Journalism Quarterly

Perfetti V., Dalle Carbonare S., Vecchio S., Paglino C., Secondino S., Tringali M., Pedrazzoli P., Dellagiovanna M.

Biosimilars of hemopoietic growth factors present an important saving opportunity in oncology. However, while pharmacologists are aware of their potential benefits, biosimilars are still under-used in Italy. Improved information and guided clinical experience may help to increase the clinical acceptance of these drugs. To this aim, a collaborative educational project was set between an Hospital Oncology Unit and the Local Health Care Authority in Pavia, Italy. The project lasted 12 months. The strategy included an education-information seminar at startup, a reporting meeting at $+6$ months, electronic prescription monitoring and implementation of pharmacovigilance. The target was set to reach 90% of all naïve patients treated with biosimilars. At the end of the study (2013), a dramatic relative increase in the prescription of biosimilar drugs was noted, with virtually 100% of new patients receiving biosimilar drugs during the last 4 months, with a positive impact on average per capita drug expenses. Active pharmacovigilance did not report any serious adverse drug reactions. An anonymous questionnaire showed that oncologists judged the experience quite positively, acquired a positive attitude toward these drugs and considered biosimilars a relevant saving opportunity, while adherence to prescription guidelines was maintained. Analysis of the year following the end of the project, 2014, showed a persistent prescription change. Results from this local experience suggests that specifically designed pragmatic interventions focused on information-education and monitoring may help in promoting the use and acceptance of biosimilar drugs in the real clinical setting.

El Hachem M., Bonamonte D., Diociaiuti A., Mantuano M., Teruzzi C.

Infantile hemangioma (IH) is the most common childhood benign tumour. A recent phase II/III study has demonstrated the success of propranolol for involution of infantile hemangioma as well as a better efficacy and safety when indirectly compared with corticosteroids. The purpose of this study was to estimate the cost-utility of propranolol (Hemangiol), a new medicinal product and the first to be authorized for this specific paediatric indication, versus corticosteroids in the treatment of proliferating infantile hemangioma requiring systemic therapy. A life-time mixed decision tree and Markov model was developed to describe the pathway of infants with infantile hemangioma and to assess costs and outcomes in terms of Quality Adjusted Life Years (QALYs) from the perspective of the Italian National Health Service. Clinical inputs were derived from the MA holder’s pivotal trial and literature review, and were validated by disease key opinion leaders in Italy. The economic evaluation considered direct medical costs associated with infantile hemangioma, derived from public sources. Atopic dermatitis utilities were used as a proxy for infantile hemangioma. Probabilistic sensitivity analysis was performed to investigate model parameter variabilities. The cumulative costs were €2,399.32 and €1,859.68, while cumulative QALYs were 19.11 and 18.95, respectively for propranolol and corticosteroids (Prednisolone-Deltacortene), corresponding to an incremental cost-utility ratio of €3,372.75 per QALY. Probabilistic sensitivity analysis showed that 94.60% of the 1,000 iterations fall within an a priori €30,000/QALY cost-effectiveness threshold. Propranolol oral solution for the treatment of proliferating infantile hemangioma requiring systemic therapy can be considered cost-effective compared to corticosteroids from the Italian National Health Service (NHS) perspective at a threshold fixed at €30,000/QALY.

Ravasio R., Pedone M.P., Ratti M.

Marcellusi A., Viti R., Capone A., Mennini F.S.

The hepatitis C virus (HCV) induces several pathological conditions worldwide with a substantial medical and economic burden. The objective of this study was to estimate the average annual cost incurred by the National Health Service (NHS) as well as society due to HCV in Italy. A probabilistic incidence-based cost of illness model was developed to estimate an aggregate measure of the economic burden associated with HCV-induced diseases either in terms of direct or indirect costs. Indirect costs were calculated on the basis of productivity lost according to the human capital approach. A systematic literature review was carried out to identify epidemiological and economic data which were subsequently used to inform the model. Furthermore, a one-way probabilistic sensitivity analysis with 5,000 Monte Carlo simulations was performed, in order to test the robustness of results and define the proper 95% CI. Overall, the total economic burden associated with HCV-induced diseases was estimated in €1.05 (95% CI: €0.61–€1.61) billion. A percentage equal to 61.4% was associated with indirect costs (95% CI:€0.37–€0.99 billion) and 38,6% with direct costs (95% CI: €0.23–€0.63 billion). For chronic hepatitis C, cirrhosis, hepatocellular carcinoma (HCC), liver transplantation and death from causes related to HCV was estimated an average annual economic burden amounting to €0.26 (95% CI: €0.14–€0.41), €0.55 (95% CI: €0.30–€0.87), €0.051 (95% CI: €0.0001–€0.25) €0.05 (95% CI: €0.03–€0.08) and €0.15 (95% CI: €0.06–€0.27) billion, respectively. Italy is one of the European countries with the highest number of people with chronic HCV infection, the leading cause of cirrhosis, HCC and liver-related death. HCV-induced diseases cause a significant cost for Italian NHS, especially for each case of liver transplantation. These highly debilitating and life-threatening complications generate a rather large amount of indirect costs for the Italian society as well.

