BY-COVID Work Package (WP) 5 develops multiple use cases to address evolving research questions that arise during a pandemic, requiring data from multiple domains, sources, and countries. This evolving BY-COVID demonstrator is continuously enriched with new data, new evidence, and new hypotheses as part of Task 5.1. The use cases implemented in Task 5.2, Task 5.3 and Task 5.4 serve as concrete examples of adaptable and responsive workflows and methodologies designed to tackle the changing research challenges of a pandemic. The ‘Baseline Use Case’ developed in Task 5.2 provides a standard workflow, methodology and supporting technology that enables it to address any well-defined research question relevant for policy making. The proposed use case aims to demonstrate how mobilisation and linkage of heterogeneous real-world population data sources hosted at multiple sites can enhance the understanding of the direct and indirect effects of the pandemic on health outcomes in populations crossing jurisdictional borders. The proposed methodological framework provides guidance in the form of a systematic approach to address federated cross-national causal research questions in a privacy-preserving way, while tackling challenges at different layers of interoperability (legal, organisational, semantic, technical). This flexible workflow can evolve with new data types (e.g., socioeconomic and genomic), new data sources (e.g., registries, bio-samples, surveillance systems), new sites (e.g., other countries), and new hypotheses (e.g., COVID-19 Disease Maps).