title: Surrogate endpoints for clinical trials in primary sclerosing cholangitis: Review and results from an International PSC Study Group consensus process.
abstract: Primary sclerosing cholangitis (PSC) is a rare, but serious, cholestatic disease for which, to date, no effective therapy exists to halt disease progression toward end-stage liver disease. Clinical trial design to study drugs that improve prognosis is hampered by the relatively low event rate of clinically relevant endpoints. To overcome this shortcoming, there is an urgent need to identify appropriate surrogate endpoints. At present, there are no established surrogate endpoints. This article provides a critical review and describes the results of a consensus process initiated by the International PSC Study Group to delineate appropriate candidate surrogate endpoints at present for clinical trials in this frequently dismal disease. The consensus process resulted in a shortlist of five candidates as surrogate endpoints for measuring disease progression: alkaline phosphatase (ALP); transient elastography (TE); histology; combination of ALP+histology; and bilirubin. Of these, histology, ALP, and TE came out as the most promising. However, the expert panel concluded that no biomarker currently exceeds level 3 validation. Combining multiple endpoints is advisable.
  
  
  CONCLUSIONS
  At present, there are insufficient data to support level 2 validation for any surrogate endpoint in PSC. Concerted efforts by all stakeholders are highly needed. Novel, promising noninvasive biomarkers are under study and should be incorporated as exploratory endpoints in clinical trials.
authors.affiliation: Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cyriel Y
authors.initials: CY
authors.lastname: Ponsioen
authors.affiliation: Department of Gastroenterology & Hepatology, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Chapman
authors.affiliation: AP-HP, Hôpital Saint-Antoine, Service d'Hépatologie and Sorbonne Universités, UPMC Univ Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Chazouillères
authors.affiliation: Center for Liver Research and NIHR Biomedical Research Unit University of Birmingham, Birmingham, United Kingdom.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.affiliation: Norwegian PSC Research Center, Oslo University Hospital, Oslo, Norway.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.affiliation: Department of Medicine, University Medical Center Hamburg, Eppendorf, Germany.
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.affiliation: Division of Medicine, University College London, UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pinzani
authors.affiliation: Norwegian PSC Research Center, Oslo University Hospital, Oslo, Norway.
authors.forename: Erik
authors.initials: E
authors.lastname: Schrumpf
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D015209:Cholangitis, Sclerosing / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D032921:Consensus; D018450:Disease Progression; D058625:End Stage Liver Disease / Q000401:mortality / Q000503:physiopathology* / Q000601:surgery; D019317:Evidence-Based Medicine; D005260:Female; D006801:Humans; D038622:Internationality; D016031:Liver Transplantation / Q000379:methods; D008297:Male; D020380:Needs Assessment; D017410:Practice Guidelines as Topic; D035583:Rare Diseases; D018570:Risk Assessment; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers