Clinical aspects of reimbursement policies for orphan drugs in Central and Eastern European countries.

Objectives: The aim of this study was to characterize the reimbursement policy for orphan drugs (ODs) in Central and Eastern European (CEE) countries in relation to the availability and impact of clinical evidence, health technology assessment (HTA) procedure, selected economic indicators, and the drug type according to indications. Materials and methods: A list of authorized medicines with orphan designation and information about active substance, Anatomical Therapeutic Chemical (ATC) classification, and therapeutic area was extracted from the web-based register of the European Medicines Agency (EMA). A country-based questionnaire survey was performed between September 2021 and January 2022 in a group of selected experts from nine CEE countries (an invitation was sent to 11 countries). A descriptive and statistical analysis was conducted to determine statistical significance, correlations, between the drug or country characteristic and the positive recommendation or reimbursement of ODs. Results: The proportion of reimbursed orphan drugs differed between countries, ranging from 17.7% in Estonia to 49.6% in Hungary (p < 0.001). The odds that ODs were reimbursed were reduced in countries with a "strong" level of impact of drug safety and efficacy on reimbursement decisions (p=0.018), the presence of other additional specific clinical aspects (e.g., genomic data) considered in the reimbursement decision (p < 0.001) and mandatory (without exception) safety assessments (p=0.004). The probability that ODs were reimbursed was increased in countries with a "moderate" level of impact of drug safety and efficacy on reimbursement decisions (p=0.018), when reimbursement decisions are dependent on the EMA registration status and orphan drug designation (p < 0.001), the presence of the "positive HTA recommendation guarantees reimbursement" policy (p < 0.001), higher GDP per inhabitant (p=0.003), and higher healthcare expenditure (p < 0.001). Conclusion: We found that there are differences among CEE countries in the reimbursement of orphan drugs, and we identified aspects that may influence these differences. Safety, efficacy, and specific clinical aspect issues significantly influenced reimbursement decisions. Antineoplastic and immunomodulating agents drugs were the largest group of ODs and increased the chance of getting a positive recommendation. The higher GDP per inhabitant and healthcare expenditures per inhabitant were positively linked to the chance that an OD receives reimbursement.

Provision of special diets to children in public nurseries and kindergartens in Kraków (Poland).

Background: A specialized diet could be due to an allergy or other medical needs and also religious or cultural reasons. This study aimed to assess the availability and provision of special diets in kindergartens and nurseries financed by the Municipality of Kraków. Methods: This observational cross-sectional study was based on a diagnostic survey carried out using the Computer-Assisted Web Interview method and addressed to the managers of nurseries (n = 21) and kindergartens (n = 71) and, separately, to the parents of children attending these facilities (n = 1,096). Non-parametric tests were applied for an unadjusted comparison between children at nurseries and those at kindergartens. Results: Children with particular dietary requirements received special diet meals in 95.2% of nurseries and 60.5% of kindergartens. The availability of special diets was associated with the type of facility (p = 0.001), the number of children who ate in the facility (p = 0.032), and the daily cost of meals served to children (p = 0.009). The cost of meals was higher in kindergartens that offered special diets vs. those that did not offer such diets (p < 0.001). According to parents, 96.4% of the total number of children ate meals served in the facilities. In nurseries, 16.1% of children were on a special diet (as per the doctor's recommendations in 11.7% of cases and according to parents' own choice in 4.4%). In kindergartens, a special diet was served to 12.7% of children (doctor's recommendations, 8.5%; parents' own choice, 4.2%). The most common reason for using a special diet was food allergy (8.2% of children in nurseries and 5.8% of children in kindergartens). It was reported more often by the parents of children attending nurseries than by the parents of children attending kindergartens (8.0% vs. 4.2%, p = 0.007). The requirement for a special diet was found to be associated with the age of children (p < 0.033) and the use of oral treatment for chronic disease (p < 0.001). Conclusion: Providing special diets for children is better in nurseries than in kindergartens. Legal regulations are urgently needed to ensure equal access to adequate nutrition for all children with special dietary needs in childcare facilities.

Comparative safety of tyrosine kinase inhibitors in the treatment of metastatic renal cell carcinoma: a systematic review and network meta-analysis.

