Survival in stage IV ovarian cancer with increased use of debulking surgery and bevacizumab.

OBJECTIVES: Advanced ovarian cancer has a poor prognosis, with a 5 year survival probability of <30%. Attempts to improve survival have focused on debulking surgery and systemic therapy. We assessed the evolution of treatment patterns and survival of patients with advanced epithelial ovarian cancer with specific attention to changes in survival after introducing bevacizumab. METHODS: Population based data from the Belgian Cancer Registry were coupled with administrative reimbursement data from the compulsory health insurance organizations and the national database where date of death is registered, based on the patient's unique national number. Patients with epithelial ovarian cancer stage IV diagnosed in 2004-17 were included. The proportion of patients who underwent debulking surgery and received bevacizumab was calculated per incidence year. Survival was compared for the three incidence periods (2004-08, 2009-13, 2014-17) and before and after the introduction of bevacizumab. RESULTS: 2034 patients with stage IV epitheial ovarian cancer were included. From 2012 onwards, uptake of bevacizumab increased, with 50% of patients with stage IV ovarian cancer diagnosed in 2017 receiving bevacizumab. The proportion of stage IV patients who underwent debulking surgery also increased over time, from 21.1% in 2004-08 to 50.4% and 45.4% in 2009-13 and 2014-17, respectively. The 3 year observed survival probability fluctuated between 27% and 42% without a trend over time. The increase in debulking surgery was associated with improved survival (hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.79 to 0.98) but the introduction of bevacizumab was not (HR 0.94, 95% CI 0.85 to 1.03). For patients diagnosed in 2004, the mean cost per patient treated with oncological drugs was about €12 500, which doubled to about €25 000 for patients diagnosed in 2014 or later. CONCLUSIONS: Despite a rise in the use of debulking surgery and the introduction of bevacizumab into clinical practice, no improvement in 3 year survival probability was observed for patients with advanced ovarian cancer in Belgium.

High Impact of Pediatric Inflammatory Bowel Disease on Caregivers' Work Productivity and Daily Activities: An International Prospective Study.

OBJECTIVES: To evaluate the longitudinal evolution of work productivity loss and activity impairment in caregivers of children with inflammatory bowel disease (IBD). We also evaluated the associations between these impairments, IBD-related factors, and caregivers' health-related quality of life (HRQOL) and estimated the indirect costs related to work absenteeism. STUDY DESIGN: Since January 2017, children with newly diagnosed IBD were enrolled prospectively in the Pediatric Inflammatory Bowel Disease Network for Safety, Efficacy, Treatment and Quality improvement of care study. The impact of pediatric-onset IBD on caregivers' socioeconomic functioning (work and daily activities) and HRQOL was assessed using the Work Productivity and Activity Impairment for caregivers questionnaire and the European Quality of Life Five Dimension Five Level questionnaire, at diagnosis and 3 and 12 months of age. Generalized estimating equation models were applied to evaluate outcomes longitudinally, adjusted for IBD type, disease activity, and child's age at diagnosis. RESULTS: Up to July 2021, 491 children with IBD were eligible for analysis of caregivers' Work Productivity and Activity Impairment questionnaire. At diagnosis, the mean caregivers' employment rate was 78.4%; the adjusted mean work productivity loss was 44.6% (95% CI, 40.2%-49.0%), and the adjusted mean activity impairment was 34.3% (95% CI, 30.8%-37.7%). Work productivity loss and activity impairment significantly decreased over time and were associated with disease activity, but not with IBD type or child's age. Caregivers' HRQOL was associated with both impairments. Costs related to work absenteeism were at least €6272 ($7276) per patient during the first year after diagnosis. CONCLUSIONS: Caregivers of children with IBD experience significant impairments in work and daily activities, especially at diagnosis. The impact decreases thereafter and is associated with disease activity and caregivers' HRQOL. Work absenteeism results in high indirect costs.

CARDIOVASCULAR SCREENING OF YOUNG ATHLETES: A REVIEW OF ECONOMIC EVALUATIONS.

