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

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

Drug Policy in Estonia.

The aim of this article was to present a general overview of the health care system as well as pricing and reimbursement environment in Estonia. In Estonia the main stakeholders in the pharmaceutical sector are the Ministry of Social Affairs, the State Agency of Medicine, and the Estonian Health Insurance Fund. The national health insurance scheme is public, and approximately 95% of the population is covered by it. It is a social insurance, and universal and equal access to health care based on national health insurance is granted. The Estonian Health Insurance Fund is financed from social taxes and state budget and is responsible for the reimbursement of pharmaceuticals in the hospital setting. It acts as an advisory body to the Ministry of Social Affairs on the process of reimbursement regarding cost effectiveness. Pharmaceutical products' reimbursement dossiers submission and decisions are dealt with on the state level. Health technology assessment analyses are required by the authorities and the Baltic Guidelines for Economic Evaluations of Pharmaceuticals have to be followed. The reimbursement lists are positive lists only, and the criteria upon which reimbursement decisions are based are officially defined. Revisions of reimbursement are performed depending on the need and they are based on the prices of reference countries.

What does the Cantril Ladder measure in adolescence?

INTRODUCTION: The Cantril Scale (CS) is a simple visual scale which makes it possible to assess general life satisfaction. The result may depend on the health, living, and studying conditions, and quality of social relations. The objective of this study is to identify key factors influencing the CS score in Polish adolescents. MATERIAL AND METHODS: The survey comprised 1,423 parent-child pairs (54% girls; age range: 10-17; 67.3% urban inhabitants; 89.4% of parents were mothers). Linear and logistic models were estimated; the latter used alternative divisions into "satisfied" and "dissatisfied" with life. In addition to age and gender, child-reported KIDSCREEN-52 quality of life indexes were taken into account, along with some information provided by parents - child physical (CSHCN) and mental (SDQ) health, and family socio-economic conditions. RESULTS: According to the linear model, nine independent predictors, including six dimensions of KIDSCREEN-52, explain 47.2% of the variability of life satisfaction on the Cantril Scale. Self-perception was found to have a dominating influence (ΔR2 = 0.301, p < 0.001). Important CS predictors also included Psychological Well-being (ΔR2 = 0.088, p < 0.001) and Parent Relations (ΔR2 = 0.041, p < 0.001). The impact of socioeconomic factors was more visible in boys and in older adolescents. According to logistic models, the key factors enhancing the chance of higher life satisfaction are Moods and Emotions (cut-off point CS > 5) and School Environment (CS > 8 points). None of the models indicated a relationship between the CS and physical health. CONCLUSIONS: The Cantril Scale can be considered a useful measurement tool in a broad approach to psychosocial adolescent health.

Drug Policy in Croatia.

We presented a general overview of the health care system as well as the pricing and reimbursement environment in Croatia. In Croatia, most of the public funding for health care is collected from employers, through mandatory health care contributions for all the employed citizens. This contribution is a dedicated tax reserved for the health care system derived from employees' salaries. The rest of the public funds is mainly from taxes used by the Ministry of Finance to complement the overall health budget each year. The population is covered by a basic health insurance plan provided by statute and optional insurance, administered by the Croatian Health Insurance Fund. Reimbursement decisions are based on the Ordinance of Ministry of Health issued in 2013, which is an ordinance establishing the criteria for inclusion of medicinal products in the Croatian Health Insurance Fund basic and supplementary drug lists. A health technology assessment agency was established in 2007 as a legal, public, independent, nonprofit institution under the Act on Quality of Health Care. Budget impact analysis is obligatory, and cost-effectiveness analysis is beneficial. Two reimbursement lists exist: the basic (100% drug coverage) and the supplementary (co-payment from 10% to 90%) lists. The basic list covers both hospital and retail drugs. There is also a special drug list for expensive drugs (mainly hospital drugs). International reference pricing is also in place. List updates are done on an yearly basis. Real-world evidence can be required for health technology assessment as evidence for the budget impact models and cost-effective analysis; it is, however, not mandatory.

Drug Policy in Latvia.

