Search

47 p. ill., Les progrès de la médecine ont permis de nombreuses avancées ; l'arrivée régulière sur le marché de nouveaux médicaments innovants contre le cancer est une bonne chose en soi. Hélas une grande partie de ces médicaments sont remboursés par l’assurance maladie belge sans preuves suffisantes d’un réel bénéfice pour les patients. Le KCE plaide pour un système plus transparent qui mette davantage l’accent sur la véritable valeur ajoutée pour le patient de chaque nouveau médicament. De cette manière, les moyens limités de l'assurance maladie pourront être utilisés de manière plus responsable et plus efficace. 1. INTRODUCTION 7 -- 1.1. LES MÉDICAMENTS CONTRE LE CANCER COÛTENT DE PLUS EN PLUS CHER 7 -- 1.2. LES BÉNÉFICES POUR LES PATIENTS SONT-ILS SUFFISAMMENT PROUVÉS ? 7 -- 1.3. L’OBLIGATION DE CONFIDENTIALITÉ REND LE SYSTÈME DE PLUS EN PLUS OPAQUE 8 -- 2. QUESTIONS ET MÉTHODES DE RECHERCHE 9 -- 2.1. QUESTIONS DE RECHERCHE 9 -- 2.2. COMMENT AVONS-NOUS PROCÉDÉ? 11 -- 2.2.1. Données observationnelles 11 -- 2.2.2. Analyse de la littérature 12 -- 3. ÉVOLUTION DE LA SURVIE GLOBALE ET DE L’IMPACT BUDGÉTAIRE DES MÉDICAMENTS INNOVANTS 13 -- 3.1. REMARQUES PRÉLIMINAIRES 13 -- 3.2. RÉSUMÉ DES RÉSULTATS 14 -- 4. LIMITATIONS DES DONNÉES OBSERVATIONNELLES 20 -- 5. RAPPORT COÛT-EFFICACITÉ 21 -- 6. PISTES POUR MIEUX ÉVALUER LA VALEUR AJOUTÉE DES MÉDICAMENTS INNOVANTS À L’AVENIR 23 -- 6.1. INCERTITUDES ISSUES DES ESSAIS CLINIQUES 23 -- 6.1.1. Les essais contrôlés randomisées restent le ‘gold standard’ 23 -- 6.1.2. La survie n’est pas le principal outcome 24 -- 6.1.3. Les comparateurs ne sont pas toujours adéquats 25 -- 6.1.4. Les résultats se mesurent par substitution 26 -- 6.1.5. La qualité de vie est la grande oubliée des essais cliniques 27 -- 6.2. INCERTITUDES LIÉES AUX MEA 30 -- 6.2.1. Les mécanismes de compensation des MEA et taxes payées par l’industrie pharmaceutique . 31 -- 6.2.2. L’industrie n’est pas encouragée à fournir les données probantes manquantes 32 -- 6.2.3. Les prix confidentiels génèrent un manque de transparence aux conséquences négatives 35 -- 7. QUELQUES AFFIRMATIONS SUPPLÉMENTAIRES QUI MÉRITENT D'ÊTRE NUANCÉES 36 -- 8. CONCLUSION 39

1116 p. ill., APPENDIX 1. BREAST CANCER 56 -- APPENDIX 1.1. BCR DATA 56 -- Appendix 1.1.1. Descriptive statistics 56 -- Appendix 1.1.2. Uptake of selected drugs 92 -- APPENDIX 1.2. REIMBURSEMENT CRITERIA FOR SELECTED DRUGS 94 -- APPENDIX 1.3. MEDICAL LITERATURE: SEARCH FOR EVIDENCE 100 -- Appendix 1.3.1. Search medical literature (systematic reviews) 100 -- Appendix 1.3.2. Critical appraisal systematic reviews 104 -- Appendix 1.3.3. Search strategy 107 -- APPENDIX 1.4. ECONOMIC LITERATURE 118 -- Appendix 1.4.1. Search economic literature (HTA reports) 118 -- Appendix 1.4.2. Results economic literature (HTA reports) 121 -- APPENDIX 2. CHRONIC MYELOID LEUKAEMIA 147 -- APPENDIX 2.1. BCR DATA 147 -- Appendix 2.1.1. Descriptive statistics 147 -- Appendix 2.1.2. Uptake of selected drugs 166 -- APPENDIX 2.2. REIMBURSEMENT CRITERIA FOR SELECTED DRUGS 167 -- APPENDIX 2.3. MEDICAL LITERATURE: SEARCH FOR EVIDENCE 173 -- Appendix 2.3.1. Search medical literature (systematic reviews) 173 -- Appendix 2.3.2. Critical appraisal systematic reviews 177 -- Appendix 