US Orphan Research Articles

Pressure for drug development in lysosomal storage disorders - a quantitative analysis thirty years beyond the US orphan drug act.

BackgroundLysosomal 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.MethodsAnalysis of the FDA database for orphan drug designations through descriptive and comparative statistics.ResultsBetween 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.ConclusionsDrug 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.

A 30-year retrospective: National Organization for Rare Disorders, the Orphan Drug Act, and the role of rare disease patient advocacy groups

A 30-year retrospective: National Organization for Rare Disorders, the Orphan Drug Act, and the role of rare disease patient advocacy groups Mary Dunkle National Organization for Rare Disorders, Danbury, CT, USA Abstract: This 30-year retrospective looks at the history of the US Orphan Drug Act and how it originally came to be enacted, with particular emphasis on the role of patient advocacy organizations. The article explores how rare-disease patient advocacy groups learned to work with government partners in the National Institutes of Health and US Food and Drug Administration, members of Congress, and the media to promote their cause. It also discusses their awakening to the value of collaboration, which led to the formation of an umbrella organization to represent their shared interests. Milestones over the years are briefly discussed, and current areas of focus for rare disease patient organizations – most notably, globalization – are also examined. Keywords: rare diseases, orphan products, NORD, Rare Disease Day, global patient communities, EURORDIS, NZORD, TFORD, CORD, rare disease research

The Pharmaceutical Market’s Adverse Effects

The Pharmaceutical Market’s Adverse Effects

Competing for the treasure in exceptions

Competing for the treasure in exceptions

PHP94 The US Orphan Drug Landscape: Before and After EU Orphan Drug Legislation of 2000

To encourage the development of orphan drug (OD) products, the European Union (EU) approved OD legislation in 2000, mirroring the US legislation passed in 1983. For the first time in history, these products were recognized as different from other drug products on a global level. Given this new global incentive for OD development, an increased focus on developing these products was expected. The objective of this research is to quantify a change in the rate of global OD development as measured by the rate of US Food & Drugs Administration (FDA) OD designations. All history within the OD database from the FDA website was included. The OD status, designation date, and contact company fields were analyzed to evaluate the OD designation rate and location of developers (US or non-US categories). There was a sharp increase in the number of FDA OD designations after the year 2000, with the rate of OD designations increasing by 475% compared to the prior period. From 1983 until 2000, 516 products received an FDA OD designation and the average increase in OD designation was 2.5 per year. From 2000 through 2011, the number of designations was 1266 and average increase in OD designation was 14.7 per year. After 2000, the proportion of OD designations from non-US countries increased until 2009 when nearly one-third of products with a new FDA OD designation were from non-US companies. The implementation of EU OD legislation may have contributed to a change in the number of FDA OD designations per year and the types of companies developing ODs for the US. With developing markets preparing OD legislation, these policy changes may further stimulate the growth of the OD industry around the world.

What the Orphan Drug Act Has Done Lately for Children With Rare Diseases: A 10-Year Analysis

The 1983 US Orphan Drug Act (ODA) provided incentives to stimulate treatment product development for patients with rare disease. This article highlights a decade of ODA contributions to this goal for children with RDs. An internal US Food and Drug Administration database was the information source for orphan designations, marketing approvals, and prevalence numbers for 2000 to 2009. Product categorization was based on the disease age of onset for which they received designation. Category 1 products were for diseases with onset exclusively in Childhood; Category 2 products were for diseases with onset at any age; and Category 3 products were for diseases with adult onset only. Disease prevalence distributions were analyzed by using population intervals of 20 000. From 2000 to 2009, 1138 orphan drugs were designated and 148 received marketing approval, of which 38 (26%) were for pediatric diseases. The proportion of approvals for pediatric products increased from 17.5% (10 of 57) in the first half of the decade, to 30.8% (28 of 91) in the second. More products received designation and marketing approval for pediatric diseases with prevalence numbers fewer than 20 000 than for any other prevalence subgroup. The median disease prevalence for all pediatric orphan designations that received marketing approval was 8972. Among the pediatric orphan drug approvals categorized by therapeutic class, the endocrine/metabolic drugs had the largest representation (39%). The ODA incentives have led to increased product availability for RDs overall, with an increasing number of marketing approvals for children this past decade.

