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In managing drug prices at the national level, orphan drugs represent a special case because the price of these agents is higher than that determined according to value-based principles. A common practice is to set the orphan drug price in an inverse relationship with the number of patients, so that the price increases as the number of patients decreases. Determination of prices in this context generally has a purely empirical nature, but a theoretical basis would be needed. The present paper describes an original exponential model that manages the relationship between price and number of patients for orphan drugs. Three real examples are analysed in detail (eculizumab, bosentan, and a data set of 17 orphan drugs published in 2010). These analyses have been aimed at identifying some objective criteria to rationally inform this relationship between prices and patients and at converting these criteria into explicit quantitative rules. © 2016 by the authors; licensee MDPI, Basel, Switzerland.

Tulli G.,Regional Health Service | Messori A.,HTA Unit | Trippoli S.,HTA Unit | Marinai C.,HTA Unit
International Journal of Antimicrobial Agents | Year: 2017

This study examined the literature on the treatment of ventilator-associated pneumonia (VAP) using colistin or standard care (SC). Based on this clinical material, a meta-analysis was conducted and a non-inferiority test was performed. Studies were selected for inclusion based on the following criteria: (a) patients with VAP; (b) experimental arm based on intravenous or aerosolized colistin; and (c) control arm based on SC. The meta-analysis employed a fixed-effect model, and the endpoint was the rate of clinical response. No pre-specified non-inferiority threshold for the upper boundary of the 95% confidence interval was adopted; instead, the intention was to perform a retrospective evaluation of whether the threshold suggested by the results was acceptable on clinical grounds. In total, eight controlled studies were included. The pooled risk ratio was 1.019 for colistin compared with SC (95% confidence interval 0.895–1.16); this result corresponds to a non-significant 1.9% increase in cure rate with colistin compared with SC (range +16% to −10.5%). Heterogeneity was minimal (0%). The post-hoc non-inferiority threshold for colistin compared with SC was −10.5% in terms of relative cure rate (pooled risk ratio = 0.895). This margin was considered to be acceptable on clinical grounds. This analysis found that colistin can play a role in the treatment of VAP, particularly when given as a combination of aerosolized and intravenous drug. © 2017 Elsevier B.V. and International Society of Chemotherapy

Zaccara G.,San Giovanni Of Dio Hospital | Giovannelli F.,San Giovanni Of Dio Hospital | Maratea D.,HTA Unit | Fadda V.,HTA Unit | Verrotti A.,University of Chieti Pescara
Seizure | Year: 2013

Purpose Analysis of overall tolerability and neurological adverse effects (AEs) of eslicarbazepine acetate (ESL), lacosamide (LCM) and oxcarbazepine (OXC) from double-blind, placebo-controlled trials. Indirect comparisons of patients withdrawing because of AEs, and the incidence of some vestibulocerebellar AEs between these three antiepileptic dugs (AEDs). Methods We searched MEDLINE for all randomized, double-blind, placebo-controlled trials investigating therapeutic effects of fixed oral doses of ESL, LCM and OXC in patients with drug resistant epilepsy. Withdrawal rate due to AEs, percentages of patients with serious AEs, and the proportion of patients experiencing any neurological AE, nausea and vomiting were assessed for their association with the experimental drug. Analyses were performed between recommended daily doses of each AED according to the approved summary of product characteristics (SPC). Risk differences were used to evaluate the association of any AE [99% confidence intervals (CIs)] or study withdrawals because of AEs (95% CIs) with the experimental drug. Indirect comparisons between withdrawal rate and AEs dizziness, coordination abnormal/ataxia and diplopia were estimated according to network meta-analysis (Net-MA). Results Eight randomized, placebo-controlled, double-blind trials (4 with ESL, 3 with LCM, and 1 with OXC) were included in our analysis. At high doses (OXC 1200 mg, ESL 1200 mg and LCM 400 mg) there was an increased risk of AE-related study withdrawals compared to placebo for all drugs. Several AEs were associated with the experimental drug. Both number and frequency of AEs were dose-related. At high recommended doses, patients treated with OXC withdrew from the experimental treatment significantly more frequently than patients treated with ESL and LCM. Furthermore, the AEs coordination abnormal/ataxia and diplopia were significantly more frequently observed in patients treated with OXC compared to patients treated with LCM and ESL. Conclusions The overall tolerability of AEDs and the incidence of several neurological AEs were clearly dose-dependent. Indirect comparisons between these AEDs, taking into account dose-effect, showed that OXC may be associated with more frequent neurological AEs than LCM and ESL. © 2013 British Epilepsy Association.