2.3.3. Search strategy 180 -- APPENDIX 2.4. ECONOMIC LITERATURE 189 -- Appendix 2.4.1. Search economic literature (HTA reports) 189 -- Appendix 2.4.2. Results economic literature (HTA reports) 192 -- APPENDIX 3. COLORECTAL CANCER 207 -- APPENDIX 3.1. BCR DATA 207 -- Appendix 3.1.1. Descriptive statistics 207 -- Appendix 3.1.2. Uptake of selected drugs 244 -- APPENDIX 3.2. REIMBURSEMENT CRITERIA FOR SELECTED DRUGS 246 -- APPENDIX 3.3. MEDICAL LITERATURE: SEARCH FOR EVIDENCE 249 -- Appendix 3.3.1. Search medical literature (systematic reviews) 249 -- Appendix 3.3.2. Critical appraisal systematic reviews 256 -- Appendix 3.3.3. Search strategy 258 -- APPENDIX 3.4. ECONOMIC LITERATURE 274 -- Appendix 3.4.1. Search economic literature (HTA reports) 274 -- Appendix 3.4.2. Results economic literature (HTA reports) 276 -- APPENDIX 4. HEAD & NECK CANCER 290 -- APPENDIX 4.1. BCR DATA 290 -- Appendix 4.1.1. Descriptive statistics 290 -- Appendix 4.1.2. Uptake of selected drug 341 -- APPENDIX 4.2. REIMBURSEMENT CRITERIA FOR SELECTED DRUGS 342 -- APPENDIX 4.3. MEDICAL LITERATURE: SEARCH FOR EVIDENCE 343 -- Appendix 4.3.1. Search medical literature (systematic reviews) 343 -- Appendix 4.3.2. Critical appraisal systematic reviews 346 -- Appendix 4.3.3. Search strategy 347 -- APPENDIX 4.4. ECONOMIC LITERATURE 350 -- Appendix 4.4.1. Search economic literature (HTA reports) 350 -- Appendix 4.4.2. Results economic literature (HTA reports) 352 -- APPENDIX 5. MELANOMA 358 -- APPENDIX 5.1. BCR DATA 358 -- Appendix 5.1.1. Descriptive statistics 358 -- APPENDIX 5.2. REIMBURSEMENT CRITERIA FOR SELECTED DRUGS 419 -- APPENDIX 5.3. MEDICAL LITERATURE: SEARCH FOR EVIDENCE 421 -- Appendix 5.3.1. Search medical literature (systematic reviews) 421 -- Appendix 5.3.2. Melanoma: Critical appraisal systematic reviews. 426 -- Appendix 5.3.3. Search strategy 428 -- APPENDIX 5.4. ECONOMIC LITERATURE 438 -- Appendix 5.4.1. Search economic literature (HTA reports) 438 -- Appendix 5.4.2. Results economic literature (HTA reports) 441 -- APPENDIX 6. MESOTHELIOMA 471 -- APPENDIX 6.1. BCR DATA 471 -- Appendix 6.1.1. Descriptive statistics 471 -- Appendix 6.1.2. Descriptive statistics 498 -- Appendix 6.1.3. Uptake of selected drugs 525 -- APPENDIX 6.2. REIMBURSEMENT CRITERIA FOR SELECTED DRUGS 525 -- APPENDIX 6.3. MEDICAL LITERATURE: SEARCH FOR EVIDENCE 525 -- Appendix 6.3.1. Search medical literature (systematic reviews) 525 -- Appendix 6.3.2. Critical appraisal systematic reviews 527 -- Appendix 6.3.3. Search strategy 528 -- APPENDIX 6.4. ECONOMIC LITERATURE 533 -- Appendix 6.4.1. Search economic literature (HTA reports) 533 -- Appendix 6.4.2. Results economic literature (HTA reports) 534 -- APPENDIX 7. MULTIPLE MYELOMA 538 -- APPENDIX 7.1. BCR DATA 538 -- Appendix 7.1.1. Descriptive statistics 538 -- Appendix 7.1.2. Uptake of selected drugs 545 -- APPENDIX 7.2. REIMBURSEMENT CRITERIA FOR SELECTED DRUGS 546 -- APPENDIX 7.3. MEDICAL LITERATURE: SEARCH FOR EVIDENCE 549 -- Appendix 7.3.1. Search medical literature (systematic reviews) 549 -- Appendix 7.3.2. Critical appraisal systematic reviews 553 -- Appendix 7.3.3. Search strategy 556 -- APPENDIX 7.4. ECONOMIC LITERATURE 562 -- Appendix 7.4.1. Search economic literature (HTA reports) 562 -- Appendix 