Adopting the estimand framework in prophylactic vaccine trials
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.
Authors
- F. Beckers (ORCID: https://orcid.org/0000-0003-3073-0832)
- Haiyu Zhou (ORCID: https://orcid.org/0000-0002-3328-6792)
- Stefan Englert (ORCID: https://orcid.org/0000-0002-7516-833X)
- Lei Huang (ORCID: https://orcid.org/0000-0002-5337-9101)
- Tulin Shekar
- Michael P. Fay (ORCID: https://orcid.org/0000-0002-8643-9625)
- Daniela Casula (ORCID: https://orcid.org/0000-0001-7111-5946)
- Naveen Karkada (ORCID: https://orcid.org/0000-0002-7543-1345)
- Holly Janes (ORCID: https://orcid.org/0000-0002-3237-984X)
- Ilse Van Dromme
- Lawrence H. Moulton (ORCID: https://orcid.org/0000-0001-7041-7387)
- Ye Yang
- Bart Spiessens
- J. C. Scott
- Florian Klinglmüller
- Qiqi Deng
Institutions
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Center for Biologics Evaluation and Research (US)
- United States Food and Drug Administration (US)
- Sanofi (France) (FR)
- University for Foreigners of Siena (IT)
- Fred Hutch Cancer Center (US)
- GlaxoSmithKline (Belgium) (BE)
- Moderna Therapeutics (United States) (US)
- Johnson & Johnson (Germany) (DE)
- National Institute of Allergy and Infectious Diseases (US)
- Pfizer (Canada) (CA)
- Austrian Agency for Health and Food Safety (AT)
Publication Details
- Journal
- Vaccine
- Published
- 2025-09-03
- DOI
- https://doi.org/10.1016/j.vaccine.2025.127645
- Primary Topic
- Statistical Methods in Clinical Trials
- Type
- article
- Field-Weighted Citation Impact
- 0.00