Randomized Controlled Trials and Real‐World Evidence in Allergen Immunotherapy: A Critical Reflection on Methodological Paradigms, Ethical Implications, and Industry Influence

BACKGROUND: Allergen immunotherapy (AIT) is the only intervention capable of modifying the natural history of allergic diseases. The evidence supporting its effectiveness comes from two distinct but complementary methodological approaches: randomized controlled trials (RCTs), traditionally considered the gold standard for establishing causality, and real-world evidence (RWE), which reflects everyday clinical practice. The tension between these two paradigms is methodological, ethical, and political. OBJECTIVE: Critically examine the epistemological foundations, limitations, and strengths of RCTs and RWE in evaluating AIT, exploring the ethical implications and influence of the pharmaceutical industry in the construction of clinical evidence. METHODS: Narrative and reflective review of methodological and bioethical literature on RCTs and RWE, with a focus on AIT studies. The analysis considers internal and external validity, generalizability, data governance, conflicts of interest, and regulatory implications. RESULTS: RCTs offer internally valid estimates of effectiveness, but these are difficult to generalize; RWE captures the complexity of clinical practice but is vulnerable to confounding and bias. The ethical dimensions differ: RCTs raise issues of equivalence and informed consent, while RWE raises issues of privacy and secondary use of data. The industry utilizes considerable influence on both paradigms, contributing to systematic distortions of the evidence. CONCLUSIONS: Neither RCTs nor RWE, taken in isolation, provide a sufficient picture of the efficacy and safety of AIT. Only an integrated approach, combining methodological rigor and pragmatic relevance, accompanied by independent monitoring of conflicts of interest and greater transparency, can support truly evidence-based medicine.