Arzneimittel für seltene Krankheiten (orphan drugs) : Das schweizerische Heilmittelrecht im Vergleich mit der orphan drug Regulierung der EU

Arzneimittel für seltene Krankheiten (orphan drugs) lassen sich unter normalen Marktbedingungen kaum kostendeckend erforschen, entwickeln und vermarkten, was zu einem Mangel an geeigneten Therapien und zugelassenen Arzneimitteln für seltene Krankheiten führt. Um den fortdauernden Ausschluss von betroffenen Patienten vom medizinischen Fortschritt zu verhindern und die Defizite in der Erforschung und Entwicklung von orphan drugs zu beseitigen, schuf die Europäische Union – nach US-amerikanischem Vorbild – ein Anreizsystem. Der vorliegende Beitrag erläutert die regulatorischen Rahmenbedingungen für orphan drugs in der EU und zeigt auf, dass die Schweiz in der Schaffung günstiger Rahmenbedingungen für Patientinnen und Patienten, die an einer seltenen Krankheit leiden, anderen Ländern um Jahre hinter her hinkt, sich aber allmählich etwas tut.

Orphan drugs and paediatric medicinal products

While the safety and availability of medicinal products for the majority of adult patients has steadily improved in recent decades, for children and people suffering from rare diseases (orphan diseases) there is a lack of approved medicinal products for these patient populations. Since the research and development of medicinal products is associated with high costs, the costs for paediatric medicinal products and medicines for rare diseases (orphan drugs) may barely be covered under normal market conditions due to the small patient populations. In order to prevent the continued exclusion of children and persons suffering from rare diseases from medical progress and to eliminate the deficits in the research and development of medicinal products for these patient groups, the European Union created, along the lines of the U.S. model, a system of incentives and constraints. Since 2000, under Regulation (EC) No. 141/2000 (Orphan Drug Regulation) there has been an incentive system to encourage the research and development of orphan drugs. With the goal of improving the health of children in Europe, Regulation (EC) No. 1901/2006 (Paediatric Regulation) combines economic incentives with the requirement to conduct paediatric studies. This article explains and comments on the specific regulatory framework for orphan drugs and paediatric medicinal products in the European Union.

Report of the National Conference on Orphan Drugs : the path to promise : May 18-19, 1988, George Washington University, Washington, D.C. / [sponsored jointly by] the National Institutes of Health and the Pharmaceutical Manufacturers Association.

Mode of access: Internet.

Value Assessment of Orphan Drugs and Treatments for Rare Diseases

Thesis (Master's)--University of Washington, 2016-06

Evaluating health policy and legal responses : how to reduce barriers and improve access to orphan drugs for rare diseases in Canada

Abstract : Rare diseases are debilitating conditions often leading to severe clinical manifestations for affected patients. Orphan drugs have been developed to treat these rare diseases affecting a small number of individuals. Incentives in the legal framework aimed to recoup the research and development cost of orphan drugs for pharmaceutical companies have been implemented in the United States and the European Union. At the present time, Canada is still lacking a legal and policy framework for orphan drugs. Several problems at the federal and provincial levels remain: lack of research funds for rare diseases, discrepancies on orphan drug policies between provinces, difficulties to access and reimburse these high price drugs. Recommendations and measures are proposed, such as a pan-Canadian (national) scientific committee to establish evidence-based guidelines for patients to access orphan drugs uniformly in all provinces with a disease specific registry, a formal agreement for a centralized Canadian public funding reimbursement procedure, and increasing the role of “guardian” for prices by the Patented Medicines Review Board in Canada. These recommendations and measures will be beneficial for the implementation of a policy framework for orphan drugs in Canada.

Impact of economic, regulatory, and patent policies on innovation in cancer chemoprevention.