7.4.2. Results economic literature (HTA reports) 565 -- APPENDIX 8. NON HODGKIN 587 -- APPENDIX 8.1. BCR DATA 587 -- Appendix 8.1.1. Descriptive statistics 587 -- Appendix 8.1.2. Uptake of selected drugs 611 -- APPENDIX 8.2. REIMBURSEMENT CRITERIA FOR SELECTED DRUGS 612 -- APPENDIX 8.3. MEDICAL LITERATURE: SEARCH FOR EVIDENCE 614 -- Appendix 8.3.1. Search medical literature (systematic reviews) 614 -- Appendix 8.3.2. Critical appraisal systematic reviews 620 -- Appendix 8.3.3. Search strategy 628 -- APPENDIX 8.4. ECONOMIC LITERATURE 664 -- Appendix 8.4.1. Search economic literature (HTA reports) 664 -- Appendix 8.4.2. Results economic literature (HTA reports) 667 -- Appendix 8.4.3. Mantel-cell lymphoma 681 -- APPENDIX 9. NON-SMALL CELL LUNG CANCER 684 -- APPENDIX 9.1. BCR DATA 684 -- Appendix 9.1.1. Descriptive statistics 684 -- Appendix 9.1.2. Uptake of selected drugs 720 -- APPENDIX 9.2. REIMBURSEMENT CRITERIA FOR SELECTED DRUGS 721 -- APPENDIX 9.3. MEDICAL LITERATURE: SEARCH FOR EVIDENCE 724 -- Appendix 9.3.1. Search medical literature (systematic reviews) 724 -- Appendix 9.3.2. Critical appraisal systematic reviews 732 -- Appendix 9.3.3. Search strategy 736 -- APPENDIX 9.4. ECONOMIC LITERATURE 747 -- Appendix 9.4.1. Search economic literature (HTA reports) 747 -- Appendix 9.4.2. Results economic literature (HTA reports) 751 -- APPENDIX 10. OVARIAN CANCER 786 -- APPENDIX 10.1. BCR DATA 786 -- Appendix 10.1.1. Descriptive statistics 786 -- Appendix 10.1.2. Uptake of selected drugs 873 -- APPENDIX 10.2. REIMBURSEMENT CRITERIA FOR SELECTED DRUGS 874 -- APPENDIX 10.3. MEDICAL LITERATURE: SEARCH FOR EVIDENCE 876 -- Appendix 10.3.1. Search medical literature (systematic reviews) 876 -- Appendix 10.3.2. Critical appraisal systematic reviews 878 -- Appendix 10.3.3. Search strategy 880 -- APPENDIX 10.4. ECONOMIC LITERATURE 887 -- Appendix 10.4.1. Search economic literature (HTA reports) 887 -- Appendix 10.4.2. Results economic literature (HTA reports) 889 -- APPENDIX 11. PROSTATE CANCER 898 -- APPENDIX 11.1. BCR DATA 898 -- Appendix 11.1.1. Descriptive statistics 898 -- Appendix 11.1.2. Uptake of selected drugs 951 -- APPENDIX 11.2. REIMBURSEMENT CRITERIA FOR SELECTED DRUGS 951 -- APPENDIX 11.3. MEDICAL LITERATURE: SEARCH FOR EVIDENCE 952 -- Appendix 11.3.1. Search medical literature (systematic reviews) 952 -- Appendix 11.3.2. Critical appraisal systematic reviews 956 -- Appendix 11.3.3. Search strategy 958 -- APPENDIX 11.4. ECONOMIC LITERATURE 965 -- Appendix 11.4.1. Search economic literature (HTA reports) 965 -- Appendix 11.4.2. Results economic literature (HTA reports) 967 -- APPENDIX 12. RENAL CELL CARCINOMA (RCC) 979 -- APPENDIX 12.1. BCR DATA 979 -- Appendix 12.1.1. Descriptive statistics 979 -- Appendix 12.1.2. Uptake of selected drugs 1031 -- APPENDIX 12.2. REIMBURSEMENT CRITERIA FOR SELECTED DRUGS 1033 -- APPENDIX 12.3. MEDICAL LITERATURE: SEARCH FOR EVIDENCE 1037 -- Appendix 12.3.1. Search medical literature (systematic reviews) 1037 -- Appendix 12.3.2. Critical appraisal systematic reviews 1043 -- Appendix 12.3.3. Search strategy 1045 -- APPENDIX 12.4. ECONOMIC LITERATURE 1054 -- Appendix 12.4.1. Search economic literature (HTA reports) 1054 -- Appendix 12.4.2. Results economic literature (HTA reports) 1057 -- APPENDIX 13. OVERVIEW FINDINGS MEDICAL LITERATURE 1083 -- APPENDIX 14. DRUG PRICES 1094 -- APPENDIX 14.1. BREAST CANCER 1095 -- APPENDIX 14.2. CHRONIC MYELOID LEUKAEMIA (CML) 1097 -- APPENDIX 14.3. COLORECTAL CANCER 1100 -- APPENDIX 14.4. HEAD AND NECK CANCER 1102 -- APPENDIX 14.5. MELANOMA 1103 -- APPENDIX 14.6. MESOTHELIOMA 1105 -- APPENDIX 14.7. MULTIPLE MYELOMA 1106 -- APPENDIX 14.8. NON-HODGKIN LYMPHOMA (NHL) 1108 -- APPENDIX 14.9. NON-SMALL-CELL LUNG CARCINOMA (NSCLC). 1110 -- APPENDIX 14.10. OVARIAN CANCER 1112 -- APPENDIX 14.11. PROSTATE CANCER 1114 -- APPENDIX 14.12. RENAL CELL CARCINOMA 1115

45 p. ill., FOREWORD 1 -- KEY MESSAGES 2 -- SUMMARY 4 -- 1. INTRODUCTION 6 -- 1.1. CANCER MEDICINE IS BECOMING MORE AND MORE EXPENSIVE 6 -- 1.2. ARE THE BENEFITS FOR THE PATIENT SUFFICIENTLY PROVEN? 6 -- 1.3. THE CONFIDENTIALITY OBLIGATION MAKES THE SYSTEM EVEN LESS TRANSPARENT 7 -- 2. RESEARCH QUESTIONS AND METHODS 8 -- 2.1. RESEARCH QUESTIONS 8 -- 2.2. HOW DID WE PROCEED? 9 -- 2.2.1. Observational data 9 -- 2.2.2. Literature study 10 -- 3. EVOLUTION OF THE OVERALL SURVIVAL AND BUDGETARY IMPACT OF THE INNOVATIVE -- MEDICINES 11 -- 3.1. PRELIMINARY REMARKS 11 -- 3.2. SUMMARY OF RESULTS 12 -- 4. RESTRICTIONS OF OBSERVATIONAL DATA 19 -- 5. COST EFFECTIVENESS 20 -- 6. WAYS TO BETTER ASSESS THE ADDED VALUE OF INNOVATIVE MEDICINES IN THE FUTURE 21 -- 6.1. UNCERTAINTIES IN CLINICAL STUDIES 22 -- 6.1.1. Randomised controlled studies remain the ‘golden standard’ 22 -- 6.1.2. Survival is not always the primary outcome measure 22 -- 6.1.3. New medicines are not always compared with the right treatment 23 -- 6.1.4. The outcome is measured by surrogate endpoints 24 -- 6.1.5. Quality of life is one thing that is often overlooked in clinical studies. 25 -- 6.2. UNCERTAINTIES WITH REGARD TO MEAS 28 -- 6.2.1. Refund mechanisms of the MEAs and taxes paid by the pharmaceutical industry 29 -- 6.2.2. The industry is not encouraged to provide the missing evidence 30 -- 6.2.3. Confidential pricing creates a lack of transparency with negative consequences 32 -- 7. ADDITIONAL STATEMENTS THAT DESERVE THE NECESSARY NUANCE 34 -- 8. CONCLUSION 37 -- RECOMMENDATIONS 38 -- REFERENCES 43

47 p. ill., Medische ontwikkelingen hebben tot veel vooruitgang geleid en het feit dat er regelmatig nieuwe, innovatieve geneesmiddelen tegen kanker op de markt komen is een reden tot vreugde. Helaas wordt een groot deel van deze kankermedicijnen reeds terugbetaald door de Belgische ziekteverzekering zonder dat de echte voordelen voor de patiënten voldoende bewezen zijn. Het KCE dringt erop aan om tot een meer transparant systeem te komen dat de nadruk legt op de werkelijke meerwaarde van elk nieuw kankergeneesmiddel voor de patiënt. Op die manier kunnen de beperkte middelen van de ziekteverzekering op een meer verantwoorde en efficiënte manier worden gebruikt. VOORWOORD 1 -- KERN BOODSCHAPPEN 2 -- SAMENVATTING 5 -- 1. INLEIDING 7 -- 1.1. GENEESMIDDELEN TEGEN KANKER WORDEN STEEDS DUURDER 7 -- 1.2. ZIJN DE VOORDELEN ERVAN VOOR DE PATIËNT VOLDOENDE BEWEZEN? 7 -- 1.3. DE VERPLICHTING TOT VERTROUWELIJKHEID MAAKT HET SYSTEEM STEEDS -- ONDOORZICHTIGER 8 -- 2. ONDERZOEKSVRAGEN EN METHODEN 9 -- 2.1. ONDERZOEKSVRAGEN 9 -- 2.2. HOE ZIJN WE TE WERK GEGAAN? 