Orphan drugs: pricing, reimbursement and patient access

PurposeThis article aims to provide a description of principal aspects of policy and practice associated with orphan drugs and treatments of rare diseases, and give perspectives for 2011 on new and emerging approaches for addressing patient access.Design/methodology/approachInformation has been synthesized from a wide variety of sources including the authors' experience and familiarity with this topic, having over the past ten years developed market access strategies for many orphan drugs. This is supplemented by pertinent information from conferences, meetings and articles published over the last 20 years and from policy documents released by relevant regulatory bodies.FindingsWhile a small number of people suffer from any one rare disease, approximately 30 million in the EU and 25 million in the USA are affected by such diseases. Annual orphan drug treatment costs may approach $500,000. High costs coupled with relatively sparse supportive clinical data and difficulty in meeting standard cost‐effectiveness benchmarks raise significant issues for payers in allocating finite budgetary resources. Since the US (1983) and European (European Parliament, 2000) orphan drug regulations were approved, hundreds of agents have been granted orphan status although many fewer have achieved marketing authorization. Agencies have introduced a slew of incentives to help sponsors develop and market orphan medicinal products. The nature and focus of the programs are undergoing a metamorphosis as access to funding is becoming as important as supporting development.Originality/valueThe article represents a contemporary examination of orphan drug policy and practice, bringing together historic elements which influenced practice up to 2010 and the latest, emerging trends and approaches which stakeholders are now embracing and which will shape procedures from 2011.

Medical Foods for Alzheimerʼs Disease

Alzheimer's disease (AD) is a neurodegenerative condition associated with cognitive loss, behavioural changes, functional ability decline and caregiver burden. Given the worldwide public health impact of AD, novel interventions to reduce suffering experienced by AD patients need to be developed. Foods may offer a mechanism for intervention complementary to drugs, devices, biologicals and vaccines. Apart from foods with health claims (including dietary supplements), medical foods are also being explored as an intervention option. The purpose of this article is to describe how medical foods may complement other interventions for AD patients by: (i) defining what a medical food is; (ii) discussing whether AD is a condition amenable to medical food intervention; (iii) reviewing current clinical trial data on medical foods used in participants with AD; and (iv) highlighting steps needed to establish a more comprehensive framework for developing medical foods for AD. While medical foods may be defined differently in other countries, the US Orphan Drug Act of 1998 defined a medical food as a food formulated for enteral intake, taken under physician supervision, and intended to meet the distinctive nutritional requirements identified for a disease or condition. For AD to be amenable to medical food intervention, it must: (i) result in limited or impaired capacity to ingest, digest, absorb or metabolize ordinary foodstuff or certain nutrients; or (ii) have unique, medically determined nutrient requirements; and (iii) require dietary management that cannot be achieved by modification of the normal diet alone. While these criteria are most likely met in advanced AD, identifying unique nutritional requirements in early AD that cannot be met by normal diet modification requires a better understanding of AD pathophysiology. A PubMed search using the terms 'medical food' and 'Alzheimer', limited to clinical trials published in English with human participants with AD aged >65 years and supplemented by other articles known to meet the inclusion criteria, revealed that only two medical foods, AC-1202 and Souvenaid® with Fortasyn Connect™, have clinical trial results available for discussion. As medical food development for AD is a relatively new endeavour, a window of opportunity exists for all stakeholders to develop a comprehensive framework for assuring that medical food interventions for AD achieve the highest possible scientific and ethical standards to warrant commercialization.

