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221 p. ill., SCIENTIFIC REPORT 13 -- 1 INTRODUCTION, AIMS AND SCOPE OF THIS REPORT 13 -- 1.1 BACKGROUND 13 -- 1.2 THE REGULATORY SYSTEM OF MEDICINAL PRODUCTS AND MEDICAL DEVICES 17 -- 1.3 HEALTH TECHNOLOGY ASSESSMENT AND COVERAGE OF HEALTHCARE 17 -- 1.4 NEW EU REGULATIONS FOR MEDICAL DEVICES AND PHARMACEUTICALS 19 -- 1.5 AIMS AND SCOPE OF THIS PROJECT 20 -- 2 METHODS 22 -- 3 LEGAL AND ETHICAL CONSIDERATIONS 23 -- 3.1 INTRODUCTION: THE LEGAL AND ETHICAL FRAMEWORKS ON EVIDENCE REQUIREMENTS 23 -- 3.2 METHODOLOGY 24 -- 3.3 APPLICABLE RULES 25 -- 3.4 EVIDENTIARY REQUIREMENTS FOR MEDICINAL PRODUCTS AND MEDICAL DEVICES 28 -- 3.4.1 Ethical rules for the conduct of clinical trials 28 -- 3.4.2 Research and human rights 32 -- 3.4.3 Evidentiary requirements in the marketing authorisation process for medicines 33 -- 3.4.4 Evidentiary requirements in the CE-marking process for high-risk medical devices 47 -- 3.4.5 The role of ethics committees in reviewing the evidence and the Belgian situation 61 -- 3.5 TRANSPARENCY REQUIREMENTS FOR CLINICAL DATA 64 -- 3.5.1 Ethical rules regarding the transparency on clinical trials data 64 -- 3.5.2 Transparency requirements in the regulatory framework for medicines 65 -- 3.5.3 Transparency requirements for Medical devices 69 -- 3.5.4 Transparency of national reimbursement decisions 73 -- 3.5.5 Enforcement and penalties 73 -- 3.6 CONCLUSION / DISCUSSION REGARDING LEGAL FRAMEWORK 75 -- 4 ANALYSIS OF RIZIV-INAMI DOSSIERS 76 -- 4.1 METHODS 76 -- 4.2 FINDINGS 77 -- 4.2.1 Applications for reimbursement of 18 medicinal products 77 -- 4.2.2 Applications for reimbursement of 18 medical devices 81 -- 5 LITERATURE REVIEW 85 -- 5.1 METHODS 85 -- 5.1.1 Search strategy 85 -- 5.1.2 Selection procedure 86 -- 5.1.3 Selection criteria 87 -- 5.2 OVERVIEW OF THE LITERATURE ON MEDICINAL PRODUCTS 87 -- 5.2.1 Introduction 87 -- 5.2.2 Evidence gaps at market entry (and in the post-market period) 93 -- 5.2.3 Evidence gaps and reimbursement decisions 97 -- 5.2.4 Need for more collaboration (e.g. between regulators and HTA bodies) 98 -- 5.2.5 Use of surrogate endpoints 101 -- 5.2.6 Early patient access, conditional marketing authorisation and managed entry agreements 103 -- 5.3 OVERVIEW OF LITERATURE ON MEDICAL DEVICES 105 -- 5.3.1 Introduction 105 -- 5.3.2 The selected publications 109 -- 5.3.3 Recurring issues in the articles: 115 -- 6 DISCUSSION AND POSSIBLE SOLUTIONS 117 -- 6.1 THE TENSION BETWEEN BUSINESS PRIORITIES AND PATIENT BENEFIT 117 -- 6.1.1 The healthcare economy, important but not the scope of this project 117 -- 6.1.2 Hard law or ethical rules to manage business priorities versus patient benefit? 118 -- 6.1.3 The assessment of true innovation requires a direct comparison of patient benefit 119 -- 6.1.4 Horizon scanning and current limitations affecting the impact of early dialogue and common scientific advice 120 -- 6.1.5 The failed promise of post-marketing trials, coverage with evidence development and managed entry agreements 120 -- 6.2 TOWARDS A CLINICAL DEVELOPMENT PATHWAY THAT BETTER MEETS THE DEMANDS OF REGULATORS AND HTA BODIES 124 -- 6.2.1 The need for a better collaboration between regulators and HTA bodies 124 -- 6.2.2 The split between regulators and HTA bodies, an example of inefficient governance? 125 -- 6.3 EVIDENCE GAPS GROUPED ACCORDING TO THE PICOTS FRAMEWORK 125 -- 6.3.1 Population: keep the randomization but include the routine care patients, all evidence in patient subpopulations should be detailed 126 -- 6.3.2 Intervention: knowledge of optimal dose and duration is key, routine care to be reflected as much as possible 126 -- 6.3.3 The (active) comparator: the Helsinki declaration and the EMA 126 -- 6.3.4 Outcomes: focus on patient-relevant outcomes instead of surrogates that are not validated 128 -- 6.3.5 Study design and time periods, the opportunities and risks of relying only on observational real-world data 129 -- 6.3.6 Should the evidence bar be lower for medical devices? 133 -- 6.4 ON TRANSPARENCY AND REPORTING 135 -- 6.4.1 The case of medicinal products 135 -- 6.4.2 The case of medical devices 135 -- 6.5 PUBLISHED POLICY RECOMMENDATIONS 136 -- 7 RECOMMENDATIONS 139 -- 7.1 FOR THE EUROPEAN COMMISSION AND MEMBER STATES GOVERNMENTS 139 -- 7.2 FOR MEDICAL AND SURGICAL SCIENTIFIC SOCIETIES 140 -- 7.3 FOR (HIGH-RISK) MEDICAL DEVICE INDUSTRY 140 -- 7.4 FOR ALL ETHICS COMMITTEES IN BELGIUM AND ABROAD 141 -- 7.5 FOR ALL CONSUMER ORGANISATIONS AND PATIENT ORGANISATIONS 141 -- 7.6 TO RIZIV-INAMI, HTA AGENCIES AND PAYERS 141 -- 7.7 TO RIZIV-INAMI, INTERNATIONAL HTA AGENCIES, AND JOURNAL EDITORS 141 -- APPENDICES 142

