Recommendations from the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL)

International audienceAbstractRare diseases are an important public health issue with high unmet need. The introduction of the EU Regulation on orphan medicinal products (OMP) has been successful in stimulating investment in the research and development of OMPs. Despite this advancement, patients do not have universal access to these new medicines. There are many factors that affect OMP uptake, but one of the most important is the difficulty of making pricing and reimbursement (P&R) decisions in rare diseases. Until now, there has been little consensus on the most appropriate assessment criteria, perspective or appraisal process. This paper proposes nine principles to help improve the consistency of OMP P&R assessment in Europe and ensure that value assessment, pricing and funding processes reflect the specificities of rare diseases and contribute to both the sustainability of healthcare systems and the sustainability of innovation in this field. These recommendations are the output of the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL), a collaboration between rare disease experts, patient representatives, academics, health technology assessment (HTA) practitioners, politicians and industry representatives. ORPH-VAL reached its recommendations through careful consideration of existing OMP P&R literature and through a wide consultation with expert stakeholders, including payers, regulators and patients. The principles cover four areas: OMP decision criteria, OMP decision process, OMP sustainable funding systems and European co-ordination. This paper also presents a guide to the core elements of value relevant to OMPs that should be consistently considered in all OMP appraisals. The principles outlined in this paper may be helpful in drawing together an emerging consensus on this topic and identifying areas where consistency in payer approach could be achievable and beneficial. All stakeholders have an obligation to work together to ensure that the promise of OMP’s is realised

Cytochrome P-450-based resistance mechanism and pyrethroid resistance in the field Anopheles albimanus resistance management trial

The relative rates of cytochrome P-450 selection in southern Mexican Anopheles albimanus populations were investigated during a 3 years indoor residual house spraying intervention with a pyrethroid (PYR) or DDT, a mosaic of organophosphate (OP)-PYR, and the annual rotation of OP-PYR-carbamate (CARB). This insecticide resistance mechanism, initially evenly spread in the mosquito population, correlated with PYR resistance during the second treated year, when cytochrome P-450 contents increased in most villages of the PYR, rotation and mosaic schemes. However, by the third year, mean cytochrome P-450 contents declined to susceptible levels in mosquitoes of the rotation and one mosaic group but not in the PYR-treated villages. In DDT-treated villages, a continuous decrement of cytochrome P-450 levels occurred since the first treatment year, and susceptible levels were observed at the end of the intervention. Most correlations of cytochrome P-450 levels and PYR resistance were lost during the third year, indicating that another mechanism evolved in resistant mosquito populations. (C) 2007 Elsevier Inc. All rights reserved

Changes in glutathione S-transferase activity in DDT resistant natural Mexican populations of Anopheles albimanus under different insecticide resistance management strategies

Biochemical assays on Anopheles albimanus collected for 3 years in southern Mexico villages after house spraying of a single insecticide [DDT or a pyrethroid (PYR)], a two insecticide mosaic [organophosphate (OP)/PYR] or a three insecticide annual rotation (OP-PYR-carbamate), defined he relative rates of selection of glutathione S-transferase-based resistance. After 3 years of rotation, mosaic and single PYR strategies, there was a decrease in the glutathione S-transferase (GST) activity, returning to susceptible levels, with few variations. In the rotation strategy, GST activity increased significantly in one group of villages, when OP treatment was replaced by the PYR in the 2nd treatment year. While, GST activity increased only in one village out of six continuously PYR-treated in the 1st year. In the DDT-treated villages, one group had increased activity in the 1 st year, but this declined in years 2 and 3; GST activity of the other DDT-treated group were unchanged during the trial. (c) 2006 Elsevier Inc. All rights reserved

Towards a Genetic Map for Anopheles albimanus: Identification of Microsatellite Markers and a Preliminary Linkage Map for Chromosome 2

