nucleos(t)ide analogues in HBeAg-negative patients 24 -- 3.1.7 Nucleos(t)ide analogues in patients with cirrhosis or advanced fibrosis 25 -- 3.2 RECOMMENDATIONS FOR THE TREATMENT 28 -- 3.2.1 The BASL 2007 recommendations 28 -- 3.2.2 The EASL 2009 recommendations 28 -- 3.2.3 Treatment strategies 29 -- 3.2.4 Management of antiviral resistance to current NA therapy 31 -- 4 SITUATION IN BELGIUM 38 -- 4.1 HISTORY OF REIMBURSEMENT OF ANTIVIRAL DRUGS 38 -- 4.2 THE PROSPECTIVE STUDY 39 -- 4.2.1 Rationale 39 -- 4.2.2 Objectives 40 -- 4.2.3 Ethics and privacy protection 40 -- 4.2.4 Study design and schedule 41 -- 4.3 RESULTS OF THE STUDY 43 -- 4.3.1 Patient characteristics 43 -- 4.3.2 Estimation of the number of patients by disease stage, visiting a medical specialist for chronic HBV infection in Belgium. 46 -- 4.3.3 Conclusion for situation in Belgium 50 -- 4.3.4 Quality of life results 50 -- 4.3.5 Conclusion for quality of life assessment 52 -- 5 REVIEW OF THE COST-EFFECTIVENESS LITERATURE 53 -- 5.1 METHODS 53 -- 5.1.1 Literature search strategy 53 -- 5.1.2 Selection criteria 53 -- 5.1.3 Selection process 54 -- 5.2 OVERVIEW OF THE ECONOMIC EVALUATIONS - TRANSVERSAL 56 -- 5.2.1 Analytical technique 56 -- 5.2.2 Perspective 56 -- 5.2.3 Time horizon and discount rate 56 -- 5.2.4 Population 57 -- 5.2.5 Interventions 57 -- 5.2.6 Outcomes 58 -- 5.2.7 Effectiveness / modelling 61 -- 5.2.8 Costs 64 -- 5.2.9 Results 65 -- 5.3 OVERVIEW OF THE ECONOMIC EVALUATIONS - INDIVIDUAL 67 -- 5.4 GENERAL DISCUSSION AND CONCLUSIONS 70 -- 6 APPENDIXES 72 -- 7 REFERENCES 98