OBJECTIVES: Some experts have promoted preparticipative cardiovascular screening programs for young athletes and have claimed that such programs were cost-effective without performing a critical analysis of studies supporting this statement. In this systematic review, a critical assessment of economic evaluations on these programs is performed to determine if they really provide value for money. METHODS: A systematic review of economic evaluations was performed on December 24, 2014. Web sites of health technology assessment agencies, the Cochrane database of systematic review, the National Health Service Economic Evaluation Database of the Cochrane Library, EMBASE, Medline, Psychinfo, and EconLit were searched to retrieve (reviews of) economic evaluations. No language or time restrictions were imposed and predefined selection criteria were used. Selected studies were critically assessed applying a structured data extraction sheet. RESULTS: Five relevant economic evaluations were critically assessed. Results of these studies were mixed. However, those in favor of screening made (methodological) incorrect choices, of which the most important one was not taking into account a no-screening alternative as comparator. Compared with no screening, other strategies (history and physical examination or history and physical examination plus electrocardiogram) were not considered cost-effective. CONCLUSIONS: Results of primary economic evaluations should not be blindly copied without critical assessment. Economic evaluations in this field lack the support of robust evidence. Negative consequences of screening (false positive findings, overtreatment) should also be taken into account and may cause more harm than good. A mass screening of young athletes for cardiovascular diseases does not provide value for money and should be discouraged.

Contingent non-invasive prenatal testing: an opportunity to improve non-genetic aspects of fetal aneuploidy screening.

BACKGROUND: Several countries today struggle with suboptimal performances in many aspects of the fetal aneuploidy screening process and consider introducing non-invasive prenatal screening (NIPT) as a solution. In this study, costs and benefits of different scenarios for contingent NIPT screening in Belgium are evaluated with respect to partial redistribution of the national screening budget into quality improving measures for those screening activities that will be maintained when full NIPT screening is implemented. METHODS: Data from the Belgian National Institute for Health and Disability Insurance and the Study Centre for Perinatal Epidemiology were used in modeled calculations of medical and economic impact of NIPT after prior conventional screening (1) at thresholds 1:300 and 1:600, and (2) at current and improved screening sensitivity. RESULTS: Contingent NIPT screening under current screening conditions would maintain today's 7.9(0)/000 live birth prevalence of Down syndrome (LBPD) at an 11% reduction of overall short-term costs. Lowering the screening threshold to 1:600 or increasing sensitivity by 10% would reduce LBPD to 7(0)/000 at a maximum 3% increase of overall short-term costs. CONCLUSION: Today, in Belgium and in many other countries, full NIPT screening is considered too expensive for immediate introduction into the national fetal aneuploidy screening program. Contingent NIPT screening is both clinically and economically beneficial. A temporary contingent NIPT protocol allows for reinvesting economic savings into optimization of those screening aspects, which are to be maintained in parallel to full NIPT screening.

Which quality of life measures fit your relative effectiveness assessment?

BACKGROUND: Health-related quality of life (HRQoL) is an important endpoint of many healthcare interventions. This study develops guidance on how to select appropriate HRQoL measures for inclusion in a clinical trial, given the purposes of the HRQoL measurement. METHODS: The guidance is based on a systematic literature review, discussions with members of the European Network for Health Technology Assessment (EUnetHTA) and two rounds of public consultation. RESULTS: A set of twelve recommendations was developed, addressing the requirements for HRQoL data for relative effectiveness assessment, for cost-utility analyses and for informing clinical decision making. Recommendations relate to the choice of the type of measure as well as to aspects such as measurement frequency, target population and presentation. CONCLUSIONS: The purpose and context of HRQoL measurement is crucial for the relevance of the data obtained with a specific HRQoL measure. It is recommended to always include a generic HRQoL instrument in clinical trials to cover a wide range of possible future uses of the HRQoL data.

Endpoints for relative effectiveness assessment (REA) of pharmaceuticals.

