Orphan Drug Development Research Articles

Zulassung und Erstattung von Orphan Drugs im internationalen Vergleich

This paper analyses schemes to promote the authorisation of and reimbursement for orphan drugs. 8 countries - Australia, Canada, Germany, Great Britain, France, Netherlands, Switzerland, USA - were studied to compare specific regulations for orphan drugs regarding drug admission, health technology assessment (HTA), decision-making for reimbursement, and off-label and compassionate use. Information was obtained by reviewing published and grey literature. Expert interviews were also conducted. The comparison of orphan drug legislation reveals that the EU and the USA offer the greatest incentives for the development of orphan drugs, whereas there is a tendency for Australia and Switzerland to profit from incentives in other countries. Although not explicitly stated, economic evaluation of orphan drugs takes the special circumstances for orphan drugs into account. In addition to common reimbursement practices, special schemes or programmes for the reimbursement of high-priced orphan drugs exist in all countries that were analysed. Therefore access to orphan drugs seems to be warranted. However, due to co-payments of 5%, the USA may form an exception. On the one hand, the use of special criteria for drug admission, HTA, and reimbursement promotes R&D for orphan drugs. On the other hand, high opportunity costs arise, because huge efforts are made for a minority of patients. A solution for this moral dilemma may be the application of "rule of rescue" or of "no cure, no pay" programmes.

Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism

The lecture dedicated to Professor Horst Bickel describes the advances, successes, and opportunities concerning the understanding of the biochemical and molecular basis of phenylketonuria and the innovative treatment strategies introduced for these patients during the last 60 years. These concepts were transferred to other inborn errors of metabolism and led to significant reduction in morbidity and to an improvement in quality of life. Important milestones were the successful development of a low-phenylalanine diet for phenylketonuria patients, the recognition of tetrahydrobiopterin as an option to treat these individuals pharmacologically, and finally market approval of this drug. The work related to the discovery of a pharmacological treatment led metabolic researchers and pediatricians to new insights into the molecular processes linked to mutations in the phenylalanine hydroxylase gene at the cellular and structural level. Again, phenylketonuria became a prototype disorder for a previously underestimated but now rapidly expanding group of diseases: protein misfolding disorders with loss of function. Due to potential general biological mechanisms underlying these disorders, the door may soon open to a systematic development of a new class of pharmaceutical products. These pharmacological chaperones are likely to correct misfolding of proteins involved in numerous genetic and nongenetic diseases.

Issues Surrounding Orphan Disease and Orphan Drug Policies in Europe

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.

Orphan Drug Development: Opportunities and Challenges from a Midsized to Large Company Perspective

Orphan diseases may be one of the last frontiers in drug development. With an estimated 50 million or more people affected across Europe and North America by over 6,000 rare diseases, the unmet medical need is daunting. This research explores the question of whether the opportunities outweigh the challenges and provide incentives for midsized to large pharmaceutical and biotechnology companies to invest in this area.

Gaucher disease: clinical profile and therapeutic developments

Gaucher disease is a rare inborn error of glycosphingolipid metabolism due to deficiency of lysosomal acid β-glucocerebrosidase; the condition has totemic significance for the development of orphan drugs. A designer therapy, which harnesses the mannose receptor to complement the functional defect in macrophages, ameliorates the principal clinical manifestations in hematopoietic bone marrow and viscera. While several aspects of Gaucher disease (particularly those affecting the skeleton and brain) are refractory to treatment, enzyme (replacement) therapy has become a pharmaceutical blockbuster. Human β-glucocerebrosidase was originally obtained from placenta and the Genzyme Corporation (Allston, MA) subsequently developed a recombinant product. After purification, the enzyme is modified to reveal terminal mannose residues which facilitate selective uptake of the protein, imiglucerase (Cerezyme®), in macrophage-rich tissues. The unprecedented success of Cerezyme has attracted fierce competition: two biosimilar agents, velaglucerase-alfa, VPRIV® (Shire Human Genetic Therapies, Dublin, Ireland) and taliglucerase-alfa (Protalix, Carmiel, Israel), are now approved or in late-phase clinical development as potential ‘niche busters’. Oral treatments have advantages over biological agents for disorders requiring lifelong therapy and additional stratagems which utilize small, orally active molecules have been introduced; these include two chemically distinct compounds which inhibit uridine diphosphate glucose: N-acylsphingosine glucosyltransferase, the first step in the biosynthesis of glucosylceramide – a key molecular target in Gaucher disease and other glycosphingolipidoses. Academic and commercial enterprises in biotechnology have combined strategically to expand the therapeutic repertoire in Gaucher disease. The innovative potential of orphan drug legislation has been realized – with prodigious rewards for companies embracing its humanitarian precepts. In the era before enzyme therapy, bone marrow transplantation was shown to correct systemic disease in Gaucher patients by supplying a source of competent donor macrophages. As a radical advance on cell- or protein-replacement techniques, contemporary methods for transferring genes to autologous hematopoietic stem cells, and to the brain, merit further exploration. At present, the inflated pharmaceutical niche of Gaucher disease appears to be resilient, but if the remaining unmet needs of patients are to be convincingly addressed and commercial development sustained, courageous scientific investment and clinical experimentation will be needed.

