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Markus Ries - One of the best experts on this subject based on the ideXlab platform.
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fda Orphan Drug designations for lysosomal storage disorders a cross sectional analysis
PLOS ONE, 2020Co-Authors: Sven F Garbade, Matthias Zielonka, Konstantin Mechler, Stefan Kolker, Georg F Hoffmann, Christian Staufner, Eugen Mengel, Markus RiesAbstract:Purpose To provide a quantitative clinical-regulatory insight into the status of FDA Orphan Drug designations for compounds intended to treat lysosomal storage disorders (LSDs). Methods Assessment of the Drug pipeline through analysis of the FDA database for Orphan Drug designations with descriptive and comparative statistics. Results Between 1983 and 2019, 124 Orphan Drug designations were granted by the FDA for compounds intended to treat 28 lysosomal storage diseases. Orphan Drug designations focused on Gaucher disease (N = 16), Pompe disease (N = 16), Fabry disease (N = 10), MPS II (N = 10), MPS I (N = 9), and MPS IIIA (N = 9), and included enzyme replacement therapies, gene therapies, and small molecules, and others. Twenty-three Orphan Drugs were approved for the treatment of 11 LSDs. Gaucher disease (N = 6), cystinosis (N = 5), Pompe disease (N = 3), and Fabry disease (N = 2) had multiple approvals, CLN2, LAL-D, MPS I, II, IVA, VI, and VII one approval each. This is an increase of nine more approved Drugs and four more treatable LSDs (CLN2, MPS VII, LAL-D, and MPS IVA) since 2013. Mean time between Orphan Drug designation and FDA approval was 89.7 SD 55.00 (range 8–203, N = 23) months. Conclusions The Drug development pipeline for LSDs is growing and evolving, with increased focus on diverse small-molecule targets and gene therapy. CLN2 was the first and only LSD with an approved therapy directly targeted to the brain. Newly approved products included “me-too”–enzymes and innovative compounds such as the first pharmacological chaperone for the treatment of Fabry disease.
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thirty years of Orphan Drug legislation and the development of Drugs to treat rare seizure conditions a cross sectional analysis
PLOS ONE, 2016Co-Authors: Jan Henje Doring, Georg F Hoffmann, Anette Lampert, Markus RiesAbstract:Background Epilepsy is a serious chronic health condition with a high morbidity impairing the life of patients and afflicted families. Many epileptic conditions, especially those affecting children, are rare disorders generating an urgent medical need for more efficacious therapy options. Therefore, we assessed the output of the US and European Orphan Drug legislations. Methods Quantitative analysis of the FDA and EMA databases for Orphan Drug designations according to STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) criteria. Results Within the US Orphan Drug Act 40 designations were granted delivering nine approvals, i.e. clobazam, diazepam viscous solution for rectal administration, felbamate, fosphenytoin, lamotrigine, repository corticotropin, rufinamide, topiramate, and vigabatrin. Since 2000 the EMA granted six Orphan Drug designations whereof two compounds were approved, i.e. rufinamide and stiripentol. In the US, two Orphan Drug designations were withdrawn. Orphan Drugs were approved for conditions including Lennox-Gastaut syndrome, infantile spasms, Dravet syndrome, and status epilepticus. Comparing time to approval for rufinamide, which was approved in the US and the EU to treat rare seizure conditions, the process seems faster in the EU (2.2 years) than in the US (4.3 years). Conclusion Orphan Drug development in the US and in the EU delivered only few molecular entities to treat rare seizure disorders. The development programs focused on already approved antiepileptic Drugs or alternative pharmaceutical formulations. Most Orphan Drugs approved in the US are not approved in the EU to treat rare seizures although some were introduced after 2000 when the EU adopted the Orphan Drug Regulation.