OBJECTIVES: Clinical endpoints are defined as valid measures of clinical benefit or harm due to treatment, that describe the impact of treatment on how a patient feels, functions, and survives. The choice of endpoints and the manner in which they are reported have a major impact on the relative effectiveness assessment (REA) of pharmaceuticals. The aim of this article is to describe the guideline development process and the key findings that set a framework for appropriate use of endpoints in REAs in Europe. METHODS: A multi-health technology assessment (HTA)-agency collaborative process in EUnetHTA JA1 was used to scope, draft, and finalize methodological guidelines for REA in Europe. RESULTS: Patient-relevant clinical endpoints can be broadly categorized into: mortality, morbidity and health-related quality of life. A clinical endpoint is a main symptom or sign of a disease that is clinically relevant, valid, reproducible and responsive to change. Preference is for long-term or final endpoints whenever possible. Surrogate endpoints may be used when there is compelling evidence of a clear and consistent correlation of treatment effects on the surrogate and final outcome of interest. CONCLUSIONS: The relevance and hierarchy of the different types of clinical endpoints depend on the research question, disease, and the treatment investigated. Not only the primary endpoint, but also other relevant endpoints are assessed in comparison to adequate comparator(s). This simultaneous assessment of all relevant endpoints is a hallmark of REA.

Belgian guidelines for economic evaluations: second edition.

OBJECTIVES: The aim of this study was to present the updated methodological guidelines for economic evaluations of healthcare interventions (drugs, medical devices, and other interventions) in Belgium. METHODS: The update of the guidelines was performed by three Belgian health economists following feedback from users of the former guidelines and personal experience. The updated guidelines were discussed with a multidisciplinary team consisting of other health economists, assessors of reimbursement request files, representatives of Belgian databases and representatives of the drugs and medical devices industry. The final document was validated by three external validators that were not involved in the previous discussions. RESULTS: The guidelines give methodological guidance for the following components of an economic evaluation: literature review, perspective of the evaluation, definition of the target population, choice of the comparator, analytic technique and study design, calculation of costs, valuation of outcomes, definition of the time horizon, modeling, handling uncertainty and discounting. We present a reference case that can be considered as the minimal requirement for Belgian economic evaluations of health interventions. CONCLUSIONS: These guidelines will improve the methodological quality, transparency and uniformity of the economic evaluations performed in Belgium. The guidelines will also provide support to the researchers and assessors performing or evaluating economic evaluations.

Survival of patients with unfavorable prognosis cutaneous melanoma with increased use of immunotherapy agents: a population-based study in Belgium.

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.

Effectiveness of catheter ablation of atrial fibrillation in Belgian practice: a cohort analysis on administrative data.

AIM: To assess the outcome and cost of catheter ablation of atrial fibrillation (AF) in Belgium. METHODS AND RESULTS: From a nationwide health insurers' database, we retrieved claims data of all patients that underwent a catheter ablation of AF from November 2007 through December 2008. Based on data on reimbursed procedures and drugs, we assessed AF recurrence using different models. Costs related to the index hospitalization were calculated. During the observation period, 830 patients underwent a first catheter ablation of AF. Two-year follow-up data were available for all patients, with an average follow-up of 30.2 months. Seventy-seven percent of patients were treated for paroxysmal AF. Recurrence of AF was defined as the occurrence of one of the following events: a repeat catheter ablation, an electric cardioversion or an antiarrhythmic drug (AAD) prescription, the latter two taking into account a blanking period of 3 months. Atrial fibrillation recurred in 59.8% of patients after 1 year and in 65.9% of them after 2 years. If AAD prescription was considered as an indicator for ablation failure only if it occurred after a 1 month AAD-free period, recurrence of AF occurred in 37.3% of patients after 1 year and in 49.9% after 2 years. Based on the prescription of rate and rhythm control drugs before the ablation, we conclude that up to 15.8% of patients underwent catheter ablation as first-line therapy. Catheter ablation of AF in Belgium on average costs about €9600 for the initial intervention. CONCLUSION: Since the effectiveness of catheter ablation of AF appears to be less favourable in real-world practice as compared with results reported in clinical trials, and given the high initial cost of the procedure, we suggest to strictly limiting the intervention to patients in whom it is currently believed to be most beneficial, i.e. those with severely symptomatic and drug-refractory paroxysmal AF with no or minimal structural heart disease.

The cost-utility of catheter ablation of atrial fibrillation: a systematic review and critical appraisal of economic evaluations.