38 p. ill., SUMMARY 1 -- 1. INTRODUCTION, OBJECTIVE AND METHODOLOGY 3 -- 1.1. MARKET ACCESS IS REGULATED AT THE EUROPEAN LEVEL, WHILE REIMBURSEMENT IS DETERMINED BY THE MEMBER STATES. 3 -- 1.1.1. Medicinal products 4 -- 1.1.2. Medical devices 5 -- 1.1.3. Changes in the European regulations 5 -- 1.2. INITIATIVES THAT HAVE INCREASED THE EVIDENCE GAP AND INITIATIVES TO REDUCE THE EVIDENCE GAP 6 -- 1.3. OBJECTIVE OF THIS STUDY AND STUDY QUESTIONS 6 -- 2. ETHICAL AND LEGAL CONSIDERATIONS 9 -- 2.1. ETHICAL STANDARDS ON THE PROVISION OF EVIDENCE AND TRANSPARENCY 9 -- 2.2. EUROPEAN LEGISLATION ON MEDICINAL PRODUCTS 10 -- 2.2.1. Evidence requirements 10 -- 2.2.2. Procedure for the authorisation of clinical studies 10 -- 2.2.3. Transparency requirements 10 -- 2.3. EUROPEAN LEGISLATION ON MEDICAL DEVICES 10 -- 2.3.1. Evidence requirements 11 -- 2.3.2. Authorisation procedure for clinical research 11 -- 2.3.3. Transparency requirements 11 -- 2.4. EUROPEAN EVALUATION OF HEALTH TECHNOLOGY 12 -- 3. ANALYSIS OF THE INAMI/RIZIV DOSSIERS 12 -- 3.1.1. Results for the 18 assessment dossiers for medicinal products 13 -- 3.1.2. Results for the 18 assessment dossiers for medical devices 13 -- 4. LITERATURE STUDY 14 -- 4.1. MEDICINAL PRODUCTS 14 -- 4.2. MEDICAL DEVICES 15 -- 5. DISCUSSION AND POSSIBLE SOLUTIONS 16 -- 5.1. THE SEPARATION BETWEEN REGULATORY BODIES AND HTA BODIES; MORE COLLABORATION NECESSARY 16 -- 5.1.1. Study population requirements 19 -- 5.1.2. Requirements regarding the intervention 19 -- 5.1.3. Requirements regarding the comparator 19 -- 5.1.4. Requirements regarding outcomes 21 -- 5.1.5. Toward more efficient clinical studies; limitations of observational ‘real-world data’ 21 -- 5.1.6. Should the threshold of evidence for medical devices be lower? 22 -- 5.2. TRANSPARENCY REQUIREMENTS 23 -- 5.2.1. For medicinal products 23 -- 5.2.2. For medical devices 23 -- 5.3. PUBLISHED POLICY RECOMMENDATIONS 23 -- RECOMMENDATIONS 27 -- REFERENCES 32