11 -- 2.2.1. Observationele gegevens 11 -- 2.2.2. Literatuuroverzicht 12 -- 3. EVOLUTIE VAN DE TOTALE OVERLEVING EN BUDGETTAIRE IMPACT VAN DE INNOVATIEVE -- GENEESMIDDELEN 13 -- 3.1. VOORAFGAANDE OPMERKINGEN 13 -- 3.2. SAMENVATTING VAN DE RESULTATEN 14 -- 4. BEPERKINGEN VAN OBSERVATIONELE DATA 20 -- 5. KOSTENEFFECTIVITEIT 21 -- 6. PISTES OM DE MEERWAARDE VAN INNOVATIEVE GENEESMIDDELEN IN DE TOEKOMST -- BETER TE BEOORDELEN 23 -- 6.1. ONZEKERHEDEN IN DE KLINISCHE STUDIES 23 -- 6.1.1. Gerandomiseerde gecontroleerde studies blijven de ‘gouden standaard’ 23 -- 6.1.2. Overleving is niet altijd de primaire uitkomstmaat 24 -- 6.1.3. Nieuwe geneesmiddelen worden niet altijd met de juiste behandeling vergeleken 25 -- 6.1.4. De uitkomsten worden gemeten door surrogaateindpunten 26 -- 6.1.5. Wat in het bijzonder over het hoofd wordt gezien in klinische studies is de levenskwaliteit 27 -- 6.2. ONZEKERHEDEN IN VERBAND MET MEA'S 30 -- 6.2.1. Compensatiemechanismen van de MEA’s en door de farmaceutische industrie betaalde heffingen 31 -- 6.2.2. De industrie wordt niet aangemoedigd om de ontbrekende bewijskrachtige gegevens te -- verstrekken 32 -- 6.2.3. Vertrouwelijke prijzen zorgen voor een gebrek aan transparantie met negatieve gevolgen 35 -- 7. BIJKOMENDE STATEMENTS DIE DE NODIGE NUANCE VERDIENEN 36 -- 8. CONCLUSIE 39 -- AANBEVELINGEN 40 -- REFERENTIES 45

346 p. ill., SCIENTIFIC REPORT 22 -- 1 INTRODUCTION 22 -- 1.1 SETTING THE SCENE 22 -- 1.1.1 Increasing expenditures for oncology drugs 22 -- 1.1.2 The increasing cancer drug prices 23 -- 1.1.3 Patient benefit, no longer a hard requirement for marketing authorisation 24 -- 1.2 ARE THE EXTRA EXPENDITURES ASSOCIATED WITH PATIENT BENEFITS? 26 -- 1.2.1 Cancer drugs as one of many contributors to cancer survival 26 -- 1.2.2 Small and uncertain patient benefit of new cancer medicines 27 -- 2 OBJECTIVES 28 -- 2.1 OPPORTUNITY COST OR DISPLACEMENT EFFECT 28 -- 2.2 RESEARCH QUESTIONS 28 -- 3 METHODOLOGY 29 -- 3.1 PART 1: DATABASES, STATISTICAL ANALYSES, AND PRESENTATION OF RESULTS 29 -- 3.1.1 Belgian Cancer Registry (BCR) data selection and linkage with Intermutualistic Agency (IMA) data and vital status 29 -- 3.1.1.1 Selection of the study population in the Belgian Cancer Registry database 29 -- 3.1.1.2 Linkage with health insurance data 32 -- 3.1.1.3 Vital status 32 -- 3.1.2 Statistical analyses 33 -- 3.1.2.1 Descriptive analyses 33 -- 3.1.2.2 Survival analysis 33 -- 3.1.2.3 Statistical software 34 -- 3.1.3 Graphics and Tables 34 -- 3.2 PART 2: SELECTION OF DRUGS 35 -- 3.2.1 Selection criteria and process 35 -- 3.2.2 Selected cancer types and drugs 37 -- 3.3 PART 3: LITERATURE SEARCHES 37 -- 3.3.1 Search medical literature 37 -- 3.3.2 Search economic literature 38 -- 3.4 PART 4: RIZIV REIMBURSEMENT CRITERIA 39 -- 4 RESULTS PER CANCER TYPE 40 -- 4.1 BREAST CANCER 40 -- 4.1.1 Introduction 40 -- 4.1.2 Observational data 42 -- 4.1.2.1 Patient characteristics, survival and expenditures 42 -- 4.1.2.2 Drug uptake for a selection of drugs during the first 5 years after diagnosis 47 -- 4.1.3 Medical literature: efficacy 48 -- 4.1.3.1 HER2(+) Breast cancer: neo-adjuvant and adjuvant setting (pertuzumab) 48 -- 4.1.3.2 HER2(+) Breast cancer: metastatic disease