BACKGROUND: A health technology assessment (HTA) of catheter ablation for atrial fibrillation (CA-AF) was commissioned by the Belgian government and performed by the Belgian Health Care Knowledge Centre (KCE). In this context, a systematic review of the economic literature was performed to assess the procedure's value for money. METHODS: A systematic search for economic literature about the cost-effectiveness of CA-AF was performed by consulting various databases: CRD (Centre for Reviews and Dissemination) HTA and CDSR (Cochrane Database of Systematic Reviews) Technology Assessment, websites of HTA institutes, NHS EED (NHS Economic Evaluation Database), Medline (OVID), EMBASE and EconLit. No time or language restrictions were imposed and pre-defined selection criteria were used. The two-step selection procedure was performed by two persons. References of the selected studies were checked for additional relevant citations. RESULTS: Out of 697 references, seven relevant studies were selected. Based on current evidence and economic considerations, the rationale to support catheter ablation as first-line treatment was lacking.The economic evaluations for second-line catheter ablation included several assumptions that make the results rather optimistic or subject to large uncertainty. First, overall AAD (antiarrhythmic drugs) use after ablation was higher in reality than assumed in the economic evaluations, which had its impact on costs and effects. Second, several models focused on the impact of ablation on preventing stroke. This was questionable because there was no direct hard evidence from RCTs to support this assumption. An indirect impact through stroke on mortality should also be regarded with caution. Furthermore, all models included an impact on quality of life (QoL)/utility and assumed a long-term impact. Unfortunately, none of the RCTs measured QoL with a generic utility instrument and information on the long-term impact on both mortality and QoL was lacking. CONCLUSIONS: Catheter ablation is associated with high initial costs and may lead to life-threatening complications. Its cost-effectiveness depends on the belief one places on the impact on utility and/or preventing stroke, and the duration of these effects. Having no hard evidence for these important variables is rather troublesome. Although the technique is widely spread, the scientific evidence is insufficient for drawing conclusions about the intervention's cost-effectiveness.

Cost-effectiveness of continuous-flow left ventricular assist devices.

OBJECTIVES: Mechanical circulatory support through left ventricular assist devices (LVADs) improves survival and quality of life for patients with end-stage heart failure who are ineligible for cardiac transplantation. Our aim was to calculate the cost-effectiveness of continuous-flow LVADs. METHODS: A cost-utility analysis from a societal perspective was performed. A lifetime Markov model was set up in which continuous-flow LVAD was compared with optimal medical therapy (OMT). The treatment effect was modeled indirectly combining the results of the REMATCH trial comparing OMT with a pulsatile-flow LVAD and the HeartMate II Destination Therapy Trial comparing a pulsatile-flow LVAD with a continuous-flow LVAD. Cost data were based on real-world financial data of sixty-nine patients with a HeartMate II implantation from the University Medical Centre Utrecht (the Netherlands). One-way and probabilistic sensitivity analyses were performed. RESULTS: Comparing the continuous-flow HeartMate II with OMT, 3.23 (95 percent confidence interval [CI], 2.18-4.49) life-years were gained (LYG) or 2.83 (95 percent CI, 1.91-3.90) quality-adjusted life-years (QALYs). The cost of an LVAD implant was approximately €126,000, of which the device itself represented the largest cost, being €70,000. Total incremental costs amounted to €299,100 (95 percent CI, 190,500-521,000). This resulted in an incremental cost-effectiveness ratio of €94,100 (95 percent CI, 59,100-160,100) per LYG or €107,600 (95 percent CI, 66,700-181,100) per QALY. Sensitivity analyses showed these results were robust. CONCLUSIONS: Although LVAD destination therapy improves survival and quality of life, it remains a relatively expensive intervention which renders the reimbursement of this therapy questionable.

Gaps in the evidence underpinning high-risk medical devices in Europe at market entry, and potential solutions.