Ravasio R., Pedone M.P., Ratti M.

Oral dabigatran etexilate is indicated for the prevention of systemic thromboembolic events in patients with non-valvular atrial fibrillation (NVAF). Based on the RE-LY study we investigated the cost-effectiveness of dabigatran etexilate versus warfarin and versus others new oral anticoagulants (rivaroxaban and apixaban) in the Italian setting. A Markov decision model with a 3-month cycles and a lifetime horizon were adopted. Efficacy and quality of life were estimated from clincal trials and published literature. The cost-effectiveness analysis was performed form the perspective of the Italian National Health Service. We considered Quality-Adjusted Life-Years (QALYs) and direct medical costs. Benefits and costs were discounted (3%). Costs were assessed in 2014 Euros. A sensitivity analyses on key clinical and economic parameters was performed. The incremental cost-effectiveness ratio (ICER) of dabigatran was €6,800/QALY versus warfarin and €5,787/QALY versus apixaban. Compared with rivaroxaban, dabigatran was the dominant strategy. Sensitivity analysis confirmed the base case results. This economic evaluation, based on estimates derived from different trials, suggested that dabigatran is cost-effective versus warfarin and apixaban and dominant versus rivaroxaban in treatment for the prevention of systemic thromboembolic events in patients with NVAF in the Italian healthcare setting.

Allen R., Brainsky A., Grotzinger K., Roccia T.

Grossi F., Buffoni L., Favaretto A., Lucioni C., Mazzi S., Soto Parra H.

Vinorelbine and Cisplatin is a standard treatment in non small cell lung cancer; oral Vinorelbine is registered in 45 countries. Pemetrexed and Cisplatin are recommended in front-line chemotherapy of non-squamous non small cell lung cancer (NS-NSCLC). An economic evaluation of oral Vinorelbine plus Cisplatin and Pemetrexed plus Cisplatin was implemented in NS-NSCLC patients, adopting specific costs and clinical settings reflecting the Italian practice. A cost evaluation was conducted from the perspective of the Italian National Health Service, based on a randomized phase II study in NS-NSCLC (NAVoTRIAL01), with 100 oral Vinorelbine + Cisplatin patients (arm A) and 51 Pemetrexed + Cisplatin patients (arm B). Overall, Arm A/Arm B reported respectively: Disease Control Rate, including combination (4 cycles) and maintenance periods, of 75%/76.5%; median Progression Free and Overall Survival of 4.2/4.3 and 10.2/10.8 months. Costs considered in the analysis were for anti-cancer drugs, administration settings (i.e. out-patient/in-patient/at home), serious adverse events (defined as involving hospitalization and suspected to be due to anti-cancer drugs), concomitant medications, blood transfusions. Unit costs used for anti-cancer drugs were official ex-factory prices, with further percent deductions enforced by law. The distribution of administration settings was re-modelled according to the respective frequencies found for the subset of Italian patients participating in NAVoTRIAL01; for out/in-patient settings, DRG (Diagnosis-Related Group) and other tariffs (day-hospital or one day admission) were used (no cost was charged when administration was at home). Hospitalization costs were assessed for serious adverse events on the basis of appropriate DRG tariffs. For concomitant medications, prices were ex-factory or 50% of retail price. Blood transfusions were evaluated using public tariffs. The average cost per patient for the overall treatment was €4,511 (of which: €1,763 for anti-cancer drugs, €1,801 for administration settings, and €611 for serious adverse events) in arm A; the respective costs were €14,793 (€13,615, €344, €567) in arm B. Given the reported efficacy outcomes with both regimens, oral Vinorelbine + Cisplatin followed by maintenance with oral Vinorelbine provides substantial savings (€10,282 per patient on average), appearing a cost-effective treatment option in advanced non-squamous non small cell lung cancer. Sensitivity analysis shows the robustness of the results, which should be confirmed by a phase III trial.