Messori A.,HTA Unit
International Journal of Clinical Pharmacology and Therapeutics | Year: 2016

Background: PCSK9 inhibitors (evolocumab and alirocumab) pose a challenge of sustainability because the potential patients are extremely numerous and the budget impact at the drugs' full price would be prohibitive. We have studied the reimbursability of these agents by constructing a series of price-volume simulations that used a model previously employed for sofosbuvir. Methods: Our price-volume model is based on the following parameters: I) total patients candidate to the treatment; II) patients actually treated; III) treatment full cost per patient; IV) estimated nationwide budget impact in the absence of any price-volume intervention; V) price-halving population (PHP), which is the main model parameter. Treated patients ranged from 30,000 to 100,000. The full nominal yearly cost per patient was set at 10,000 €. Results: In 9 price-volume simulations (testing three values of PHP at 25,000 or 50,0000 or 100,000 patients), the total national expenditure varied from 204 to 721 million €. In the least expensive scenario (PHP = 25,000 patients), the expenditure ranged from 204 to 338 million € while the average treatment cost per year was 3,382 €. At more than 100,000 treated patients, the treatment cost reduced to 626 €. On the other hand, the scenarios based on PHP = 50,000 and PHP = 100,000 patients were very unlikely to be acceptable for national health systems. Conclusions: Our study offered a pattern of different scenarios among which some national health systems in Europe could select the "true" decision on PCSK9 inhibitors. This decision is expected to be made over the next few months. ©2016 Dustri-Verlag Dr. K. Feistle.

Several cases of expensive drugs designed for large patient populations (e.g. sofosbuvir) have raised a complex question in terms of drug pricing. Even assuming value-based pricing, the treatment with these drugs of all eligible patients would have an immense budgetary impact, which is unsustainable also for the richest countries. This raises the need to reduce the prices of these agents in comparison with those suggested by the value-based approach and to devise new pricing methods that can achieve this goal. The present study discusses in detail the following two methods: (i) The approach based on setting nation-wide budget thresholds for individual innovative agents in which a fixed proportion of the historical pharmaceutical expenditure represents the maximum budget attributable to an innovative treatment; (ii) The approach based on nation-wide price–volume agreements in which drug prices are progressively reduced as more patients receive the treatment. The first approach has been developed in the USA by the Institute for Clinical and Economic Review and has been applied to PCSK9 inhibitors (alirocumab and evolocumab). The second approach has been designed for the Italian market and has found a systematic application to manage the price of ranibizumab, sofosbuvir, and PCSK9 inhibitors. While, in the past, price–volume agreements have been applied only on an empirical basis (i.e. in the absence of any quantitative theoretical rule), more recently some explicit mathematical models have been described. The performance of these models is now being evaluated on the basis of the real-world experiences conducted in some European countries, especially Italy. © 2016, Springer International Publishing Switzerland.