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pressure for Drug development in lysosomal storage disorders a quantitative analysis thirty years beyond the us Orphan Drug act
Orphanet Journal of Rare Diseases, 2015Co-Authors: Konstantin Mechler, Georg F Hoffmann, William K Mountford, Markus RiesAbstract:Lysosomal storage disorders are a heterogeneous group of approximately 50 monogenically inherited Orphan conditions. A defect leads to the storage of complex molecules in the lysosome, and patients develop a complex multisystemic phenotype of high morbidity often associated with premature death. More than 30 years ago the Orphan Drug Act of 1983 passed the United States legislation intended to facilitate the development of Drugs for rare disorders. We directed our efforts in assessing which lysosomal diseases had Drug development pressure and what distinguished those with successful development and approvals from diseases not treated or without Orphan Drug designation. Analysis of the FDA database for Orphan Drug designations through descriptive and comparative statistics. Between 1983 and 2013, fourteen Drugs for seven conditions received FDA approval. Overall, Orphan Drug status was designated 70 times for 20 conditions. Approved therapies were enzyme replacement therapies (N = 10), substrate reduction therapies (N = 1), small molecules facilitating lysosomal substrate transportation (N = 3). FDA approval was significantly associated with a disease prevalence higher than 0.5/100,000 (p = 0.00742) and clinical development programs that did not require a primary neurological endpoint (p = 0.00059). Orphan Drug status was designated for enzymes, modified enzymes, fusion proteins, chemical chaperones, small molecules leading to substrate reduction, or facilitating subcellular substrate transport, stem cells as well as gene therapies. Drug development focused on more common diseases. Primarily neurological diseases were neglected. Small clinical trials with either somatic or biomarker endpoints were successful. Enzyme replacement therapy was the most successful technology. Four factors played a key role in successful Orphan Drug development or Orphan Drug designations: 1) prevalence of disease 2) endpoints 3) regulatory precedent, and 4) technology platform. Successful development seeded further innovation.
Harald E. Heemstra - One of the best experts on this subject based on the ideXlab platform.
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characteristics of Orphan Drug applications that fail to achieve marketing approval in the usa
Drug Discovery Today, 2011Co-Authors: Harald E. Heemstra, Hubert G M Leufkens, Kui Xu, R Channing P Rodgers, Bettie C G Voordouw, Miles M BraunAbstract:The US Orphan Drug Act has fostered the development of Drugs for patients with rare diseases by granting ‘Orphan designations’, although several Orphan Drugs for which a marketing application has been submitted to the FDA have failed to obtain approval. This study identified the clinical trial design, the level of experience of the sponsor and the level of interaction with the FDA to be associated with non-approval. Sponsors, therefore, should engage in dialogue with the FDA and thoughtfully design pivotal clinical trials in accordance with FDA guidance documents.
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Predictors of Orphan Drug approval
Orphanet Journal of Rare Diseases, 2010Co-Authors: Harald E. HeemstraAbstract:Results More Orphan Drugs were developed in the US during the first ten years of the US Orphan Drug Act (1983-1992, N=73) and during the first ten years of the EU Regulation on Orphan Medicinal products (2000-2009, N=112) than in the EU (2000-2009, N=59). Orphan Drug approval was strongly associated with previous experiences of the sponsor in obtaining approval for another Orphan Drug (OR=17.3, 95% CI=5.6-53.1). Furthermore, existing synthetic entities compared to biotechnology products tended to have a higher likelihood of reaching approval status (OR=3.9, 95% CI=0.9-16.6).
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From research on rare diseases to new Orphan Drug development
2010Co-Authors: Harald E. HeemstraAbstract:Rare diseases have a prevalence of lower than 5 in 10,000 inhabitants and are life-threatening or chronically debilitating. It is estimated that worldwide more than 5000 rare diseases exist, which account for over 55 million patients in the EU and the US together. However, the development of Drugs for rare diseases, so called Orphan Drugs has not been an area of high priority for the pharmaceutical industry so far. Therefore, dedicated Orphan Drug legislation has been introduced that aims to stimulate the development of these high medical need products. This thesis identifies strategies for enhancing the development and marketing of Orphan Drugs. In the first chapter, bottlenecks and opportunities for translating biomedical research on rare diseases into early Orphan Drug development were studied. This chapter highlighted the importance of basic biomedical research for Orphan Drug development. Moreover, the studies determined the importance of strong pharmaceutical innovation in general, including patent applications, R&D expenditure and the existence of small and medium enterprises in the pharmaceutical industry, for the successful translation of biomedical research into Orphan Drug development. The second chapter focussed on characteristics of Orphan Drugs associated with a positive or negative outcome of the marketing authorisation application (by the FDA or EMEA). First, sponsors with prior experience in (Orphan) Drug development were more likely to develop another Orphan Drug. Orphan Drugs based on existing molecules had also more chance to get market approval. Second, the choice of the target population for the Orphan Drug and the choice of the primary endpoint in the pivotal clinical trial was determined to be associated with the outcome of the regulatory assessment. Finally, a higher level of interaction between sponsors and regulators was shown to be positively associated with successful market authorisation. The third chapter of the thesis described the challenges of Orphan Drugs after approval. As a result of differences in healthcare systems and other reasons, including the sometimes-high prices of Orphan Drugs, not all Orphan Drugs are available to the patients throughout the EU. In the thesis, the use of Orphan Drugs is compared to other centrally authorised Drugs in the EU and this appeared not to be significantly different. Second, due to the limited clinical experience with Orphan Drugs before approval, the risk for unexpected adverse events of Orphan Drugs may be higher than for other Drugs. We reveal that the number of written safety warnings and black box warnings for Orphan Drugs is not significantly different from that for other Drugs.
