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Introduction
Published in Wei Zhang, Fangrong Yan, Feng Chen, Shein-Chung Chow, Advanced Statistics in Regulatory Critical Clinical Initiatives, 2022
Wei Zhang, Fangrong Yan, Feng Chen, Shein-Chung Chow
A rare disease is defined by the Orphan Drug Act of 1983 as a disorder or condition that affects less than 200,000 persons in the United States. Most rare diseases are genetic related, and thus are present throughout the person's entire life, even if symptoms do not immediately appear. Many rare diseases appear early in life, and about 30%of children with rare diseases will die before reaching their fifth birthday. FDA is to advance the evaluation and development of products including drugs, biologics and devices that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions. Along this line, FDA evaluates scientific and clinical data submissions from sponsors to identify and designate products as promising for rare diseases and to further advance the scientific development of such promising medical products. Following the Orphan Drug Act, FDA also provides incentives for sponsors to develop products for rare diseases. The program has successfully enabled the development and marketing of over 600 drugs and biological products for rare diseases since 1983.
The FDA New Animal Drug Approval Process
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
Jacob Michael Froehlich, Alice Ignaszewski, Anna O’Brien
Under the Act, seven animal species are defined as “major species”: dogs, cats, horses, cattle, pigs, chickens, and turkeys. All other species are considered “minor species.” Under this dichotomy, ferrets are considered a minor species, as are goats, scarlet macaws, leopard geckos, red-eyed tree frogs, bettas, and, yes, even honeybees! Similarly, the Act defines a “minor use” as the use of a new animal drug in a major species for a condition which occurs either infrequently or in a limited geographical area and in a small number of animals per year. Examples of a minor use in a major species could be a rare cardiac disorder which occurs in fewer than the published “small number of animals” for dogs (currently 70,000) or an uncommon metabolic disorder in horses (the current small number is 50,000). These definitions are important to the new animal drug approval process, as the Minor Use and Minor Species Animal Health Act of 2004 (which amended the Act itself) established incentives for sponsors to pursue drug approvals for uncommon conditions in major species (similar to the Orphan Drug Act of 1983 which created financial incentives for development of a drug or biologic to treat rare or neglected tropical diseases in humans) and species with small populations. These incentives are available through the Office of Minor Use and Minor Species Animal Drug Development (OMUMS) within the FDA-CVM.
Implications for Risk Management
Published in Samuel C. Morris, Cancer Risk Assessment, 2020
The most extensive application of probability of causation or assigned share, as some would rather call it, has been for cancers attributed to radiation exposure. The Orphan Drug Act of 1983 included a clause directing the Secretary of Health and Human Services to “devise and publish” tables estimating the likelihood that persons with cancers, who received specific doses of radiation prior to the onset of the cancer, developed their cancer as a result of the radiation exposure. It was hoped that this would lead to greater rationality and consistency in court cases awarding damages to cancer victims who had been exposed to radiation. The National Institutes of Health produced these tables (NIH, 1985), but difficulties remain in their application and interpretation.
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].
Clinical development on the frontier: gene therapy for duchenne muscular dystrophy
Published in Expert Opinion on Biological Therapy, 2020
Damon R. Asher, Khampaseuth Thapa, Sachi D. Dharia, Navid Khan, Rachael A. Potter, Louise R. Rodino-Klapac, Jerry R. Mendell
These conventional small-molecule clinical study paradigms are challenged when applied in the development of therapeutics for rare diseases. As established by the Orphan Drug Act of 1983, a drug qualifies for orphan status if it is intended to treat a rare disease or condition affecting less than 200,000 persons in the U.S. [35]. Many life-threatening rare diseases primarily impact pediatric patients, highlighting both the challenges and urgency of effective drug development [36]. Sparse rare disease patient populations, disease heterogeneity, and geographic dispersion create difficulties in enrolling representative, homogenous cohorts for clinical studies [30]. Adding further complexity are challenges specifically associated with gene therapies. For example, development of antibodies to the vector upon gene therapy administration serves as a barrier to receiving future gene therapies derived from that vector and may also exclude them from participation in other clinical trials. This has implications to the conventional practice of dosing healthy volunteers as these volunteers may then be precluded from receiving gene therapies should a future need arise. Similarly, conventional dose escalation studies need to be reexamined in the context of gene therapy given that patients receiving subefficacious doses may still develop immunity that would block future doses of a vector. This not only raises an ethical imperative to make the best efforts to give all patients a potentially efficacious dose, but it also puts an especially high burden on the preclinical work to establish an optimal dose range for safety and efficacy.
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.