Boyers D., Jia X., Jenkinson D., Mowatt G.

Yang H., Craig D., Epstein D., Bojke L., Light K., Bruce I.N., Sculpher M., Woolacott N.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of golimumab (Schering-Plough/Centocor) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of active and progressive psoriatic arthritis (PsA) in patients who have responded inadequately to previous disease-modifying anti-rheumatic drugs (DMARDs). The Centre for Reviews and Dissemination and the Centre for Health Economics at the University of York were commissioned to act as the Evidence Review Group (ERG) to critically appraise the evidence presented by the manufacturer. This article provides a description of the company submission, the ERG review and the resulting NICE guidance. The ERG critically reviewed the evidence presented in the manufacturer’s submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. The main clinical effectiveness data were derived from a single phase III randomized controlled trial (GO-REVEAL) that compared golimumab with placebo for the treatment of active and progressive patients who were symptomatic despite the use of previous DMARDs or NSAIDs. The 14-week data showed that, compared with placebo, golimumab 50 mg significantly improved joint disease response as measured by American College of Rheumatology (ACR) 20 (relative risk [RR] 5.73, 95% CI 3.24, 10.56) and Psoriatic Arthritis Response Criteria (PsARC) [RR 3.45, 95% CI 2.49, 4.87], and significantly improved skin disease response as measured by Psoriasis Area and Severity Index (PASI) 75 (RR 15.95, 95% CI 4.62, 59.11). The 24-week absolute data showed that these treatment benefits were maintained. There was a significant improvement in patients’ functional status as measured by Health Assessment Questionnaire change from baseline at 24 weeks (−0.33;p<0.001). The open-label extension data showed that these beneficial effects were also maintained at 52 and 104 weeks. The ERG identified several issues relating to the clinical effectiveness results. Analyses of the 24-week data were less robust, failing to adjust for treatment contamination due to patient crossover at week 16. It was also unclear if these results were generalizable to clinical practice. No randomized controlled trial compared the effectiveness of different biologic therapies head-to-head. To compare the effectiveness of the biologics etanercept, infliximab, adalimumab and golimumab, the manufacturer conducted a network meta-analysis, including the comparator palliative care (usual care including use of NSAIDs or DMARDs). The ERG considered the assumption of exchangeability between the trials for the purpose of the network meta-analysis to be acceptable and the statistical approach to be reliable. The results indicated somewhat lower efficacy with golimumab than with comparator biologics. The ERG identified a number of issues relating to the cost-effectiveness results. The manufacturer calculated incremental cost-effectiveness ratios (ICERs) incorrectly by comparing golimumab with palliative care instead of the most cost-effective alternative (etanercept). Despite the manufacturer’s claim that golimumab was a cost-effective treatment option, the manufacturer’s own model showed that golimumab was unlikely to be cost effective, relative to currently accepted thresholds, when the ICERs were correctly calculated using an incremental analysis (i.e. comparing each treatment to the next best alternative). None of the sensitivity analyses carried out by the manufacturer or the ERG regarding uncertainty in the estimates of clinical effectiveness, the acquisition and administration cost of drugs, the cost of treating psoriasis and the utility functions estimated to generate health outcomes changed this conclusion. However, a key area in determining the cost effectiveness of biologics was whether they should be treated as a class. The ERG concluded that if all biologics were considered equally effective, then etanercept, adalimumab and golimumab had almost equal costs and equal QALYs, and all had an ICER of about £15 000 per QALY versus palliative care, whilst infliximab, with a higher acquisition cost, was dominated by the other biologics. The Appraisal Committee altered its position between the Appraisal Consultation Document and the Final Appraisal Determination. It ultimately recommended that golimumab be provided as an option for the treatment of active and progressive PsA in adults only if (i) it is used as described for other tumour necrosis factor inhibitor treatments in ‘Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis’ (NICE clinical guideline 199); and (ii) the manufacturer provides the 100 mg dose of golimumab at the same cost as the 50 mg dose.