Objective: This study aimed to compare the safety profile of tyrosine kinase inhibitors (TKIs) approved for use as monotherapy or combination therapy for the first-line treatment of adult patients with metastatic clear cell renal cell carcinoma (RCC). Methods: A systematic review with frequentist network meta-analysis (NMA) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included randomized controlled trials (RCTs) investigating the use of: cabozantinib, pazopanib, sorafenib, sunitinib, tivozanib, cabozantinib + nivolumab, lenvatinib + pembrolizumab, axitinib + avelumab, and axitinib + pembrolizumab in previously untreated adult patients with metastatic clear cell RCC. Eligible studies were identified by two reviewers in MEDLINE (via PubMed), EMBASE, and Cochrane Library. The risk of bias for RCTs was assessed using the Cochrane Collaboration tool. The P score was used to determine the treatment ranking. The mean probability of an event along with the relative measures of the NMA was considered with the treatment rankings. Results: A total of 13 RCTs were included in the systematic review and NMA. Sorafenib and tivozanib used as monotherapy were the best treatment options. Sorafenib achieved the highest P score for treatment discontinuation due to adverse events (AEs), fatigue, nausea, vomiting of any grade, and hypertension of any grade or grade ≥3. Tivozanib achieved the highest P score for AEs, grade ≥3 AEs, dose modifications due to AEs, and grade ≥3 diarrhea. Sunitinib was the best treatment option in terms of diarrhea and dysphonia of any grade, while cabozantinib, pazopanib, and axitinib + pembrolizumab-in terms of grade ≥3 fatigue, nausea, and vomiting. TKIs used in combination were shown to have a poorer safety profile than those used as monotherapy. Lenvatinib + pembrolizumab was considered the worst option in terms of any AEs, grade ≥3 AEs, treatment discontinuation due to AEs, dose modifications due to AEs, fatigue of any grade, nausea, vomiting, and grade ≥3 nausea. Axitinib + avelumab was the worst treatment option in terms of dysphonia, grade ≥3 diarrhea, and hypertension, while cabozantinib + nivolumab was the worst option in terms of grade ≥3 vomiting. Interestingly, among the other safety endpoints, cabozantinib monotherapy had the lowest P score for diarrhea and hypertension of any grade. Conclusion: The general safety profile, including common AEs, is better when TKIs are used as monotherapy vs. in combination with immunological agents. To confirm these findings, further research is needed, including large RCTs.

Indirect Costs of Inflammatory Bowel Diseases: A Comparison of Patient-Reported Outcomes Across 12 European Countries.

BACKGROUND: National studies report a high variability of indirect costs of inflammatory bowel disease (IBD). In this study, selected aspects of the societal burden of IBDs were compared between 12 European countries. METHODS: A questionnaire-based study among adult patients with IBD was performed. Data on patient characteristics, productivity loss, and informal care were collected. The costs of productivity loss were assessed from the social perspective. The cost of absenteeism and presenteeism was valuated using the gross domestic product per worker. Informal care was measured by time inputs of relatives and friends to assist patients. Productivity loss among informal caregivers outside their paid work was valuated with the average wage. The results were adjusted for confounders and multiplicity. RESULTS: Responses from 3687 patients (67% employed) were analyzed. Regular activity (outside paid work) impairment did not differ between countries, but a significant difference in informal care and productivity loss was observed. There were no differences in indirect costs between the types of IBD across the countries. The mean annual cost of absenteeism, presenteeism, and informal care varied from €1253 (Bulgaria) to €7915 (Spain), from €2149 (Bulgaria) to €14 524 (Belgium), and from €1729 (Poland) to €12 063 (Italy), respectively. Compared with patients with active disease, those with IBD in remission showed a lower indirect cost by 54% (presenteeism, P < .001) or 75% (absenteeism, informal care, P < .001). CONCLUSIONS: The study showed a high relevance of the indirect cost of IBD in the context of economic evaluation, as well as a between-country variability of work-related impairment or informal care.

The study showed a high relevance of the indirect cost of inflammatory bowel disease in the context of economic evaluation, as well as a between-country variability of work-related impairment or informal care.

Out-of-pocket expenses of patients with inflammatory bowel disease: a comparison of patient-reported outcomes across 12 European countries.

