Sensitivity analysis for causality in observational studies for regulatory science.

The United States Congress passed the 21st Century Cures Act mandating the development of Food and Drug Administration guidance on regulatory use of real-world evidence. The Forum on the Integration of Observational and Randomized Data conducted a meeting with various stakeholder groups to build consensus around best practices for the use of real-world data (RWD) to support regulatory science. Our companion paper describes in detail the context and discussion of the meeting, which includes a recommendation to use a causal roadmap for study designs using RWD. This article discusses one step of the roadmap: the specification of a sensitivity analysis for testing robustness to violations of causal model assumptions. We present an example of a sensitivity analysis from a RWD study on the effectiveness of Nifurtimox in treating Chagas disease, and an overview of various methods, emphasizing practical considerations on their use for regulatory purposes. Sensitivity analyses must be accompanied by careful design of other aspects of the causal roadmap. Their prespecification is crucial to avoid wrong conclusions due to researcher degrees of freedom. Sensitivity analysis methods require auxiliary information to produce meaningful conclusions; it is important that they have at least two properties: the validity of the conclusions does not rely on unverifiable assumptions, and the auxiliary information required by the method is learnable from the corpus of current scientific knowledge. Prespecified and assumption-lean sensitivity analyses are a crucial tool that can strengthen the validity and trustworthiness of effectiveness conclusions for regulatory science.

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© The Author(s) 2023.

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ID reports consulting fees from Bayer AG. EK is employed by Microsoft Research. MA is employed by Novartis. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement by, FDA/HHS, or the US Government.