Background and Objectives: We studied the effect of achieving sustained virological response (SVR) on the risk of developing hepatocellular carcinoma (HCC) in patients with hepatitis C receiving anti-hepatitis C virus treatment. Avoiding HCC is considered the main long-term benefit of successful antiviral treatment. Methods: Our literature search extended up to June 2015. We identified all studies that assessed the risk of HCC in patients achieving or not achieving SVR. Meta-analysis was based on a standard random-effect model. The end-point was occurrence of HCC compared between patients with and without SVR; this end-point was expressed as an odds ratio and percent reduction in risk and was also presented separately for patients with and without cirrhosis. All results estimates presented with 95 % confidence intervals (CIs). The presence of any temporal trend in these indexes was investigated by standard meta-regression. Results: Our search identified 25 observational studies (19,822 patients). The odds ratio of HCC for SVR versus no-SVR was 0.19 (95 % CI 0.15–0.24) in the overall series of 25 studies. The difference in this index between patients with any stage of fibrosis/cirrhosis and those with cirrhosis was small. With regard to risk difference, the 25 studies indicated an overall reduction of 10 % (95 % CI 8.00–12.0); this effect was much less pronounced in the group with any stage of fibrosis/cirrhosis (risk difference 6.7 %) than in the selected group with cirrhosis (risk difference 22 %). Meta-regression showed no temporal trend. Conclusion: Our analysis was successful in providing an updated overview on this controversial topic. Some pharmacoeconomic assessments are also presented to interpret the clinical results of our analysis. © 2015, Springer International Publishing Switzerland.

Badiani B.,HTA Unit | Maratea D.,HTA Unit | Messori A.,HTA Unit
World Journal of Clinical Oncology | Year: 2015

Aim: To study the effectiveness of second-line treatments for advancer gastric cancer by application of Bayesian network meta-analysis. Methods: Our search covered the literature up to February 2015. The following 6 treatments were evaluated: (1) irinotecan (camptothecins); (2) paclitaxel (taxanes class); (3) docetaxel (taxanes); (4) everolimus (mammalian target of rapamycin inhibitors); (5) ramucirumab (vascular endothelial growth factor receptor 2 inhibitors); (6) ramucirumab + paclitaxel. Our methodology was based on standard models of Bayesian network meta-analysis. The reference treatment was best supportive care (BSC). The endpoint was overall survival. Median survival was the outcome measure along with 95% credible intervals. Results: Our search identified a total of 7 randomized controlled trials. These trials included 2298 patients (in 15 treatment arms) in whom a total of 6 active treatments were evaluated as well as BSC. There were 21 head-to-head comparisons (6 direct, 15 indirect). The difference in survival between each of two active treatments (paclitaxel and ramucirumab + paclitaxel) vs BSC was statistically significant, while the other 4 showed no statistical difference. In the 6 head-to-head comparisons between active treatments, no significant survival difference was demonstrated. Conclusion: Our results indicate that both paclitaxel monotherapy and ramucirumab + paclitaxel determine a significant prolongation in survival as compared with BSC. © 2015 Baishideng Publishing Group Inc. All rights reserved.

Messori A.,HTA Unit | Trippoli S.,HTA Unit | Biancari F.,University of Oulu
BMJ Open | Year: 2013

Background: Transcatheter aortic valve implants (TAVIs) is indicated as an alternative to surgical valve replacement for patients unfit for surgery. No systematic review has studied survival after 2 years and limited information is available on between-study heterogeneity. Objectives: A systematic review and meta-analysis on intermediate survival after TAVI. Data sources: PubMed, EMBASE, Scopus and references of selected articles. Study eligibility criteria: Clinical studies evaluating TAVI, published between 2010 and 2012, reporting survival at 2 or more years. Participants: About 3500 patients from 14 studies. Study appraisal and synthesis methods: Proportion meta-analysis with 95% CI and heterogeneity assessment (I2 and Cochran's Q). Metaregression analysis was performed as well. Results: Pooled immediate postoperative death rate was 7.8% (95% CI 6.2% to 9.8%, I2=40.8%; Cochran's Q=97.7 with 92.9 df, p<0.0001) and stroke rate was 3.8% (95% CI 2.8% to 5.0%, I2=34.3%; Cochran's Q=96.5 with 92.9 df, p<0.0001). Pooled death rates at 1, 2 and 3 years were 23.2%, 31.0% and 38.6%, respectively. Among studies reporting on concomitant percutaneous coronary intervention, pooled death rates at 30 days, 1 year and 2 years were 6.3%, 17.8% and 25.8%, respectively. Limitations: Although our analysis examined a total of about 3500 patients, only a minority of these were actually followed up after 2 years. Conclusions: Pooled survival rates after TAVI (at 2 years:69.0%; at 3 years:61.4%) can be considered excellent, particularly in the light of the high-risk profile of this patient population. Implications of key findings: The favourable intermediate outcome in patients subjected to TAVI seems to justify its use in patients unfit for surgery. Such pooled results indicate that TAVI is a valid alternative to surgical valve replacement, but lack of data on late durability after TAVI prevents its use in low-risk patients with long expectancy of life.