status: published

25 p. ill, FOREWORD 1 -- SYNTHESIS 2 -- 1. INTRODUCTION 4 -- 1.1. DOWN SYNDROME 4 -- 1.2. NIPT 4 -- 1.3. SCOPE, RESEARCH QUESTIONS AND METHODS 5 -- 2. LITERATURE REVIEW 6 -- 3. CONTEXT-SPECIFIC MODELLING 6 -- 3.1. PREGNANCIES AND CHILDREN BORN WITH DOWN SYNDROME 6 -- 3.2. CURRENT PRENATAL SCREENING 7 -- 3.3. THE INVASIVE DIAGNOSTIC TEST PROCEDURES 11 -- 3.4. DECISIONS WITH REGARD TO PREGNANCY TERMINATION 11 -- 3.5. OUTCOMES AND TIME HORIZON 12 -- 3.6. INPUT VARIABLES FOR THE MODEL 12 -- 4. RESULTS OF THE MODEL 15 -- 4.1. NIPT FOR TRIAGE IN AT RISK WOMEN AFTER CURRENT SCREENING 15 -- 4.1.1. NIPT in 5% screen positives at a 1:300 risk cut-off 15 -- 4.1.2. NIPT in 20% screen positives at a 1:1700 risk cut-off 15 -- 4.2. PRIMARY NIPT SCREENING 15 -- 4.2.1. Primary NIPT screening with current uptake 15 -- 4.2.2. Increased NIPT uptake of 90% 16 -- 5. CONCLUSIONS 18 -- 5.1. STRENGTHS AND LIMITATIONS OF THE STUDY 18 -- 5.2. INFORMED DECISION MAKING 18 -- 5.3. A HIGHER SENSITIVITY 19 -- 5.4. A HIGHER SPECIFICITY 20 -- 5.5. OPTIONS FOR INTRODUCING NIPT 20 -- RECOMMENDATIONS 21 -- REFERENCES 23

27 p. Ill.

35-41 Objectives: We studied the cost-effectiveness of tenofovir and entecavir in e antigen positive (CHBe+) and negative (CHBe-) chronic hepatitis B. Methods: Using a multicenter survey including 544 patients we measured patient quality of life and attributable costs by clinical disease stage. Natural disease progression was studied in 278 patients in a single center. A Markov model was constructed to follow hypothetical cohorts of treated and untreated 40-year-old CHBe+ and CHBe- patients and 50-year-old patients with compensated cirrhosis. Results: We did not find an improvement in quality of life when viral load was reduced under treatment. Transition rates to liver cirrhosis were found to be age-dependent. Assuming equal effectiveness, tenofovir dominates the entecavir strategy because of its lower price in Belgium. The incremental cost-effectiveness ratio (ICER) of tenofovir after 20 years is more favorable for treating Caucasian cirrhotic patients (mean ICER €29,000/quality-adjusted life-year [QALY]) compared with treating non-cirrhotic patients (mean ICER €110,000 and 131,000/QALY for CHB e+ and e-, respectively). Within the non-cirrhotic patients the ICER decreases with increasing cohort starting age from 30 to 50 years. Conclusions: Results of long-term models for tenofovir or entecavir treatment of CHB need to be interpreted with caution as long-term trials with hard end points are lacking. Especially the effect on HCC remains highly uncertain. Based on cost-effectiveness considerations such antiviral treatment should be targeted at patients with cirrhosis or at risk of rapid progression to this disease stage.