BACKGROUND: There is a high variability of out-of-packet patient costs of inflammatory bowel diseases (IBDs), but the issue is not widely recognised. Therefore, we compared patient costs of IBDs between 12 European countries. METHODS: A questionnaire-based study was conducted among adult patients with IBD. Data on patient characteristics and out-of-pocket expenses were anonymously collected. Ordered logit regression models were used to analyse the responses provided by patients. The results were adjusted for confounders and multiplicity. RESULTS: The questionnaires obtained from 3687 patients were analysed. Patients with comorbidities and active disease indicated higher out-of-pocket expenses than those without comorbidities and with disease in remission, respectively. Compared with other IBD, patients with ulcerative colitis indicated higher expenses on medications prescribed or recommended by physicians [odds ratio (OR) 1.99, 95% CI 1.48-2.67]. Expenses on dietary supplements, special diet or equipment, ostomy pouches, and transportation to a medical facility differed slightly between patients at different ages and were lower among men than among women (OR 0.71, 95% CI 0.54-0.93). The expenses differed significantly between countries. An adjusted mean patient cost per month varied from €77 (patient with Crohn disease in remission from Denmark) to €376 (patient with active ulcerative colitis from Romania). Compared with active disease, patients with IBD in remission had a lower out-of-pocket cost by 29-62% (€10-€22 monthly; p < 0.001). CONCLUSIONS: The study revealed a high relevance of the out-of-pocket cost of IBD in the context of economic evaluation and a high variability of the cost between countries.

Comparative safety of high-efficacy disease-modifying therapies in relapsing-remitting multiple sclerosis: a systematic review and network meta-analysis.

OBJECTIVE: This study aimed to compare the safety profile of high-efficacy disease-modifying therapies (DMTs) natalizumab, fingolimod, alemtuzumab, cladribine, ocrelizumab, ofatumumab, ozanimod, as well as a potentially high-efficacy DMT, ponesimod, in adult patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: A systematic review with frequentist network meta-analysis (NMA) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We included randomized controlled trials (RCTs) with at least 48-week follow-up investigating the use of natalizumab, fingolimod, alemtuzumab, cladribine, ocrelizumab, ofatumumab, ozanimod, and ponesimod, as well as other DMTs, in adult patients with RRMS. Eligible studies were identified by two reviewers in MEDLINE (via PubMed), EMBASE, and Cochrane Library. The Cochrane Collaboration tool to assess the risk of bias for RCTs was used. RESULTS: A total of 33 RCTs were included in the systematic review and NMA. A higher rate of adverse events (AEs) was revealed for alemtuzumab versus all other high-efficacy DMTs; for alemtuzumab (average probability of an event: 98.2%) versus placebo (86.2%); for cladribine (3.5 mg; 90.5%) versus ozanimod (1 mg; 84.2%) and placebo; as well as for ocrelizumab (95.5%) versus ozanimod, ofatumumab (88.9%), fingolimod (87.4%), natalizumab (82.8%), and placebo. No significant differences were found between drugs in terms of serious AEs except for cladribine (3.5 mg, 17.3%) versus ocrelizumab (10.3%) and ofatumumab (16.6%) versus ocrelizumab. Significant differences in AEs leading to the discontinuation of study drug were found only for ponesimod (10.1%) versus alemtuzumab (12 mg, 3.0%) and placebo (4.2%). No differences were found in terms of upper respiratory tract infections, nasopharyngitis, fatigue, and nausea between individual high-efficacy DMTs as well as between DMTs and placebo. The results of the NMA indicated a higher risk of infections for alemtuzumab (12 mg) versus ocrelizumab, for cladribine (3.5 mg) versus ofatumumab and placebo, and for ofatumumab versus placebo. For serious infections and urinary tract infections, a significant increase was found only for alemtuzumab (12 mg) versus ocrelizumab, while no differences were found between the other DMTs or between DMTs and placebo. Headache was more common for alemtuzumab (12 mg) as compared with all the other high-efficacy DMTs and placebo, as well as for cladribine versus natalizumab and fingolimod versus natalizumab. CONCLUSION: The commonly reported AEs are generally similar among high-efficacy DMTs. However, based on P scores for most analyzed endpoints, natalizumab and ocrelizumab were shown to be the safest DMTs. Considering the limitations of indirect comparisons, further research is needed to confirm our findings, preferably head-to-head RCTs and large observational studies.

Effectiveness of fixed-dose combination therapy in hypertension: systematic review and meta-analysis.