or locally advanced disease – first line (pertuzumab) 49 -- 4.1.3.3 HER2(+) Breast cancer: metastatic disease or locally advanced disease – second line (pertuzumab, trastuzumab emtansine) 49 -- 4.1.3.4 HER2(-) Breast cancer: metastatic disease or locally advanced disease 50 -- 4.1.3.5 Discussion 50 -- 4.1.4 Economic literature: cost-effectiveness 51 -- 4.1.5 Summary 57 -- 4.2 CHRONIC MYELOID LEUKAEMIA 59 -- 4.2.1 Introduction 59 -- 4.2.2 Observational data 60 -- 4.2.2.1 Patient characteristics, survival and expenditures 60 -- 4.2.2.2 Drug uptake for a selection of drugs during the first 5 years after diagnosis 67 -- 4.2.3 Medical literature: efficacy 67 -- 4.2.3.1 First-line treatment 68 -- 4.2.3.2 Second- and third-line treatment 70 -- 4.2.3.3 Discussion 70 -- 4.2.4 Economic literature: cost-effectiveness 71 -- 4.2.5 Summary 76 -- 4.3 COLORECTAL CANCER 78 -- 4.3.1 Introduction 78 -- 4.3.2 Observational data 79 -- 4.3.2.1 Patient characteristics, survival and expenditures 79 -- 4.3.2.2 Drug uptake for a selection of drugs during the first 5 years after diagnosis 84 -- 4.3.3 Medical literature: efficacy 84 -- 4.3.3.1 First-line treatment 85 -- 4.3.3.2 Second-line (or later) treatment 86 -- 4.3.3.3 Discussion 87 -- 4.3.4 Economic literature: cost-effectiveness 87 -- 4.3.5 Summary 91 -- 4.4 HEAD AND NECK CANCER 93 -- 4.4.1 Introduction 93 -- 4.4.2 Observational data 94 -- 4.4.2.1 Patient characteristics, survival and expenditures 94 -- 4.4.2.2 Drug uptake for a selection of drugs during the first 5 years after diagnosis 100 -- 4.4.3 Medical literature: efficacy 100 -- 4.4.3.1 Discussion 102 -- 4.4.4 Economic literature: cost-effectiveness 103 -- 4.4.5 Summary 106 -- 4.5 MELANOMA 107 -- 4.5.1 Introduction 107 -- 4.5.2 Observational data 108 -- 4.5.2.1 Patient characteristics, survival and expenditures 108 -- 4.5.2.2 Drug uptake for a selection of drugs during the first 5 years after diagnosis 119 -- 4.5.3 Medical literature: efficacy 120 -- 4.5.3.1 BRAF and MEK inhibitors melanoma 121 -- 4.5.3.2 Immunotherapy in melanoma 122 -- 4.5.3.3 Discussion 123 -- 4.5.4 Economic literature: cost-effectiveness 124 -- 4.5.5 Summary 129 -- 4.6 MESOTHELIOMA 132 -- 4.6.1 Introduction 132 -- 4.6.2 Observational data 132 -- 4.6.2.1 Patient characteristics, survival and expenditures 132 -- 4.6.2.2 Drug uptake for a selection of drugs during the first 5 years after diagnosis 139 -- 4.6.3 Medical literature: efficacy 139 -- 4.6.3.1 Discussion 140 -- 4.6.4 Economic literature: cost-effectiveness 141 -- 4.6.5 Summary 142 -- 4.7 MULTIPLE MYELOMA 143 -- 4.7.1 Introduction 143 -- 4.7.2 Observational data 145 -- 4.7.2.1 Patient characteristics, survival and expenditures 145 -- 4.7.2.2 Drug uptake for a selection of drugs during the first 5 years after diagnosis 150 -- 4.7.3 Medical literature: efficacy 150 -- 4.7.3.1 Multiple Myeloma: First-line treatment in adult patients ineligible for stem-cell -- transplantation 151 -- 4.7.3.2 Multiple myeloma: first-line treatment in adult patients eligible for stem-cell -- transplant 152 -- 4.7.3.3 Multiple myeloma: treatment of relapsed or refractory disease 152 -- 4.7.3.4 Discussion 153 -- 4.7.4 Economic literature: cost-effectiveness 154 -- 4.7.5 Summary 158 -- 4.8 NON-HODGKIN LYMPHOMA 