European Medicines Agency support mechanisms fostering orphan drug development

A legislative framework introducing European public health measures on orphan medicinal products came into force in the European Union in April 2000. The aim of the orphan legislation is to stimulate research and development of medicinal products for rare diseases by providing incentives to the sponsors. Incentives include, among others, an unreserved access to the centralized procedure with a 10-year period of market exclusivity and fee reductions including free scientific advice for drug development. Nine years after the implementation of the orphan legislation, more than 690 products have been designated and 58 have received marketing authorizations in Europe. The orphan designations granted to date cover a wide variety of diseases for which there are either no authorized treatments or only limited treatment options with a need for improvement. At the dawn of the tenth anniversary of the orphan legislation, the aim of this article is to review how the European Medicines Agency has supported the mechanisms fostering development of orphan medicines in the E.U. since 2000.

Clinical trial design and management

The randomised, controlled trial (RTC) is considered the gold standard for the assessment of the effect of any therapeutic intervention. However, rare diseases carry several issues in terms of population size, life-threatening nature of the condition and lack of other available treatments, which basically render this approach not always feasible. Alternative methodological approaches are being developed to better suit the need of an orphan drug development.

Translation of rare disease research into orphan drug development: disease matters

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.

Pivotal studies of orphan drugs approved for neurological diseases

To identify design elements of clinical trials leading to US Food and Drug Administration approval of drugs for neurological diseases with and without orphan indications. We used publicly available information to identify approvals for drugs for neurological diseases with an orphan indication (n = 19) and compared them with recent approvals for drugs for neurological diseases without an orphan indication (n = 20). We identified "pivotal trials" from drug labels and drug approval packages, and assessed them on four elements of clinical trial design: control, blinding, randomization, and size. All drugs for neurological diseases (100%) approved without an orphan indication included at least two randomized, double-blind, placebo-controlled trials. In comparison, 32% of drugs with an orphan indication had at least two such trials (p < 0.001) and 74% had at least one (p = 0.02). Thirty-three pivotal trials were conducted for the 19 drugs approved with an orphan indication. Of the 33 trials, 11 (33%) did not use a placebo control, 9 (27%) were not double blind, and 4 (12%) were not randomized. Drugs approved without an orphan indication had more pivotal trials per drug (3.8 vs 1.7 trials; p < 0.001) and a larger mean trial size (506 vs 164 trial participants; p < 0.001). The US Food and Drug Administration has approved orphan drugs for neurological diseases without randomized, doubled-blind, placebo-controlled pivotal trials. As orphan drug development grows, demand will likely increase for alternative designs for conducting adequate and well-controlled studies to demonstrate drug efficacy.

Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs?

Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non-orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non-orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.

Orphan drug development is not taking off

Although, by definition, rare diseases involve few patients, there are so many – about 7000 (http://www.orpha.net/testor/cgi-bin/OTmain.php?&UserCell=publications) – that their epidemiological impact is impressive: 6–8% of the population is affected worldwide, with 30–40 million patients in the European Union (EU). This makes rare diseases a major public health issue [1]. However, the fragmented market means it is an area of little commercial interest for pharmaceutical companies, and the high price of orphan drugs tends to put them out of reach for the National Health Service [2].

Research priorities in epilepsy for the next decade—A representative view of the European scientific community: Summary of the ILAE Epilepsy Research Workshop, Brussels, 17–18 January 2008

Research priorities in epilepsy for the next decade—A representative view of the European scientific community: Summary of the ILAE Epilepsy Research Workshop, Brussels, 17–18 January 2008

The Many “Small COPDs”: COPD Should Be an Orphan Disease

The Many “Small COPDs”: COPD Should Be an Orphan Disease

Orphan drug development across Europe: bottlenecks and opportunities

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.

Orphan drug legislation: lessons for neglected tropical diseases

In the last 20 years, orphan drug legislation (ODL) has been adopted in several countries around the world (USA, Japan, Australia, and the European Union) and has successfully promoted R&D investments to develop new pharmaceutical products for the treatment of rare diseases. Without these incentives, many life-saving new drugs would have not been developed and produced. For economic reasons, the development of medicines for the treatment of diseases prevalent in the developing world (or tropical diseases) is lagging behind. Among several factors, the low average per-capita income makes pharmaceutical markets in developing countries appear relatively unprofitable and therefore unattractive for R&D-oriented companies. The case of ODL may offer some useful insights and perspectives for the fight against neglected tropical diseases. First, the measures used in ODL may also be effective in boosting R&D for neglected tropical diseases, if appropriately adapted to this market. Second, small-sized companies, which have played a successful role in the development of orphan drugs for rare diseases, may also represent a good business strategy for the case of tropical diseases.