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translation of rare disease research into Orphan Drug development disease matters
Drug Discovery Today, 2009Co-Authors: Harald E. Heemstra, Sonja Van Weely, Hans A Buller, Hubert G M Leufkens, Remco L A De VruehAbstract:More than 25 years of Orphan Drug regulations have yielded several new treatments for patients with rare diseases. Here, we show that successful translation of rare disease research into an Orphan Drug discovery and development programme is dependent on the disease class, its prevalence and the disease-specific scientific output. Our findings indicate that current Orphan Drug legislation alone is not sufficient to stimulate Orphan Drug development for diseases with a very low prevalence. Consequently, additional incentives should focus on stimulating the specific needs of rare disease research at disease class level.
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Orphan Drug development across europe bottlenecks and opportunities
Drug Discovery Today, 2008Co-Authors: Harald E. Heemstra, Remco L A De Vrueh, Sonja Van Weely, Hans A Buller, Hubert G M LeufkensAbstract:With the assignment of the 500th European Union Orphan Drug designation in 2007, the Regulation on Orphan Medicinal Products truly begins to show its potential for delivering new medicines to patients with rare diseases. Here, we analysed European Orphan Drug development at a national level and unveil a strong relationship between Orphan Drug development and pharmaceutical innovation performance in Europe. Moreover, we identify gaps in transition from science into Orphan Drug development as important bottlenecks that exist in several European countries. Our findings underline the importance of innovation-based policies to enhance the development of Orphan Drugs in Europe.
Steven Simoens - One of the best experts on this subject based on the ideXlab platform.
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shining a light in the black box of Orphan Drug pricing
Orphanet Journal of Rare Diseases, 2014Co-Authors: Eline Picavet, David Cassiman, Thomas Morel, Steven SimoensAbstract:The pricing mechanism of Orphan Drugs appears arbitrary and has been referred to as a “black box”. Therefore, the aim of this study is to investigate how Drug- and disease-specific variables relate to Orphan Drug prices. Additionally, we aim to explore if certain country-specific pricing and reimbursement policies affect the price level of Orphan Drugs. Annual treatment costs per indication per patient were calculated for 59 Orphan Drugs with a publicly available price in Belgium, the Netherlands, Czech Republic, France, Italy and the United Kingdom. A multiple linear regression model was built with 14 Drug- and disease-specific variables. A Mann-Whitney U test was used to explore whether there is a correlation between annual treatment costs of Orphan Drugs across countries with different pricing and reimbursement policies. Repurposed Orphan Drugs, orally administered Orphan Drugs or Orphan Drugs for which an alternative treatment is available are associated with lower annual treatment costs. Orphan Drugs with multiple Orphan indications, for chronic treatments or for which an improvement in overall survival or quality-of-life has been demonstrated, are associated with higher annual treatment costs. No association was found between annual treatments cost of Orphan Drugs across countries and the different pricing and reimbursement systems. This study has shown that prices of Orphan Drugs are influenced by factors such as the availability of an alternative Drug treatment, repurposing, etc. Current debate about the affordability of Orphan Drugs highlights the need for more transparency in Orphan Drug price setting.
