title: A small n sequential multiple assignment randomized trial design for use in rare disease research.
abstract: BACKGROUND
  Clinical trials in rare diseases are difficult to conduct due to the limited number of patients available with each disorder. We developed a Phase 2 trial which is a small n sequential multiple assignment randomized trial (snSMART) design to test several treatments for a rare disease for which no standard therapy exists.
  
  
  OBJECTIVE
  This paper illustrates the design, sample size estimation and operating characteristics of an snSMART.
  
  
  METHODS
  We investigate the performance of a class of weighted Z statistics via computer simulations.
  
  
  RESULTS
  We demonstrate the increase in power over traditional single stage designs, and indicate how the power changes as a function of the weight given to each stage.
  
  
  CONCLUSIONS
  The snSMART design is promising in a rare disease setting where several alternative treatments are under consideration and small sample sizes are necessary.
authors.affiliation: Health Informatics Institute, University of South Florida, Tampa, FL, United States. Electronic address: roy.tamura@epi.usf.edu.
authors.forename: Roy N
authors.initials: RN
authors.lastname: Tamura
authors.affiliation: Health Informatics Institute, University of South Florida, Tampa, FL, United States. Electronic address: jeffrey.krischer@epi.usf.edu.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Krischer
authors.affiliation: Department of Rheumatology, University of Toronto, Canada. Electronic address: Cpagnoux@mtsinia.on.ca.
authors.forename: Christian
authors.initials: C
authors.lastname: Pagnoux
authors.affiliation: Departments of Dermatology and Medicine, University of Pennsylvania, Philadelphia, PA, United States. Electronic address: Robert.Micheletti@uphs.upenn.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Micheletti
authors.affiliation: Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal Diseases, Bethesda, MD, United States. Electronic address: peter.grayson@nih.gov.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Grayson
authors.affiliation: Division of Biometrics 3, Office of Biostatistics, US Food and Drug Administration, Silver Spring, MD, United States. Electronic address: YehFong.Chen@fda.hhs.gov.
authors.forename: Yeh-Fong
authors.initials: YF
authors.lastname: Chen
authors.affiliation: Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, United States. Electronic address: Peter.Merkel@uphs.upenn.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Merkel
mesh_terms: D017322:Clinical Trials, Phase II as Topic; D003198:Computer Simulation; D006801:Humans; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D035583:Rare Diseases; D018401:Sample Size; D013223:Statistics as Topic / Q000379:methods*
keywords: Binary data; Re-randomization; Weighted Z statistic