Chemoprevention agents are an emerging new scientific area that holds out the promise of delaying or avoiding a number of common cancers. These new agents face significant scientific, regulatory, and economic barriers, however, which have limited investment in their research and development (R&D). These barriers include above-average clinical trial scales, lengthy time frames between discovery and Food and Drug Administration approval, liability risks (because they are given to healthy individuals), and a growing funding gap for early-stage candidates. The longer time frames and risks associated with chemoprevention also cause exclusivity time on core patents to be limited or subject to significant uncertainties. We conclude that chemoprevention uniquely challenges the structure of incentives embodied in the economic, regulatory, and patent policies for the biopharmaceutical industry. Many of these policy issues are illustrated by the recently Food and Drug Administration-approved preventive agents Gardasil and raloxifene. Our recommendations to increase R&D investment in chemoprevention agents include (a) increased data exclusivity times on new biological and chemical drugs to compensate for longer gestation periods and increasing R&D costs; chemoprevention is at the far end of the distribution in this regard; (b) policies such as early-stage research grants and clinical development tax credits targeted specifically to chemoprevention agents (these are policies that have been very successful in increasing R&D investment for orphan drugs); and (c) a no-fault liability insurance program like that currently in place for children's vaccines.

The distribution of sales revenues from pharmaceutical innovation.

OBJECTIVE: This report updates our earlier work on the returns to pharmaceutical research and development (R&D) in the US (1980 to 1984), which showed that the returns distributions are highly skewed. It evaluates a more recent cohort of new drug introductions in the US (1988 to 1992) and examines how the returns distribution is emerging for drugs with life cycles concentrated in the 1990s versus the 1980s. DESIGN AND SETTING: Methods were described in detail in our earlier reports. The current sample included 110 new drug entities (including 28 orphan drugs), and sales data were obtained for the period 1988 to 1998, which represented between 7 and 11 years of sales for the drugs included. 20 years was chosen as the expected market life for this cohort, and a 2-step procedure was used to project future sales for the drugs--during the period until patent expiry and then beyond patent expiry until the 20-year time-horizon was completed. Thus, the values in the first half of the life cycle are essentially based on realised sales, while those in the second half are projected using information on patent expiry and other inputs. MAIN OUTCOME MEASURES AND RESULTS: Peak annual sales for the top decile of drugs introduced between 1988 and 1992 in the US amounted to almost $US1.1 billion compared with peak sales of less than $US175 million (1992 values) for the mean compound. In particular, the top decile accounted for 56% of overall sales revenue. Although the sales distributions were skewed in both our earlier and current analysis, the top decile in the later time-period exhibited more rapid rates of growth after launch, a peak that was more than 50% greater in real terms than for the 1980 to 1984 cohort, and a faster rate of expected decline in sales after patent expiry. One factor contributing to the distribution of sales revenues becoming more skewed over time is the orphan drug phenomenon (i.e. most of the orphan drugs are concentrated at the bottom of the distribution). CONCLUSION: The distribution of sales revenues for new drug compounds is highly skewed in nature. In this regard, the top decile of new drugs accounts for more than half of the total sales generated by the 1988 to 1992 cohort analysed. Furthermore, the distribution of sales revenues for this cohort is more skewed than that of the 1980 to 1984 cohort we analysed in previous research.

Doenças Raras e Medicamentos Órfãos em Portugal: Impacto Económico dos Medicamentos Órfãos na Região da Beira Interior