INTRODUCTION: Clinical studies have revealed that fixed-dose combinations (FDCs) of drugs can have a better effect on blood pressure than free-equivalent combinations (FECs). Our objectives were to perform an up-to-date assessment of the effectiveness of FDCs and FECs in antihypertensive therapy, to provide more accurate results by using a stratified meta-analysis. MATERIAL AND METHODS: A systematic review was performed in PubMed, Web of Science, and Cochrane databases according to PRISMA guidelines. The outcomes were adherence (compliance), persistence to medication, reduction of blood pressure and the safety profile. We used the Newcastle Ottawa scale or the Delphi list for the assessment of the quality of cohort studies or clinical trials, respectively. Heterogeneity was assessed using the Cochrane Q test and I2 statistic. RESULTS: Of 301 abstracts screened, 26 primary studies and 2 other meta-analyses were identified, of which 12 studies were included in the meta-analyses and 3 studies were included in the narrative review. The FDC treatment is associated with a significant improvement in adherence and persistence in comparison with FEC treatment, e.g., the average medicine possession ratio increased with FDC by 13.1% (p < 0.001). For endpoints correlated with higher adherence (e.g., a reduction in blood pressure), a nonsignificant benefit was observed for FDCs. Moreover, it was demonstrated that higher adherence can lead to a lower risk of cardiovascular events. CONCLUSIONS: In comparison with FECs, the FDC treatment is associated with a significant improvement in the cooperation between a doctor and a patient and with increased patients' adherence to the treatment schedule.

Impact of Biologic Treatment of Crohn's Disease on the Rate of Surgeries and Other Healthcare Resources: An Analysis of a Nationwide Database From Poland.

Background: There is conflicting evidence on the impact of biologic treatment on the rate of complications and surgeries in Crohn's disease (CD). We aimed to assess real-world consequences of biologic treatment of CD. Methods: All adult patients with CD treated with infliximab and adalimumab in the years 2012-2014 were identified from the database of the National Health Fund in Poland. Mixed models were used to assess the impact of biologics on medical resource utilization by comparing the periods before and after the first use of biologics (pre-index vs. post-index). The additional analyses including quintile of total exposure to biologic treatment were performed. Results: Data on 1393 patients (age, 31.9 years; males, 52.6%) were analyzed over a median of 1064 days (range: 71, 1148). During the post-index period, patients received from one to four treatments with biologic agents (maximum allowed period of 12 months per treatment). We observed a reduction in the rates of surgeries (by 27%, p = 0.001), hospitalizations for CD excluding surgical procedures (by 45%, p < 0.001), as well as consumption of antibiotics (by 31%, p < 0.001) and steroids (by 35%, p < 0.001) in the post-index compared with the pre-index period. The reduction in the rate of surgeries, hospitalizations for CD, and steroid intake increased with the increase of exposure to biologic agents. Conclusion: Biologic treatment changed the management patterns by lowering the rate of surgeries and other healthcare resources related to complications or worsening of CD. The reduction in the resource utilization was dependent on the level of exposure to treatment, suggesting that limitation of the treatment period itself may be inadequate.

Cost-Effectiveness Analysis of Crohn's Disease Treatment with Vedolizumab and Ustekinumab After Failure of Tumor Necrosis Factor-α Antagonist.

OBJECTIVE: The aim was to evaluate the cost-effectiveness of Crohn's disease (CD) treatment with vedolizumab and ustekinumab after failure of therapy with tumor necrosis factor-α antagonists (anti-TNFs). METHODS: The Markov model incorporated the lifetime horizon, synthesis-based estimates of biologics' efficacy in relation to anti-TNF exposure, and administration of biologics reflecting clinical practice (e.g., sequence of biologics, retreatment, 12-month treatment). The utilities, non-medical costs and indirect costs were derived from a study of 200 adult patients with CD, while the healthcare costs were from a study of 1393 adults with CD who used biologics in Poland. The quality-adjusted life years (QALYs) and costs (the societal perspective) were discounted with the annual rates of 3.5 and 5%, respectively. RESULTS: The addition of vedolizumab (ustekinumab) to the sequence of available anti-TNFs (after first-line infliximab or after second-line adalimumab) led to a gain of 0.364 (0.349) QALYs at an additional cost of €5600.24 (€6593.82). The incremental cost-effectiveness ratios (ICERs) were €15,369 [95% confidence interval (CI) 7496-61,354] and €18,878 (95% CI 9213-85,045) per QALY gained with vedolizumab and ustekinumab, respectively. Sensitivity analyses revealed a high impact on the ICERs of the relapse rate after discontinuation of biologic treatment. The highest value of vedolizumab/ustekinumab was estimated after the failure of therapies with both anti-TNFs. CONCLUSIONS: CD treatment with ustekinumab or vedolizumab after failure of anti-TNF therapy appears to be cost-effective at a threshold of €31,500. The replacement of the second-line anti-TNF with ustekinumab/vedolizumab and the course of the disease after discontinuation of biologics are influential drivers of the cost-effectiveness.

