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

Specific oxidative stress parameters differently correlate with nailfold capillaroscopy changes and organ involvement in systemic sclerosis.

Oxidative stress is suggested to be involved in the pathogenesis of systemic sclerosis (SSc). The aim of the present study was to clarify such a hypothesis by determination of four different plasmatic parameters of oxidative stress, and to define its role in the microvascular damage, assessed by nailfold capillaroscopy (NC). Plasma samples of 18 patients with SSc were analyzed. The biomarkers measured were: total antioxidant capacity, hydroperoxides (ROOHs), and sulfhydryl (SH) and carbonyl (CO) groups. Each patient had a detailed clinical assessment and underwent an NC. The results showed significantly increased ROOHs in SSc patients compared to control group (5.02 +/- 0.24 vs 3.28 +/- 0.19 micromol/l; p < 0.05). Plasmatic levels of SH groups were significantly lower in SSc (0.466 +/- 0.08 mmol/l) compared to control group (0.542 +/- 0.04 mmol/l; p < 0.002). Plasma levels of ROOHs correlated with the capillaroscopy semiquantitative rating scale score (p < 0.05) and with the rating system for avascular areas (p < 0.03). The levels of CO groups inversely correlated with modified Rodnan's skin score (p < 0.039) and were lower in patients with pulmonary fibrosis (p < 0.045), while the levels of SH groups were lower in those presenting gastrointestinal involvement (p < 0.029). The obtained data indicate augmented free radical-mediated injury in SSc and also show correlations among oxidative abnormalities, some clinical findings, and signs of a more severe microvascular involvement. These results give more evidence to the connection between oxidative impairment and SSc

Patterns of non-adherence to supplementation with calcium and vitamin D in persistent postmenopausal women are similar at start and one year later: a qualitative longitudinal study

Background: Osteoporosis is a chronic disease and adherence can fluctuate over time. Therefore, longer observation is necessary to investigate the stability of patients’ adherence. The study aim was to compare the overall adherence (OA) with supplementation with the fixed combination of calcium and vitamin D (Ca/D) in postmenopausal women at baseline and after 1 year, and to evaluate the fluctuation of the OA in individual months. Furthermore, we studied whether adherence is influenced by signing of informed consent and routine medical check-up.Methods: This was a longitudinal, observational study. The data were obtained from the Osteocenter of University Hospital in Hradec Kralove, Czech Republic. Adherence was measured using electronic bottles type Medication Events Monitoring System (MEMS). The study was carried out in two 3-month periods; the baseline in 2013 (signing of informed consent while medical check-up) and the follow-up (medical check-up) in 2014. The adherence and adherence-related outcomes were studied in patients who had initiated osteoporosis treatment and were persistent.Results: 21 (49%) out of 43 patients who avoided drug dispenser and were persistent both at baseline and at follow-up, completed the study and were included. Median age was 76. Evaluating the whole 3-month periods, the OA did not differ significantly at baseline and at follow-up, the OA was 71% and 68% respectively. However, the adherence in month 1 at baseline was significantly higher than the adherence in month 2 at baseline (p < 0.001) and also than the adherence in month 1 at follow-up (p = 0.010). Analysing the study period without month 1, a stable adherence was observed in 48% of patients. About 33% of doses were omitted at baseline and 34% at follow-up. As many as 71% of the patients took drug holidays at baseline, and 76% at follow-up. Conclusion: The OA was insufficient, around 70% both at baseline and at follow-up. One half of the patients showed a stable adherence. The patterns of non-adherence were very similar at follow-up. Signing of the informed consent seems to act as bias more than regular medical check-up

How General Practitioners and Their Patients Adhere to Osteoporosis Management: A Follow-Up Survey among Czech General Practitioners

Introduction: General practitioners (GPs) are key participants in osteoporosis (OP) management. The aim was to evaluate their adherence to lege artis management of the disease, potential barriers, and to discuss differences observed in comparison with the baseline survey carried out in 2007; the focus was on secondary prevention.Methods: On behalf of two professional associations, 2-round postal survey among randomly selected GPs (&gt;1/4 of all Czech GPs) was performed in 2014. The questionnaire covered areas concerning GP's role in the fight against OP, knowledge about OP, management of OP-related fractures, barriers to the management of OP, system- and patient-related in particular, and availability and use of information sources.Results: The overall questionnaire return rate was 37% (551 respondents); mean age of the respondents was 53 year (37% men). The GP's role in the treatment of OP was rated as essential in 28 and 37% of men and women, respectively (P = 0.012). The guideline for diagnosis and treatment of OP for GPs was considered accessible by 92% of respondents. As much as 60% of the respondents were adherent to the guideline, i.e., used it repeatedly. The knowledge of several risk factors was very good, however, recommended daily intake of calcium was stated correctly by only 41% of respondents, and daily intake of vitamin D by only 40%. Three quarters reported active steps after a fracture: referral to a specialist, life-style recommendations, prescription of calcium/vitamin D supplements. Half of the respondents focus on fall prevention. System-related barriers, such as lack of possibility to prescribe selected drugs (61%) and financial limits set by health insurance company (44%) were most frequently reported. Patient-related barriers were also common, patient's non-adherence (reported by 29%) and patient's reluctance to go to a specialist (18%).Conclusion: GPs adhered to OP management more than in 2007. Knowledge of risk factors and involvement in post-fracture care was relatively high. Compared to baseline survey, patient-related barriers, patient non-adherence in particular, were more common. Prescribing conditions are still an important issue. Among GPs, education should be focused on calcium and vitamin D intake, doses, sources, and supplements

