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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.

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. 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. 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. 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.

Although several evidence-based analyses have found that in patients with moderate-to-severe psoriasis, biological agents for subcutaneous use show no difference in efficacy (no proof of difference), there is limited evidence on whether or not there is also proof of no difference.The clinical material was the same as that reported in previous meta-analyses. Our methodology was a combination of meta-analysis and equivalence testing. The endpoint was the rate of Psoriasis Area and Severity Index (PASI) 75 achievement. The agents examined for equivalence testing included etanercept, high-dose etanercept, adalimumab, ustekinumab, and high-dose ustekinumab. The equivalence margin [±18 % as risk difference (RD)] was derived from statistical power information from the original trials; a more conservative margin at ±10 % was also tested.Our analysis involved 16 randomized trials including 8,257 patients. Ten head-to-head indirect comparisons were made and the respective values of RD were estimated. The 95 % confidence intervals for RDs remained within the margins of ±18 and ±10 % in six and two cases, respectively. A post hoc margin of about ±25 % was satisfied in all cases. All analyses assumed α = 2.5 %.Our study indicates that some of these five biological treatments can be equivalent, but results are strongly influenced by the margins adopted. Our findings can be helpful to develop local acquisition tenders on these drugs.

Objective: To describe and evaluate, in comparison with traditional approaches, a technique of survival meta-analysis (the ‘intermediate’ method) that reconstructs individual patient data (IPD) from the graphs of survival curves. Patients: The examples considered in this paper were oncology patients (three data sets) and intensive-care unit patients (one data set). Results: In two data sets from oncology patients, the intermediate method reconstructed IPD from the graphs of the survival curves. In the comparison between true IPD and estimated IPD (two data sets), the correlation analysis showed an excellent concordance between true survival times and estimated survival times (correlation ranging from r = 0.989 to r = 1). Conclusion: This technique is a compromise between meta-analysis of ‘true’ IPD and meta-analysis of aggregate data without patient-level information. This intermediate method of survival meta-analysis is suitable for small research groups that do not have the resources required to conduct a survival meta-analysis based on true IPD.

Some clinical trials have shown that long-term treatment with alpha interferon (IFN) in patients with multiple myeloma can improve survival in comparison with patients not given IFN, but other studies have found no survival benefit in patients treated with IFN. We utilised the clinical material reported in these trials to conduct a meta-analysis on long-term survival. The survival curves published in each of these studies were analysed to determine the mean lifetime survival (MLS) for treated patients and controls using Gompertz’ extrapolation to infinity of the survival curves. Values of MLS were then pooled using standard meta-analytic techniques. Our meta-analysis showed that maintenance treatment with IFN did not improve MLS at levels of statistical significance. The MLS was 3.9 years per patient in the IFN group versus 3.4 years per patient in the controls (p = 0.095). Because the level of statistical significance was borderline, a lifetime cost-effectiveness analysis was undertaken to determine the cost per life-year gained using IFN. This cost was found to be around $US84 000 per life-year gained, a value suggesting an unfavourable pharmacoeconomic profile. We conclude that the survival advantage of maintenance treatment with IFN in myeloma patients, if any, has a small clinical relevance and demonstrates an intermediate or unfavourable pharmacoeconomic ranking.

The prophylactic administration of immunoglobulins to preterm neonates has a controversial effectiveness in reducing the incidence of nosocomial infections. Since the clinical trials conducted so far have given conflicting results, a metaanalysis was carried out to summarise the overall information presently available on this issue. Eight randomised clinical trials were identified by our literature search that met the inclusion criteria of our meta-analysis. In each study, the effectiveness of intravenous immunoglobulins was compared with that of no treatment or placebo. The overall number of patients included in our metaanalysis was 3739. The end-point was the incidence of proven infections. The results of our meta-analysis demonstrate that prophylactic immunoglobulins significantly reduced the incidence of proven infections (pooled odds ratio = 0.79, 95% CI: 0.69 to 0.91; p = 0.0014; reduction in the incidence of infection from 23.2 to 19.3%). There was, however, a significant intertriai heterogeneity. A cost-effectiveness analysis indicated that the prophylactic administration of immunoglobulins implies a cost of approximately $US8000 to prevent each case of infection in premature infants. This cost seems to be at least equal to the cost of treating an episode of sepsis in an infant.

A meta-analysis of published randomised clinical trials was performed to determine the efficacy of recombinant and lymphoblastoid interferon-α (IFNα) in the induction and maintenance of remission in patients with chronic C or non-A non-B hepatitis. Studies were identified using standard computer techniques for literature searches and by reviewing all references of the papers examined. Each trial evaluated the efficacy of IFNα (recombinant and lymphoblastoid)1 in comparison with a control group receiving either placebo or no treatment. Since the end-point of the analysis was of a censored-type [i.e. normalisation of alanine aminotransferase (ALT) levels over time], a specific method of meta-analysis was employed that allowed the inclusion of trials of different durations and permitted determination of the probability of therapeutic success over time. Two separate meta-analyses were carried out to address (a) the efficacy of IFNα during treatment (first meta-analysis) and (b) the relapse risk after drug discontinuation (second meta-analysis). 21 trials were included in the evaluation: 16 used recombinant IFNα and 5 used lymphoblastoid IFNα. Results of the first meta-analysis indicated that IFNα was highly effective at inducing ALT normalisation [log-rank odds-ratio (95% CI): 8.4 (6.3–11.2) at 24 weeks and 8.2 (6.2–10.9) at 48 weeks]. The pooled meta-analytical rate of ALT normalisation in the treatment group was 37% at 24 weeks and 44% at 48 weeks. Results of the second meta-analysis conducted in the subgroup of patients that achieved stable ALT normalisation following IFNα treatment revealed that remission was maintained after drug discontinuation in 47% of patients (pooled meta-analytical rate after a follow-up period of 12 to 60 weeks). Relapse-free remission during the follow-up period was 59% in patients treated with lymphoblastoid IFNα versus 43% in patients treated with recombinant IFNα. Taking into consideration the results of both meta-analyses, the global rate of success, i.e. the probability of achieving remission with treatment and of maintaining remission after drug discontinuation, is 17.4% at 24 weeks of IFNα therapy. If the studies are stratified according to the type of IFNα administered, the global rates of success are 16% for recombinant IFNα and 25% for lymphoblastoid IFNα.

To evaluate the cost-effectiveness profile of topiramate as adjunctive treatment in patients with refractory epilepsy.Lifetime cost-utility analysis based on a pharmacoeconomic model.Effectiveness data (seizure frequency reduction) were derived from the most recent placebo-controlled clinical trial, whilst quality of life and cost data were retrieved from the published literature. Our pharmacoeconomic model was based on a patient-level approach that incorporated the clinical data of the randomised, controlled trial.Our analysis showed that chronic topiramate treatment costs pound21 353 per quality-adjusted life year (QALY) gained (incremental lifetime cost of pound1 024 941 and incremental utility of 48 QALYs, for every 100 patients) [discounted values with a yearly rate of 3%] (year of costing 2001). Sensitivity analyses suggested a range from pound19 915 to pound24 518 per QALY gained.Our results showed that adjunctive topiramate therapy has a favourable pharmacoeconomic profile in patients with refractory epilepsy.