Prevalence and drug treatment practices of inflammatory bowel diseases in Poland in the years 2012-2014: an analysis of nationwide databases.

BACKGROUND: Inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn's disease (CD) are chronic autoimmune disorders that constitute a major societal and economic burden for individual patients, their families and the society. The aim of this study was to assess the current prevalence and treatment patterns of IBD in Poland. PATIENTS AND METHODS: We carried out a retrospective analysis of the nationwide databases of the National Health Fund for the years from 2012 to 2014 to obtain data on the prevalence and treatment patterns of IBD. Patients with IBD were identified according to the ICD-10 codes indicated in medical records and the type of medical resource utilized during the study. Pharmacotherapy for IBD by age group, sex and IBD types was presented. RESULTS: The prevalence of IBDs was 157/100 000 individuals, including 35 patients with CD per 100 000 individuals. The use of drugs differed by age and diagnosis (P<0.001). Biologics, steroids and immunosuppressants were used more often by patients with CD than those with UC (13.2 vs. 0.3%, 54.5 vs. 37.5%, and 44.8 vs. 15.1%, respectively). Aminosalicylates were used more often by patients with UC than those with CD. Biologics were used most often by the youngest patients (≤18 years) and seldom by patients aged 65 years or older (7.7 and 0.1%, respectively). CONCLUSION: Our study showed a moderate prevalence of IBD in Poland. Treatment patterns depended on the patient's age and IBD type. The use of biologics was higher among young patients with CD than among older patients with other IBDs. Although not recommended, aminosalicylates were still commonly used in patients with CD, even during biologic and/or immunosuppressive treatment.

Quality of life related to oral, subcutaneous, and intravenous biologic treatment of inflammatory bowel disease: a time trade-off study.

OBJECTIVES: Novel oral treatments (including biologics) of inflammatory bowel disease (IBD) are emerging. Apart from improvement of health, treatment convenience may be of value to patients. This 'process utility' can be estimated under the quality-of-life framework. We investigated the process utility associated with subcutaneous and intravenous biologic treatments compared with a hypothetical oral biologic treatment of IBD. MATERIALS AND METHODS: A time trade-off study to estimate utilities for health states among adult patients with IBD was carried out. Respondents rated the anchor state (no description of the route of administration; the reference) and three states described: the once-daily oral, 2-weekly subcutaneous, and 8-weekly intravenous administration of biologic treatment for advanced IBD. RESULTS: Data from 127 respondents (age, 34.4 years; women, 52.9%) were collected. The oral state was valuated higher than the anchor state more frequently than subcutaneous and intravenous states (P=0.001). The process utility of the oral state adjusted for confounders was estimated at 0.147 (95% confidence interval: 0.087-0.208) and 0.164 (95% confidence interval: 0.096-0.233) in comparison with subcutaneous and intravenous states, respectively. The results were consistent across the respondents irrespective of their characteristics and unaffected by the change in the assumptions of data analysis. CONCLUSION: Oral administration is preferred over the available routes of administration of biologics by patients with IBD. The utility gains from oral treatment were significant, indicating higher value of that treatment within a cost-utilitarian approach. The additional process-related benefit can justify higher expenditures for the research of oral biologics.

Health-Related Quality of Life Impairment and Indirect Cost of Crohn's Disease: A Self-Report Study in Poland.

