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Review
. 2025 Oct 3:64:127645.
doi: 10.1016/j.vaccine.2025.127645. Epub 2025 Sep 3.

Adopting the estimand framework in prophylactic vaccine trials

Francois Beckers  1 , Naveen Karkada  2 , Ye Yang  3 , John Scott  3 , Lei Huang  3 , Florian Klinglmüller  4 , Michael P Fay  5 , Stefan Englert  6 , Bart Spiessens  7 , Ilse Van Dromme  7 , Tulin Shekar  8 , Honghong Zhou  9 , Qiqi Deng  9 , Daniela Casula  10 , Holly Janes  11 , Lawrence H Moulton  12
Affiliations
Review

Adopting the estimand framework in prophylactic vaccine trials

Francois Beckers et al. Vaccine. .

Abstract

The estimand framework as outlined in ICH E9(R1) has been extensively discussed and implemented in clinical trials of therapeutic products. However, there is limited literature on the application of the framework in preventive vaccine trials, which has many unique characteristics, including emphasis on estimating the per-protocol or "biological" effect. We provide a comprehensive review of the application of the framework to preventive vaccine trials evaluating clinical outcome and immunogenicity, focusing on commonly encountered intercurrent events including but not limited to: noncompliance with vaccination schedule and blood sampling window, infection not meeting protocol definition, death, and use of prohibited products. We discuss various considerations in choosing strategies to handle intercurrent events in terms of their utility in addressing the scientific questions. Finally, we provide considerations and examples for summarizing study estimands and data handling which may be incorporated into the protocol and statistical analysis plan.

Keywords: Estimand; ICH E9(R1); Vaccine.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Francois Beckers is an employee of Sanofi and reports administrative support from the same. Naveen Karkada is an employee of GSK. Stefan Englert is an employee of Janssen-Cilag GmbH and holds equity or stocks in the company. Bart Spiessens reports employment by Janssen Pharmaceutica NV and GlaxoSmithKline Biologicals SA, and holds equity or stocks in both. Ilse Van Dromme is employed by Janssen Pharmaceutica NV and holds equity or stocks in the company. Tulin Shekar is an employee of Merck & Co., Inc., Rahway, NJ, USA. Honghong Zhou and Qiqi Deng are employees of Moderna Inc., own equity or stocks in the company, and declare financial support provided by Moderna Inc. Daniela Casula is employed by CSL Seqirus. Holly Janes declares financial support provided by the National Institutes of Health. Lawrence Moulton reports board membership and consulting or advisory roles with Merck Research Laboratories, Pfizer Inc., Kentucky BioProcessing, and Medicago Inc., and is employed by Pfizer Canada ULC. Ye Yang, John Scott, Lei Huang, Florian Klinglmüller, and Michael P. Fay declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

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