Why Regulatory Acceptance is Not a Post-hoc Outcome — But a Design Principle

Real-world evidence (RWE) has become integral to post-authorization safety studies (PASS), but ensuring that the evidence is accepted by the Pharmacovigilance Risk Assessment Committee (PRAC) requires more than scientific rigor alone. It depends on how well the regulatory question, study design, data source, and analytic strategy align from the outset.

Over recent years, the European Medicines Agency (EMA) expectations around RWE have continued to evolve, with increasing emphasis on methodological robustness, transparency, operational quality, and fit-for-purpose data. For sponsors, this creates both opportunity and complexity: how can studies be designed to meet evolving standards without compromising feasibility, timelines, or available data?

In practice, PRAC feedback of PASS protocols often centres on a few recurring themes:

• • Misalignment between research question and study design. If the comparator, population of follow-up window does not reflect the clinical reality or regulatory question, the study’s interpretability may be challenged

• • Limited pre-specification. Protocols that rely heavily on post hoc or data-driven analyses can raise concerns about robustness, reproducibility and credibility

• • Insufficient bias mitigation. Confounding and time-related biases are expected in observational research –  but regulators increasingly expect them to be proactively addressed and tested

• • Data not fit for purpose. If outcomes or key variables are not well captured or validated, results may not be considered reliable. Questions often arise around whether the selected data source can adequately capture the relevant clinical context, exposures, outcomes, confounders, and patient pathways needed to answer the regulatory question with sufficient validity and transparency

• • Lack of transparency. Unclear protocol decisions, feasibility constraints undocumented changes can delay review and undermine confidence in the evidence generated

A common lesson from PASS development is that feasibility alone is not enough. Regulatory acceptability depends on a clear line of sight between the safety question, the design choices, and the limitations of the underlying data. So, what helps in practice? Complete the form to access the full blog.