We present a general overview of the health care system as well as the pricing and reimbursement environment in Latvia. Overall, the pharmaceutical sector in Latvia, including pricing and reimbursement, is strictly regulated. The main Latvian stakeholder in the pharmaceutical sector is the Ministry of Health. The State Agency of Medicines and the National Health Service (NHS) are also important institutions for regulation of pharmaceuticals, including pricing and reimbursement. The NHS is the most important institution for regulation of reimbursement of pharmaceuticals. It is responsible for health technology assessment and also for implementing decisions regarding the reimbursement of pharmaceuticals by including medicines in the positive reimbursement lists for outpatient care and defining positive lists of medicinal products for inpatient use. The reimbursement of expenditures for medicinal products and medicinal devices for outpatient care is a main part of drug funding in Latvia. Reference pricing is in place and prices are revised 4 times a year. The positive reimbursement list for outpatient care consists of three parts: list A, list B, and list C. All the medicines in the positive list are classified into one of three reimbursement categories (100%, 75%, or 50%) depending on the illnesses for which they have been approved. Pharmaceuticals used for inpatient care are included in the cost of inpatient services and are provided free of charge to patients. Inpatient drugs are purchased by health service providers.

The direct costs of drug-induced skin reactions.

[b] Abstract Objective.[/b] The aim of the study was an assessment of direct costs of patients hospitalised for for skin adverse drug reactions during 2002-2012 in the Department of Dermatology at the Military Institute of Medicine (Ministry of Defence) in Warsaw. The analysis was carried out from the perspectives of the public payer and service provider. [b]Materials and method. [/b]The retrospective study was carried out in a group of 164 adult patients due to skin adverse drug reactions. Analysis was based on data from patient medical records and medical orders which provided information on the used resources, including diagnostic tests, medical consultations, medicinal products, hospitalisation duration, together with cost estimation, regardless of the treatment being the cause of the skin reaction. [b]Results[/b]. According to the International Statistical Classification of Diseases and Related Health Problems(ICD) diagnosis and scores, assigned by the National Healthcare Fund, it has been estimated that patient hospitalisation at the Department of Dermatology for skin drug reaction incurred costs at the average amount of €717.00 per patient. The complex diagnostics and pharmacotherapy of the same group of patients generated costs for the hospital at the average amount of €680 per patient. [b]Conclusions[/b]. As a result of the analysis, the therapy for skin adverse drug effects generates significant costs, both for the payer and the service provider. Since the costs are comparable, it seems that the pricing of medical procedures by the public payer is adequate for the costs incurred by the medical service provider.

Treatment patterns of schizophrenia based on the data from seven Central and Eastern European Countries.

OBJECTIVE: The aim is to analyze how schizophrenia is pharmacologically treated in seven CEE countries: Croatia, Estonia, Hungary, Poland, Serbia, Slovakia and Slovenia. METHODS: Psychiatrists from selected centers in each of participating countries were asked to complete a pre-defined questionnaire on their current clinical practice. Information on protocols and resource utilization in schizophrenia treatment was included and derived from randomly selected patient medical records. Expert opinions on country-wide treatment patterns were additionally sought. This sub-analysis focuses on pharmacological treatment patterns in the last six months and over the course of the disease. RESULTS: 961 patients' data show that during last six months the most commonly prescribed medications were oral atypical antipsychotics: olanzapine (n=268), clozapine (n=234) and risperidone (n=160). The most frequently prescribed atypical antipsychotics over course of disease were: risperidone (54.5%), olanzapine (52.4%) and clozapine (35.1%), along with haloperidol (39.3%). Experts reported risperidone (four countries) and olanzapine (three countries) as first-line treatment, with the same two medications prescribed as second-line treatment. Clozapine was the most reported medication for refractory patients. Approximately 22% of patients received polypharmacy with antipsychotics in at least one period over the disease course. Mean time since diagnosis was 13.1 years and on average 4.8 treatment courses received during that period. Anxiolytics (70%), antidepressants (42%), mood-stabilizers (27%) were also prescribed, with diazepam (35.4%), sertraline (10.5%), valproic acid (17.5%) the most commonly reported, respectively, in each group. The most frequently reported treatment change was switch from one oral atypical antipsychotic to another (51%). CONCLUSION: Oral atypical antipsychotics, mostly older drugs (risperidone, olanzapine, clozapine), were most commonly prescribed for schizophrenia treatment in participating countries. Given that results are from the first large-scale analysis of RWD, we believe these findings can be a benchmark for future real-world studies, which could contribute to the optimization of treatment for this debilitating disease.

Schizophrenia causes significant burden to patients' and caregivers' lives.

