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Background: Although metastatic cutaneous melanoma is associated with an unfavorable prognosis, innovative therapies including immunomodulating agents and targeted therapies have shown survival benefits in clinical trials. We assessed the impact of the introduction of innovative drugs into clinical practice on the survival of patients with metastatic cutaneous melanoma during the period 2004–2017, in Belgium. The evolution of associated expenses was also analyzed. Methods: This is a retrospective population‐based study using data from the national Belgian Cancer Registry, compulsory health insurance, and administrative survival data. The immunomodulating drugs were ipilimumab, nivolumab and pembrolizumab, while targeted therapies included vemurafenib, dabrafenib and trametinib. Results: We did not identify a trend for improvement over time. Median survival (years) was 1.5 (95% CI: 1.1–1.8) in 2004–2008, 1.1 (95% CI: 0.8–1.5) in 2009–2013, and 1.6 (95% CI: 1.3–2.4) in 2014–2017, respectively. In contrast, survival improved in those with unknown primary tumor localization. In this group, median survival time was 2.0 (95% CI: 1.4–2.9) in the most recent period, while it was 1.1 (95% CI: 0.7–1.3) in 2009–2013, and 0.9 (95% CI: 0.6–1.2) in 2004–2008. The uptake of innovative drugs remained modest, with no drug being used by more than 30% of patients. Yearly expenditure was almost non‐existent, and gradually increased, reaching several million euros in 2014–2017. Conclusion: Patients with metastatic cutaneous melanoma who were diagnosed between 2004 and 2017 showed no apparent improvement in survival. In contrast, increased survival was observed in the subgroup of patients with unknown primary tumor localization. [ABSTRACT FROM AUTHOR]

Background: Orphan medicinal products are designed to diagnose or treat rare diseases that are serious, life threatening or chronically debilitating and that affect 50 or fewer people in every 100 000 in the EU. In Belgium, the Drug Reimbursement Committee (DRC) evaluates reimbursement requests for orphan drugs based on multiple criteria: the therapeutic value, price and proposed reimbursement tariff; the importance of the drug in clinical practice; and the budget impact of the drug. Objectives: This study aimed to assess reimbursement dossiers of orphan drugs in Belgium and to compare them with the clinical evidence submitted to the European Medicines Agency (EMA). Methods: A qualitative analysis examined all reimbursement dossiers of orphan drugs that were submitted in Belgium between January 2002 and June 2008. The following information was extracted from each dossier: description of the orphan drug; indication; reimbursement status; therapeutic value and needs; budget impact; and number of registered indications. For selected orphan drugs, an in-depth analysis extracted and compared information about the clinical trials, their primary endpoints and results from EMA documents (i.e. the marketing authorization application file, European public assessment report and summary of product characteristics) and the Belgian reimbursement dossiers. Results: Reimbursement was awarded to the majority of orphan drugs. In addition to the official criteria, other negotiable factors, such as price adjustments, employment incentives, patient population restrictions and funding of diagnostic tests by the company, seemed to play a role in the reimbursement decision. Despite the low number of patients, randomized controlled trials were conducted for many orphan drugs. Budget-impact analyses were simplistic and did not consider the impact across multiple indications. Some differences were also observed between the clinical evidence submitted to the EMA and that submitted to the Belgian DRC. Conclusions: In addition to the official criteria, other negotiable factors, such as price adjustments and employment incentives, may play a role in Belgian reimbursement decisions of orphan drugs. Some differences have also been noted between the clinical evidence reported in EMA documents and the evidence included in Belgian reimbursement dossiers of orphan drugs. There appears to be a need for further standardization of Belgian reimbursement applications and for European cooperation in sharing clinical evidence of orphan drugs. [ABSTRACT FROM AUTHOR]

The Food and Drug Administration and European Medicines Agency typically approve market access for cancer drugs based on surrogate end-points, which do not always translate into substantiated improvements in outcomes that matter the most to patients, i.e. survival and quality of life. These drugs often, also, have a high price tag. We assessed whether there was an increase in cancer drug expenditure for a broad selection of indications, and whether this correlates with increased overall survival. This cohort study used Belgian Cancer Registry data from 125,692 patients (12 cancer indications, incidence period 2004–2017), which was linked to reimbursement and survival data. This reliably represents the Belgian situation. One-to-five year observed survival probability, median survival time, oncology drug expenditure and mean oncology drug cost per patient were reviewed. In almost all indications, total expenditure and average treatment cost for oncology drugs increased over the years (2004–2017). In contrast, mixed findings are observed for the evolution in overall survival probability and median survival time. While an absolute improvement in the 3-year survival probability of about 10% is noticed in non-small-cell lung cancer and chronic myeloid leukaemia, improvements in about half of the other indications are limited or even absent. The Belgian observational data indicate that assuming 'innovative' oncology drugs always add value in terms of improved survival is often unjustified. The literature also highlights the problem of using surrogate end-points, and the lack of comparative evidence showing an added value of oncology drugs for both survival and quality of life at market approval or during the post-marketing phase. Comparative studies should be conducted in the pre-marketing phase that are suitable for registration purposes, aid reimbursement decisions and support physicians and patients when making treatment decisions. • Food and Drug Administration and European Medicines Agency typically approve cancer drugs based on surrogate end-points. • Overall survival (OS) and quality of life data are often not available to decision makers. • Evolution in OS and drug expenditure (12 cancer types, 125 692 patients) is described. • Substantial increases in drug expenditure often do not coincide with clear OS gains. • Comparative pre-marketing studies should include OS and quality of life as patient-relevant outcomes. [ABSTRACT FROM AUTHOR]

