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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.

I

Incapacitated subject

An incapacitated subject means a subject who, for reasons other than the age of legal competence to give informed consent, is incapable of giving informed consent according to the law of the Member State concerned (Art. 2(2)(19) EU Clinical Trials Regulation 536/2014). Typical situations are dementia, severe psychiatric illness, intensive care and emergency settings, and neurological conditions affecting decision-making capacity.

Art. 31 CTR allows clinical trials on incapacitated subjects only under cumulative conditions: informed consent is obtained from a legally designated representative; the subject receives information adapted to their capacity; the investigator respects the explicit wish of a subject capable of forming an opinion to refuse or withdraw; no incentives are given; the trial is essential for that population and cannot be conducted on capable adults; it relates directly to the subject's condition; and it is expected to produce a direct benefit outweighing the risks, or only minimal risk and burden. Art. 35 provides a derogation for emergency situations where consent may be obtained afterwards.

From a data protection perspective, the incapacitated subject remains the data subject. The information required by Art. 13 GDPR must be given to the representative and, where possible, to the subject in accessible form; rights are exercised through the representative; and the trial's DPIA should treat the population as vulnerable, with heightened attention to minimisation, confidentiality and the handling of capacity assessments, which are themselves health data.