Orphan diseases are those affecting fewer than 200,000 persons in the United States. Some of these diseases are very rare worldwide, but some, like malaria, are common in developing countries. Here we discuss the former types of disease. In our section on tropical disease, we discuss our work with malaria.
Very rare diseases are challenging to study because the affected populations are small and often scattered over major geographic areas. The natural histories of orphan diseases may also be little known, or even unknown.
Statistics Collaborative, Inc. (SCI) has experience working with the particular statistical challenges affecting orphan disease trials. Because of the many unknowns involved in the study of rare diseases, in doing this work we collaborate closely with experts in the subject matter. We show sensitivity to the issues presented by small sample size, which can lead to baseline imbalance, failure of distributional assumptions, large variability, and low power.
Examples of SCI’s work in orphan diseases:
- Phenylketonuria (PKU): For a series of Phase 2 and 3 trials, SCI assisted BioMarin Pharmaceutical, Inc. with design and analysis to support the approval of KUVAN® for children. SCI also provided statistical support for the clinical study report (CSR), the Integrated Efficacy Report, and post-approval commitments for PKU.
- Mucopolysaccharidosis type 6 (MPS6): For BioMarin’s pivotal Phase 3 and extension studies of Naglazyme®, an enzyme-replacement therapy for individuals with MPS6, SCI’s involvement has ranged from outcome exploration during protocol development to analysis and interpretation for CSRs for submission to the FDA and the European Medicines Agency (EMEA).
- Hereditary angioedema (HAE): SCI performed interim monitoring for a pivotal efficacy trial in patients experiencing acute attacks of HAE. We reassessed the sample size midway through to ensure that the trial had adequate power to detect the hypothesized treatment effect.
Examples of papers:
- Lee P, Crombez E, Wasserstein M, Waber L, Wolff J, Wendel U, Dorenbaum A, Bebchuk J, Christ-Schmidt H, Seashore M, Giovannini M, Burton BK, Treacy EP, Morris AA, The Sapropterin Research Group. Safety and efficacy of 22 weeks of treatment with sapropterin dihydrochloride in patients with phenylketonuria. Am J Med Genet 2009 to appear;
- Harmatz P, Giugliani R, Schwartz IV, Guffon N, Teles EL, Miranda MC, Wraith JE, Beck M, Arash L, Scarpa M, Ketteridge D, Hopwood JJ, Plecko B, Steiner R, Whitley CB, Kaplan P, Yu Z, Swiedler SJ, Decker C. Long-term follow-up of endurance and safety outcomes during enzyme replacement therapy for mucopolysaccharidosis VI: Final results of three clinical studies of recombinant human N-acetylgalactosamine 4-sulfatase. Mol Genet Metab 2008; 94:469-475.
- Levy HL, Milanowski A, Chakrapani A, Cleary M, Lee P, Trefz FK, Whitley CB, Feillet F, Feigenbaum AS, Bebchuk JD, Christ-Schmidt H, Dorenbaum A. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study. Lancet 2007; 370:504-510.