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'Threshold crossing': a useful way to establish the counterfactual in clinical trials?

Research output: Contribution to Journal/MagazineJournal articlepeer-review

  • Hans-Georg Eichler
  • Brigitte Bloechl-Daum
  • Peter Bauer
  • Frank Bretz
  • Jeffrey Brown
  • Lisa Victoria Hampson
  • Peter Honig
  • Michael Krams
  • Hubert Leufkens
  • Robyn Lim
  • Murray Lumpkin
  • Martin Murphy
  • Francesco Pignatti
  • Martin Posch
  • Sebastian Schneeweiss
  • Mark Trusheim
  • Franz Koenig
<mark>Journal publication date</mark>12/2016
<mark>Journal</mark>Clinical Pharmacology & Therapeutics
Number of pages13
Pages (from-to)699-712
Publication StatusPublished
Early online date19/10/16
<mark>Original language</mark>English


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.