Population norms for the EQ-5D-3L and EQ-5D-5L in Romania.

BACKGROUND: The majority of patient reported outcome measures (PROMs) don't have population norms in Romania. This is the case with the EQ-5D as well. Therefore, we aimed to estimate population norms for the Romanian versions of the EQ-5D-5L, EQ-5D-3L, their indexes, and the EQ-VAS. METHODS: A cross-sectional survey was conducted in all regions of Romania from November 2018 to November 2019. A three-stage probability sampling procedure stratified by region and settlement size was used to select a representative sample. Interviews were computer-assisted and conducted in respondents' homes by trained interviewers. Health status was assessed with the EQ-5D-5L, the EQ-5D-3L and the EQ VAS. Descriptive statistics were used to estimate population norms by age groups and sex for the EQ-5D-5L, the EQ-5D-3L, their indexes and the EQ VAS. Population norms were weighted using survey weights. Indexes for the EQ-5D questionnaires were estimated using the recently developed Romanian value sets. RESULTS: Data from 1,649 interviews was analysed in the present study. Survey weights were used so that sex and place of residence ratios for the weighted sample matched the Romanian general population distribution. Participants' mean age was 47.4 years (SE = 1.157) and 50.3% of them reported being in good health. The dimension for which people reported the highest number of problems for both questionnaires was the pain/discomfort dimension. Men aged 35 plus reported fewer problems with pain/discomfort than women for both the EQ-5D-5L and EQ-5D-3L. Health decreased with age as shown by the decrease from age group 18-24 to age group 75 plus in the indexes of both questionnaires: from 0.977 (SE = 0.005) to 0.765 (SE = 0.017) for EQ-5D-5L and from 0.981 (SE = 0.005) to 0.784 (SE = 0.019) for EQ-5D-3L. There was 29.9 points drop in the EQ VAS score between the youngest and oldest group. CONCLUSIONS: Population norms for the Romanian versions of the EQ-5D-5L, EQ-5D-3L, their indexes, and the EQ VAS are now available. These can now be used as reference values by healthcare professionals, researchers and decision-makers leading to a further development of health-related quality of life research in Romania.

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.

EQ-5D-5L: a value set for Romania.

OBJECTIVE: We aimed to develop an EQ-5D-5L value set for Romania. METHODS: In line with the EuroQoL standardized valuation protocol, computer-assisted interviews were conducted face-to-face in a representative sample in Romania (November 2018-November 2019). Valuation methods included composite time trade-off and discrete choice experiment tasks. Several models were tested, including models that accounted for data censoring, panel structure of the data, heteroscedasticity, conditional logit, and hybrid models. The final model was selected based on logical consistency, theoretical considerations, and use of all available data. We compared our value set with other value sets from Central and Eastern Europe region. RESULTS: Data from 1493 respondents was used to estimate the value set. A censored hybrid model corrected for heteroscedasticity was selected to represent the value set. The highest decrements in utility were observed for the pain/discomfort dimension (0.375), followed by the mobility dimension (0.293). Health utilities ranged from 1.000 to - 0.323 and 1.3% of the values were negative. The model was corrected with survey weights to better reflect the representativeness of the sample, but the first two coefficients of the self-care dimension stopped being logically consistent. Differences were found between the Romanian, Hungarian and Polish EQ-5D-5L value sets. Good agreement was noted with the Romanian EQ-5D-3L value set, with a swap between pain/discomfort and mobility in ranking of dimensions. CONCLUSION: A value set for EQ-5D-5L is now available for Romania. This will push one-step further the development of health technology assessment and encourage more health-related quality-of-life research to be conducted locally.

Estimating an EQ-5D-3L Value Set for Romania Using Time Trade-Off.

OBJECTIVE: To provide health-related quality of life (HRQoL) data to support health technology assessment (HTA) and reimbursement decisions in Romania, by developing a country-specific value set for the EQ-5D-3L questionnaire. METHODS: We used the cTTO method to elicit health state values using a computer-assisted personal interviewing approach. Interviews were standardized following the most recent version of the EQ-VT protocol developed by the EuroQoL Foundation. Thirty EQ-5D-3L health states were randomly assigned to respondents in blocks of three. Econometric modeling was used to estimate values for all 243 states described by the EQ-5D-3L. RESULTS: Data from 1556 non-institutionalized adults aged 18 years and older, selected from a national representative sample, were used to build the value set. All tested models were logically consistent; the final model chosen to generate the value set was an interval regression model. The predicted EQ-5D-3L values ranged from 0.969 to 0.399, and the relative importance of EQ-5D-3L dimensions was in the following order: mobility, pain/discomfort, self-care, anxiety/depression, and usual activities. CONCLUSIONS: These results can support reimbursement decisions and allow regional cross-country comparisons between health technologies. This study lays a stepping stone in the development of a health technology assessment process more driven by locally relevant data in Romania.