160 -- 4.8.1 Introduction 160 -- 4.8.2 Observational data 161 -- 4.8.2.1 Patient characteristics, survival and expenditures 161 -- 4.8.2.2 Drug uptake for a selection of drugs during the first 5 years after diagnosis 175 -- 4.8.3 Medical literature: efficacy 176 -- 4.8.3.1 CLL/SLL 176 -- 4.8.3.2 DLBCL 178 -- 4.8.3.3 Mantle cell lymphoma 179 -- 4.8.3.4 Discussion 181 -- 4.8.4 Economic literature: cost-effectiveness 183 -- 4.8.4.1 Chronic lymphocytic leukaemia 183 -- 4.8.4.2 Mantel-cell lymphoma 188 -- 4.8.5 Summary 190 -- 4.8.5.1 CLL/SLL 190 -- 4.8.5.2 DLBCL 191 -- 4.8.5.3 Mantle cell lymphoma 192 -- 4.9 NON-SMALL CELL LUNG CANCER 193 -- 4.9.1 Introduction 193 -- 4.9.2 Observational data 194 -- 4.9.2.1 Patient characteristics, survival and expenditures 194 -- 4.9.2.2 Drug uptake for a selection of drugs during the first 5 years after diagnosis 199 -- 4.9.3 Medical literature: efficacy 199 -- 4.9.3.1 Anti-EGFR therapy in NSCLC 200 -- 4.9.3.2 ALK inhibitors for non-small cell lung cancer 203 -- 4.9.3.3 Immunotherapy 203 -- 4.9.3.4 Discussion 205 -- 4.9.4 Economic literature: cost-effectiveness 205 -- 4.9.5 Summary 209 -- 4.10 OVARIAN CANCER 211 -- 4.10.1 Introduction 211 -- 4.10.2 Observational data 211 -- 4.10.2.1 Patient characteristics, survival and expenditures 211 -- 4.10.2.2 Drug uptake for a selection of drugs during the first 5 years after diagnosis 220 -- 4.10.3 Medical literature: efficacy 220 -- 4.10.3.1 Bevacizumab in ovarian cancer 221 -- 4.10.3.2 Discussion 222 -- 4.10.4 Economic literature: cost-effectiveness 222 -- 4.10.5 Summary 226 -- 4.11 PROSTATE CANCER 227 -- 4.11.1 Introduction 227 -- 4.11.2 Observational data 227 -- 4.11.2.1 Patient characteristics, survival and expenditures 227 -- 4.11.2.2 Drug uptake for a selection of drugs during the first 5 years after diagnosis 233 -- 4.11.3 Medical literature: efficacy 233 -- 4.11.3.1 Discussion 235 -- 4.11.4 Economic literature: cost-effectiveness 235 -- 4.11.5 Summary 238 -- 4.12 RENAL CELL CARCINOMA (RCC) 239 -- 4.12.1 Introduction 239 -- 4.12.2 Observational data 241 -- 4.12.2.1 Patient characteristics, survival and expenditures 241 -- 4.12.2.2 Drug uptake for a selection of drugs during the first 5 years after diagnosis 247 -- 4.12.3 Medical literature: efficacy 249 -- 4.12.3.1 Targeted therapy – first line treatment 250 -- 4.12.3.2 Targeted therapy – second line treatment 250 -- 4.12.3.3 Immunotherapy 251 -- 4.12.3.4 Discussion 252 -- 4.12.4 Economic literature: cost-effectiveness 253 -- 4.12.5 Summary 259 -- 5 USE OF ANTICANCER DRUGS AT THE END OF LIFE 261 -- 6 SUMMARY 266 -- 7 DISCUSSION 276 -- 7.1 REAL-WORLD OBSERVATIONAL DATA 276 -- 7.1.1 Data from the Belgian Cancer Registry (BCR) and Intermutualistic Agency (IMA) – strengths/limitations and nuance needed 276 -- 7.1.2 Limitations inherent to the use of observational data – no good estimate of treatment effect 280 -- 7.2 LIMITED BENEFITS IN OVERALL SURVIVAL 284 -- 7.3 QOL AS AN IMPORTANT ENDPOINT 287 -- 7.3.1 A patient-relevant endpoint in clinical trials 287 -- 7.3.2 Measuring QoL with a generic utility instrument 287 -- 7.3.3 Improvement needed in measuring and reporting QoL, and using the results in economic evaluations 288 -- 7.3.4 An example to show (the importance