Background

This case study applies the estimand framework from ICH E9(R1) to a clinical trial comparing the efficacy and safety of a fixed combination of two components with each component used in monotherapy for patients with bilateral ocular hypertension or open-angle glaucoma. The randomized, double-masked, multicenter trial enrolled 335 patients and assessed intraocular pressure (IOP) at various timepoints over a 3-month period after washout of prior ocular hypotensive therapy.

Challenge 

To apply the estimand framework to define the treatment effect of the fixed combination versus its individual components in patients with ocular hypertension or open-angle glaucoma.

Defining the Estimand

We define the estimand based on the ICH E9(R1) framework:

  1. Treatment

Fixed combination vs. comparator arms of each monotherapy

  1. Population

Modified Intention-to Treat (mITT): All patients randomized to therapy who received at least one dose

  1. Variable (Endpoint)

Primary variable: Change from baseline to Month 3 in intraocular pressure (IOP) in the worst eye at baseline

  1. Intercurrent Events and Strategies

Key intercurrent events:

  • Discontinuation of study
  • Discontinuation of treatment
  • Use of rescue medication or additional IOP-lowering therapy
  • Missing data

Strategies:

  • Treatment policy strategy: Includes data regardless of discontinuation or rescue therapy to reflect real-world use. If data is missing from the worst eye, a mixed effects model with a correlation structure for inter-eye correlation as well as a the unstructured correlation among visits will be used.
  • Composite strategy (exploratory): Patients needing rescue therapy could be considered non-responders for sensitivity analysis
  1. Population-level Summary
  • Summary measure: Mean percent reduction in IOP from baseline at month 3
  • Secondary: Proportion of patients achieving a predefined threshold IOP reduction (e.g., ≥25%)

Primary Estimand

Attribute Definition
Treatment 2-drug fixed combination vs. drug 1 monotherapy or drug 2 monotherapy
Population Adults with ocular hypertension or open-angle glaucoma who completed a washout of hypotensive meds
Variable Change in IOP from baseline to Month 3 in the worst eye
Intercurrent Events Discontinuation, rescue medication, missing data
Strategy Treatment policy strategy with exploratory composite strategy for sensitivity analysis
Summary Measure Mean % IOP reduction and mean mmHg change from baseline

Discussion

The use of an estimand framework ensures clarity in interpreting the treatment effect of the combination versus monotherapies. The treatment policy strategy allows inclusion of all randomized patients regardless of discontinuation or rescue medication, making the analysis more reflective of real-world effectiveness. Sensitivity analyses using composite strategies help gauge robustness of findings.

Conclusion

This ophthalmology trial illustrates the practical application of the estimand framework. By clearly specifying the treatment effect of interest, how intercurrent events are handled, and what summary measures are used, the trial provides a transparent and reproducible assessment of the IOP-lowering efficacy and safety of a fixed combination therapy.

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