Health technology assessment and reimbursement policy for oncology orphan drugs in Central and Eastern Europe.

BACKGROUND: The reimbursement of orphan drugs (OD) is an increasingly important for country policymakers, and still insufficiently understood, especially in Central and Eastern Europe. The aim of this research was to provide a comprehensive description of country-specific health technology assessment (HTA) policies as well as evaluate the percentage of HTA recommendations and reimbursement decisions for oncology OD. In addition, the study was designed to elucidate the impact of reimbursement of these drugs on the public budget and the agreement between HTA recommendations and reimbursement decisions in the analysed countries. A questionnaire survey was used to collect data on the reimbursement status, HTA recommendation, marketing authorisation, and public expenses on reimbursement in 2014, 2015, and 2016 for all oncology drugs with an orphan designation by the European Medicine Agency in 2017 in Bulgaria, Croatia, Czechia, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, and Slovakia. The agreement between the HTA recommendation and reimbursement status was assessed using the kappa coefficient. The Pearson's correlation was used to analyse the relationship between gross domestic product (GDP) and GDP per capita and reimbursement expenses. RESULTS: A total of 36 drugs were analysed (25% conditionally approved; 5.56% approved under exceptional circumstances). The share of reimbursed drugs ranged from 11.11% in Latvia to 41.67% in Poland. The highest share of positive recommendations was observed for Bulgaria and Estonia (36.11%), and the lowest, for Latvia (11.11%). The agreement varied from 0.4 for Poland to 1 for Latvia, Hungary, and Slovakia. Expenses were correlated with GDP (0.95 [0.81-0.99]), and not with GDP per capita (0.54 [- 0.136 to 0.873]). Expenses per capita were not correlated with GDP per capita (0.52 [- 0.15 to 0.87]). CONCLUSIONS: In Hungary, Latvia, and Slovakia, a positive recommendation was associated with a reimbursement, and a negative one, with the lack of reimbursement. The reimbursement of oncology OD is associated with a growing burden for public budget, and the expenses are correlated with the total GDP. The highest share of drugs with any recommendation was observed in Poland, and the lowest, in Latvia and Romania. The share of reimbursed drugs was the lowest in Latvia and the highest in Poland.

Analysis of the Indirect Costs of Rheumatoid Arthritis in Romania.

Rheumatoid arthritis (RA) is associated with increased costs generated by resource utilization and loss of work productivity. We have studied 206 RA patients and analyzed indirect costs of RA in Romania (estimated using the human capital approach) in comparison with reported data for other countries. Data were collected using self-reported questionnaires. The average age at inclusion was 55 years, with mean disease duration of 9.4 years; 55 patients had permanent work disability due to RA; 6.35 days of sick leave per patient were reported for the entire year of follow-up; the cost of permanent work disability was 1256€ per patient. From a societal perspective, the average indirect costs for a patient with RA were 1506€, significantly lower than the ones reported by other countries, especially due to the low monetary value of paid work.

Measuring health-related quality of life in the general population and Roma communities in Romania: study protocol for two cross-sectional studies.

INTRODUCTION: The importance of health-related quality of life (HRQoL) is increasing and many healthcare authorities recommend the use of measures that account for both mortality and morbidity. This study will determine, for the first time in Romania, value sets for EuroQoL-five-dimensions-3-level (EQ-5D-3L) and EQ-5D-5L questionnaires and their population norms (study 1). It will also compare the HRQoL (measured with EQ-5D-5L) of Roma communities in Romania with that of the general population (study 2). METHODS AND ANALYSIS: Cross-sectional studies of face-to-face interviews conducted in representative samples of the Romanian general population and Romanian Roma communities. 1614 non-institutionalised adults older than 18 years will be interviewed using a computer-assisted interview for study 1. Participants will complete EQ-5D-3L and 5L, 13 composite time trade-off tasks (cTTO), 7 discrete choice experiment questions (DCE) and sociodemographic questions. For study 2, 606 non-institutionalised self-identified Roma people older than 18 years will be interviewed using a pencil-and-paper interview. Participants will complete EQ-5D-5L and the same sociodemographic questions as for study 1. The 3L value set will be estimated using econometric models and the cTTO data. cTTO and DCE data will be used for the 5L value set. Population norms will be reported by age and gender. The ORs for reporting different levels of problems and the most common health states in the population will be estimated. For study 2, t-tests and analysis of variance will be used to explore differences between groups in HRQoL and for each EQ-5D. ETHICS AND DISSEMINATION: Ethics approval was given by the National Bioethics Committee of Medicines and Medical Devices Romania and Newcastle University's Research Ethics Committee. Results will be published in peer-reviewed journals, presented at scientific conferences and on the project's website. The EQ-5D-5L anonymised datasets will be deposited in a centralised repository. Two public workshops with local authorities, physicians and patients' associations will be held.