Regulatory policy, value of knowledge assets and innovation strategy: The case of the Orphan Drug Act

The U.S. Orphan Drug Act provides R&D incentives to drug-makers that go beyond statutory patent protection. The study explores the act's effect on financial returns to innovation and on the strategy of orphan drug development. Results indicate that the financial return to orphan drug development is positive. The findings suggest that when market size is small and cumulative innovation is an important phenomenon the policy that extends effective patent duration or subsidizes R&D activity improves incentives to innovate.

Maladies rares : quelles sources d'information pour les professionnels de santé et les malades ?

The concept of rare diseases originated in the USA in the early eighties thanks to a patients' advocacy group which wanted to see drugs developed for their very rare disease. Europe adopted a regulation to stimulate the development of orphan drugs in 1999, following active lobbying by France. In Europe a disease is considered to be rare when its prevalence is lower than 1 in 2.000. This is the threshold below which the disease is not taught to medical students and the market is considered to be too limited to be of interest to pharmaceutical companies. Information is perceived as the key issue in relation to the rarity of the disease. Responding to this need in 1997, the French Ministry of Health and the French Health and Research Institute (Inserm) established an information service ( www.orpha.net). The Orphanet concept is to offer a summary of information on each rare disease and a directory of expert services in Europe. To serve the needs of professionals facing emergency situations, a series of factsheets is being developed, in partnership with learned societies to support good practice in the field of emergency medicine for rare diseases.

Mode 2 knowledge production: evidence from orphan drug networks

This paper seeks to contribute to the understanding of public participation in the process of science policy-making and the lay public's contribution to scientific knowledge production. Nowotny et al (2001) claim that the traditional boundaries between expert and lay knowledge are being transgressed and science and technology are thereby enriched. I provide empirical evidence that a new post-academic model of innovation has emerged where contextual knowledge is socially constructed and integrated into the innovation process. This research indicates that patients and lay experts do not simply speak to science (Nowotny et al, 2001) but in the case of orphan drug development contribute to complex political and regulatory negotiations and collaborate in knowledge production working alongside scientists, clinicians, industry and academics as equal partners, demonstrating the relationships between scientific expertise, public policy-making and the public.

Orphan drugs: Unmet societal need for non-profitable privately supplied new products

Due to the severity of rare diseases, the societal need for biopharmaceutical treatments for these diseases is high, despite low numbers of patients. Therefore, we investigated the barriers currently hindering the willingness to develop orphan drugs in the Netherlands. To this end, a robust, small sample, exploratory analysis of Dutch multi-actor development of orphan drugs was performed. Various factors that were expected to stimulate the adoption of orphan drug development were found to be important barriers. Concerted actions of producers, users, and especially regulators are necessary to overcome these barriers, but the prerequisite of a shared problem definition is lacking.

Tuesday July 4, 2006 Tuesday July 4, 2006 7:30-9:00 Hall 1 Orphan Drug Symposium

Abstract 1 M. Baulac ( 1 Service de Neurologie, Hopital Pitie-Salpetriere, Paris, France ) Although epilepsy is one of the commonest neurological disorders, certain epileptic syndromes or diseases are nonetheless fulfilling all the criteria, in terms of epidemiology and severity, for being qualified as rare diseases. These epileptic conditions indeed are distinct entities, affecting no more than 5 in 10,000 persons in Europe, carrying a risk of chronic impairment, severe debilitation, and mortality, and there is a lack of specific treatments with durable effects on the seizures and the neuropsychological disorders. Most of the epileptic encephalopathies can be qualified as rare diseases. They include Ohtahara syndrome / early myoclonic encephalopathy, migrating partial seizures in infancy, West syndrome, Dravet syndrome or severe myoclonic epilepsy in Infancy (1/30,000), Lennox-Gastaut syndrome (2/10,000), Landau-Kleffner syndrome, continuous spike-wave during sleep, etc… In these specific conditions, the intense ictal and interictal epileptic activity contributes to the progressive disturbance in brain function. These epileptic encephalopathies can themselves be caused by rare mutations or other rare diseases, for instance tuberous sclerosis in West syndrome. Orphan drugs, which are still in development, have been designated by the EMEA for the Dravet syndrome (stiripentol) and for the Lennox-Gastaut syndrome (rufinamide). In other situations, epilepsy is the predominant clinical expression of a disease of genetic, metabolic or inflammatory origin, which is responsible for progressive brain damage. Progressive myoclonic epilepsies (less than 1/20,000) for which brivaracetam was recently designated, and Rasmussen encephalopathy (approximately 1 case per big center per year) are good examples. It is very important for our patients and their families to ensure that these conditions are well acknowledged as rare diseases, and that they can benefit from the various governmental and EU incentives dedicated to specific research and Orphan drugs development.