BACKGROUND AND AIMS: Evidence on indirect cost of Crohn's disease (CD) is available but typically provides information on the loss of productivity at paid work of patients. In the present study, the quality of life and indirect costs of CD patients were assessed (overall and by disease severity). METHODS: A self-report questionnaire-based study among adult Polish patients with CD was performed. We collected data on patients' characteristics, quality of life, loss of productivity, consumption of medical resources, and out-of-pocket expenses. The disease severity was determined using the patient's version of the Harvey-Bradshaw index. Productivity costs were assessed from the social perspective, using a human capital approach. The cost of absenteeism, presenteeism and permanent work disability was valuated using the gross domestic product per worker. The patients' productivity loss at unpaid work was measured by time inputs of others to assist patients. The productivity loss among informal caregivers and patients' productivity loss at unpaid work were valuated with the average wage in Poland. The results were adjusted for confounders. RESULTS: The responses from 200 patients (47% in remission) were analysed. The mean utility index was 0.839 (SD 0.171). The total indirect cost was estimated at €462.47 per patient per month (24.0%, absenteeism; 35.0%, work disability; 30.4%, presenteeism; 0.4%, productivity loss at unpaid work; and 10.4%, informal care). A significant correlation of the quality of life and productivity losses with disease severity was observed. Compared with active disease, the remission subgroup had a higher utility index by 16% (p<0.001) and lower indirect costs by 71% (p = 0.003) for absenteeism, 41% (p = 0.030) for presenteeism, 76% (p<0.001) for productivity loss at unpaid work, and 75% (p<0.001) for informal care. CONCLUSIONS: Our study revealed the social burden of CD and high dependency of indirect costs and quality of life on the severity of CD in Poland.

Economic evaluation of single-pill combination of indapamide and amlodipine in the treatment of arterial hypertension in the Polish setting.

BACKGROUND: Arterial hypertension is a common disorder that affects around 9 million adults in Poland. Single-pill combinations (SPCs) for the treatment of arterial hypertension have significant advantages over the free combinations, resulting in lower risk of cardiovascular events and lower consumption of medical resources. The current ESC/ESH 2013 guidelines for the first time recommend treatment with a combination of thiazide-like diuretic with calcium channel blocker. Currently, no such combination is reimbursed from public funds in Poland. AIM: To assess the economic value of treatment with SPC of indapamide and amlodipine (Tertens-AM®) for hypertensive patients compared with free combination therapy (FC), in the Polish setting. METHODS: As there are currently no published data directly estimating the additional effect of using indapamide + amlo-dipine SPC vs. FC, two extreme approaches are presented: with difference in effectiveness due to improved adherence to the treatment estimated from published studies on other molecules used in hypertension such as SPCs and FCs - the base-case approach (1); and assuming no difference of effectiveness or adherence between SPC and FC of indapamide and amlodipine - the conservative approach (2). Modelling was carried out based on the Markov process in lifetime horizon. In the base-case approach, with the difference in effectiveness between SPC and FC, it was assumed that the differences in compliance translate into the differences in systolic blood pressure. Patients' characteristics were correlated with the risk of events associated with cardiovascular disease, based on the prediction algorithms from the Framingham Heart Study. Costs were considered from a National Health Fund (NHF) perspective and NHF and patient's perspective, and therefore direct medical costs were only included. RESULTS: The treatment with SPC of indapamide and amlodipine in place of FC resulted in 7.6 additional days of life in full health and longer overall patient survival by 2.9 days. The replacement of FC with SPC would result in national savings from both NHF perspective and NHF and patient's perspective, irrespective of the assumption of the difference in adherence between SPC and FC. The savings would amount to 1.602-3.954 million PLN and 16.498-19.186 million PLN from NHF perspective and NHF and patient's perspective, respectively. CONCLUSIONS: The treatment with SPC of indapamide and amlodipine for hypertensive patients was found to be dominant over FC or at least less expensive than treatment with FC when the difference in effectiveness was neglected. The replacement of FC with SPC would result in savings from both NHF perspective and NHF and patient's perspective.

Economic evaluation of sipuleucel-T immunotherapy in castration-resistant prostate cancer.

The objective is to examine the cost-utility of sipuleucel-T immunotherapy in asymptomatic or minimally symptomatic castration-resistant prostate cancer patients. The addition of sipuleucel-T immunotherapy to standard treatment led to a gain of 0.37 quality-adjusted life-year (QALY) at an additional cost of US$104,536. The incremental cost-utility ratio was US$283,000 per QALY saved. Threshold sensitivity analyses indicated that a price reduction of at least 53%, or application in a group of patients resulting in the relative reduction in the mortality rate of at least 39%, ought to augment the economic value of this regimen. Sipuleucel-T immunotherapy treatment at the current price with 96.5% certainty is not cost-effective. The specific group of patients who will benefit more from the treatment should be revealed and treated, or the cost of the vaccine should be lowered significantly to increase its economic value. Accounting for crossover treatment in control patients improves sipuleucel-T's value (US$132,000 per QALY saved) although further investigation is necessary.