Reimbursement Legislations and Decision Making for Orphan Drugs in Central and Eastern European Countries.

BACKGROUND: Reimbursement policies influence access of patients to orphan drugs in the European countries. OBJECTIVES: To provide a comprehensive description of orphan drug reimbursement policies and to assess reimbursement decision-making process in the EU-CEE countries as well as the impact of the type of approval and disease on reimbursement decisions. METHODS: For each drug, the information regarding conditional approval or approval under exceptional circumstances was obtained from the EMA website. The reimbursement status for analyzed drugs was collected in a questionnaire survey performed in a group of experts in reimbursement policy. The agreement between countries was assessed using the κ coefficient, nominal variables tests were compared using the χ2 test or the Fisher exact test. The impact of the EMA's conditional approval and approval under exceptional circumstances was assessed using logistic regression and presented as an odds ratio (OR). RESULTS: The analysis revealed that most orphan drugs were authorized for the treatment of oncological or metabolic diseases [36 drugs (38%) and 22 drugs (23%), respectively]. The shares of reimbursed orphan drugs varied significantly (p = 0.0031) from 6.3% in Latvia to 27.4% in Poland. No correlation (r = 0.02; p = 0.9583) with GDP per capita was observed. The highest agreement in reimbursement decisions was observed between Estonia and Lithuania, and the lowest - between Estonia and Latvia, with kappa of 0.69 and 0.11, respectively. Significant impact of the type of approval and reimbursement status was observed for Czechia, Lithuania and Slovakia where conditional approval and exceptional circumstances negatively influenced reimbursement decision. Type of disease has significant influence on reimbursement decision in 4 out of 10 analyzed countries with significant outweigh of positive decisions for oncological diseases. CONCLUSION: In considered countries specific regulations on reimbursement of orphan drugs are valid but in Lithuania and Romania no formal HTA process was employed; in case of some countries higher ICER values for orphans are used. The share of reimbursed orphan drugs varied significantly across the countries, but it was not associated with GDP per capita.

Perception on adverse drug reaction reporting by physicians working in southern romania.

AIM: The purpose of our study was to investigate and to assess the perceptions of Romanian doctors towards adverse drug reactions (ADRs) reporting. METHOD: A questionnaire with 20 items accompanied by a letter presenting the study was circulated using Internet and face to face interviews to 532 doctors in Bucharest and two neighboring regions from Romania (Muntenia and Oltenia). RESULTS: 204 (56.2%) of the total number of responders expressed their opinion that the daily number of ADRs observed to be under 5 309 (58%) of responders were never informed about ADRs reporting, 439 (82.52%) did not know that the Romanian College of Physicians is scoring this activity under the "Continuous medical education program". Factors that might encourage voluntary reporting of adverse reactions were identified to be: the easiness of reporting, their periodic information and the training about all adverse reactions reported by doctors and the measures taken. Factors discouraging voluntary reporting of an adverse drug reaction were: the lack of information on where, when and how to report ADRs, the uncertain causality. CONCLUSION: Currently, the pharmacovigilance activities including reporting of ADRs in Romania are more of an accidental nature, doctors are less or not at all informed about this activity. Doctors have a favorable attitude towards reporting ADRs - as the majority believes that the reporting should be either voluntary or mandatory as opposed to a small number that would expect to be paid for this activity.

Generic Substitution Issues: Brand-generic Substitution, Generic-generic Substitution, and Generic Substitution of Narrow Therapeutic Index (NTI)/Critical Dose Drugs.

Doctors accuse individual variability or lack of quality of generic drugs for adverse reactions or lack of efficacy. The variability of effect of generic substitution, although accepted by clinicians as possible, is little discussed or even understood by them. The situation is really serious in the case of generic substitution of drugs with narrow therapeutic index (NTI) or critical dose. In this paper we review the basic notions of variability and effectiveness of generic medication and change of attitude that would improve the use of these drugs.