75 p. Ill., INTRODUCTION 8 -- 1.1 OBJECTIVES 8 -- 1.2 THE STUDY TEAM . 8 -- 1.3 RADIOTHERAPY A ND INNOVATION 8 -- 1.4 INNOVATIVE RADIOTHERAPY TECHNIQUES AND THEIR INDICATIONS 9 -- 1.4.1 Novel radiotherapy techniques for treating early breast cancer. 9 -- 1.4.2 Stereotactic body radiation therapy (SBRT). 11 -- 1.4.3 Research funding, registration of activities and clinical outcome. 12 -- 2 METHODOLOGY 14 -- 2.1 WHY AN ABC ANALYSIS? 14 -- 2.2 SELECTION AND PARTICIPATION OF RADIOTHERAPY CENTRES 14 -- 2.3 DEFINITION OF RADIOTHERAPY TREATMENTS 15 -- 2.4 TIME-DRIVEN ABC OF RADIOTHERAPY 15 -- 2.5 ACTIVITIES 15 -- 2.6 COSTS AND RESOURCE USE 16 -- 2.6.1 Personnel cost 19 -- 2.6.2 Equipment costs 19 -- 2.6.3 Indirect material costs 19 -- 2.6.4 Pharmaceuticals, radio-isotopes and gold markers 19 -- 2.6.5 Overhead 20 -- 2.6.6 Direct costs 20 -- 2.7 COST ALLOCATION 20 -- 2.7.1 Time based allocation of personnel and equipment costs to patient related activities 20 -- 2.7.2 Allocating activities, materials and overhead to treatments 21 -- 2.8 TOTAL COST PERTREATMENT .22 -- 2.9 DATA COLLECTION TEMPLATES 22 -- 3 RESULTS 23 -- 3.1 CENTRE’S PROFILE 23 -- AVERAGE COST OVER ALL TREATMENTS 25 -- 3.3 SBRT, FOCUS ON THE LUNG 27 -- 3.4 SBRT OF SPINAL, LIVER, PANCREAS, BONE AND OLIGOMETASTASES 30 -- 3.5 BREAST CANCER 31 -- 3.6 PROSTATE CANCER 36 -- 3.7 HEAD AND NECK CANCER 36 -- 3.8 RECTUM CANCER 37 -- 3.9 PALLIATIVE RADIOTHERAPY 38 -- 3.10 COST DETERMINANTS AND EFFICIENCY 39 -- 4 DISCUSSION OF THE RESULTS 42 -- 4.1 THE 10 CENTRES AND THE OVERALL RESULTS 42 -- 4.1.1 General findings . 43 -- 4.1.2 Cost determinants and efficiency 45 -- 4.2 COST OF SBRT COMPARED WITH OTHER MODALITIES . 46 -- 4.2.1 Focus on the lung 46 -- 4.2.2 SBRT of spinal, liver, pancreas, bone and oligometastases 47 -- 4.3 BREAST CANCER, FOCUS ON APBI AND IORT BOOST 48 -- 4.4 COST OF OTHER COMMON TREATMENTS 50 -- 4.5 COSTS, FINANCING AND BUDGET CONSIDERATIONS 50 -- 4.6 INTRODUCING INNOVATIONS IN HEALTH CARE 51

