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Is Intention to Treat Still the Gold Standard or Should Health Technology Assessment Agencies Embrace a Broader Estimands Framework?

Insights and Perspectives From the National Institute for Health and Care Excellence and Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E9 (R1) Addendum
Published:September 20, 2022DOI:https://doi.org/10.1016/j.jval.2022.08.008

      Highlights

      • The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E9 (R1) addendum, through the estimand framework, has affirmed the desirability, in certain circumstances, of estimating treatment effects in randomized controlled trials on the basis of strategies that depart from the intention-to-treat principle.
      • To the best of our knowledge, there have been limited attempts to date to assess the implications of the addendum for health technology assessment decision making.
      • To help with this shortfall, we discuss the perspectives of 2 agencies, the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen and the National Institute for Health and Care Excellence, on the intention-to-treat principle, building on our understanding of published methods guidance, publicly available agency documents, and our experience of working with these agencies.

      Abstract

      Objectives

      The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E9 (R1) addendum will have an important impact on the design and analysis of randomized controlled clinical trials, which represent crucial sources of evidence in health technology assessments, and on the intention-to-treat (ITT) principle in particular. This article brings together a task force of health economists and statisticians in academic institutes and the pharmaceutical industry, to examine the implications of the addendum from the perspective of the National Institute for Health and Care Excellence (NICE) and the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) and to address the question of whether the ITT principle should be considered the gold standard for estimating treatment effects.

      Methods

      We review the ITT principle, as introduced in the ICH E9 guideline. We then present an overview of the ICH E9 (R1) addendum and its estimand framework, highlighting its premise and the proposed strategies for handling intercurrent events, and examine some cases among submissions to IQWiG and NICE.

      Results

      IQWiG and NICE appear to have diverging perspectives around the relevance of the ITT principle and, in particular, the acceptance of hypothetical strategies for estimating treatment effects, as suggested by examples where the sponsor proposed an alternative approach to the ITT principle when accounting for treatment switching for interventional oncology trials.

      Conclusions

      The ICH E9 (R1) addendum supports the use of methods that depart from the ITT principle. The relevance of estimands using these methods depends on the perspectives and objectives of payers. It is challenging to design a study that meets all stakeholders’ research questions. Different estimands may serve to answer different relevant questions or decision problems.

      Keywords

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