Cost-utility analysis of Ruconest(®) (conestat alfa) compared to Berinert(®) P (human C1 esterase inhibitor) in the treatment of acute, life-threatening angioedema attacks in patients with hereditary angioedema.

INTRODUCTION: Administration of human C1 esterase inhibitor (Berinert(®) P) from target import is the most widespread treatment strategy for patients with hereditary angioedema (HAE). However, a therapeutic health program including Ruconest(®) (conestat alfa) could shorten a patient's expectancy for a life-saving treatment. AIM: To evaluate the cost-utility of Ruconest(®) (conestat alfa) financed from public funds within the newly introduced therapeutic health program compared with Berinert(®) P (human C1 esterase inhibitor) in the treatment of acute angioedema attacks in adults with HAE. MATERIAL AND METHODS: The cost-utility analysis from the Polish healthcare payer's perspective was performed for 1 year (2012). The costs and health outcomes were simulated for three pairs of eligible HAE patient groups (active treatment and corresponding placebo). The incremental costs of each intervention compared with placebo were listed together (direct or indirect comparisons between options were impossible due to limited clinical data available). RESULTS: The incremental cost-utility ratios (ICURs) for the evaluated interventions compared with placebo were as follows: EUR 15,226 per QALY (Ruconest(®)) and EUR 27,786 per QALY (Berinert(®) P). The probability of cost-utility (ICUR < EUR 24,279 per QALY) assessed for Ruconest(®) administered in the case of acute angioedema attack was 61% and 41% for Berinert(®) P. CONCLUSIONS: The administration of Ruconest(®) in acute life-threatening angioedema attacks is economically justified from the Polish healthcare payer's perspective, results in lower costs and is characterized by higher cost-utility probability compared with Berinert(®) P.

[The evaluation of cost-effectiveness and cost-utility of valganciclovir for the prophylaxis of cytomegalovirus disease to 200 days after kidney transplantation]. / Ocena kosztowej efektywnosci i kosztowej uzytecznosci stosowania walgancyklowiru w profilaktyce wystapienia choroby cytomegalowirusowej do 200. dnia od przeszczepu nerki.

UNLABELLED: Standard procedure for cytomegalovirus disease (CMV) prophylaxis in kidney transplant patients was the administration of valganciclovir for up to 110 days after organ transplant. This prophylaxis has been extended up to 200 days in Poland since 2011. The decision was based on the results of clinical trials which showed significant clinical benefit in case of prolonged administration of the drug. The aim of the analysis was to provide the economic evaluation of extending the CMV prophylaxis with co-financed from public funds Valcyte (valganciclovirum; 60 tab. a 450 mg; Roche Polska Sp. z o.o.) from 110 to 200 days, in the high risk patients group after kidney transplant (seronegative recipient and infected donor, D+/R-). The analysis was performed from the Polish healthcare payer's perspective. MATERIAL AND METHODS: All methods used in the following study were consistent with the Requirements of the Polish HTA Agency (AHTAPOL). The cost-effectiveness and the cost-utility analysis were performed on the basis of a randomised study which was identified as a result of the systematic search of the medical databases, comparing 200 days valgancyclovir administration with 100 days drug use as a prophylaxis of CMV disease in the patients group mentioned above. The Markov model was developed, simulating the disease evolution over time considering a high risk patient after kidney transplant treated with valgancicloviras the CMV disease prophylaxis. The disease period was divided into health states that are the most probable for this condition and the transitions probabilities between them were identified and assigned. Based on the clinical trial results, registry database of health conditions usability and experts' opinion, all health states (i.e. death, kidney transplant, CMV disease) were attributed with utilities and costs. The direct costs, important from the Polish healthcare payer's perspective, were included in the analysis. Extension of the proposed model in the series of one month time cycles made it possible to assess long-term (assumed time horizon was median patient's life expectancy--23,5 years) costs and clinical effects of the compared technologies. RESULTS: The Incremental Cost-Effectiveness Ratio (ICER) was 39 669 008 PLN and The Incremental Cost-Utility Ratio (ICUR) was 48 008 PLN in the specified time horizon. The result is well below the accepted threshold of profitability in Poland (assuming tripled GDP per capita cost-utility threshold, i.e. 99 543 PLN), which means that the therapy is cost-effective. CONCLUSIONS: The results of the analysis confirmed that the 200 days use of valganciclovirin the prevention of CMV disease compared to standard 110 days therapy is economically justified from the Polish healthcare payer's perspective.

