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Term of the Day

Natural history study

A natural history study is a preplanned observational study intended to track the course of a disease over time, identifying demographic, genetic, environmental and other variables that correlate with its development and outcomes in the absence of intervention, or under standard of care. Designs may be retrospective (chart review of existing records) or prospective (longitudinal follow-up of a cohort or registry).

Natural history data is particularly important in rare and paediatric diseases, where randomised placebo-controlled trials may be infeasible or unethical. The FDA (guidance on rare disease natural history studies, 2019) and the EMA accept well-designed natural history studies to define endpoints and biomarkers, identify patient subgroups, estimate sample sizes and, in some cases, serve as external or historical control arms for single-arm trials supporting orphan products.

Because they are non-interventional, natural history studies fall outside the CTR and are governed by national law (for example France's MR-003 or MR-004 reference methodologies) and by the GDPR. They typically involve secondary use of medical records, long-term follow-up, genetic data and small populations in which anonymisation is rarely achievable, so pseudonymisation, a DPIA and a robust research legal basis under Art. 9(2)(j) are essential. Registries maintained by patient organisations or academic consortia raise additional questions of joint controllership and data access governance.

S

Source data verification (SDV) and source documents

Source data verification (SDV) is the process by which a sponsor's monitor compares the data recorded in the case report form with the source documents, the original records in which trial data were first recorded, such as hospital medical records, laboratory reports, pharmacy dispensing logs, participant diaries and imaging, to confirm that the trial data are accurate, complete and verifiable. ICH E6 GCP defines source data and source documents and requires that trial data be traceable to them (ALCOA+ principles); the CTR requires the investigator to grant direct access to source documents for monitoring, audit and inspection (Art. 47 and Annex I).

Traditionally, monitors performed 100% SDV on site. Following FDA (2013) and EMA (2013) guidance on risk-based monitoring and ICH E6(R2) and (R3), sponsors now combine targeted SDV of critical data, centralised statistical monitoring and source data review (checking quality and protocol compliance rather than transcription), which reduces cost and focuses on data that matter for participant safety and trial results. Remote SDV, in which monitors access site records through secure portals or redacted copies, expanded during the pandemic and is now addressed by national guidance, with acceptance varying across EU Member States.

SDV is the moment at which the sponsor's representatives see directly identifying health data of participants, which the sponsor otherwise receives only in pseudonymised form. The GDPR conditions for this access should be secured in advance: the informed consent form must inform participants that monitors, auditors and inspectors will access their medical records under confidentiality; the clinical trial agreement must frame the access, state that no identifiable data may be copied or removed and address remote access modalities; monitors must be bound by confidentiality and trained; and monitoring reports must describe findings without recording names or identifiers. For remote SDV, the DPIA should assess the platform used, the redaction process, access logging and whether the arrangement creates a transfer where monitors sit outside the EEA. Site staff personal data in delegation logs and training records reviewed during monitoring also needs to be covered by the site-staff information notice.