AIM: To determine the level of evidence for innovative high-risk medical devices at market entry. METHODS: We reviewed all Belgian healthcare payer (RIZIV-INAMI) assessor reports on novel implants or invasive medical devices (n = 18, Class IIb-III) available between 2018 to mid-2019 on applications submitted for inclusion on their reimbursement list. We also conducted a review of the literature on evidence gaps and an analysis of relevant legal and ethical frameworks within the European context. FINDINGS: Conformity assessment of medical devices is based on performance, safety, and an acceptable risk-benefit balance. Information submitted for obtaining CE marking is confidential and legally protected, limiting access to clinical evidence. Seven out of the 18 RIZIV-INAMI assessor reports (39%) included a randomized controlled trial (RCT) using the novel device, whilst 2 applications (11%) referred to an RCT that used a different device. The population included was inappropriate or unclear for 3 devices (17%). Only half of the applications presented evidence on quality of life or functioning and 2 (11%) presented overall survival data. Four applications (22%) included no data beyond twelve months. The findings from the literature demonstrated similar problems with the study design and the clinical evidence. DISCUSSION AND CONCLUSIONS: CE marking does not indicate that a device is effective, only that it complies with the law. The lack of transparency hampers evidence-based decision making. Despite greater emphasis on clinical benefit for the patient, the provisions of the European Medical Device Regulation (MDR) are not yet fully aligned with international ethical standards for clinical research. The MDR fails to address key issues, such as the lack of access to data submitted for CE marking and a failure to require evidence of clinical effectiveness. Indeed, a first report shows no improvement in the clinical evidence for implantable devices generated under the MDR. Thus, patients may continue to be exposed to ineffective or unsafe novel devices. The Health Technology Assessment Regulation plans for Joint Scientific Consultations for specific high-risk devices before companies begin their pivotal clinical investigations. The demanded comparative evidence should facilitate payer decisions. Nevertheless, there is also a need for legislation requiring comparative RCTs assessing patient-relevant outcomes for high-risk devices to ensure implementation, including development and implementation of common specifications for study designs.

Belgian observational survival data (incidence years 2004-2017) and expenditure for innovative oncology drugs in twelve cancer indications.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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.

Pre-market clinical evaluations of innovative high-risk medical devices in Europe.

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.

Using threshold values for cost per quality-adjusted life-year gained in healthcare decisions.

BACKGROUND: In many countries, the incremental cost-effectiveness ratio (ICER) is used to assess whether an intervention is worth its costs. At the same time, policy makers often feel uncomfortable with refusing reimbursement of any intervention purely on the basis of the fact that the ICER exceeds a specific threshold value. Reluctance to define a single threshold value for the ICER seems to have been stronger in social security systems than in national healthcare services systems. This study explores how basic differences between healthcare systems impact upon the potential usefulness of an ICER threshold value. METHODS: This study is a narrative review of literature about the theoretical foundations of the ICER threshold value approach and its practical relevance in different types of healthcare systems. RESULTS: A single ICER threshold value cannot be maintained, defined, or measured and should not be used as a policy-making tool. None of the solutions presented up until now to make the ICER threshold approach a valuable policy-making tool overcome the important weaknesses of the approach. CONCLUSIONS: ICERs and ICER threshold values are insufficient for assessing interventions' value for money. Rather, they should be considered as one element in the decision-making process. Complete rationalization of the decision-making process by means of quantitative decision criteria is undesirable and not feasible. Increasing transparency in the criteria used for a decision and explicitness about the relative importance of each criterion should, therefore, be the major goal.

Identifying Health Economic Considerations to Include in the Research Protocol of a Randomized Controlled Trial (the REDUCE-RISK Trial): Systematic Literature Review and Assessment.