Medicamentos órfãos destinam-se ao diagnóstico, prevenção ou tratamento de doenças muito graves ou que causem risco de vida, que são raras e não afetam mais do que 5 em cada 10.000 pessoas na União Europeia. Estes medicamentos são apelidados de órfãos, já que em condições normais de mercado, não existe interesse para as empresas farmacêuticas desenvolver tais medicamentos, devido ao baixo retorno financeiro causado pela raridade. O objetivo deste trabalho consiste em avaliar a utilização de medicamentos órfãos em Portugal e analisar o impacto económico destes medicamentos na região da Beira Interior. Os dados recolhidos permitiram avaliar retrospetivamente o consumo de medicamentos no período de janeiro a dezembro de 2013 em Portugal e em particular nos hospitais: Centro Hospitalar Cova da Beira, Unidade Local de Saúde da Guarda e Unidade Local de Saúde de Castelo Branco. A informação dos dados refere-se ao consumo dos Hospitais e Instituições do Serviço Nacional de Saúde, reportada mensalmente ao INFARMED (Autoridade Nacional do Medicamento e Produtos de Saúde, I.P.). Foram identificados 48 medicamentos órfãos com Autorização de Introdução no Mercado na Europa, 47 são medicamentos com Autorização de Introdução no Mercado português, sendo a Mercaptopurina o único medicamento órfão que necessita de Autorização de Utilização Especial. O Tafamidis foi o medicamento que envolveu maior custo económico a nível nacional no tratamento destas doenças. O valor total de consumo no Centro Hospitalar Cova da Beira é de 11% em relação ao consumo total de medicamentos nesta unidade. As doenças Lisossomais são o grupo mais representativo, do qual faz parte a doença de Pompe. No entanto, a doença com uma prevalência mais elevada é a Hipertensão Arterial Pulmonar. Esta e as doenças oncológicas são as doenças comuns nas três unidades hospitalares. Na Unidade Local de Saúde da Guarda a doença com maior consumo de medicamentos órfãos é a Hipertensão Arterial Pulmonar e na Unidade Local de Saúde de Castelo Branco são as doenças oncológicas. O valor acumulado de medicamentos órfãos na região da Beira Interior no ano de 2013 representa1% do valor global de consumo destes medicamentos em Portugal. A representatividade de consumo destes medicamentos em Portugal em relação ao consumo total de medicamentos em meio hospitalar é de cerca de 7,7%.Em conclusão, o consumo de medicamentos órfãos é bastante elevado em relação aos restantes medicamentos, tanto na Beira Interior como no resto do país, apesar disso é bastante importante que continuem a existir medidas no sentido de incentivar os fabricantes e melhorar o acesso a estes medicamentos.

Vyndaqel (Tafamidis)

The main objective of this pedagogical case study is to analyse the market entry dynamics of pharmaceutical innovative drugs in Portugal, and the role and impact of the different stakeholders in this process. The case focuses on the market entry of Vyndaqel (Tafamidis) Pfizer’s orphan innovative product to treat TTR-FAP, “paramiloidose”, a highly incapacitating rare disease that has more than 2.000 diagnosed patients in Portugal, one of the highest prevalence worldwide and an incidence of 100 new patients every year. In terms of methodology it were used two main sources of information. Regarding secondary data sources it was made an exhaustive search using the main specialty search engines regarding the Tafamidis case, market access, orphan drugs and market entry context in Portugal and Europe. In terms of primary data it were conducted 7 direct interviews with the main case stakeholders. The pedagogical case study focuses on 5 main questions that provide the base of the discussion for the classes. First it is analysed the rationale behind the introduction of Tafamidis in Portugal, and its relevance for Pfizer, namely due to the previous investment made with the acquisition of FoldRX by $400M, the company that developed the product in the first place. It is also analysed the point of view of the NHS, and the reasoning behind drug reimbursement that considered not only the technical (efficacy and safety) and financial benefits of the drug, but also the social impact, due to the major role played by patient associations’ actions and coverage provided by the media that impacted the reimbursement decision. Finally it is analysed the vertical financing methodology that was selected by the Ministry of Health for drug acquisition by 2 public hospitals, that served as reference centres for the treatment of this disease

Bullous pemphigoid: therapeutic algrorithm and practical management

Introduction: Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucosae. BP typically affects the elderly and manifests with severe itch, localised or generalised eczematous, urticated and/or bullous lesions. Its morbidity and impact on the quality of life are important. The disease is significantly associated with neurological disorders, such as stroke, Parkinson disease, major cognitive impairment and multiple sclerosis. Diagnosis of BP critically relies on immunopathologic examinations, particularly direct immunofluorescence microscopy studies. Areas covered: This paper looks at the evidence of therapies commonly used in bullous pemphigoid. Expert opinion: Treatment of BP has been a challenge, given the relative rarity of the disease, lack of good quality randomised controlled trials, the presence of co-morbidities in the affected elderly population and the high mortality rate. Recent controlled studies have indicated that potent topical corticosteroids constitute a more effective therapy for BP when compared to oral corticosteroids in terms of control of the disease, side effect profile and overall survival. Other therapies have been employed with varying success, but are not validated yet. Improved knowledge of the pathophysiology of BP will hopefully allow the development of new immunomodulatory treatments for this debilitating disease.

