When there’s no registry: Building rare disease evidence that supports regulatory scrutiny

Key takeways

• Credibility in small populations depends on characterizing representativeness, prior investigational exposure, and missing-data mechanisms, since limited sample sizes constrain statistical adjustment and amplify residual uncertainty.
• Submission readiness requires early mapping to FDA-supported standards, an auditable provenance trail, independent quality control, and privacy-by-design governance, including data minimization to reduce re-identification risk.
• An autoimmune hematologic program assembled >300 patients across eight countries with independent QC and submission-level traceability, enabling external-control evidence to support FDA approval despite no prior registry.
• Fit-for-purpose rare disease RWE begins by defining intended regulatory use, which drives cohort criteria, endpoints, follow-up, and traceability, preventing decision-inadequate data collection.
• Lack of registries necessitates building multinational datasets with prespecified index dates and aligned endpoint definitions, while harmonizing heterogeneous documentation across notes, labs, imaging, and EHR systems.