BACKGROUND: The REDUCE-RISK trial was set up to compare the effectiveness of weekly subcutaneously administered methotrexate with daily oral azathioprine or 6-mercaptopurine in low-risk Crohn disease (CD) or subcutaneously administered adalimumab (ADA) in high-risk CD in a pediatric population (age 6-17 years). OBJECTIVE: The aim of this study is to perform a systematic review to provide input into the research protocol to gather the necessary information to improve the performance of an evidence-based economic evaluation when the trial is finished. METHODS: The Centre for Reviews and Dissemination (CRD) Health Technology Assessment (HTA) database, websites of HTA institutes, CRD's National Health Service Economic Evaluation Database, MEDLINE (OVID), and Embase databases were consulted to retrieve (reviews of) relevant economic evaluations. Studies were eligible if they included a pediatric or adult population with inflammatory bowel diseases (CD and ulcerative colitis [UC]) treated with ADA (Humira). There were no restrictions on the comparator. Only economic evaluations expressing outcomes in life years gained or quality-adjusted life years gained were selected. RESULTS: A total of 12 primary studies were identified. None of these studies included a pediatric population because of a lack of supporting trials. The economic evaluations identified in our systematic review indicate that ADA is an appropriate intervention for inclusion in such a trial. From a health economic point of view, it is important to make an incremental analysis comparing such an intervention with standard care and not immediately versus another (expensive) biological treatment. Information on the impact of children's school attendance and parents' productivity is currently lacking in economic evaluations, and none of the underlying trials measured quality of life (QoL) using a generic utility instrument. CONCLUSIONS: The review of the economic literature on ADA for the treatment of patients with CD supports the performance of a trial with biologicals in pediatric patients, including making a distinction according to disease severity. Conducting an economic literature review enabled us to decide which variables should be added to the research protocol from an economic point of view. Measurements for children's and parents' QoL (EuroQol 5-Dimension questionnaires), children's school attendance, and parents' productivity (WPAI-CD-CG questionnaire) were added to the research protocol. This will provide support for the calculation of the cost-effectiveness of the interventions evaluated in the REDUCE-RISK trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT02852694; https://clinicaltrials.gov/ct2/show/NCT02852694.

Does tiotropium lower exacerbation and hospitalization frequency in COPD patients: results of a meta-analysis.

BACKGROUND: International guidelines recommend long-acting bronchodilators in patients who remain symptomatic despite adequate treatment with short-acting bronchodilators. The purpose of this study is to estimate the effect of tiotropium, a long-acting anticholinergic inhalant, on exacerbation and hospitalisation frequency. METHODS: Electronic databases (Medline, Embase, INAHTA, CRD databases, and the Cochrane Library) were searched for randomised controlled trials, comparing tiotropium to placebo, or other bronchodilators. Outcomes were the exacerbation frequency and hospitalisation frequency. Data were pooled using the generic inverse variance method for continuous outcomes. RESULTS: Nine studies reported comparisons with placebo (n = 8), ipratropium (short-acting anticholinergic inhalant, n = 1), and salmeterol (long-acting ß2-agonist inhalant, n = 1). Only two studies reported adequate concealment of allocation. Tiotropium reduces the number of exacerbations per patient year by 0.31 (95% CI 0.46- 0.17) compared to placebo, and by 0.23 (95% CI 0.31- 0.15) compared to ipratropium. A significant difference in exacerbation frequency between tiotropium and salmeterol was found (-0.16; 95% CI -0.29 - -0.03) based on approximations of the results of one study.The number of hospitalisations is reduced by 0.04 (95% CI 0.08- 0.01) per patient year compared to placebo and by 0.06 (95% CI -0.09 - -0.03) per patient year compared to ipratropium. CONCLUSIONS: Statistically significant but clinically small effects were found for tiotropium compared to placebo and ipratropium. The comparison with salmeterol is significant for exacerbation frequency but not for hospitalisation frequency. Publication bias may be present.

Tiotropium's cost-effectiveness for the treatment of COPD: a cost-utility analysis under real-world conditions.

BACKGROUND: Tiotropium is reimbursed since March 2004 in Belgium for the treatment of Chronic Obstructive Pulmonary Disease (COPD). Questions however remain on this product's value for money. The purpose of this study is to calculate tiotropium's cost-effectiveness under real-world conditions. METHODS: Strengths of both observational and RCT data were combined in a model. A large longitudinal (2002-2006) observational dataset of regular tiotropium users (56,321 patients) was analysed to retrieve the baseline risk for exacerbations and exacerbation-related hospitalisations the year before the first delivery of tiotropium. The relative treatment effect from the UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) trial was then applied to this baseline risk to reflect the effect of tiotropium treatment and calculate the intervention's incremental cost-effectiveness ratio (ICER). RESULTS: After 1000 Latin Hypercube simulations, the incremental benefit expressed as quality-adjusted life years (QALY) gained is on average 0.00048 (95% confidence interval (CI) 0.00009-0.00092). In combination with a substantial mean incremental cost of €373 per patient (95% CI 279-475), this results in an unfavourable average ICER of €1,244,023 (95% CI 328,571-4,712,704) per QALY gained. Results were most sensitive to the treatment effect on hospitalisations. Based on our large observational database, up to 89% of the patients were not hospitalised for COPD in the year before the first tiotropium delivery. CONCLUSIONS: The main cause for tiotropium's unfavourable cost-effectiveness ratio is a combination of a relative high price for tiotropium, a low number of hospitalisations without tiotropium treatment (on average 0.14/year) and a non-significant treatment effect (on average 0.94) with respect to avoiding exacerbation-related hospitalisations. From an economic point of view, a revision of reimbursement modalities (e.g. with a lower price) would be justified and would entail a more efficient use of resources.

