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Rare Diseases and Orphan Products: Accelerating Research and Development
understood condition. Longitudinal studies of various sorts may also illuminate treatment effects.
Although natural history studies are not the primary focus of government- or industry-funded research, NIH and pharmaceutical companies as well as other entities do sponsor natural history studies of varying scope and complexity.3 For example, members of the NIH Rare Diseases Clinical Research Network (see Chapter 5 and Appendix E) are undertaking such studies for a number of rare conditions, including several neurological disorders and several forms of vasculitis. Understanding the natural history of a disease is an important step in the development of therapies. As discussed in Chapter 3, FDA staff have identified the lack of such studies as a problem with some applications for approval of orphan drugs.
In 2008, participants in a workshop sponsored by the National Heart, Lung, and Blood Institute and the Office of Rare Diseases Research at the NIH discussed models for analyzing genotype-phenotype associations in rare diseases and made recommendations for more longitudinal studies and also for refinements in study protocols and better tools to evaluate the resulting data (NHLBI, 2008a). It is too early to judge whether these recommendations will yield more high-quality proposals, an improved infrastructure, and more funding for such studies, which are challenging even for common conditions. Recommendations in Chapters 4 and 5 address problems with tissue banking practices and arrangements that limit or complicate their use for natural history and other studies.
Many epidemiologic data for rare diseases come from studies of single diseases. These studies are sponsored by a multitude of different sources and employ a range of methods and data. Data for prevalence or incidence calculations may come from birth certificates or death certificates; hospital discharge, insurance claims, and other administrative databases; patient registries; special surveillance studies; and newborn and other screening programs.
National data collection programs tend to focus on more common conditions, but information about the prevalence and incidence of some
For example, a search of the database ClinicalTrials.gov yielded 50 studies using the search term “natural history study” and 1,613 studies using the term “natural history.” Among the NIH-supported natural history studies that involved rare conditions were studies of sickle cell disease (NCT00081523), neurofibromatosis type I (NCT00924196), hereditary hemorrhagic telangiectasia (NCT00004649), Rett syndrome (NCT00299312), stiff person syndrome (NCT00030940), Smith-Magenis syndrome (NCT00013559), and acromegaly (NCT00001981). The last cited study began in 1985 and continues. Examples of pharmaceutical company-funded studies include metachromatic leukodystrophy (NCT00639132, Shire); mucopolysaccharidosis I (NCT00144794, Genzyme); and infantile globoid cell leukodystrophy (NCT00983879, Zymenex A/S). (The numbers in parentheses are identifiers used for the ClinicalTrials.gov database, which was developed by NIH and FDA.)