Exploring the feasibility of using the ICER Evidence Rating Matrix for Comparative Clinical Effectiveness in assessing treatment benefit and certainty in the clinical evidence on orphan therapies for paediatric indications.

BACKGROUND: The evaluation of clinical evidence takes account of health benefit (efficacy and safety) and the degree of certainty in the estimate of benefit. In orphan indications practical and ethical challenges in conducting clinical trials, particularly in paediatric patients, often limit the available evidence, rendering structured evaluation challenging. While acknowledging the paucity of evidence, regulators and reimbursement authorities compare the efficacy and safety of alternative treatments for a given indication, often in the context of the benefits of other treatments for similar or different conditions. This study explores the feasibility of using the Institute for Clinical and Economic Review (ICER) Evidence Rating Matrix for Comparative Clinical Effectiveness in structured assessment of both the magnitude of clinical benefit (net health benefit, NHB) and the certainty of the effect estimate in a sample of orphan therapies for paediatric indications. RESULTS: Eleven systemic therapies with European Medicines Agency (EMA) orphan medicinal product designation, licensed for 16 paediatric indications between January 2017 and March 2020 were identified using OrphaNet and EMA databases and were selected for evaluation with the ICER Evidence Rating Matrix: burosumab; cannabidiol; cerliponase alfa; chenodeoxycholic acid (CDCA); dinutuximab beta; glibenclamide; metreleptin; nusinersen; tisagenlecleucel; velmanase alfa; and vestronidase alfa. EMA European Public Assessment Reports, PubMed, EMBASE, the Cochrane Library, Clinical Key, and conference presentations from January 2016 to April 2021 were searched for evidence on efficacy and safety. Two of the identified therapies were graded as "substantial" NHB: dinutuximab beta (neuroblastoma maintenance) and nusinersen (Type I SMA), and one as "comparable" NHB (CDCA). The NHB grade of the remaining therapies fell between "comparable" and "substantial". No therapies were graded as having negative NHB. The certainty of the estimate ranged from "high" (dinutuximab beta in neuroblastoma maintenance) to "low" (CDCA, metreleptin and vestronidase alfa). The certainty of the other therapies was graded between "low" and "high". The ICER Evidence Rating Matrix overall rating "A" (the highest) was given to two therapies, "B+" to 6 therapies, "C+" to five therapies, and "I" (the lowest) to three therapies. The scores varied between rating authors with mean agreement over all indications of 71.9% for NHB, 56.3% for certainty and 68.8% for the overall rating. CONCLUSIONS: Using the ICER Matrix to grade orphan therapies according to their treatment benefit and certainty is feasible. However, the assessment involves subjective judgements based on heterogenous evidence. Tools such as the ICER Matrix might aid decision makers to evaluate treatment benefit and its certainty when comparing therapies across indications.

Comparative effectiveness of mepolizumab and omalizumab in severe asthma: An indirect treatment comparison.

BACKGROUND: Severe asthma is a heterogeneous disease. Patients with both eosinophilic and allergic asthma phenotypes may be eligible for treatment with mepolizumab and omalizumab. Evidence on the relative effectiveness of these treatments in this 'overlap' population would be informative for clinical and payer decision making. METHODS: A systematic literature review and indirect treatment comparison (Bayesian framework) were performed to assess the comparative effectiveness and tolerability of mepolizumab and omalizumab, as add-ons to standard of care. Studies included in the primary analysis were double-blind, randomized controlled trials, ≥12 weeks' duration enrolling patients with severe asthma with a documented exacerbation history and receiving high-dose inhaled corticosteroids plus ≥1 additional controller. Two populations were examined: patients potentially eligible for 1) both treatments (Overlap population) and 2) either treatment (Trial population). RESULTS: In the Overlap population, no differences between treatments in clinically significant exacerbations and exacerbations requiring hospitalization were found, although trends favored mepolizumab (rate ratio [RR]:0.66 [95% credible intervals (Crl):0.37,1.19]; 0.19[0.02,2.32], respectively). In the Trial population, mepolizumab treatment produced greater reductions in clinically significant exacerbations (RR:0.63 [95% CrI:0.45,0.89]) but not exacerbations requiring hospitalization compared with omalizumab (RR:0.58 [95% Crl: 0.16,2.13]), although the trend favored mepolizumab. Both treatments had broadly comparable effects on lung function, and similar tolerability profiles. CONCLUSIONS: Whilst this analysis has limitations due to a restricted evidence base and residual heterogeneity, it showed that in patients with severe asthma, mepolizumab seems to be at least as effective as omalizumab and that the tolerability profiles of the two treatments did not meaningfully differentiate.