[Administration of conestat alfa, human C1 esterase inhibitor and icatibant in the treatment of acute angioedema attacks in adults with hereditary angioedema due to C1 esterase inhibitor deficiency. Treatment comparison based on systematic review results]. / Konestat alfa, ludzki inhibitor C1 esterazy oraz ikatybant w leczeniu ostrych ataków obrzeku u osób doroslych z dziedzicznym obrzekiem naczynioruchowym spowodowanym niedoborem inhibitora C1 esterazy. Porównanie opcji terapeutycznych na podstawie przegladu systematycznego.

INTRODUCTION: Hereditary angioedema (HAE) is a genetic disease caused by C1-esterase inhibitor deficiency, characterized by recurrent attacks of intense, massive, localized subcutaneous oedema that can involve all parts of the body. The aim of this study is a comparison of the clinical effectiveness of conestat alfa, human C1 esterase inhibitor (C1INH), and icatibant in the treatment of acute angioedema attacks in adults with HAE. MATERIALS AND METHODS: A systematic review of literature published up to May 2012 was performed to assess the efficacy and safety of conestat alfa, C1INH, and icatibant in the treatment of acute angioedema attacks in adults with HAE. Databases were searched at MEDLINE (PubMed), EMBASE, and Cochrane. The general search structure was designed as a combination of keywords or synonyms: (hereditary angioedema) AND (conestat alfa OR human C1 esterase inhibitor concentrate OR synonyms OR icatibant). Only randomized clinical studies were selected. RESULTS: Systematic review yielded no clinical trials directly comparing the therapeutic options mentioned. Two randomized clinical trials were found which compared each of the following: conestat alfa, C1INH, and icatibant with placebo. Based on the gathered evidence it was demonstrated that taking any of the medicinal substances mentioned in the treatment of acute angioedema attack results in shorter time to beginning of relief of symptoms, time to minimal symptoms, the probability of the treatment response after 4 hours is increased, and the safety profile is comparable to placebo. CONCLUSIONS: Due to significant heterogeneity of identified trials, the scientific evidence available was insufficient to point out the most effective therapeutic option in the treatment of acute oedemas in HAE.

Sipuleucel-T immunotherapy for castration-resistant prostate cancer. A systematic review and meta-analysis.

INTRODUCTION: Sipuleucel-T is a novel active cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC). It is assumed to be associated with less adverse events than conventional docetaxel-based chemotherapy. MATERIAL AND METHODS: A systematic review of literature published between January, 1 1966 and February, 6 2012 was performed to assess the efficacy and safety of sipuleucel-T in patients with mCRPC. Databases were searched: Medline, EMBASE, Cochrane, CancerLit as well as ASCO and ESCO websites. RESULTS: Three randomized clinical trials with a total of 737 participants fulfilled established criteria. The overall survival of patients who received sipuleucel-T in comparison to the control group was significantly longer with a hazard ratio (HR) of 0.73 (95% CI: 0.61-0.88; p = 0.001). Time to disease progression was not prolonged using sipuleucel-T compared to placebo, HR = 0.89 (95% CI: 0.75-1.05; p = 0.18). Relative benefit (RB) of serum PSA level reduction of at least 50% for sipuleucel-T compared to placebo did not meet statistical significance, RB = 1.97 (95% CI: 0.48-8.14; p = 0.38). The safety population consisted of 729 patients with mCRPC. Compared to the control group, the pooled relative risks (RR) of all adverse events - RR = 1.03 (95% CI: 1.00-1.05; p = 0.06), grade 3 to 5 adverse events - RR = 0.98 (95% CI: 0.79-1.22; p = 0.86) and cerebrovascular events - RR = 1.93 (95% CI: 0.73-5.09; p = 0.18) were not significantly higher for men treated with sipuleucel-T. CONCLUSIONS: The use of sipuleucel-T prolonged the overall survival among men with mCRPC. No effect on time to disease progression was observed and the safety profile was acceptable.