VIII, 111 p. ill. En collaboration avec des médecins spécialistes des maladies du foie, le Centre fédéral d’expertise des soins de santé (KCE) a réalisé une étude sur l’évolution et les possibilités de traitement de l’hépatite B chronique. Ces dernières années, de nouveaux antiviraux ont fait leur apparition sur le marché et sont remboursés depuis peu. Souvent, ces traitements doivent être pris à vie. Leur but est d’empêcher le développement de complications à long terme, tels la cirrhose ou le cancer du foie. L’efficacité et la sécurité de ces traitements ont été démontrées à court terme, mais pas encore en cas de prise prolongée. En l’absence de telles données de long terme, il est actuellement difficile d’évaluer le rapport entre le coût des ces traitements et leurs bénéfices en terme de santé, bénéfices non encore démontrés. 1 AIMS AND METHODS 5 -- 1.1 AIMS 5 -- 1.2 METHODS 5 -- 1.3 OVERVIEW OF THE REPORT, PART 1 AND PART 2 5 -- 2 NATURAL HISTORY AND EPIDEMIOLOGY 6 -- 2.1 HEPATITIS B: TRANSITION AND NATURAL EVOLUTION 6 -- 2.1.1 Introduction 6 -- 2.1.2 Natural history of infections with the HBV 6 -- 2.1.3 Methods 8 -- 2.1.4 Results 9 -- 2.2 HBV IN BELGIUM AND SURROUNDING COUNTRIES 12 -- 2.2.1 Introduction and search strategy 12 -- 2.2.2 Epidemiology for Belgium, France, Germany and The Netherlands 12 -- 2.2.3 General Conclusion 16 -- 3 TREATMENT 17 -- 3.1 INDICATIONS FOR TREATMENT 17 -- 3.1.1 Treatment goals 17 -- 3.1.2 Definition of response 17 -- 3.1.3 Treatment options 18 -- 3.1.4 Interferon and pegylated interferon 18 -- 3.1.5 Nucleos(t)ide analogues in HBeAg-positive patients 20 -- 3.1.6 Nucleos(t)ide analogues in HBeAg-negative patients 24 -- 3.1.7 Nucleos(t)ide analogues in patients with cirrhosis or advanced fibrosis 25 -- 3.2 RECOMMENDATIONS FOR THE TREATMENT 28 -- 3.2.1 The BASL 2007 recommendations 28 -- 3.2.2 The EASL 2009 recommendations 28 -- 3.2.3 Treatment strategies 29 -- 3.2.4 Management of antiviral resistance to current NA therapy 31 -- 4 SITUATION IN BELGIUM 38 -- 4.1 HISTORY OF REIMBURSEMENT OF ANTIVIRAL DRUGS 38 -- 4.2 THE PROSPECTIVE STUDY 39 -- 4.2.1 Rationale 39 -- 4.2.2 Objectives 40 -- 4.2.3 Ethics and privacy protection 40 -- 4.2.4 Study design and schedule 41 -- 4.3 RESULTS OF THE STUDY 43 -- 4.3.1 Patient characteristics 43 -- 4.3.2 Estimation of the number of patients by disease stage, visiting a medical specialist for chronic HBV infection in Belgium. 46 -- 4.3.3 Conclusion for situation in Belgium 50 -- 4.3.4 Quality of life results 50 -- 4.3.5 Conclusion for quality of life assessment 52 -- 5 REVIEW OF THE COST-EFFECTIVENESS LITERATURE 53 -- 5.1 METHODS 53 -- 5.1.1 Literature search strategy 53 -- 5.1.2 Selection criteria 53 -- 5.1.3 Selection process 54 -- 5.2 OVERVIEW OF THE ECONOMIC EVALUATIONS - TRANSVERSAL 56 -- 5.2.1 Analytical technique 56 -- 5.2.2 Perspective 56 -- 5.2.3 Time horizon and discount rate 56 -- 5.2.4 Population 57 -- 5.2.5 Interventions 57 -- 5.2.6 Outcomes 58 -- 5.2.7 Effectiveness / modelling 61 -- 5.2.8 Costs 64 -- 5.2.9 Results 65 -- 5.3 OVERVIEW OF THE ECONOMIC EVALUATIONS - INDIVIDUAL 67 -- 5.4 GENERAL DISCUSSION AND CONCLUSIONS 70 -- 6 APPENDIXES 72 -- 7 REFERENCES 98

161-170 OBJECTIVES: The cost-effectiveness of adding a human papillomavirus (HPV) vaccination program in 12-year-old females to the recommended cervical cancer screening in Belgium is examined. Moreover, the health and economic consequences of a potential decline in screening uptake after initiation of a HPV vaccination program are investigated. METHODS: A static Markov model is developed to estimate the direct effect of vaccination on precancerous lesions and cervical cancers. RESULTS: Vaccination is estimated to avoid 20 percent of the cervical cancers occurring in a 12-year-old girls' cohort and to cost 32,665 euro per quality-adjusted life-year (QALY) gained (95 percent credibility interval [CrI]: 17,447 euro to 68,078 euro), assuming a booster injection after 10 years, a limited duration of protection and discounting costs and effects at 3 percent and 1.5 percent, respectively. Assuming lifelong protection, HPV vaccination is estimated to cost 14,382 euro (95 percent CrI: 9,238 euro to 25,644 euro) per QALY gained, while avoiding 50 percent of the cervical cancer cases. In the base-case, a 10 percent reduction in screening compliance after vaccination obliterates the effect of vaccination on cervical cancer cases avoided, whereas further declines in the level of screening compliance even turned out to be detrimental for the cohort's health, inducing a mean loss in QALYs and life-year gained compared with the situation prevaccination. CONCLUSIONS: An HPV vaccination program should only be considered if the level of screening after vaccination can be maintained.

146-59 OBJECTIVES: Although trastuzumab is traditionally used in metastatic breast cancer treatment, studies reported on the efficacy and safety of trastuzumab in adjuvant setting for the treatment of early stage breast cancer in HER2+ tumors. We estimated the cost-effectiveness and budget impact of reimbursing trastuzumab in this indication from a payer's perspective.