Strategies for composite estimands in confirmatory clinical trials: Examples from trials in nasal polyps and steroid reduction

Pharm Stat. 2019 Jan;18(1):78-84. doi: 10.1002/pst.1909. Epub 2018 Oct 29.

Abstract

The draft addendum to the ICH E9 regulatory guideline asks for explicit definition of the treatment effect to be estimated in clinical trials. The draft guideline also introduces the concept of intercurrent events to describe events that occur post-randomisation that may affect efficacy assessment. Composite estimands allow incorporation of intercurrent events in the definition of the endpoint. A common example of an intercurrent event is discontinuation of randomised treatment and use of a composite strategy would assess treatment effect based on a variable that combines the outcome variable of interest with discontinuation of randomised treatment. Use of a composite estimand may avoid the need for imputation which would be required by a treatment policy estimand. The draft guideline gives the example of a binary approach for specifying a composite estimand. When the variable is measured on a non-binary scale, other options are available where the intercurrent event is given an extreme unfavourable value, for example comparison of median values or analysis based on categories of response. This paper reviews approaches to deriving a composite estimand and contrasts the use of this estimand to the treatment policy estimand. The benefits of using each strategy are discussed and examples of the use of the different approaches are given for a clinical trial in nasal polyposis and a steroid reduction trial in severe asthma.

Trial registration: ClinicalTrials.gov NCT03085797 NCT01691508.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Asthma / diagnosis
  • Asthma / drug therapy*
  • Asthma / physiopathology
  • Data Interpretation, Statistical
  • Drug Dosage Calculations
  • Endpoint Determination / statistics & numerical data
  • Humans
  • Models, Statistical
  • Nasal Polyps / complications
  • Nasal Polyps / diagnosis
  • Nasal Polyps / drug therapy*
  • Randomized Controlled Trials as Topic / methods
  • Randomized Controlled Trials as Topic / statistics & numerical data*
  • Research Design / statistics & numerical data*
  • Severity of Illness Index
  • Steroids / administration & dosage*
  • Steroids / adverse effects
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal, Humanized
  • Steroids
  • mepolizumab

Associated data

  • ClinicalTrials.gov/NCT03085797
  • ClinicalTrials.gov/NCT01691508