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evaluating and improving Orphan Drug regulations in europe a delphi policy study
Health Policy, 2012Co-Authors: Eline Picavet, David Cassiman, Steven SimoensAbstract:To encourage the development of Orphan Drugs, the European Union has implemented specific policies in 2000. However, the political, social, scientific and economic context has changed since the implementation of these policies. For that reason, the aim of this article is to evaluate Orphan Drug policies in Europe. Firstly, key issues on the Orphan Drug policy were identified based on desk research. Secondly, a Delphi policy study with 47 European Orphan Drug experts from different backgrounds was carried out to explore these issues. In the round one of the Delphi, responses were received from 18 experts (38.3%) and from ten (55.5%) in the round two. Experts agree that the Orphan Drug policies in Europe have not outlived their usefulness. Additionally, the importance of reducing country-dependent inequalities in patient access to Orphan Drugs has been emphasized. Still, there is room for further refinement of the Orphan Drug policies. Within that context, we formulated several policy recommendations (e.g. enforcing the policy that is in place to reduce the period of market exclusivity for profitable Orphan Drugs, stating the level of clinical evidence needed to authorize Orphan Drugs, etc.) with the overall goal to optimize patient access to Orphan Drugs.
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paying for the Orphan Drug system break or bend is it time for a new evaluation system for payers in europe to take account of new rare disease treatments
Orphanet Journal of Rare Diseases, 2012Co-Authors: Wills Hugheswilson, Ad Schuurman, Ana Palma, Steven SimoensAbstract:Since its enactment in 2000, the European Orphan Medicinal Products Regulation has allowed the review and approval of approaching 70 treatments for some 55 different conditions in Europe. Success does not come without a price, however. Many of these so-called “Orphan Drugs” have higher price points than treatments for more common diseases. This has been raising debate as to whether the treatments are worth it, which, in turn risks blocking patient access to treatment. To date, Orphan Drugs have only accounted for a small percentage of the overall Drug budget. It would appear that, with increasing numbers of Orphan Drugs, governments are concerned about the future budget impact and their cost-effectiveness in comparison with other healthcare interventions. Orphan Drugs are under the spotlight, something that is likely to continue as the economic crisis in Europe takes hold and governments respond with austerity measures that include cuts to healthcare expenditures. Formally and informally, governments are looking at how they are going to handle Orphan Drugs in the future. Collaborative proposals between EU governments to better understand the value of Orphan Drugs are under consideration. In recent years there has been increasing criticism of behaviours in the Orphan Drug field, mainly centring on two key perceptions of the system: the high prices of Orphan Drugs and their inability to meet standard cost-effectiveness thresholds; and the construct of the system itself, which allows companies to gain the benefits that accrue from being badged as an Orphan Drug. The authors hypothesise that, by examining these criticisms individually, one might be able to turn these different “behaviours” into criteria for the creation of a system to evaluate new Orphan Drugs coming onto the market. It has been acknowledged that standard methodologies for Health Technology Assessments (HTA) will need to be tailored to take into account the specificities of Orphan Drugs given that the higher price-points claimed by Orphan Drugs are unlikely to meet current cost-effectiveness thresholds. The authors propose the development of a new assessment system based on several evaluation criteria, which would serve as a tool for Member State governments to evaluate each new Orphan Drug at the time of pricing and reimbursement. These should include rarity, disease severity, the availability of other alternatives (level of unmet medical need), the level of impact on the condition that the new treatment offers, whether the product can be used in one or more indications, the level of research undertaken by the developer, together with other factors, such as manufacturing complexity and follow-up measures required by regulatory or other authorities. This will allow governments to value an Orphan Drug that fulfilled all the criteria very differently from one that only met some of them. An individual country could determine the (monetary) value that it places on each of the different criteria, according to societal preferences, the national healthcare system and the resources at its disposal – each individual government deciding on the weighting attributed to each of the criteria in question, based on what each individual society values most. Such a systematic and transparent system will help frame a more structured dialogue between manufacturers and payers, with the involvement of the treating physicians and the patients; and foster a more certain environment to stimulate continued investment in the field. A new approach could also offer pricing and reimbursement decision-makers a tool to handle the different characteristics amongst new Orphan Drugs and to redistribute the national budgets in accordance with the outcome of a differentiated assessment. The authors believe that this could, therefore, facilitate the approach for all stakeholders.