278-284 Objectives: High-quality clinical evidence is most often lacking when novel high-risk devices enter the European market. At the same time, a randomized controlled trial (RCT) is often initiated as a requirement for obtaining market access in the US. Should coverage in Europe be postponed until RCT data are available? We studied the premarket clinical evaluation of innovative high-risk medical devices in Europe compared with the US, and with medicines, where appropriate. Methods: The literature and regulatory documents were checked. Representatives from industry, Competent Authorities, Notified Bodies, Ethics Committees, and HTA agencies were consulted. We also discuss patient safety and the transparency of information. Results: In contrast to the US, there is no requirement in Europe to demonstrate the clinical efficacy of high-risk devices in the premarket phase. Patients in Europe can thus have earlier access to a potentially lifesaving device, but at the risk of insufficiently documented efficacy and safety. Variations in the stringency of clinical reviews, both at the level of Notified Bodies and Competent Authorities, do not guarantee patient safety. We tried to document the design of premarket trials in Europe and number of patients exposed, but failed as this information is not made public. Furthermore, the Helsinki Declaration is not followed with respect to the registration and publication of premarket trials. Conclusions: For innovative high-risk devices, new EU legislation should require the premarket demonstration of clinical efficacy and safety, using an RCT if possible, and a transparent clinical review, preferably centralized.

status: published

In this scientific policy advice report, the Superior Health Council provides recommendations and policy options which are fostering an ethically and medically appropriate offer of direct-to-consumer genetic tests, as the one provided through the healthcare system in Belgium

VII, 25 p. ill. 1 WHY THIS REPORT? 2 -- 2 DEFINITION, SCOPE AND METHODS 4 -- 2.1 MEDICAL DEVICE DEFINITION 4 -- 2.2 STUDY SCOPE 4 -- 2.3 STUDY METHODS 5 -- 3 CLINICAL DEVELOPMENT OF DRUGS AND DEVICES 6 -- 3.1 CLINICAL DEVELOPMENT PHASES 6 -- 3.2 HEALTH TECHNOLOGY ASSESSMENT 7 -- 4 PRE-MARKET DEVICE REVIEW IN THE US 10 -- 5 PRE-MARKET EVALUATION IN EUROPE 12 -- 5.1 THE SYSTEM OF CE MARKING 12 -- 5.2 PRE-MARKET CLINICAL TRIALS 13 -- 5.3 REGULATIONS 14 -- 6 ETHICAL AND MEDICO-LEGAL ASPECTS 16 -- 6.1 PATIENT INFORMED CONSENT 16 -- 6.2 THE ROLE OF AN ETHICS COMMITTEE 17 -- 6.3 LIABILITY 18 -- 7 CONCLUSIONS AND RECOMMENDATIONS 19 -- 7.1 THE LONG-TERM PERSPECTIVE AT THE EUROPEAN LEVEL 19 -- 7.2 TRANSIENT SOLUTIONS AT MEMBER STATE LEVEL 22 -- 8 REFERENCES 23

