Target Trial Emulation of Oral Antivirals for B-Cell-Depleted COVID-19 Patients—Reply to Chen et al

To The Editor—Chen et al [1] raise important points regarding our target trial emulation (TTE) evaluating nirmatrelvir/ritonavir and molnupiravir in patients receiving B-cell-depleting therapy (BCDT) who developed coronavirus disease 2019 (COVID-19) [2]. We agree that careful attention to statistical methods is essential and welcome the opportunity to clarify several methodological aspects. At its core, our study uses a conventional propensity score (PS) analysis with inverse-probability-of-treatment weighting. The added value comes from explicitly applying the TTE framework, which requires prespecification of a hypothetical randomized trial protocol and thereby clarifies assumptions and helps prevent common observational pitfalls, such as vague or shifting estimands and ad hoc covariate adjustment [3]. Importantly, TTE applies randomized clinical trial design principles to observational data, aiming to enable more rigorous estimation of treatment effects by clarifying design and assumptions. It does not require a perfect replica of a randomized trial but provides a transparent structure for describing how real-world data approximate that ideal and where they necessarily depart from it [4].