Allen R., Brainsky A., Grotzinger K., Roccia T.

Gasparini R., Lucioni C., Mazzi S., Amicizia D., Panatto D.

According to WHO, seasonal influenza affects 5–15% of population. Its burden (hospitalizations and deaths) is particularly heavy on elderly people. The only effective means of combating influenza is vaccination, and adjuvanted vaccines optimize the immune response. This work aims at evaluating the economic convenience of a virosomal vaccine in preventing hospitalization for influenza and pneumonia in the elderly in Italy; it is designed as a cost-benefit analysis, comparing vaccination costs with corresponding savings from hospitalization reduction. The analysis is based on a published case-control study performed in the elderly population (>64 years) residing in Genoa (Italy). The study period was the 2010–2011 season. A 95.2% vaccine effectiveness (p=0.004) was estimated. The present analysis is conducted from the perspective of the National Health Service, at the whole country level. The vaccine cost was evaluated at discounted price and the hospitalizations with a weighted DRG tariff. Assuming to treat with a virosomal vaccine the Italian elderly population not covered (42%, i.e. 5,166,646 people), the campaign would cost €84.4 million (of which one third due to the cost of vaccine). Coeteris paribus, this strategy would prevent 41,280 hospitalizations, with savings amounting to €121.9 million—giving a net benefit of €37.5 million. A one-way sensitivity analysis (exploring: the uncertainty around the vaccine effectiveness; the herd immunity effect; a 75% coverage of the elderly population, corresponding to the Italian Ministry of Health target) substantially confirmed the favourable base case result, with net benefits ranging from −€4 million to €47.5 million.

Boyers D., Jia X., Jenkinson D., Mowatt G.

Iannazzo S., De Francesco M., Coco B., Brunetto M.R., Tomic R., Paolini D., Palmieri G., Bonino F.

Treatment options for chronic hepatitis B (CHB) are the direct inhibition of viral replication by continuous administration of nucleoside analogues (NUCs) or a finite 48-week course of peg-interferon (PEG). PEG can induce the off-therapy immune control of CHB leading to HBsAg loss/anti-HBs seroconversion, but with a low success rate. On the other hand life-long treatment with NUCs is expensive. Currently in Italy, around 67% of naïve patients receive treatment with NUCs. However, exploiting the early identification of PEG-non-responders by combined HBV-DNA and HBsAg quantification at week 12 (stopping-rule) is a new sequential therapeutic strategy that may benefit both patients and third payers. We measured the impact on the Italian National Health Service (NHS) budget of the strategy PEG-week-12-stopping-rule in the treatment of HBeAg-negative CHB. A Markov model, developed over a 5 year time horizon, comprises the following states: CHB, virologic response, relapse, HBsAg clearance, compensated and decompensated cirrhosis, hepatocarcinoma, liver transplant, post-liver transplant and death. The target population (treatment-naïve CHB patients) was determined based on Italian national population projections and epidemiological data. The current mix of treatment with NUCs (entecavir, tenofovir, adefovir, lamivudine and telbivudine) and PEG (without stopping-rule) was compared with a mix based on a hypothetical adoption of PEG (with stopping-rule). The percentage of patients adopting PEG instead of NUCs started at 25% of current NUCs patient share, increasing over time. The estimated impact on the Italian NHS budget, over a 5 year treatment, resulted in savings of approximately €19.3 million, of which drug cost accounted for more than 99%. The beneficial impact of the stopping-rule became clear from the second year, when the break-even point was reached. The large estimated savings in drug costs following the adoption of PEG + stopping-rule in the treatment of HBeAg-negative CHB patients, together with previously published cost-effectiveness results, demonstrate a potentially advantageous profile of this strategy, that could enable a more efficient use of health care resources.