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a comparative study of european rare disease and Orphan Drug markets
Health Policy, 2010Co-Authors: Alain Denis, Lut Mergaert, Christel Fostier, Irina Cleemput, Steven SimoensAbstract:Objectives This article aims to compare regulatory aspects of rare disease and Orphan Drug markets in Belgium, France, Italy, the Netherlands, Sweden and the United Kingdom.Methods Information was derived from the international literature, analysis of legal texts, and a survey completed by national experts.Results These countries adopted varying approaches towards regulating rare disease and Orphan Drug markets and, hence, the availability, pricing and reimbursement of Orphan Drugs vary between countries. Strategies to keep down prices include public procurement in Sweden, profit controls in the United Kingdom, and price comparisons with other countries. To gain reimbursement, the cost-effectiveness and/or budget impact of Orphan Drugs is considered in some countries. Other societal considerations, such as whether the Drug treats a life-threatening disease, are sometimes taken into account.Conclusions Extensive government intervention exists in rare disease and Orphan Drug markets in the countries studied. Our recommendations are to define priorities for research on rare diseases and Orphan Drugs at the European level, to set up disease and patient registries with a view to investigating the long-term effectiveness and cost-effectiveness of Orphan Drugs, to assess the profitability of Orphan Drugs, and to take into account societal considerations when evaluating Orphan Drugs.
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Issues surrounding Orphan disease and Orphan Drug policies in Europe
Applied Health Economics and Health Policy, 2010Co-Authors: Alain Denis, Lut Mergaert, Christel Fostier, Irina Cleemput, Steven SimoensAbstract:An Orphan disease is a disease with a very low prevalence. Although there are 5000–7000 Orphan diseases, only 50 Orphan Drugs (i.e. Drugs developed to treat Orphan diseases) were marketed in the EU by the end of 2008. In 2000, the EU implemented policies specifically designed to stimulate the development of Orphan Drugs. While decisions on Orphan designation and the marketing authorization of Orphan Drugs are made at the EU level, decisions on Drug reimbursement are made at the member state level. The specific features of Orphan diseases and Orphan Drugs make them a high-priority issue for policy makers. The aim of this article is to identify and discuss several issues surrounding Orphan disease and Drug policies in Europe. The present system of Orphan designation allows for Drugs for non-Orphan diseases to be designated as Orphan Drugs. The economic factors underlying Orphan designation can be questioned in some cases, as a low prevalence of a certain indication does not equal a low return on investment for the Drug across its indications. High-quality evidence about the clinical added value of Orphan Drugs is rarely available at the time of marketing authorization, due to the low number of patients. A balance must be struck between ethical and economic concerns. To this effect, there is a need to initiate a societal dialogue on this issue, to clarify what society wants and accepts in terms of ethical and economic consequences. The growing budgetary impact of Orphan Drugs puts pressure on Drug expenditure. Indications can be extended for an Orphan Drug and the total prevalence across indications is not considered. Finally, cooperation needs to be fostered in the EU, particularly through a standardized approach to the creation and use of registries. These issues require further attention from researchers, policy makers, health professionals, patients, pharmaceutical companies and other stakeholders with a view to optimizing Orphan disease and Drug policies in Europe.
Remco L A De Vrueh - One of the best experts on this subject based on the ideXlab platform.
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translation of rare disease research into Orphan Drug development disease matters
Drug Discovery Today, 2009Co-Authors: Harald E. Heemstra, Sonja Van Weely, Hans A Buller, Hubert G M Leufkens, Remco L A De VruehAbstract:More than 25 years of Orphan Drug regulations have yielded several new treatments for patients with rare diseases. Here, we show that successful translation of rare disease research into an Orphan Drug discovery and development programme is dependent on the disease class, its prevalence and the disease-specific scientific output. Our findings indicate that current Orphan Drug legislation alone is not sufficient to stimulate Orphan Drug development for diseases with a very low prevalence. Consequently, additional incentives should focus on stimulating the specific needs of rare disease research at disease class level.