Messori A.,HTA Unit | Fadda V.,HTA Unit | Maratea D.,HTA Unit | Trippoli S.,HTA Unit | Marinai C.,HTA Unit
Diabetes Therapy | Year: 2014

Background: In studying the therapeutic evidence of innovative drug treatments, increasing attention is being devoted to differentiating between results that indicate no significant differences among the treatments under examination (“no proof of difference”) and results that demonstrate the therapeutic equivalence among the treatments (“proof of no difference”).Aim: Our analysis was aimed at evaluating the degree of therapeutic equivalence for dipeptidylpeptidase-4 (DPP-4) inhibitors given in type 2 diabetes as monotherapy or in combination with metformin.Methods: Equivalence was determined by developing a standard Forest plot that incorporated the information on margins previously reported in randomized trials on these agents. The end point was HbA1c change from baseline; the equivalence margin was set at ±0.25% change in HbA1c. The clinical material was obtained from a systematic review on this topic.Results: Given as monotherapy, linagliptin, sitagliptin, and vildagliptin (but not saxagliptin) met the equivalence criterion when compared with one another. Given in combination with metformin, linagliptin, saxagliptin, sitagliptin, and vildagliptin showed an equivalent effect whereas alogliptin did not satisfy the equivalence criterion.Conclusions: Considering the most recent therapeutic guidelines, our results are of interest particularly as regards the information on DPP-4 inhibitors in combination with metformin. Four of the five DPP-4 inhibitors under examination clearly showed to have the same effectiveness; the fifth agent—alogliptin—failed to meet the equivalence criterion, but only because its superiority could not be excluded. © 2014, The Author(s).

Messori A.,HTA Unit | Fadda V.,HTA Unit | Maratea D.,HTA Unit | Trippoli S.,HTA Unit | Marinai C.,HTA Unit
International Journal of Clinical Pharmacology and Therapeutics | Year: 2015

Background: In studying the comparative effectiveness of novel oral anticoagulants (NOACs) in orthopedic surgery and in non-valvular atrial fibrillation, previous meta-analyses have found no proof of difference in head-to-head indirect comparisons between individual agents. However, the question of their therapeutic equivalence remains unanswered. Objectives: The objective of this analysis was to test the equivalence of three NOACs (dabigatran, rivaroxaban, apixaban) in orthopedic surgery and four NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) in non-valvular atrial fibrillation. Methods: Standard pairwise meta-analysis and network meta-analysis for indirect comparisons were combined with equivalence testing. The endpoint was venous thromboembolism in orthopedic surgery and a composite of stroke or systemic embolism in atrial fibrillation. Comparisons were expressed as risk difference (RD). Margins for equivalence testing were derived from the original trials. Results: Our results indicate that rivaroxaban and apixaban (but not dabigatran) are equivalent for thromboprophylaxis in orthopedic surgery. In atrial fibrillation, all the four NOACs we tested were found to meet the criterion of therapeutic equivalence. Some concern, however, is raised by some findings focused on adverse events of these agents, in which the equivalence was not proven in all analyses. Conclusions: Regardless of clinical implications, our results can be the basis to develop local acquisition tenderings on NOACS. In Italy, a new law has been issued according to which equivalence analyses have become a mandatory prerequisite for local tenderings. ©2014 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965.

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