BACKGROUND: Schizophrenia is a serious public health problem and is ranked among the most disabling diseases in the world. The sub-study presented here was part of a larger project to characterize the burden of schizophrenia on healthcare systems and on individuals living with the disease in Central and Eastern Europe (CEE). AIMS: This sub-study aimed to assess and analyze the impact of schizophrenia on many aspects of the lives of patients and caregivers. METHODS: Psychiatrists from selected centers in seven Central and Eastern European countries were asked to complete a questionnaire in order to collect information about the disease history, characteristics, treatment protocols and resources used for each randomly selected patient. All data were statistically analyzed and compared between countries. RESULTS: Data from 961 patients with schizophrenia (mean age 40.7 years, 45.1% female) were included in the analysis. The mean number of days spent in hospital per patient per year across all seven countries was 25.3 days. Hospitalization occurred on average once per year, with psychiatrist visits 9.4 times per year. Of the patients in the study, 61% were single, 12% divorced and 22% married or cohabiting. Almost 84% were living with relatives or a partner; only 17% lived alone and, on average, 25% of patients received support from social workers. Relatives provided care for approximately 60% of patients and 4% of them had to stop working in order to do so. Twenty-nine percent of the patients were unemployed, and 56% received a disability pension or were retired, with only 19% in full-time employment or education. CONCLUSION: Schizophrenia has a significant effect on the lives of patients and caregivers and impacts their social integration.

Epidemiology and Treatment Guidelines of Negative Symptoms in Schizo-phrenia in Central and Eastern Europe: A Literature Review.

AIM: To gather and review data describing the epidemiology of schizophrenia and clinical guidelines for schizophrenia therapy in seven Central and Eastern European countries, with a focus on negative symptoms. Methods : A literature search was conducted which included publications from 1995 to 2012 that were indexed in key databases. Results : Reports of mean annual incidence of schizophrenia varied greatly, from 0.04 to 0.58 per 1,000 population. Lifetime prevalence varied from 0.4% to 1.4%. One study reported that at least one negative symptom was present in 57.6% of patients with schizophrenia and in 50-90% of individuals experiencing their first episode of schizophrenia. Primary negative symptoms were observed in 10-30% of patients. Mortality in patients with schizophrenia was greater than in the general population, with a standardized mortality ratio of 2.58-4.30. Reasons for higher risk of mortality in the schizophrenia population included increased suicide risk, effect of schizophrenia on lifestyle and environment, and presence of comorbidities. Clinical guidelines overall supported the use of second-generation antipsychotics in managing negative symptoms of schizophrenia, although improved therapeutic approaches are needed. Conclusion : Schizophrenia is one of the most common mental illnesses and poses a considerable burden on patients and healthcare resources alike. Negative symptoms are present in many patients and there is an unmet need to improve treatment offerings for negative symptoms beyond the use of second-generation antipsychotics and overall patient outcomes.

[Clinical efficacy and safety of prolonged use of the valganciclovir for the treatment of cytomegalovirus disease in patients after kidney transplantation]. / Skutecznosc kliniczna oraz bezpieczenstwo przedluzonego stosowania walgancyklowiru w leczeniu choroby cytomegalowirusowej u chorych po przeszczepie nerki.

UNLABELLED: Cytomegalovirus infection is particularly dangerous for patients undergoing solid organs transplantation. Among these patients cytomegalovirus disease (CMV) may occur. CMV disease is associated with increased mortality, organ damage and reduced graft survival. THE AIM OF THE STUDY was to determine the clinical outcomes (clinical efficacy and safety profile) for the use of valganciclovir administered for 200 days compared to standard period of 100 days in the prevention of cytomegalovirus disease in seronegative patients after kidney transplantation from infected donor (high risk patients). MATERIAL AND METHODS: A systematic review of literature published during the period: 1st January 1966-31st October 2010, was performed in order to assess the efficacy and safety of valganciclovir in the treatment of cytomegalovirus disease. Databases MEDLINE (PubMed), EMBASE and Cochrane were searched. RESULTS: A systematic review yielded 1 randomized and 3 nonrandomized clinical trials. 200 days prophylaxis with valganciclovir significantly decreased a risk of: cytomegalovirus disease, CMV viral load, opportunistic infections; percentage of patients with high viral load was also significantly decreased compared to 100 days therapy. The safety profile of extended therapy was similar to that observed within 100 days prophylaxis. The higher risk of leucopenia in the 200 days than 100 days group was the only one adverse event that met statistical significance. The results of non-randomized trials were comparable to those mentioned above. CONCLUSION: Prolonged prophylaxis of cytomegalovirus till 200 days in high-risk patients (D+/B-) is safe and provides significant therapeutic benefits.

[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.