Registering New Drugs for Low-Income Countries: The African Challenge

Registering New Drugs for Low-Income Countries: The African Challenge

Location, Location, Location

Location, Location, Location

Orphan drugs: ten years of experience with the EU framework on stimulating innovation for treating rare diseases

This paper reviews the European Union’s (EU’s) legislative framework on orphan medicinal products in terms of the deliberations prior to its enactment as well as the key criteria, institutions and procedures established by it. This paper further examines the economic incentives, particularly the market exclusivity incentive, created for stimulating innovation by pharmaceutical companies for treating rare diseases. A quantitative analysis of the impact this innovation policy has had to date is provided by analysing the development of the number of active orphan drug designations and corresponding marketing authorisations during the ten-year period since the enactment of this legislation. The EU framework is compared to the US Orphan Drug Act and critical perspectives, such as pricing, patient access and off-label use, are discussed.

Predictors of orphan drug approval

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).

Therapies for Inborn Errors of Metabolism: What Has the Orphan Drug Act Delivered?

The 1983 US Orphan Drug Act established a process through which promising therapies are designated as orphan products and, later, with satisfactory safety and efficacy data, receive marketing approval and fiscal incentives. We examined accomplishments in drug development for inborn errors of metabolism (IEMs). Food and Drug Administration data were used to identify orphan product designations and approvals for IEMs, and the trends for the past 26 years were summarized. Individual clinical development times (CDTs) from filing investigational new drug application to marketing approval were determined. We examined 1956 orphan product designations from 1983 through 2008 and found 93 (4.8%) for IEMs. Of those, 24 (25.8%) received marketing approval. This proportion of approval was significantly (P = .036) higher than that for non-IEM orphan products (17%). Among the IEM products, disorders of complex molecules received the most designations and approvals (61 and 11, respectively). Among the subgroups, lysosomal storage diseases received the most designations and approvals (43 and 9, respectively), whereas mitochondrial diseases (other than fatty acid oxidation disorders) received 7 designations with no approvals. We then examined the CDTs for the approved IEM products and found a median of 6.4 years (range: 2.6-25.1 years). Biological products had significantly shorter CDTs than drugs (mean: 4.6 vs 11.0 years; P = .003). For 26 years, the Orphan Drug Act has generated new therapies for IEMs. Why some IEMs have motivated successful drug development and others have not remains enigmatic; yet the needs of IEM patients without treatment are a certainty.

Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years

The 1983 US Orphan Drug Act has stimulated the development of new therapies for rare diseases. To provide the first comprehensive overview of orphan-designated products and their indications, this article quantitatively analyses the characteristics and distribution of orphan designations and approvals by the US Food and Drug Administration from 1983 to August 2008. Of the 1,892 orphan-designated products, 326 received marketing approval, representing 247 different drugs and more than 200 different diseases. About half of the approvals had occurred by 4 years after designation was granted. The most common patient population size for orphan designations and approvals was fewer than 10,000 patients, and cancer was the most common disease area. The implications of such findings for future development and marketing of therapies for rare diseases are discussed.

The US Orphan Drug Act: Rare disease research stimulator or commercial opportunity?

This study investigates issues associated with the United States Orphan Drug Act. A comprehensive orphan drug database was compiled from FDA data and corporate annual reports of major pharmaceutical companies. Analysis allowed the generation of a descriptive orphan drug portrait as well as documentation of orphan drugs along their lifecycle. Currently, 2002 products have obtained orphan drug designation with 352 drugs obtaining FDA approval. Approximately 33% of orphan drugs are oncology products. On average, products obtain 1.7 orphan designations with approximately 70% obtaining a single designation. At least 9% of orphan drugs have reached blockbuster status with two-thirds having two or more designations. An additional 25 orphan drugs had sales exceeding US$ 100 million in 2008 alone. Since 1983, at least 14 previously discontinued products have been recycled as orphan drugs. The United States Orphan Drug Act has created issues which, in some cases, have led to commercial and ethical abuses. Orphan Drug Act reform is necessary but current incentives, including 7 year market exclusivity, should be maintained in order to favour patients as well as economic prosperity. Suggested reforms include price regulation, subsidy paybacks for profitable drugs and the establishment of an International Orphan Drug Office.

