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Estimands in clinical trials - broadening the perspective
Mouna Akacha1, Frank Bretz1, Stephen Ruberg2
1Novartis Pharma AG, Basel, Switzerland.
Statistics in Medicine
|July 21, 2016
Summary
Clinical trial estimands must clearly define scientific questions to avoid misinterpretation. Separating treatment adherence from efficacy and safety ensures transparent risk-benefit assessments for all stakeholders.
Area of Science:
- Clinical trial methodology
- Regulatory science
- Biostatistics
Background:
- Defining scientific questions in clinical trials is critical for alignment across all stages.
- Statistical analysis choices can obscure trial objectives, leading to interpretation challenges.
- The International Council for Harmonization (ICH) recognized the need for clearer regulatory guidance in 2014.
Purpose of the Study:
- To clarify relevant drug development questions and their alignment with intention-to-treat analyses.
- To examine clinical trial estimands from the perspectives of patients, physicians, regulators, and payers.
- To propose a framework for disentangling treatment adherence from efficacy and safety assessments.
Main Methods:
- Literature review and conceptual analysis of clinical trial design and statistical analysis.
- Consideration of stakeholder perspectives (patients, physicians, regulators, payers).
- Development of a classification for clinical trial estimands.
Main Results:
- Stakeholders share common interests in defining clinical trial estimands.
- Estimands can be broadly classified into those addressing non-adherence and those assessing efficacy/safety in adherent patients.
- Disentangling adherence from efficacy/safety provides a clearer risk-benefit evaluation.
Conclusions:
- Clearer definition of clinical trial estimands enhances transparency and clinical meaningfulness.
- Separating adherence issues from the assessment of treatment effects in adherent populations is crucial.
- This approach supports more robust drug development and regulatory decision-making.
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