title: Clinical trial designs for rare diseases: studies developed and discussed by the International Rare Cancers Initiative.
abstract: BACKGROUND
  The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research.
  
  
  METHODS
  The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed.
  
  
  RESULTS
  The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design.
  
  
  CONCLUSIONS
  Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.
authors.affiliation: European Organisation for Research and Treatment of Cancer, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Bogaerts
authors.affiliation: Medical Research Council Clinical Trial Unit at University College London, United Kingdom.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Sydes
authors.affiliation: Cancer Research UK, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Keat
authors.affiliation: Cancer Research UK, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: McConnell
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, United States.
authors.forename: Al
authors.initials: A
authors.lastname: Benson
authors.affiliation: Memorial Sloan Kettering Cancer Center, United States.
authors.forename: Alan
authors.initials: A
authors.lastname: Ho
authors.affiliation: Geneva University Hospital, Medical Oncology, Switzerland.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Roth
authors.affiliation: European Organisation for Research and Treatment of Cancer, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fortpied
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, United States.
authors.forename: Cathy
authors.initials: C
authors.lastname: Eng
authors.affiliation: The Royal Marsden, United Kingdom.
authors.forename: Clare
authors.initials: C
authors.lastname: Peckitt
authors.affiliation: European Organisation for Research and Treatment of Cancer, Belgium.
authors.forename: Corneel
authors.initials: C
authors.lastname: Coens
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, United States.
authors.forename: Curtis
authors.initials: C
authors.lastname: Pettaway
authors.affiliation: Hubertus Wald Tumorzentrum - University Cancer Centre Hamburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Arnold
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Hall
authors.affiliation: The University of Liverpool, United Kingdom.
authors.forename: Ernie
authors.initials: E
authors.lastname: Marshall
authors.affiliation: The Royal Marsden, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sclafani
authors.affiliation: The University of Cambridge Department of Oncology and NIHR Cambridge Biomedical Research Centre, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Hatcher
authors.affiliation: The University of Cambridge Department of Oncology and NIHR Cambridge Biomedical Research Centre, United Kingdom.
authors.forename: Helena
authors.initials: H
authors.lastname: Earl
authors.affiliation: Léon Bérard Cancer Center, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.affiliation: Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Paul
authors.affiliation: Léon Bérard Cancer Center, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.affiliation: NIHR University College London Hospitals Biomedical Research Centre, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Whelan
authors.affiliation: Memorial Sloan Kettering Cancer Center, United States.
authors.forename: Kathy
authors.initials: K
authors.lastname: Panageas
authors.affiliation: The University of Birmingham, United Kingdom.
authors.forename: Keith
authors.initials: K
authors.lastname: Wheatley
authors.affiliation: The Institute of Cancer Research, London, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Harrington
authors.affiliation: Istituto Nazionale dei Tumori Milan, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Licitra
authors.affiliation: Cancer Research UK Clinical Trials Unit and MRC Midland Hub for Trials Methodology Research, University of Birmingham, United Kingdom.
authors.forename: Lucinda
authors.initials: L
authors.lastname: Billingham
authors.affiliation: Memorial Sloan Kettering Cancer Center, United States.
authors.forename: Martee
authors.initials: M
authors.lastname: Hensley
authors.affiliation: The University of Manchester, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: McCabe
authors.affiliation: The University of Nottingham, United Kingdom.
authors.forename: Poulam M
authors.initials: PM
authors.lastname: Patel
authors.affiliation: Memorial Sloan Kettering Cancer Center, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Carvajal
authors.affiliation: Queen's University Belfast, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Wilson
authors.affiliation: Mount Vernon Cancer Centre, United Kingdom.
authors.forename: Rob
authors.initials: R
authors.lastname: Glynne-Jones
authors.affiliation: Mayo Clinic, United States.
authors.forename: Rob
authors.initials: R
authors.lastname: McWilliams
authors.affiliation: Centre hospitalier universitaire vaudois, Switzerland.
authors.forename: Serge
authors.initials: S
authors.lastname: Leyvraz
authors.affiliation: The Royal Marsden, United Kingdom.
authors.forename: Sheela
authors.initials: S
authors.lastname: Rao
authors.affiliation: Locum Consultant in Medical Oncology, United Kingdom.
authors.forename: Steve
authors.initials: S
authors.lastname: Nicholson
authors.affiliation: Gynecologic Oncology Group/NRG Oncology, United States.
authors.forename: Virginia
authors.initials: V
authors.lastname: Filiaci
authors.affiliation: European Organisation for Research and Treatment of Cancer, Belgium.
authors.forename: Anastassia
authors.initials: A
authors.lastname: Negrouk
authors.affiliation: European Organisation for Research and Treatment of Cancer, Belgium.
authors.forename: Denis
authors.initials: D
authors.lastname: Lacombe
authors.affiliation: Center for Global Health, US National Cancer Institute, United States.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Dupont
authors.affiliation: Institut National Du Cancer, France.
authors.forename: Iris
authors.initials: I
authors.lastname: Pauporté
authors.affiliation: Center for Global Health, US National Cancer Institute, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Welch
authors.affiliation: Cancer Research UK, United Kingdom.
authors.forename: Kate
authors.initials: K
authors.lastname: Law
authors.affiliation: Center for Global Health, US National Cancer Institute, United States.
authors.forename: Ted
authors.initials: T
authors.lastname: Trimble
authors.affiliation: National Institute for Health Research Clinical Research Network/Cancer, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Seymour
mesh_terms: D006801:Humans; D007391:International Cooperation; D009369:Neoplasms / Q000453:epidemiology / Q000628:therapy*; D055818:Public-Private Sector Partnerships / Q000458:organization & administration; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D035583:Rare Diseases / Q000453:epidemiology / Q000628:therapy*; D012107:Research Design
keywords: Bayesian; Clinical trials; Frequentist; Methodology; Multi-arm; Randomised controlled trials; Rare cancers