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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

Serious adverse event (SAE)

A serious adverse event (SAE) means any untoward medical occurrence that at any dose requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, results in a congenital anomaly or birth defect, is life-threatening, or results in death (Art. 2(2)(33) EU Clinical Trials Regulation 536/2014; ICH E2A). Other important medical events may be judged serious by the investigator. Seriousness is a regulatory classification based on outcome and must not be confused with severity, which grades intensity.

Under Art. 41 CTR the investigator must report all SAEs to the sponsor without undue delay and within 24 hours of becoming aware, unless the protocol exempts certain events. The sponsor assesses causality and expectedness against the reference safety information in the investigator's brochure; suspected unexpected serious adverse reactions (SUSARs) are reported to EudraVigilance within 7 days (fatal or life-threatening) or 15 days (other), and all SAEs are summarised in the annual safety report under Art. 43.

SAE reports contain detailed clinical narratives, medical history, concomitant medications and outcomes for an identified subject, often with dates and hospital details that increase identifiability. They are health data processed under legal obligation and public health (Art. 6(1)(c) and 9(2)(i) GDPR), exempt from the right to erasure and retained for the life of the product. The safety database vendor and the CRO's pharmacovigilance unit act as processors; transfers to non-EU sponsors, partners and regulators must be covered by appropriate safeguards or the public-interest derogation, and narratives should be written with only the information necessary for medical assessment.

Is a severe adverse event always a serious adverse event?

No. Severity describes intensity, whereas seriousness concerns outcomes or criteria such as death, life-threatening events, hospitalisation or significant disability. An intense symptom is not automatically serious, and an event can be serious even if its initial symptoms seem mild. Study teams should assess and record both dimensions using the applicable safety procedures.