of) transparent reporting of QoL data 292 -- 7.4 THE USE OF PROGRESSION-FREE SURVIVAL AS A SURROGATE ENDPOINT 295 -- 7.4.1 Is PFS a valid surrogate for OS?. 295 -- 7.4.2 Can PFS be considered as a surrogate for quality of life? 296 -- 7.4.3 The problem of PFS in economic evaluations 297 -- 7.4.4 Do we try hard enough? Searching for a solution that fits both goals 298 -- 7.5 SUBSTANTIAL INCREASE IN GROSS EXPENDITURES, LIMITED BY REFUNDS AND TAXES 299 -- 7.5.1 Managed entry agreement refunds 299 -- 7.5.2 Taxes and clawback 300 -- 7.6 MANAGED ENTRY AGREEMENT 301 -- 7.6.1 Managed entry agreement – when the exception becomes the rule 301 -- 7.6.2 Incentives to demonstrate survival or QoL benefits for the patients 302 -- 7.6.2.1 Before marketing approval 302 -- 7.6.2.2 After marketing approval 304 -- 7.6.3 Confidential prices 307 -- 7.6.3.1 A short-term advantage creating long-term problems and making the system intransparent 307 -- 7.6.3.2 Confidential prices making economic evaluations and policy decisions intransparent 308 -- 7.7 WHY WE MAINLY RELIED ON UK DOSSIERS FOR INFORMATION ON ECONOMIC EVALUATIONS IN THIS REPORT 309 -- 7.8 THE IMPORTANCE OF THE (DISCOUNT FOR THE) COMPARATOR 311 -- 7.9 DIFFERENT ARGUMENTS USED FROM DIFFERENT PERSPECTIVES 313 -- REFERENCES 317

p. 267-278 Because it spares many normal tissues and reduces the integral dose, proton therapy (PT) is the preferred tumor irradiation technique for treating childhood cancer. However, to the best of our knowledge, no systematic review of the clinical effectiveness of PT in children has been reported in the scientific literature. A systematic search for clinical outcome studies on PT published between 2007 and 2015 was performed in Medline (through OVID), EMBASE, and the Cochrane Library. Twenty-three primary studies were identified, including approximately 650 patients overall. The median/mean follow-up times were limited (range, 19-91 months). None of the studies were randomized, 2 were comparative, and 20 were retrospective. Most suffered from serious methodologic limitations, yielding a very low level of clinical evidence for the outcomes in all indications. For example, for retinoblastoma, very low-level evidence was found that PT might decrease the incidence of second malignancies. For chondrosarcoma, chordoma, craniopharyngioma, ependymoma, esthesioneuroblastoma, Ewing sarcoma, central nervous system germinoma, glioma, medulloblastoma, osteosarcoma, and rhabdomyosarcoma, there was insufficient evidence to either support or refute PT in children. For pelvic sarcoma (ie, nonrhabdomyosarcoma and non-Ewing sarcoma), pineal parenchymal tumor, primitive neuroectodermal tumor, and "adult-type" soft tissue sarcoma, no studies were identified that fulfilled the inclusion criteria. Although there is no doubt that PT reduces the radiation dose to normal tissues and organs, to date the critical clinical data on the long-term effectiveness and harm associated with the use of PT in the 15 pediatric cancers under investigation are lacking. High-quality clinical research in this area is needed.

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

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

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.