APPLYING TARGET TRIAL EMULATION IN VACCINE RESEARCH: METHODOLOGICAL INSIGHTS AND REGULATORY IMPLICATIONS
Author(s)
Hao Dai, PhD1, Tien-Yu Chang, MS1, Xing He, PhD1, Amanda L. Eiden, MBA, MPH, PhD2, Wei (Vivian) Wang, PhD2, Kelsie Cassell, PhD2, Yi-Ling Huang, PhD2, Yu-Han Kao, PhD2, Katrina Mott, PhD2, Dong Wang, PhD2, Jiang Bian, PhD1, Yi Zheng, PhD, MPH2;
1Indiana University, Indianapolis, IN, USA, 2Merck & Co., Inc., Rahway, NJ, USA
1Indiana University, Indianapolis, IN, USA, 2Merck & Co., Inc., Rahway, NJ, USA
OBJECTIVES: Target trial emulation (TTE) has emerged as a rigorous framework for strengthening causal inference in observational research, following the design principles of randomized clinical trials using real-world data (RWD). While TTE is increasingly applied in vaccine effectiveness and safety evaluations, its implementation, reporting practices, and alignment with regulatory standards for real-world evidence (RWE) remain poorly characterized. This review systematically evaluates the methodological rigor in observational vaccine studies using TTE.
METHODS: Following PRISMA guidelines, we searched PubMed, Embase, and Web of Science for peer-reviewed studies published between January 2021 and August 2025 that used RWD to assess vaccine effectiveness or safety. Eligible studies explicitly or implicitly emulated a target trial through comparative, causal inference-based designs. Two reviewers independently screened and extracted data on (1) adherence to TTE core design elements (i.e., eligibility, treatment strategies, assignment procedures, follow-up, outcomes, causal contrasts, and analysis plans), and (2) alignment with regulatory RWE guidance.
RESULTS: Seventy-nine studies met inclusion criteria, covering COVID-19 (n=58), influenza (n=9), human papillomavirus (n=2), and other vaccine-preventable diseases (n=12). Only 31.6% reported clearly documented protocols. Although the majority of studies delineated eligibility criteria, exposures, and outcomes, validation of operational definitions was infrequent (eligibility: 5.1%; exposure: 5.1%; outcome: 17.7%). For bias assessment and mitigation, 77.2% of studies explicitly defined time zero, a key step in reducing immortal time and selection biases, while 32.9% used negative control to assess residual bias, and only 2.5% quantitatively assessed unmeasured confounding. Despite regulatory emphasis on data credibility, systematic data quality assessments appeared in only 6.3% of studies.
CONCLUSIONS: TTE use in vaccine RWD studies is growing but lacks consistency in methodological rigor and transparency. To improve reproducibility and regulatory credibility, future research should prioritize adopting standardized TTE reporting frameworks (e.g., TARGET), ensure clearly documented protocols, and incorporate data quality assessments.
METHODS: Following PRISMA guidelines, we searched PubMed, Embase, and Web of Science for peer-reviewed studies published between January 2021 and August 2025 that used RWD to assess vaccine effectiveness or safety. Eligible studies explicitly or implicitly emulated a target trial through comparative, causal inference-based designs. Two reviewers independently screened and extracted data on (1) adherence to TTE core design elements (i.e., eligibility, treatment strategies, assignment procedures, follow-up, outcomes, causal contrasts, and analysis plans), and (2) alignment with regulatory RWE guidance.
RESULTS: Seventy-nine studies met inclusion criteria, covering COVID-19 (n=58), influenza (n=9), human papillomavirus (n=2), and other vaccine-preventable diseases (n=12). Only 31.6% reported clearly documented protocols. Although the majority of studies delineated eligibility criteria, exposures, and outcomes, validation of operational definitions was infrequent (eligibility: 5.1%; exposure: 5.1%; outcome: 17.7%). For bias assessment and mitigation, 77.2% of studies explicitly defined time zero, a key step in reducing immortal time and selection biases, while 32.9% used negative control to assess residual bias, and only 2.5% quantitatively assessed unmeasured confounding. Despite regulatory emphasis on data credibility, systematic data quality assessments appeared in only 6.3% of studies.
CONCLUSIONS: TTE use in vaccine RWD studies is growing but lacks consistency in methodological rigor and transparency. To improve reproducibility and regulatory credibility, future research should prioritize adopting standardized TTE reporting frameworks (e.g., TARGET), ensure clearly documented protocols, and incorporate data quality assessments.
Conference/Value in Health Info
2026-05, ISPOR 2026, Philadelphia, PA, USA
Value in Health, Volume 29, Issue S6
Code
MSR126
Topic
Methodological & Statistical Research
Topic Subcategory
Confounding, Selection Bias Correction, Causal Inference
Disease
STA: Vaccines