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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.

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Trial master file (TMF)

The trial master file (TMF) is the collection of essential documents relating to a clinical trial that allows the conduct of the trial and the quality of the data generated to be evaluated and demonstrates compliance with the protocol, good clinical practice and applicable regulations. Art. 57 CTR 536/2014 requires the sponsor and the investigator each to keep a TMF (the investigator's part is often called the investigator site file), and Art. 58 requires it to be archived for at least 25 years after the end of the trial, with medical files of subjects kept according to national law. The EMA guideline on the content, management and archiving of the clinical trial master file (2018) and ICH E6 GCP section 8 detail expectations, and the industry TMF Reference Model provides a standard taxonomy of artefacts and zones.

Essential documents include the protocol and amendments, investigator's brochure, regulatory and ethics committee approvals and correspondence, signed informed consent templates and, at the site, the signed forms, investigator CVs and financial disclosures, delegation and training logs, monitoring reports, IMP accountability records, safety reports, data management and statistical documentation, audit certificates, and the clinical study report. Most sponsors use validated electronic TMF (eTMF) systems with audit trails, controlled access and quality checks for completeness, timeliness and quality; the TMF is central to every GCP inspection and must be directly accessible to inspectors.

The TMF contains substantial personal data: names, CVs, signatures and contact details of investigators and site staff, monitoring reports that may narrate individual subject events, SAE reports, and at site level the signed consent forms and subject identification logs that hold the pseudonymisation key. The 25-year retention period is a legal obligation that overrides the right to erasure and must be reflected in retention schedules, information notices to staff and participants, and contracts with eTMF vendors and archiving providers acting as processors. Sponsors should ensure that subject-identifying information does not migrate into the sponsor TMF, that access to the eTMF is role-based, and that archive transfers (for example when a trial or asset is sold) are covered by appropriate transfer and controller-change arrangements.