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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.

L

Legally designated representative

A legally designated representative means a natural or legal person, authority or body which, according to the law of the Member State concerned, is empowered to give informed consent on behalf of a subject who is an incapacitated subject or a minor (Art. 2(2)(20) EU Clinical Trials Regulation 536/2014). Who qualifies is determined by national law: parents or legal guardians for minors; court-appointed guardians, persons holding a lasting power of attorney, or in some countries a spouse or next of kin for incapacitated adults.

Under Art. 31 and 32 CTR, the representative receives the trial information, gives the written consent, and may withdraw it at any time. The investigator must nevertheless inform the subject in a manner adapted to their capacity, and must respect the wish of a minor or incapacitated adult who is able to form an opinion to refuse participation or to withdraw. Where the subject regains capacity or a minor reaches the age of legal competence, their own consent must be obtained for continued participation.

The representative's identity, relationship to the subject and contact details are recorded on the consent form and in the source documents, which makes the representative a data subject in the trial's processing register alongside the participant. They must receive the Art. 13 GDPR information for their own data, and they exercise the participant's data protection rights on their behalf. The term should not be confused with the Data Protection Representative under Art. 27 GDPR or the sponsor's legal representative under Art. 74 CTR.