The Prevalence and Cost of Unapproved Uses of Top-Selling Orphan Drugs

Introduction: The Orphan Drug Act encourages drug development for rare conditions. However, some orphan drugs become top sellers for unclear reasons. We sought to evaluate the extent and cost of approved and unapproved uses of orphan drugs with the highest unit sales. Methods We assessed prescription patterns for four top-selling orphan drugs: lidocaine patch (Lidoderm) approved for post-herpetic neuralgia, modafinil (Provigil) approved for narcolepsy, cinacalcet (Sensipar) approved for hypercalcemia of parathyroid carcinoma, and imatinib (Gleevec) approved for chronic myelogenous leukemia and gastrointestinal stromal tumor. We pooled patient-specific diagnosis and prescription data from two large US state pharmaceutical benefit programs for the elderly. We analyzed the number of new and total patients using each drug and patterns of reimbursement for approved and unapproved uses. For lidocaine patch, we subcategorized approved prescriptions into two subtypes of unapproved uses: neuropathic pain, for which some evidence of efficacy exists, and non-neuropathic pain. Results: We found that prescriptions for lidocaine patch, modafinil, and cinacalcet associated with non-orphan diagnoses rose at substantially higher rates (average monthly increases in number of patients of 14.6, 1.45, and 1.58) than prescriptions associated with their orphan diagnoses (3.12, 0.24, and 0.03, respectively (p75%). Increases in lidocaine patch use for non-neuropathic pain far exceeded neuropathic pain (10.2 vs. 3.6 patients, p<0.001). Discussion In our sample, three of four top-selling orphan drugs were used more commonly for non-orphan indications. These orphan drugs treated common clinical symptoms (pain and fatigue) or laboratory abnormalities. We should continue to monitor orphan drug use after approval to identify products that come to be widely used for non-FDA approved indications, particularly those without adequate evidence of efficacy

Patient organization involvement and the challenge of securing access to treatments for rare diseases:Report of a policy engagement workshop

Plain English summary Patients with rare diseases often help to develop new treatments for their conditions. But once developed, those treatments are sometimes priced too high for many patients to access them. We became aware that this is a problem in the course of a social science research project that examines the place of rare diseases in health policy. We therefore organized a two-day workshop to try and understand why this problem occurs and what might be done about it. The people who participated in our workshop were: representatives of rare disease patient organizations, experts in matters of drug regulation and assessment of new health technologies, consultants involved with companies producing treatments for rare diseases, and social scientists researching related issues. The main conclusions to emerge from the discussions were as follows: Problems of access to treatments for rare diseases are not just due to high prices; procedures for regulating, assessing and delivering new treatments also need to be better organized. Patients and patient organizations have much to contribute to this process. However, their resources are often very limited. Consequently, more needs to be done to help them use those resources as effectively as possible. In particular, regulators and healthcare providers need to ensure that their procedures are clear and efficiently managed, so as not to waste patient organizations’ time and money. Clearer guidance is needed on what patient organizations can do to provide evidence of the effectiveness of new drugs. Insights gained in tackling rare diseases might also be applicable to common disorders. Finally, the consequences of Brexit for UK policies on rare diseases urgently need to be assessed. Abstract Since the enactment of orphan drug legislation in the USA, Europe and several other countries, an increasing number of treatments for rare diseases have been developed and many of them been approved for marketing. However, such treatments tend to be priced very high, and access to effective treatments remains a major challenge for patients with rare diseases – despite active involvement of patients and their support organizations in various stages of basic and applied research and commercial development. In order to allow patients to benefit from treatments proved effective for their diseases, we need to better understand why this challenge persists, and what steps might be taken to address it. To that end, we organized a policy-engagement workshop, bringing together individuals and organizations with direct experience of trying to secure access to a treatment for a rare disease along with individuals with relevant expertise in regulatory and commissioning processes for new medicines. With additional input from social scientists who offered different perspectives on the value of patient involvement, the workshop aimed to initiate a dialogue among the participants about how to address the challenge in a sustainable manner. Discussions at the workshop stressed that active involvement of patients is as valuable in the regulatory and commissioning processes as in the research and development of new medicines. However, it also highlighted certain risks and costs associated with such involvement. These include the costs of adjusting to abrupt changes in regulatory and commissioning processes, and the risk of being perceived as too close to commercial interests. To optimize use of scarce resources and ensure continuing active involvement, such risks and costs need to be better managed. Participants also noted that, owing to advances in genomic technologies, common diseases are also becoming divided into rare sub-categories, which are equally eligible for orphan drug designation. Consequently, involvement of wider patient communities beyond rare disease communities will be critical for continuing discussions about patients’ involvement in regulatory and commissioning processes, and to consider how patients and their support organizations can best work with other stakeholders – including companies, regulators and policymakers – to ensure access to effective medicines

Effect of Restricted Preen-Gland Access on Maternal Self Maintenance and Reproductive Investment in Mallards

As egg production and offspring care are costly, females should invest resources adaptively into their eggs to optimize current offspring quality and their own lifetime reproductive success. Parasite infections can influence maternal investment decisions due to their multiple negative physiological effects. The act of preening--applying oils with anti-microbial properties to feathers--is thought to be a means by which birds combat pathogens and parasites, but little is known of how preening during the reproductive period (and its expected disease-protecting effects) influences maternal investment decisions at the level of the egg.Here, we experimentally prevented female mallards (Anas platyrhynchos) from accessing their preen gland during breeding and monitored female immunoresponsiveness (e.g., plasma lysozyme concentration) as well as some egg traits linked to offspring quality (e.g., egg mass, yolk carotenoid content, and albumen lysozyme levels). Females with no access to their preen gland showed an increase in plasma lysozyme level compared to control, normally preening females. In addition, preen-gland-restricted females laid significantly lighter eggs and deposited higher carotenoid concentrations in the yolk compared to control females. Albumen lysozyme activity did not differ significantly between eggs laid by females with or without preen gland access.Our results establish a new link between an important avian self-maintenance behaviour and aspects of maternal health and reproduction. We suggest that higher yolk carotenoid levels in eggs laid by preen-gland-restricted females may serve to boost health of offspring that would hatch in a comparatively microbe-rich environment

Common guillemot (Uria aalge) eggs are not self-cleaning

Birds are arguably the most evolutionarily successful extant vertebrate taxon, in part because of their ability to reproduce in virtually all terrestrial habitats. Common guillemots, Uria aalge, incubate their single egg in an unusual and harsh environment; on exposed cliff ledges, without a nest, and in close proximity to conspecifics. As a consequence, the surface of guillemot eggshells is frequently contaminated with faeces, dirt, water and other detritus, which may impede gas exchange or facilitate microbial infection of the developing embryo. Despite this, guillemot chicks survive incubation and hatch from eggs heavily covered with debris. To establish how guillemot eggs cope with external debris, we tested three hypotheses: (1) contamination by debris does not reduce gas exchange efficacy of the eggshell to a degree that may impede normal embryo development; (2) the guillemot eggshell surface is self-cleaning; and, (3) shell accessory material (SAM) prevents debris from blocking pores, allowing relatively unrestricted gas diffusion across the eggshell. We show that (1) natural debris reduces the conductance of gases across the guillemot eggshell by blocking gas exchange pores. Despite this problem, we find (2) no evidence that guillemot eggshells are self-cleaning, but instead show that (3) the presence of SAM on the eggshell surface largely prevents pore blockages from occurring. Our results demonstrate that SAM is a crucial feature of the eggshell surface in a species whose eggs are frequently in contact with debris, acting to minimise pore blockages and thus ensure a sufficient rate of gas diffusion for embryo development

Variability in Avian Eggshell Colour: A Comparative Study of Museum Eggshells

Background: The exceptional diversity of coloration found in avian eggshells has long fascinated biologists and inspired a broad range of adaptive hypotheses to explain its evolution. Three main impediments to understanding the variability of eggshell appearance are: (1) the reliable quantification of the variation in eggshell colours; (2) its perception by birds themselves, and (3) its relation to avian phylogeny. Here we use an extensive museum collection to address these problems directly, and to test how diversity in eggshell coloration is distributed among different phylogenetic levels of the class Aves. Methodology and Results: Spectrophotometric data on eggshell coloration were collected from a taxonomically representative sample of 251 bird species to determine the change in reflectance across different wavelengths and the taxonomic level where the variation resides. As many hypotheses for the evolution of eggshell coloration assume that egg colours provide a communication signal for an avian receiver, we also modelled reflectance spectra of shell coloration for the avian visual system. We found that a majority of species have eggs with similar background colour (long wavelengths) but that striking differences are just as likely to occur between congeners as between members of different families. The region of greatest variability in eggshell colour among closely related species coincided with the medium-wavelength sensitive region around 500 nm. Conclusions: The majority of bird species share similar background eggshell colours, while the greatest variability among species aligns with differences along a red-brown to blue axis that most likely corresponds with variation in the presence and concentration of two tetrapyrrole pigments responsible for eggshell coloration. Additionally, our results confirm previous findings of temporal changes in museum collections, and this will be of particular concern for studies testing intraspecific hypotheses relating temporal patterns to adaptation of eggshell colour. We suggest that future studies investigating the phylogenetic association between the composition and concentration of eggshell pigments, and between the evolutionary drivers and functional impacts of eggshell colour variability will be most rewarding.Phillip Cassey, Steven J. Portugal, Golo Maurer, John G. Ewen, Rebecca L. Boulton, Mark E. Hauber and Tim M. Blackbur

Antimicrobial properties of avian eggshell-specific C-type lectin-like proteins

10.1016/j.febslet.2008.01.043FEBS Letters5825699-704FEBL