Oxidative stress parameters in different systemic rheumatic diseases

The involvement of oxidative stress in the pathogenesis of rheumatic disorders, such as systemic sclerosis (SSc) and chronic polyarthritides, has been suggested yet not thoroughly verified experimentally. We analysed 4 plasmatic parameters of oxidative stress in patients with SSc (n = 17), psoriatic arthritis (PsA) (n = 10) and rheumatoid arthritis (RA) (n = 9) compared with healthy subjects (n = 22). The biomarkers were: total antioxidant capacity (TAC) measured by ferric reducing antioxidant power (FRAP) method, hydroperoxides determined by ferrous ion oxidation in presence of xylenol orange (FOX) method and sulfhydryl and carbonyl groups assessed by spectrophotometric assays. The results showed significantly increased hydroperoxides in SSc, PsA and RA (3.97 +/- 2.25, 4.87 +/- 2.18 and 5.13 +/- 2.36 mu mol L-1, respectively) compared with the control group (2.31 +/- 1.40 mu mol L-1; P < 0.05). Sulfhydryls were significantly lower in SSc (0.466 +/- 0.081 mmol L-1), PsA (0.477 +/- 0.059 mmol L-1) and RA (0.439 +/- 0.065 mmol L-1) compared with the control group (0.547 +/- 0.066 mmol L-1; P < 0.05). TAC in all three diseases showed no difference in comparison with controls. Carbonyls were significantly higher in RA than in the control group (32.1 +/- 42 vs 2.21 +/- 1.0 nmol (mg protein)(-1); P < 0.05). The obtained data indicate augmented free radical-mediated injury in these rheumatic diseases and suggest a role for the use of antioxidants in prevention and treatment of these pathologies

Patient Access, Unmet Medical Need, Expected Benefits, and Concerns Related to the Utilisation of Biosimilars in Eastern European Countries: A Survey of Experts

This policy research aims to map patient access barriers to biologic treatments, to explore how increased uptake of biosimilars may lower these hurdles and to identify factors limiting the increased utilisation of biosimilars. A policy survey was developed to review these questions in 10 Central and Eastern European (CEE) and Commonwealth of Independent States (CIS) countries. Two experts (one public and one private sector representative) from each country completed the survey. Questions were related to patient access, purchasing, clinical practice, and real-world data collection on both original biologics and biosimilars. Restrictions on the number of patients that can be treated and related waiting lists were reported as key patient access barriers. According to respondents, for both clinicians and payers the primary benefit of switching patients to biosimilars would be to treat more patients. However, concerns with therapeutic equivalence and fear of immunogenicity may reduce utilisation of biosimilars. Similar limitations in patient access to both original biologics and biosimilars raise concerns about the appropriateness and success of current biosimilar policies in CEE and CIS countries. The conceptual framework for additional real-world data collection exists in all countries which may provide a basis for future risk-management activities including vigorous pharmacovigilance data collection

Methotrexate released in vitro from bone cement inhibits human stem cell proliferation in S/G2 phase

Methotrexate (MTX) released from bone cement showed a useful local effect in animal models of bone tumours. However, local toxic reactions such as impaired wound healing were observed in areas surrounding the MTX-loaded implant. Therefore, we hypothesised that MTX released from bone cement would have harmful effects on human mesenchymal stem cells (MSC)—one of the basic components of bone marrow and tissue reparatory processes. Moreover, elution of MTX was calculated from implants prepared either with liquid or powdered MTX. During the 28-day incubation, the cement compounded with liquid MTX showed the highest elution rate of the drug. MTX released from pellets produced a significant decrease in proliferation of MSC as a consequence of a blockade of their cell cycle in the S/G2 phase. These findings indicate impairment of stem cell function in marginal areas surrounding the MTX-loaded cement and may help to explain problems with regeneration of tissues in these locations

Table1_Clinical aspects of reimbursement policies for orphan drugs in Central and Eastern European countries.DOCX

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 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.</p