A multi-stakeholder multicriteria decision analysis for the reimbursement of orphan drugs (FinMHU-MCDA study)

Background: Patient access to orphan medicinal products (OMPs) is limited and varies between countries, reimbursement decisions on OMPs are complex, and there is a need for more transparent processes to know which criteria should be considered to inform these decisions. This study aimed to determine the most relevant criteria for the reimbursement of OMPs in Spain, from a multi-stakeholder perspective, and using multicriteria decision analysis (MCDA). Methods: An MCDA was developed in 3 phases and included 28 stakeholders closely related to the field of rare diseases (6 physicians, 5 hospital pharmacists, 7 health economists, 4 patient representatives and 6 members from national and regional health authorities). Initially [phase A], a bibliographic review was conducted to identify the potential reimbursement criteria. Then, a reduced advisory board (8 members) proposed, selected, and defined the final list of criteria that could be relevant for reimbursement. A discrete choice experiment (DCE) [phase B] was developed to determine the relevance and relative importance weight of such criteria according to the stakeholders’ preferences by choosing between pairs of hypothetical financing scenarios. A multinomial logit model was fitted to analyze the DCE responses. Finally [phase C], the advisory board review the results using a deliberative process. Results: Thirteen criteria were selected, related to 4 dimensions: patient population, disease, treatment, and economic evaluation. Nine criteria were deemed relevant for decision-making and associated with a higher relative importance: Health-related quality of life (HRQL) (23.53%), treatment efficacy (14.64%), availability of treatment alternatives (13.51%), disease severity (12.62%), avoided costs (11.21%), age of target population (7.75%), safety (seriousness of adverse events) (4.72%), quality of evidence (3.82%) and size of target population (3.12%). The remaining criteria had a < 3% relative importance: economic burden of disease (2.50%), cost of treatment (1.73%), cost-effectiveness (0.83%) and safety (frequency of adverse events) (0.03%). Conclusion: The reimbursement of OMPs in Spain should be determined by its effect on patient’s HRQL, the extent of its therapeutic benefit from efficacy and the availability of other therapeutic options. Furthermore, the severity of the rare disease should also influence the decision along with the potential of the treatment to avoid associated costs

Identificação de espécies de citros mediante polimorfismo enzimático Identification of citrus species by means of enzymatic polymorphism

Estudou-se, mediante polimorfismo enzimático em gel de poliacrilamida, a variabilidade genética das espécies de laranja-doce (Citrus sinensis); laranja-azeda (C. aurantium); tangerinas clementina (C. clementina), sunki (C. sunki), cleópatra (C. reshni) e poncã (C. rsticulata); lima-da-pérsia (C. limettioides); limão-galego (C. aurantifolia); limão-cravo (C. limonia) e trifoliata (Poncirus trifoliata). Extratos de folhas foram analisados para as isoenzimas de malato deidrogenase (MDH), enzima málica (ME), leucino amino peptidase (LAP), glutamato oxaloacetato transaminase (GOT), fosfoglucoisomerase (PGI), fosfoglucomutase (PGM) e isocitrato deidrogenase (IDH). Verificou-se grande variabilidade genética interespecífica, porém nenhuma entre os cultivares de laranja-doce. Foram encontradas algumas aloenzimas, além das referidas pela literatura em gel de amido, como aquelas de uma região próxima ao loco conhecido por Pgm-1, responsável por proteínas monoméricas. Este sistema, denominado PGM, revelou a maior diferenciação entre as espécies, tendo apresentado duas regiões distintas com 9 alelos. No sistema MDH, foram considerados dois locas codificando para proteínas diméricas com 7 alelos; no ME, um loco com 3 alelos; no LAP, possivelmente dois locos responsáveis por proteínas monoméricas com 4 alelos; no GOT, dois focos com 7 alelos; no PGI, um loco com 3 alelos e no IDH, um loco com 4 alelos.<br>The genetic diversity of citrus cultivars was studied by polyacrylamide gel electrophoresis on sweet orange (C. sinensis); tangerines (C. clementine, C. sunki, C. reshni, C. reticulata); Palestine lime (C. Iimettioides); West Indian lime (C. aurantifolia); Rangpur lime (C. limonia), Sour orange (C. aurantium) and Poncirus trifoliata. Citrus leaf extracts were analysed for isozymes of malato dehidrogenase (MDH), malic enzyme (ME), leucine aminopeptidase (LAP), glutamate oxaloacetate transaminase (GOT), phosphoglucose isomerase (PGI), phosphoglucose mutase (PGM) and isocitrate dehydrogenase (IDH). Interespecific differences were observed; but, none between intraespecific C. sinensis cultivars. Some allozymes were observed in addition to those reffered in the literature on starch gel; e.g., allozymes located next to the known Pgm-1 loci. The PGM system revealed the best differentiation between the cultivars. It showed monomeric proteins and 9 alleles. The MDH system had two loci with 7 alleles; the ME system one locus with 3 alleles; the LAP system one possible locus next to the known Lap-1 and 4 alleles; the GOT two loci for dimeric proteins with 7 alleles; the PGI one locus with 3 alleles; and, the IDH one locus with 4 alleles