X, 25 p. ill. Nieuwe medische hulpmiddelen met een hoog risico voor de patiënt, zoals een nieuw type hartklep of heupprothese, komen in Europa vaak veel vlugger op de markt dan in de VS. Reden is dat de fabrikant in Europa geen bewijs moet leveren dat de patiënt even goed of beter geholpen is met het nieuwe hulpmiddel, dan met de standaard aanpak van het probleem. Hierdoor kan de patiënt wel vlugger gebruik maken van de nieuwe technologie, maar heeft hij ook meer kans blootgesteld te worden aan nog onbekende risico’s. Het KCE onderzocht, samen met een aantal Europese zusteragentschappen, welke soort onderzoeksresultaten fabrikanten moeten voorleggen voordat zij zulke implantaten en andere nieuwe technologieën op de markt mogen brengen. Momenteel zijn de vereisten voor klinische studies veel lager dan die voor geneesmiddelen, en de gegevens over de uitgevoerde onderzoeken zijn weinig of niet toegankelijk. Het rapport beveelt aan dat de klinische veiligheid en werkzaamheid eerst voldoende zouden moeten aangetoond worden, liefst met vergelijkende studies van hoge kwaliteit. De resultaten van de studies moeten ook publiek toegankelijk zijn. 1 WHY THIS REPORT? 2 -- 2 DEFINITION, SCOPE AND METHODS 4 -- 2.1 MEDICAL DEVICE DEFINITION 4 -- 2.2 STUDY SCOPE 4 -- 2.3 STUDY METHODS 5 -- 3 CLINICAL DEVELOPMENT OF DRUGS AND DEVICES 6 -- 3.1 CLINICAL DEVELOPMENT PHASES 6 -- 3.2 HEALTH TECHNOLOGY ASSESSMENT 7 -- 4 PRE-MARKET DEVICE REVIEW IN THE US 10 -- 5 PRE-MARKET EVALUATION IN EUROPE 12 -- 5.1 THE SYSTEM OF CE MARKING 12 -- 5.2 PRE-MARKET CLINICAL TRIALS 13 -- 5.3 REGULATIONS 14 -- 6 ETHICAL AND MEDICO-LEGAL ASPECTS 16 -- 6.1 PATIENT INFORMED CONSENT 16 -- 6.2 THE ROLE OF AN ETHICS COMMITTEE 17 -- 6.3 LIABILITY 18 -- 7 CONCLUSIONS AND RECOMMENDATIONS 19 -- 7.1 THE LONG-TERM PERSPECTIVE AT THE EUROPEAN LEVEL 19 -- 7.2 TRANSIENT SOLUTIONS AT MEMBER STATE LEVEL 22 -- 8 REFERENCES 23

X, 25 p. ill. Les nouveaux dispositifs médicaux à haut risque pour le patient, tel qu’un nouveau type de valve cardiaque ou de prothèse de hanche, arrivent souvent plus rapidement sur le marché européen que sur le marché américain. La raison en est que le fabricant ne doit, en Europe, fournir aucune preuve que ce nouveau dispositif médical aidera le patient, aussi bien ou mieux que le traitement standard. Ainsi, le patient peut avoir accès plus rapidement aux nouvelles technologies, mais est aussi confronté à des risques encore inconnus. Le KCE s’est penché, en collaboration avec d’autres agences européennes similaires, sur le type de résultats de recherche que les fabricants devraient présenter avant d’introduire sur le marché des implants et d’autres nouvelles technologies médicales. A l’heure actuelle, les exigences en termes d’études cliniques sont bien moindres pour ces technologies qu’elles ne le sont pour les médicaments, et les données des essais cliniques sont pauvres ou inaccessibles. Le rapport recommande que l’efficacité et la sécurité cliniques soient suffisamment démontrées au préalable, de préférence avec des études comparatives de bonne qualité. Les résultats de ces études doivent en outre être accessibles. 1 WHY THIS REPORT? 2 -- 2 DEFINITION, SCOPE AND METHODS 4 -- 2.1 MEDICAL DEVICE DEFINITION 4 -- 2.2 STUDY SCOPE 4 -- 2.3 STUDY METHODS 5 -- 3 CLINICAL DEVELOPMENT OF DRUGS AND DEVICES 6 -- 3.1 CLINICAL DEVELOPMENT PHASES 6 -- 3.2 HEALTH TECHNOLOGY ASSESSMENT 7 -- 4 PRE-MARKET DEVICE REVIEW IN THE US 10 -- 5 PRE-MARKET EVALUATION IN EUROPE 12 -- 5.1 THE SYSTEM OF CE MARKING 12 -- 5.2 PRE-MARKET CLINICAL TRIALS 13 -- 5.3 REGULATIONS 14 -- 6 ETHICAL AND MEDICO-LEGAL ASPECTS 16 -- 6.1 PATIENT INFORMED CONSENT 16 -- 6.2 THE ROLE OF AN ETHICS COMMITTEE 17 -- 6.3 LIABILITY 18 -- 7 CONCLUSIONS AND RECOMMENDATIONS 19 -- 7.1 THE LONG-TERM PERSPECTIVE AT THE EUROPEAN LEVEL 19 -- 7.2 TRANSIENT SOLUTIONS AT MEMBER STATE LEVEL 22 -- 8 REFERENCES 23

viii, 88 p. ill.

142 p. ill.