Ewing's sarcoma drug gets US orphan status.

Ewing's sarcoma drug gets US orphan status.

US orphan drug designation granted for MGCD0103

US orphan drug designation granted for MGCD0103

The impact of the Orphan Drug Act on drug discovery

For nearly a quarter of a century the FDA Office of Orphan Products Development has administered the US Orphan Drug Act, which assists in bringing a wide variety of drug and biological (drug) products to treat rare diseases to market. Enthusiasm for rare disease product development has been sustained, seen throughout a wide spectrum of product types and disease conditions, and has resulted in clinically meaningful medical advances. Development of programmes for rare disease treatment worldwide, coupled with the development of drugs for diseases affecting developing countries, attests to the strength of this legislation. The marketing of almost 300 products in the US for rare diseases also testifies to the depth and intensity of scientific endeavour in this area.

Meeting the need for treatment: the initiatives

Many diseases prevail because are old and ineffective, or simply do not exist. Tuberculosis (TB) is a major killer in poor countries, but no new anti-TB drug has been developed since the 1960s. There are rare, often life-threatening diseases, defined in Europe as affecting fewer than one in 2000 people, for which more orphan drugs need to be developed. There are diseases that are highly prevalent, such as HIV/AIDS in southern Africa, but while new, effective medicines exist, millions of people and their governments cannot afford them or they are not available at all. Neglected tropical diseases, such as malaria, affect millions of people, but most are too poor to constitute a market that is lucrative enough to justify drug research and development (RD 46 such projects were in the pipeline in 2005, according to a Wellcome Trust report. The generic industry provides cheap copies of brand-name medicines, has pushed down drug prices overall through competition. Access-to-medicines campaigners and generic companies argue that patents are a major barrier to meet the huge demand for affordable drugs, vaccines and diagnostics in developing countries. In contrast, the R&D-based pharmaceuticals industry, which comes up with innovations and patents them to recoup the R&D costs, argues that the bottleneck is not the fault of patent restrictions, but the lack of funds to buy these products and inadequate infrastructure to deliver them. Generic industry The global generic pharmaceuticals industry produces cheap copies of patented medicines for diseases such as HIV/AIDS, often pushing down the prices of the original patented medicines in the process. India is a major exporter of generic medicines to other developing countries. Of the more than 60 000 HIV/AIDS patients in nearly 30 countries in Medecins Sans Frontieres' projects, 84% receive generic medicines made in India. The generic industry helped establish the US Orphan Drug Act of 1983 to promote the development of medicines for small patient populations by providing incentives, such as tax benefits and exclusive marketing protection. Some say this model could be used to promote the R&D for for neglected diseases. The generic industry sees several threats to its business model, such as evergreening by pharmaceutical companies to extend their patent rights and data exclusivity, i.e. denying the release of information required to advance science. Public-private partnerships Public-private partnerships show that costly drug development can be combined with social responsibility. Under a 2002 agreement with US pharmaceuticals company Chiron Corporation, the Global Alliance for TB Drug Development obtained exclusive world rights to the compound, PA-824, and its derivatives, which may be developed into a new TB medicine. Chiron agreed to make the compounds royalty free in endemic countries, while retaining the right to develop and commercialize them for non-TB indications. Another example is a 2004 agreement between the International Partnership for Microbicides and Tibotec Pharmaceuticals, a Belgian subsidiary of pharmaceutical company Johnson & Johnson, to develop a microbicide to protect women from infection with HIV. …

Extended-release tramadol [TQ 1017; TheraQuest Biosciences] has been granted a second US orphan drug designation

Extended-release tramadol [TQ 1017; TheraQuest Biosciences] has been granted a second US orphan drug designation