Boyers D., Jia X., Jenkinson D., Mowatt G.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of eltrombopag (GlaxoSmithKline) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of patients with chronic immune or idiopathic thrombocytopenic purpura (ITP), as part of the their Single Technology Appraisal (STA) process. The Aberdeen Technology Assessment Review (TAR) Group, commissioned to act as the evidence review group (ERG), critically reviewed and supplemented the submitted evidence. This paper describes the company submission, the ERG review and NICE’s subsequent decisions. The ERG critically appraised the clinical and cost-effectiveness evidence submitted by the manufacturer, independently searched for relevant literature, conducted a critical appraisal of the submitted economic models and explored the impact of altering some of the key model assumptions as well as combining relevant sensitivity analyses. Three trials were used to inform the safety and efficacy aspects of this submission; however, one high-quality randomized controlled trial (RAISE study) was the principal source of evidence and was used to inform the economic model. Eltrombopag had greater odds of achieving the primary outcome of a platelet count between 50×109/L and 400×109/L during the 6-month treatment period than placebo (odds ratio [OR] 8.2, 99% CI 3.6, 18.7). In the eltrombopag group, 50/83 (60%) of non-splenectomized patients and 18/49 (37%) of splenectomized patients achieved this outcome. The median duration of response was 10.9 weeks for eltrombopag (splenectomized 6 and non-splenectomized 13.4) compared with 0 for placebo. Eltrombopag patients required less rescue medication and had lower odds of bleeding events for both the splenectomized and the non-splenectomized patients. For a watch-and-rescue strategy of care, the comparator was placebo and the ERG found that substantial reductions in the cost of eltrombopag are needed before the incremental cost per QALY is less than £30 000. There was significant uncertainty, with the incremental cost-effectiveness ratio (ICER) reported varying from £33 561 to £103 500 per QALY (splenectomized) and £39 657 to £150 245 per QALY (non-splenectomized). All costs are presented in £, year 2008 values, as this was the costing year for the manufacturer’s model. Other than bleeding, no adverse events were modelled. In relation to the long-term treatment model, the ERG questioned the robustness of the use of non-randomized non-comparative data. The base-case results restricting the time horizon to 2 years and prescribing eltrombopag as second-line treatment post-rituximab were found to be favourable towards eltrombopag. As rituximab is not a licensed treatment for ITP, the ERG were concerned that its inclusion may not be reflective of clinical practice. None of the treatment sequences resulted in an ICER approaching the recommended threshold of £30 000 per QALY gained. Eltrombopag appears to be a safe treatment for ITP (although longterm follow-up studies are awaited) and has short-term efficacy. However, NICE found based on the evidence submitted and reviewed that there was no robust evidence on the long-term efficacy or cost effectiveness of eltrombopag and a lack of direct evidence for eltrombopag tested against other relevant comparators.

Ravasio R., Tomic R., Deodato B., Bruno R.

A recent meta-analysis pointed out that pegylated interferon α-2a is more effective than peginterferon α-2b in terms of rapid virological response (RVR) in the treatment of chronic hepatitis C (CHC). Considering the availability of triple therapy (TT—pegylated interferon, ribavirin and protease inhibitor) and the possibility to follow different treatment algorithms based on RVR achievement, verified after a 4 week lead-in period of dual therapy (DT—pegylated interferon and ribavirin), rational decisions, taking into account also economic implications, become particularly important, especially in a healthcare cost containment context. To compare the overall treatment cost in function of the decision to start the DT 4 week lead-in period with pegylated interferon α-2a plus ribavirin or with pegylated interferon α-2b plus ribavirin in the treatment of previously untreated adults (>18 years) with CHC genotype 1 and F0–F2 liver fibrosis. A cost-consequence analysis from the Italian National Health Service (NHS) perspective using two decision tree models was carried out. We considered the TT with boceprevir in the first model and the TT with telaprevir in the second. Probabilities of each event were derived from literature and an expert panel. Direct medical costs were obtained from official sources (€2013). In the boceprevir model, the average cost per patient starting the treatment with pegylated interferon α-2a plus ribavirin was estimated to be €21,570.06; the cost was estimated to be €22,060.00, starting the treatment with pegylated interferon α-2b plus ribavirin. In the telaprevir model, the average cost per patient starting the treatment with pegylated interferon α-2a plus ribavirin was estimated to be €24,320.35; the cost was estimated to be €25,696.43, starting the treatment with pegylated interferon α-2b plus ribavirin. The sensitivity analysis confirmed the results of the base case. We performed a cost consequence analysis focused on the economic implications of starting the DT 4 week lead-in period either with peginterferon α-2a or α-2b and, based on the RVR status, the consequent DT or TT therapy continuation, in the therapeutic management of CHC genotype 1 patients. Regardless of the protease inhibitor administered, from the Italian NHS perspective, starting the treatment with pegylated interferon α-2a plus ribavirin is a cost-saving strategy compared with starting with pegylated interferon α-2b plus ribavirin.