Fifty microsatellite loci were identified in the malaria vector Anopheles albimanus. Markers segregating in F2 progeny of crosses between laboratory stains of An. albinanus were used to construct a preliminary genetic map. More than 300 progeny were genotyped, but the resolution of the map was limited by the lack of polymorphisms in the microsatelite alleles. A robust linkage map for chromosome 2 was established and additional markers were assigned to the third and X chromosomes by linkage to morphological markers of known physical location. Addtional non-informative microsatellite sequencies are provided including some showing similarity to those of An. gambiae. This study significantly increases the number of genetic markers available for An. albinmanus and provides useful tools for population genetics and genetic mapping studies in this important malaria vector

The use of transcriptional profiles to predict adult mosquito age under field conditions

Age is a critical determinant of an adult female mosquito's ability to transmit a range of human pathogens. Despite its central importance, relatively few methods exist with which to accurately determine chronological age of field-caught mosquitoes. This fact is a major constraint on our ability to fully understand the relative importance of vector longevity to disease transmission in different ecological contexts. It also limits our ability to evaluate novel disease control strategies that specifically target mosquito longevity. We report the development of a transcriptional profiling approach to determine age of adult female Aedes aegypti under field conditions. We demonstrate that this approach surpasses current cuticular hydrocarbon methods for both accuracy of predicted age as well as the upper limits at which age can be reliably predicted. The method is based on genes that display age-dependent expression in a range of dipteran insects and, as such, is likely to be broadly applicable to other disease vectors

Predicting the age of mosquitoes using transcriptional profiles

The use of transcriptional profiles for predicting mosquito age is a novel solution for the longstanding problem of determining the age of field-caught mosquitoes. Female mosquito age is of central importance to the transmission of a range of human pathogens. The transcriptional age-grading protocol we present here was developed in Aedes aegypti, principally as a research tool. Age predictions are made on the basis of transcriptional data collected from mosquitoes of known age. The abundance of eight candidate gene transcripts is quantified relative to a reference gene using quantitative reverse transcriptase-PCR (RT-PCR). Normalized gene expression (GE) measures are analyzed using canonical redundancy analysis to obtain a multivariate predictor of mosquito age. The relationship between the first redundancy variate and known age is used as the calibration model. Normalized GE measures are quantified for wild-caught mosquitoes, and ages are then predicted using this calibration model. Rearing of mosquitoes to specific ages for calibration data can take up to 40 d. Molecular analysis of transcript abundance, and subsequent age predictions, should take similar to 3-5 d for 100 individuals

Nigeria Anopheles vector database: an overview of 100 years' research.

Anopheles mosquitoes are important vectors of malaria and lymphatic filariasis (LF), which are major public health diseases in Nigeria. Malaria is caused by infection with a protozoan parasite of the genus Plasmodium and LF by the parasitic worm Wuchereria bancrofti. Updating our knowledge of the Anopheles species is vital in planning and implementing evidence based vector control programs. To present a comprehensive report on the spatial distribution and composition of these vectors, all published data available were collated into a database. Details recorded for each source were the locality, latitude/longitude, time/period of study, species, abundance, sampling/collection methods, morphological and molecular species identification methods, insecticide resistance status, including evidence of the kdr allele, and P. falciparum sporozoite rate and W. bancrofti microfilaria prevalence. This collation resulted in a total of 110 publications, encompassing 484,747 Anopheles mosquitoes in 632 spatially unique descriptions at 142 georeferenced locations being identified across Nigeria from 1900 to 2010. Overall, the highest number of vector species reported included An. gambiae complex (65.2%), An. funestus complex (17.3%), An. gambiae s.s. (6.5%). An. arabiensis (5.0%) and An. funestus s.s. (2.5%), with the molecular forms An. gambiae M and S identified at 120 locations. A variety of sampling/collection and species identification methods were used with an increase in molecular techniques in recent decades. Insecticide resistance to pyrethroids and organochlorines was found in the main Anopheles species across 45 locations. Presence of P. falciparum and W. bancrofti varied between species with the highest sporozoite rates found in An. gambiae s.s, An. funestus s.s. and An. moucheti, and the highest microfilaria prevalence in An. gambiae s.l., An. arabiensis, and An. gambiae s.s. This comprehensive geo-referenced database provides an essential baseline on Anopheles vectors and will be an important resource for malaria and LF vector control programmes in Nigeria