title: Toward a functional definition of a "rare disease" for regulatory authorities and funding agencies.
abstract: BACKGROUND
  The designation of a disease as "rare" is associated with some substantial benefits for companies involved in new drug development, including expedited review by regulatory authorities and relaxed criteria for reimbursement. How "rare disease" is defined therefore has major financial implications, both for pharmaceutical companies and for insurers or public drug reimbursement programs. All existing definitions are based, somewhat arbitrarily, on disease incidence or prevalence.
  
  
  OBJECTIVE
  What is proposed here is a functional definition of rare based on an assessment of the feasibility of measuring the efficacy of a new treatment in conventional randomized controlled trials, to inform regulatory authorities and funding agencies charged with assessing new therapies being considered for public funding.
  
  
  METHODS
  It involves a five-step process, involving significant negotiations between patient advocacy groups, pharmaceutical companies, physicians, and public drug reimbursement programs, designed to establish the feasibility of carrying out a randomized controlled trial with sufficient statistical power to show a clinically significant treatment effect.
  
  
  CONCLUSIONS
  The steps are as follows: 1) identification of a specific disease, including appropriate genetic definition; 2) identification of clinically relevant outcomes to evaluate efficacy; 3) establishment of the inherent variability of measurements of clinically relevant outcomes; 4) calculation of the sample size required to assess the efficacy of a new treatment with acceptable statistical power; and 5) estimation of the difficulty of recruiting an adequate sample size given the estimated prevalence or incidence of the disorder in the population and the inclusion criteria to be used.
authors.affiliation: Hospital for Sick Children and University of Toronto, Toronto, ON, Canada. Electronic address: joeclarke@sympatico.ca.
authors.forename: Joe T R
authors.initials: JT
authors.lastname: Clarke
authors.affiliation: University of Ottawa, Ottawa, ON, Canada.
authors.forename: Doug
authors.initials: D
authors.lastname: Coyle
authors.affiliation: Kingston General Hospital and School of Medicine, Queen's University, Kingston, ON, Canada.
authors.forename: Gerald
authors.initials: G
authors.lastname: Evans
authors.affiliation: Schulich School of Medicine & Dentistry, Western University, London, ON, Canada; London Health Sciences Centre, London, ON, Canada.
authors.forename: Janet
authors.initials: J
authors.lastname: Martin
authors.affiliation: Schulich School of Medicine & Dentistry, Western University, London, ON, Canada; London Health Sciences Centre, London, ON, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Winquist
mesh_terms: D017277:Drug Approval / Q000458:organization & administration; D004345:Drug Industry / Q000458:organization & administration*; D004335:Drug and Narcotic Control / Q000458:organization & administration*; D005381:Financing, Organized / Q000458:organization & administration*; D006801:Humans; D007349:Insurance, Health, Reimbursement; D035583:Rare Diseases / Q000145:classification* / Q000188:drug therapy
keywords: drug development; drug reimbursement; orphan drugs; rare disease