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Orphan Drug development across europe bottlenecks and opportunities
Drug Discovery Today, 2008Co-Authors: Harald E. Heemstra, Remco L A De Vrueh, Sonja Van Weely, Hans A Buller, Hubert G M LeufkensAbstract:With the assignment of the 500th European Union Orphan Drug designation in 2007, the Regulation on Orphan Medicinal Products truly begins to show its potential for delivering new medicines to patients with rare diseases. Here, we analysed European Orphan Drug development at a national level and unveil a strong relationship between Orphan Drug development and pharmaceutical innovation performance in Europe. Moreover, we identify gaps in transition from science into Orphan Drug development as important bottlenecks that exist in several European countries. Our findings underline the importance of innovation-based policies to enhance the development of Orphan Drugs in Europe.
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predictors of Orphan Drug approval in the european union
European Journal of Clinical Pharmacology, 2008Co-Authors: Harald E. Heemstra, Remco L A De Vrueh, Sonja Van Weely, Hans A Buller, Hubert G M LeufkensAbstract:Objective To encourage the development of Drugs for rare diseases, Orphan Drug legislation has been introduced in the USA (1983) and in the EU (2000). Recent literature discusses factors that may influence the development of new Orphan medicinal products in the EU. This study aims to identify predictors for successful marketing authorisation of potential Orphan Drugs in the EU.
Hubert G M Leufkens - One of the best experts on this subject based on the ideXlab platform.
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characteristics of Orphan Drug applications that fail to achieve marketing approval in the usa
Drug Discovery Today, 2011Co-Authors: Harald E. Heemstra, Hubert G M Leufkens, Kui Xu, R Channing P Rodgers, Bettie C G Voordouw, Miles M BraunAbstract:The US Orphan Drug Act has fostered the development of Drugs for patients with rare diseases by granting ‘Orphan designations’, although several Orphan Drugs for which a marketing application has been submitted to the FDA have failed to obtain approval. This study identified the clinical trial design, the level of experience of the sponsor and the level of interaction with the FDA to be associated with non-approval. Sponsors, therefore, should engage in dialogue with the FDA and thoughtfully design pivotal clinical trials in accordance with FDA guidance documents.
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translation of rare disease research into Orphan Drug development disease matters
Drug Discovery Today, 2009Co-Authors: Harald E. Heemstra, Sonja Van Weely, Hans A Buller, Hubert G M Leufkens, Remco L A De VruehAbstract:More than 25 years of Orphan Drug regulations have yielded several new treatments for patients with rare diseases. Here, we show that successful translation of rare disease research into an Orphan Drug discovery and development programme is dependent on the disease class, its prevalence and the disease-specific scientific output. Our findings indicate that current Orphan Drug legislation alone is not sufficient to stimulate Orphan Drug development for diseases with a very low prevalence. Consequently, additional incentives should focus on stimulating the specific needs of rare disease research at disease class level.
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Orphan Drug development across europe bottlenecks and opportunities
Drug Discovery Today, 2008Co-Authors: Harald E. Heemstra, Remco L A De Vrueh, Sonja Van Weely, Hans A Buller, Hubert G M LeufkensAbstract:With the assignment of the 500th European Union Orphan Drug designation in 2007, the Regulation on Orphan Medicinal Products truly begins to show its potential for delivering new medicines to patients with rare diseases. Here, we analysed European Orphan Drug development at a national level and unveil a strong relationship between Orphan Drug development and pharmaceutical innovation performance in Europe. Moreover, we identify gaps in transition from science into Orphan Drug development as important bottlenecks that exist in several European countries. Our findings underline the importance of innovation-based policies to enhance the development of Orphan Drugs in Europe.
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predictors of Orphan Drug approval in the european union
European Journal of Clinical Pharmacology, 2008Co-Authors: Harald E. Heemstra, Remco L A De Vrueh, Sonja Van Weely, Hans A Buller, Hubert G M LeufkensAbstract:Objective To encourage the development of Drugs for rare diseases, Orphan Drug legislation has been introduced in the USA (1983) and in the EU (2000). Recent literature discusses factors that may influence the development of new Orphan medicinal products in the EU. This study aims to identify predictors for successful marketing authorisation of potential Orphan Drugs in the EU.