Once-daily fluticasone furoate/vilanterol versus twice daily combination therapies in asthma-mixed treatment comparisons of clinical efficacy.

BACKGROUND: Fluticasone furoate (FF)/vilanterol (VI) is a once-daily inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) combination. FF/VI, 92/22mcg and 184/22mcg, are approved in Europe as maintenance therapy in persistent asthma. We report data from mixed treatment comparisons (MTC) of once-daily FF/VI against established twice-daily ICS/LABA combination therapies on clinical efficacy outcomes. METHODS: Data from 31 parallel-group randomised controlled trials (RCTs) of ICS/LABA, of ≥8 weeks' duration in patients aged ≥12 years with asthma, identified by systematic review, were analysed using covariate-adjusted Bayesian hierarchical models for four efficacy outcomes (primary analysis). Lung function, assessed by change from baseline morning peak expiratory flow (PEF) (n = 18 studies) and forced expiratory volume in 1 s (FEV1) (n = 28), was the outcome of primary interest. Secondary objectives were assessment of relative efficacy in terms of exacerbation rates (n = 6) and health status (n = 7). Overall, 24 different treatment arms were included in the MTC; we report findings comparing FF/VI (92/22mcg and 184/22mcg) with fluticasone propionate/salmeterol (FP/SAL) (250/50mcg and 500/50mcg) and budesonide/formoterol (BUD/FORM) (320/9mcg and 640/18mcg). RESULTS: For PEF (margin = 12 l/min), FF/VI 92/22mcg demonstrated ≥94 % probability and FF/VI 184/22mcg >99 % probability of non-inferiority to corresponding doses of both FP/SAL and BUD/FORM. For FEV1 (margin = 100 ml), FF/VI demonstrated ≥98 % (92/22mcg) and >99 % (184/22mcg) probability of non-inferiority to both FP/SAL and BUD/FORM. Findings for exacerbations were inconclusive due to lack of data: FF/VI 92/22mcg demonstrated 74 % and 82 % probability of non-inferiority (margin = 10 %) to FP/SAL 250/50mcg and BUD/FORM 320/9mcg, respectively. For Asthma Quality of Life Questionnaire (AQLQ) score, FF/VI 92/22mcg demonstrated >99 % and 90 % probability of non-inferiority (margin = 0.25) to FP/SAL 250/50mcg and BUD/FORM 320/9mcg. Data were unavailable to assess non-inferiority of FF/VI 184/22mcg on exacerbations or AQLQ. CONCLUSIONS: Both strengths of once-daily FF/VI in asthma were comparable with corresponding doses of twice-daily FP/SAL and BUD/FORM in terms of lung function in this MTC analysis. FF/VI 92/22mcg was comparable with FP/SAL and BUD/FORM on AQLQ, but exacerbation results were inconclusive. Model limitations include disconnected treatment networks and variability across studies. Our data support previous RCT findings suggesting that the efficacy of once-daily FF/VI in improving lung function and health status in asthma is comparable with twice-daily ICS/LABAs.

Once-daily fluticasone furoate/vilanterol 100/25 mcg versus twice daily combination therapies in COPD - mixed treatment comparisons of clinical efficacy.