Background: Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome., Methods: We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO 2 :FiO 2 ) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 μg/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 μg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 μg/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 × 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete., Findings: Between April 4, and Dec 6, 2020, 342 patients were randomly assigned to IL-1 blockade (n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54-73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2-4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10-16) in the IL-1 blockade group versus 12 days (10-15) in the no IL-1 blockade group (hazard ratio [HR] 0·94 [95% CI 0·73-1·21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10-16) versus 12 days (11-16) in the no IL-6 blockade group (HR 1·00 [0·78-1·29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups., Interpretation: Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk., Funding: Belgian Health Care Knowledge Center and VIB Grand Challenges program., Competing Interests: Declaration of interests JD, KFAVD, BM, CB, VB, LH, LN, and EDL have received personal PhD training fellowships from FWO Flanders. SJT and LJMS have received personal postdoctoral fellowships from FWO Flanders and from the Ghent University BOF Fund. HA has received a postdoctoral personal training grant from VLAIO Flanders. US has received a grant from the European Respiratory Society. MH has received a grant from ULB Fonds Erasme on COVID-19 research, and an EU-Horizon DisCoVeRY trial grant and EU-Solid-Act trial grant on COVID-19 therapeutics; she received support for attending meetings from Pfizer and acts as the leader of the Sciensano committee, which produces the national guidelines on COVID-19 therapeutics. ND has received honoraria from Boehringer Ingelheim and support for attending meetings from Pfizer, Johnson & Johnson (J&J), and Merck Sharp & Dohme (MSD) and has served on a data and safety monitoring board (DSMB) for Roche. SA received research grants from Bristol-Myers Squibb (BMS)–Celgene and from European Hematology Association and consultancy fees from BMS–Celgene, J&J, Astellas, and Abbvie and honoraria from Pfizer and Astellas. JvdH received consultancy fess from Novartis and SOBI and honoraria from MSD, Sanofi, and J&J, and support for attending meetings from ViiV; he serves on DSMB boards for Novartis and SOBI. HS has received consultancy fees and support for attending meetings from Roche and Boehringer Ingelheim. CL has received consultancy fees from the sponsor Belgian Health Care Knowledge Center (KCE) to serve on the clinical trial board. MB owns stock of the International Drug Development Institute and Cluepoints. DS has received honoraria and support for attending meetings from AstraZeneca, Chiesi, GSK, Roche, and Merck. FB has received support from the Ghent University Hospital Clinical Research Fund. FHa has received a VIB Grand Challenge research grant, a Ghent University Special Research Fund (BOF) research grant, and a Ghent University Hospital Innovation Research Grant as well as lecture honoraria from CSL Behring. LV has received grants from University Hospital Ghent Innovation Fund, Research Foundation—Flanders–Strategic Basic Research (FWO-SBO) and FWO to do COVID-19 related research; he received consultancy fees and honoraria from Gilead and ViiV Healthcare. EvB received a grant from Ghent University Special Research Fund (BOF) and a research grant from ExeVir to do COVID-19 related research. She received honoraria from Gilead and is a member of the Sciensano committee, which produces the national guidelines on COVID-19 therapeutics. SR has received honoraria and meeting attendance support from BMS, MSD, Pfizer, Bayer, J&J, Astellas, Roche, and Ipsen; she serves on DSMBs organised by Pfizer, J&J, BMS, and MSD. IP has received research grants from FWO and honoraria from UCB Pharma and Galapagos. She serves on advisory boards from Abbvie, Amgen, Argenx, AstraZeneca, BMS, Galapagos, and Novartis. FHu is an employee of KCE The Belgian Healthcare Knowledge center, a public federal agency. BNL received an European Research Council Advanced Grant (ERC-2017-ADG-789384) and several FWO grants, as well as a University of Ghent Methusalem Grant. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: 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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

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.

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., Methods: We constructed a health economic model. Long-term consequences of preventing patients to progress to metastatic breast cancer and side effects such as congestive heart failure were taken into account. Uncertainty was handled applying probabilistic modeling and through probabilistic sensitivity analyses., Results: In the HERA scenario, applying an arbitrary threshold of euro30000 per life-year gained, early stage breast cancer treatment with trastuzumab is cost-effective for 9 out of 15 analyzed subgroups (according to age and stage). In contrast, treatment according to the FinHer scenario is cost-effective in 14 subgroups. Furthermore, the FinHer regimen is most of the times cost saving with an average incremental cost of euro668, euro-1045, and euro-6869 for respectively stages I, II and III breast cancer patients whereas the HERA regimen is never cost saving due to the higher initial treatment costs., Conclusions: The model shows better cost-effectiveness for the 9-week initial treatment (FinHer) compared to no trastuzumab treatment than for the 1-year post-chemotherapy treatment (HERA). Both from a medical and an economic point of view, the 9-week initial treatment regimen with trastuzumab shows promising results and justifies the initiation of a large comparative trial with a 1-year regimen.