title: "Threshold-crossing": A Useful Way to Establish the Counterfactual in Clinical Trials?
abstract: A central question in the assessment of benefit/harm of new treatments is: how does the average outcome on the new treatment (the factual) compare to the average outcome had patients received no treatment or a different treatment known to be effective (the counterfactual)? Randomized controlled trials (RCTs) are the standard for comparing the factual with the counterfactual. Recent developments necessitate and enable a new way of determining the counterfactual for some new medicines. For select situations, we propose a new framework for evidence generation, which we call "threshold-crossing." This framework leverages the wealth of information that is becoming available from completed RCTs and from real world data sources. Relying on formalized procedures, information gleaned from these data is used to estimate the counterfactual, enabling efficacy assessment of new drugs. We propose future (research) activities to enable "threshold-crossing" for carefully selected products and indications in which RCTs are not feasible.
authors.affiliation: European Medicines Agency, London, United Kingdom.
authors.forename: H-G
authors.initials: HG
authors.lastname: Eichler
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Bloechl-Daum
authors.affiliation: Section for Medical Statistics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Bauer
authors.affiliation: Novartis, Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Bretz
authors.affiliation: Harvard Medical School/Harvard Pilgrim Health Care Institute, Hartford, Connecticut, USA.
authors.forename: J
authors.initials: J
authors.lastname: Brown
authors.affiliation: Lancaster University, Lancaster, United Kingdom.
authors.forename: L V
authors.initials: LV
authors.lastname: Hampson
authors.affiliation: Collegeville, Pennsylvania, USA.
authors.forename: P
authors.initials: P
authors.lastname: Honig
authors.affiliation: Janssen Pharmaceutical Companies, Raritan, New Jersey, USA.
authors.forename: M
authors.initials: M
authors.lastname: Krams
authors.affiliation: Medicines Evaluation Board, Utrecht, University of Utrecht, Utrecht, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Leufkens
authors.affiliation: Health Canada, Ottawa, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Lim
authors.affiliation: Bill and Melinda Gates Foundation, Seattle, Washington, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Lumpkin
authors.affiliation: Project Data Sphere, Durham, North Carolina, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Murphy
authors.affiliation: European Medicines Agency, London, United Kingdom.
authors.forename: F
authors.initials: F
authors.lastname: Pignatti
authors.affiliation: Section for Medical Statistics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Posch
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: S
authors.initials: S
authors.lastname: Schneeweiss
authors.affiliation: MIT Sloan School of Management, Cambridge, Massachusetts, USA.
authors.forename: M
authors.initials: M
authors.lastname: Trusheim
authors.affiliation: Section for Medical Statistics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Koenig
mesh_terms: D006801:Humans; D008962:Models, Theoretical; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D004364:Pharmaceutical Preparations