BACKGROUND: Fluticasone furoate (FF)/vilanterol (VI) 100/25 mcg is a once-daily inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) treatment approved in the United States, Canada and Europe for the long-term maintenance therapy of COPD. We report data from mixed treatment comparisons (MTC) of once-daily FF/VI against established twice-daily ICS/LABA combination therapies on clinical efficacy outcomes. METHODS: Data from 33 parallel-group randomised controlled trials (RCTs) of ICS/LABAs, of ≥8 weeks' duration in patients ≥12 years of age with COPD, identified by systematic review, were analysed using covariate-adjusted Bayesian hierarchical models for three efficacy outcomes. Lung function, assessed by change from baseline in forced expiratory volume in one second (FEV1), was the outcome of primary interest (n = 28 studies). Secondary objectives were assessment of annual rate of moderate/severe exacerbations (n = 15) and patient-reported health status, measured by change from baseline in St George's Respiratory Questionnaire (SGRQ) Total score (n = 20). Overall, 25 different treatments were included in the MTC; we report findings, including probabilities of non-inferiority, for comparisons of once-daily FF/VI 100/25 mcg with twice-daily fluticasone propionate (FP)/salmeterol (SAL) 500/50 mcg and budesonide (BUD)/formoterol (FORM) 400/12 mcg. RESULTS: For FEV1, FF/VI 100/25 mcg demonstrated >99% probability of non-inferiority to FP/SAL 500/50 mcg and BUD/FORM 400/12 mcg using a 50 mL margin. For annual rate of moderate/severe exacerbations, FF/VI 100/25 mcg demonstrated 73% and 77% probability of non-inferiority to FP/SAL 500/50 mcg and BUD/FORM 400/12 mcg, respectively, using a 10% rate ratio margin. For SGRQ Total score, the corresponding probabilities of non-inferiority were 99% and 98%, respectively, on a 2-unit margin. Significant covariate effects were identified: increased age was associated with deterioration in FEV1 and reduced exacerbation frequency; shorter study duration was associated with reduced exacerbation frequency. CONCLUSIONS: FF/VI 100/25 mcg was comparable with corresponding doses of FP/SAL and BUD/FORM on lung function and health status outcomes. Non-inferiority on moderate/severe exacerbation rate was not demonstrated to the same degree of confidence, though observed rates were similar. Model limitations include a weak treatment network for the exacerbation analysis and variability across the included studies. Our data support previous RCT findings suggesting that the efficacy of FF/VI 100/25 mcg on lung function and health status in COPD is comparable with twice-daily ICS/LABAs.

Economic evaluation of highly purified human menopausal gonadotropin versus recombinant human follicle-stimulating hormone in fresh and frozen in vitro fertilization/intracytoplasmic sperm-injection cycles in Sweden.

Gonadotropin-releasing hormone-analog type, fertilization method, and number of embryos available for cryopreservation should be incorporated into economic evaluations of highly purified human menopausal gonadotropin (HP-hMG) and recombinant human follicle-stimulating hormone (r-hFSH), as they may affect treatment costs. We searched for randomized trials and meta-analyses comparing HP-hMG and r-hFSH. Meta-analysis showed no significant difference in live births (odds ratio 0.82, 95% confidence interval [CI] 0.66-1.01), but a greater number of oocytes with r-hFSH (mean difference [MD] 1.96, 95% CI 1.02-2.90). Using a cost-minimization model for Sweden, accounting for embryo availability, survival following thawing, and patient dropout, we simulated patients individually for up to three cycles. R-hFSH was found to be cost-saving, at 2,767 kr (95% CI 1,580-4,057) per patient (€315 or $411); baseline savings were 6.43% of the total HP-hMG cost. In fresh cycles only, the savings for r-hFSH were 1,752 kr (95% CI 48-3,658) per patient (€200 or $260). In univariate sensitivity analyses, savings were obtained until the price of r-hFSH increased by 30% or the dosage of HP-hMG decreased by 38%-62% of baseline value. In probabilistic sensitivity analysis, r-hFSH was cost-saving in 100% of the simulated cohort per patient and in 85% per live birth; the respective percentages for fresh cycles only were 97.3% and 73.1%. In conclusion, a greater number of oocytes with r-hFSH allows for more frozen embryo transfers, thereby reducing overall treatment cost.

Leuprolide acetate 1-, 3- and 6-monthly depot formulations in androgen deprivation therapy for prostate cancer in nine European countries: evidence review and economic evaluation.

OBJECTIVE: Leuprolide is an established luteinizing hormone-releasing hormone (LHRH) agonist used as first-line treatment in advanced prostate cancer. As different formulations and dosing schedules are likely to have economic implications, we aimed to evaluate their efficacy, safety, and costs in nine European countries: Austria, Belgium, Czech Republic, Hungary, Italy, Latvia, Netherlands, Poland, and Portugal. METHODS: Database searches identified 13 clinical trials of leuprolide 1- (1 M), 3- (3 M) and 6-monthly (6 M). Only data on leuprolide with Atrigel were compared for all three formulations, which had the same efficacy, safety, and adherence. Cost-minimization analysis accounting for cost of Eligard®, specialist consultations, and diagnostics during up to 12 months follow-up was conducted. The perspective was that of public payers. RESULTS: No significant differences were observed in the percentages of intention-to-treat patients achieving testosterone levels ≤ 50 ng/dL following treatment with Eligard® 1 M (93.3%), 3 M (98.3%), and 6 M (97.3%) (P > 0.05), and adverse event profiles of the three formulations were comparable. Overall, 6 M was the least expensive, with average total annual costs from €788 (Belgium) to €1839 (Portugal). The 3 M option was between 2.5% (Hungary) and 37.6% (Belgium) more expensive than 6 M; 1 M formulation was the most expensive, with costs 15.5% and 151.6% more expensive than 6 M for those countries, respectively. The 3 M option was 11.2%-45.3% less expensive than 1 M. Total costs were associated with frequency of visits for injection and monitoring. The 1 M required twelve visits, 3 M 4.4-4.8 visits, and 6 M 2.1-2.3 visits. Up to 50% additional visits could be funded with the savings resulting from switching eligible patients from 1 M and 3 M to 6 M. Results were stable in univariate and probabilistic sensitivity analyses. CONCLUSION: Eligard® formulations offer comparable efficacy and safety, but different dosing schedules require different number of visits. The 6 M formulation offers the greatest cost savings and should be considered the treatment of choice in eligible patients in Europe.

Atosiban versus betamimetics in the treatment of preterm labour in Italy: clinical and economic importance of side-effects.

The aim of this study was to determine the cost effectiveness of atosiban compared to betamimetics in the treatment of preterm labour within the Italian setting. A systematic literature review identified randomised controlled trials (RCTs) comparing atosiban with betamimetics. Meta-analysis of nine RCTs determined that atosiban and betamimetics had similar efficacy in delaying preterm birth by at least 48 h (p=0.910). Use of atosiban was associated with significantly fewer adverse events (p<0.008). Results demonstrate that atosiban is cost-saving versus ritodrine or isoxuprine. Atosiban cost savings are €657 per patient from the National Health Service payer's perspective; €299 at 18 h of tocolysis to €189 at 48 h from the hospital's perspective. The respective values versus isoxuprine were €303 and €199. From the combined perspective, using atosiban versus ritodrine saved from €425 to €316; and versus isoxuprine from €429 to €326. Owing to its superior safety profile, atosiban is cost-saving versus betamimetics in the treatment of preterm labour in Italy from the payer's, hospital's and combined perspectives. With the approximate 40,000 annual preterm births in Italy the annual savings could be in excess of €13 million for the payer or €3.8-6.2 million for the hospitals.

Atosiban versus betamimetics in the treatment of preterm labour in Germany: an economic evaluation.

BACKGROUND: The use of tocolytics is central in delaying birth; however, therapeutic options vary in effectiveness and adverse events profiles, which in turn could have consequences for medical resource use and cost of treatment. Betamimetics are commonly used tocolytic agents, but their mechanism of action affects multiple organ systems leading to numerous adverse events. The availability of an oxytocin receptor antagonist, specific for prevention of preterm labour, offers a treatment option that merits further evaluation. We aimed to compare economic implications of tocolysis using atosiban and betamimetics, considering treatment efficacy and safety, as well as cost consequences of treatment of associated adverse events. METHODS: A systematic literature review identified six randomised clinical trials, three of them double-blinded, comparing atosiban with betamimetics, in which tocolysis was initiated within 48 hours of admission. Cost of drug treatment was calculated based on trial protocols and German hospital drug purchase costs. G-DRG Grouper was used to obtain cost per case. The drug regimen was concordant with the German guidelines for the management of preterm labour, with two alternative modalities of fenoterol analysed: continuous or bolus administrations. RESULTS: According to the results of the meta-analysis of the three double-blinded, placebo-controlled clinical trials, atosiban and betamimetics have similar efficacy (RR = 0.99, 95%CI:0.94-1.04, p = 0.772). Compared to betamimetics, use of atosiban was associated with a significantly lower frequency of adverse events for tachycardia, palpitation, vomiting, headache, hyperglycaemia, tremor, dyspnoea, chest pain, hypocalemia and foetal tachycardia. In our economic analysis, cost savings from using atosiban versus continuous, or bolus, fenoterol was 423euro per patient from the payer's perspective. From the hospital's perspective, savings from using atosiban versus continuous fenoterol ranged from 259euro for 18 hours of tocolysis to 105euro for 48 hours; the respective values for bolus fenoterol were 244euro and 55euro. In the probabilistic sensitivity analysis atosiban was cost saving versus both continuous and bolus fenoterol in 87%-100% of scenarios. CONCLUSION: In a German setting, atosiban is cost saving versus betamimetics in the treatment of preterm labour from the payer, hospital and combined perspectives. Cost savings stem from the superior safety profile of atosiban.