Histaminergic modulation in Tourette syndrome

Introduction: Tourette syndrome is a neurodevelopmental disorder characterized by multiple motor tics and at least one vocal/phonic tic. Clinical phenotypes show a wide variability, often incorporating behavioral symptoms. The exact pathophysiology of Tourette syndrome is unknown, however genetic vulnerability and alterations in dopaminergic neurotransmission have consistently been reported. Other biochemical pathways, including histaminergic neurotransmission, are likely to be involved but have received relatively little attention until recently. Areas covered: We conducted a systematic literature review focusing on the role of histaminergic neurotransmission and its pharmacological modulation in Tourette syndrome. We identified a number of relevant original studies published over the last five years, mainly focusing on genetic aspects. Expert opinion: There is converging evidence from recent studies supporting the hypothesis that histaminergic neurotransmission may play a role in the pathophysiology of Tourette syndrome. Most studies focused on the role of the histidine decarboxylase gene and the potential usefulness of histidine decarboxylase knockout mice as an experimental model for studying neurochemical function in Tourette syndrome. There have been no large scale studies assessing the use of histaminergic medications in the management of Tourette syndrome. This would be an important area for future research, with direct implications for the clinical management of selected phenotypes.

Toward targeted treatments in tuberous sclerosis

Introduction. Tuberous Sclerosis Complex (TSC) is an autosomal-dominant disease caused by the loss of function of the heterodimeric complex hamartin/tuberin due to TSC1/TSC2 gene mutation. The consequent abnormal activation of mammalian target of rapamycin (mTOR), a serine threonine kinase regulating cellular growth, metabolism and proliferation, is responsible for the structural and functional abnormalities observed in TSC. mTOR inhibitors are a class of drugs specifically targeting the mTOR pathway with promising benefits as a specific targeted treatment of the disease. Areas covered. We have reviewed the literature focusing on the role of mTOR inhibitors in treating TSC-related conditions. They are currently approved for subependymal giant cell astrocytomas, renal angiomyolipomas and more recently for lymphangioleiomyomatosis, but a promising role has been shown also in the other clinical manifestation characteristics of TSC, such as cardiac rhabdomyomas, facial angiofibromas and epilepsy. Expert opinion. mTOR inhibition is considered a disease-modifying therapy and the best approach to prevent the progress of the natural history of the disease. For the first time we have the possibility not only to use a biologically targeted treatment, but also to address different manifestations at the same time, thus significantly improving the therapeutic outlook in this complex disease.

Taxonomy of rare congenital metabolic bone disorders

International audience

Estado de las enfermedades raras que cursan con discapacidad intelectual en Colombia

Las enfermedades raras o huérfano son una problemática que ha tomado mucha importancia en el contexto mundial del presente siglo, estas se han definido como crónicas, de difícil tratamiento de sus síntomas y con baja prevalencia en la población; muchas de estas enfermedades cursan con varios tipos de discapacidad, siendo el objetivo del presente trabajo el enfocarse en aquellas enfermedades raras que cursan con discapacidad intelectual. Para poder profundizar en estas enfermedades se realizó una revisión teórica sobre las enfermedades raras, así como de la discapacidad psíquica y su importancia a nivel mundial y nacional. A partir de estas definiciones, se revisaron en profundidad 3 enfermedades raras que cursan con discapacidad intelectual en el contexto colombiano, como son: el síndrome de Rett, el síndrome de Prader-Willi y el síndrome de X frágil. En cada una de estas enfermedades además se explicaron los tipos de diagnóstico, intervención, prevención, grupos de apoyo y tipos de evaluación que más se usan en el contexto nacional