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Single-arm trials (SATs) may be used to support regulatory submissions in settings where there is a high unmet medical need and highly promising early efficacy data undermine the equipoise needed for randomization. In this context, patient-level real-world data (RWD) may be used to create an external control arm (ECA) to contextualize the SAT results. However, naive comparisons of the SAT with its ECA will yield biased estimates of causal effects if groups are imbalanced with regards to (un)measured prognostic factors. Several methods are available to adjust for measured confounding, but the interpretation of such analyses is challenging unless the causal question of interest is clearly defined, and the estimator is aligned with the estimand. Additional complications arise when patients in the ECA are eligible for the SAT at multiple timepoints. In this paper, we use a case-study of a pivotal SAT of a novel CAR-T therapy for heavily pre-treated patients with follicular lymphoma to illustrate how a combination of the target trial and the ICH E9(R1) estimand frameworks can be used to define the target estimand and avoid common methodological pitfalls related to the design of the ECA and comparisons with the SAT. We also propose an approach to address the challenge of how to define an appropriate time zero for external controls who meet the SAT inclusion/exclusion criteria at several timepoints. Use of the target trial and estimand frameworks facilitates discussions amongst internal and external stakeholders, as well as an early assessment of the adequacy of the available RWD.