Bayesian Frameworks for Rare Disease Clinical Development Programs
Emmanuel Lesaffre, Gianluca Baio, Bruno Boulanger in Bayesian Methods in Pharmaceutical Research, 2020
These definitions arise from regional legislative acts. The earliest such regulation was established in United States, the 1983 Orphan Drug Act. The orphan drugs referred to in the act are for rare diseases or conditions, including biological products and antibiotics “orphaned” (abandoned) by drug companies due to their low sales potential, an obvious consequence of disease rarity. Following the establishment of this groundbreaking legislation, rare diseases are now often called “orphan diseases,” and orphan drugs are inclusive of biologic products (though not medical devices). More than a decade later, the second major related legislative action was the 1999 Orphan Regulation adopted by the European Parliament. Both regulations include monetary incentives, marketing exclusivities, and clinical research assistance for rare disease medicinal product development. Other than drug product development, there are other regulations or government entities (e.g. the US Rare Diseases Act in 1992 and the Spanish Rare Diseases Research Institute) that aid patient support groups and fund research projects in rare diseases. Several papers, including Gupta (2012) and Gammie et al. (2015), synthesize details and comparisons across different legislations across nations. In fact, most developed countries and regions now have well-established rare disease or orphan product programs. The US remains one of the leaders and a key player in orphan product development and rare disease research.
Towards precision medicine
Yann Joly, Bartha Maria Knoppers in Routledge Handbook of Medical Law and Ethics, 2014
Orphan drug designation is typically given to products intended to be the first treatment for a rare and/or serious disease. It is estimated that there are between 4,000 and 5,000 rare diseases worldwide for which no treatment is currently available (Sharma et al. 2010). In the Orphan Drug Act of 1983, the US defines an orphan disease as one affecting less than 200,000 people (approximately 0.06 per cent of the American population). The EU defines a rare disease as affecting 5 per 10,000 citizens (0.05 per cent), while Japan’s definition of rarity involves fewer than 50,000 patients (approximately 0.03 per cent) (Regulation (EC) No. 141/2000; Japan Pharmaceutical Manufacturers Association (JPMA) 2013). Other conditions also affect the granting of orphan drug status. In the EU, a drug must provide diagnosis, prevention or treatment of life-threatening, seriously debilitating, or serious and chronic conditions such that without incentive-driven policies, the drug would be unlikely to generate sufficient returns to justify the necessary investment and there would be no satisfactory medication for the condition. In Japan, the drug must either treat a disease condition for which there are no other treatments available or be clinically superior to a previously accepted drug (EMA 2011; Sharma et al. 2010; JPMA 2013).
Impact of Evolving Regulatory Pathways on Statistical Considerations in Oncology Clinical Trials
Satrajit Roychoudhury, Soumi Lahiri in Statistical Approaches in Oncology Clinical Development, 2018
During different stages of the drug development, the manufacturing company or the sponsor of the drug product can apply for orphan drug, fast track, and breakthrough designations. The orphan drug designation is given to products that are being developed for use in orphan diseases with a disease prevalence of less than 200,000 patients per year in the United States. This designation provides an extended market exclusivity and waiver of the application review fee. A fast track designation is based on observed preclinical activity and allows for rolling submission of different sections of the marketing application. The breakthrough designation [1] (Food and Drug Safety Innovation Act 2012) allows FDA to expedite and assist drug manufacturers in the development and review of new drugs with preliminary clinical evidence that suggests that the drug may offer substantial improvement over available therapies for patients with serious or life-threatening diseases [2] (FDA guidance 2014).
Gene therapy for inherited retinal and optic nerve degenerations
Published in Expert Opinion on Biological Therapy, 2018
Nicholas A. Moore, Nuria Morral, Thomas A. Ciulla, Peter Bracha
Inherited retinal degenerations (IRDs) are a rare and heterogenous group of diseases that collectively result in progressive retinal degeneration with resultant severe visual impairment; over 200 causative mutations have been identified. The most common IRDs include Leber’s congenital amaurosis (LCA), choroideremia, retinitis pigmentosa (RP), Usher syndrome, Stargardt disease, Leber’s hereditary optic neuropathy (LHON), achromatopsia, and X-linked retinoschisis (XLRS) [1]. The blinding nature of these conditions and lack of effective treatment highlight the need for therapeutic innovation. The fact that the disease-causing genes have been identified, together with their monogenic etiology, facilitates the potential for gene therapy. Furthermore, IRDs also attracted interest because both the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have incentivized development of therapies for rare diseases, which historically has been challenging due to small patient populations for clinical trials and post-approval marketing. In the United States, the Orphan Drug Act of 1983 defined orphan diseases as those that affected fewer than 200,000 Americans. The Orphan Drug Act provided sponsors with 7 years of exclusivity, tax credits to defray the cost of development, waived FDA fees, and provided protocol assistance. The EMA provides similar incentives.
Voretigene neparvovec-rzyl for treatment of RPE65-mediated inherited retinal diseases: a model for ocular gene therapy development
Published in Expert Opinion on Biological Therapy, 2020
Thomas A. Ciulla, Rehan M. Hussain, Audina M. Berrocal, Aaron Nagiel
The retina community has generally not been exposed to treatments approved for orphan diseases, which represented another challenge in the development and launch of VN. Historically, rare diseases have been neglected, or ‘orphaned,’ in drug development due in part to the inherent challenges of lengthy and expensive clinical trial operations in small, often geographically dispersed patient populations. In the US, the Orphan Drug Act of 1983 defined orphan diseases as those that affected fewer than 200,000 Americans [60]. The Orphan Drug Act provided sponsors with 7 years of exclusivity, tax credits to defray the cost of development, waived FDA fees, and provided protocol assistance. The European Medicines Agency (EMA) provided similar incentives in 2000, with orphan designation for products addressing life-threatening or debilitating disorders affecting 5 or fewer per 10,000 individuals [61]. There are additional incentives to develop therapies for rare pediatric diseases; in 2017, Spark Therapeutics announced that it received rare pediatric disease designation for VN [62] and was able to sell the associated priority review voucher in 2018, which provided capital to reinvest back into research and development [63].
Rarely mentioned: how we arrived at the quantitative definition of a rare disease
Published in Baylor University Medical Center Proceedings, 2022
While many consider the Orphan Drug Act of 1983 to be a source for the accepted definition of rare disease in the United States, perusal of 18 pages of arid but thoughtful legislative language fails to mention this mystical number of 200,000 that confers rare disease designation. Often the definition of rare disease and drug development issues link together. For example, in Section 256, the Act states: “The term ‘rare disease or condition’ means any disease or condition which occurs so infrequently in the United States that there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will be recovered from sales in the United States of such drug.”5 Society would have to wait for the 1984 amendments to garner a quantitative definition.
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