An evaluation of managed entry agreements in Belgium: A system with threats and (high) potential if properly applied.

OBJECTIVE: To evaluate the strengths and weaknesses of managed entry agreements (MEAs) in Belgium. METHODS: All Belgian MEAs signed between 2010 and 2015 (n = 71) were studied, including the re-evaluations of 16 reimbursement requests for which the initial MEA had ended. The analysis was supported by the findings from a systematic literature review and structured interviews with Belgian stakeholders. RESULTS: The current application of MEAs provides the short-term advantage of getting a positive reimbursement decision with lower confidential prices. However, it is not clear whether the negotiated prices are in line with the added value of the interventions. Furthermore, the contracts do not provide incentives for manufacturers to gather evidence or to set public prices at an acceptable level. CONCLUSIONS: Based on our analysis of the Belgian MEAs and discussions with Belgian stakeholders, an overview of various issues and pitfalls related to the current application of the system is given. Recommendations are made related to providing correct incentives to deliver good evidence, establishing a correct link between identified uncertainties/problems and the type and content of the MEA, reducing the risk of making the system non-transparent, the importance of international collaboration, etc. in order to optimize the potential of this system. These recommendations are addressed to both the Belgian policymakers and stakeholders in other countries making use of MEAs.

Protocol for a multinational risk-stratified randomised controlled trial in paediatric Crohn's disease: methotrexate versus azathioprine or adalimumab for maintaining remission in patients at low or high risk for aggressive disease course.

INTRODUCTION: Immunomodulators such as thiopurines (azathioprine (AZA)/6-mercaptopurine (6MP)), methotrexate (MTX) and biologics such as adalimumab (ADA) are well established for maintenance of remission within paediatric Crohn's disease (CD). It remains unclear, however, which maintenance medication should be used first line in specific patient groups. AIMS: To compare the efficacy of maintenance therapies in newly diagnosed CD based on stratification into high and low-risk groups for severe CD evolution; MTX versus AZA/6MP in low-risk and MTX versus ADA in high-risk patients. Primary end point: sustained remission at 12 months (weighted paediatric CD activity index ≤12.5 and C reactive protein ≤1.5 fold upper limit) without relapse or ongoing requirement for exclusive enteral nutrition (EEN)/steroids 12 weeks after treatment initiation. METHODS AND ANALYSIS: REDUCE-RISK in CD is an international multicentre open-label prospective randomised controlled trial funded by EU within the Horizon2020 framework (grant number 668023). Eligible patients (aged 6-17 years, new-onset disease receiving steroids or EEN for induction of remission for luminal ± perianal CD are stratified into low and high-risk groups based on phenotype and response to induction therapy. Participants are randomised to one of two treatment arms within their risk group: low-risk patients to weekly subcutaneous MTX or daily oral AZA/6MP, and high-risk patients to weekly subcutaneous MTX or fortnightly ADA. Patients are followed up for 12 months at prespecified intervals. Electronic case report forms are completed prospectively. The study aims to recruit 312 participants (176 low risk; 136 high risk). ETHICS AND DISSEMINATION: ClinicalTrials.gov Identifier: (NCT02852694), authorisation and approval from local ethics committees have been obtained prior to recruitment. Individual informed consent will be obtained prior to participation in the study. Results will be published in a peer-reviewed journal with open access. TRIAL REGISTRATION NUMBER: NCT02852694; Pre-results.