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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.

V

Vulnerable participants (vulnerable subjects)

Vulnerable participants, or vulnerable subjects, are individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation of benefits or fear of retaliation, or whose capacity to give free and informed consent is limited. ICH E6 GCP lists members of hierarchical groups (students, subordinate staff, members of the armed forces, detainees), patients with incurable diseases, persons in nursing homes, the unemployed or impoverished, patients in emergency situations, ethnic minority groups, the homeless, nomads, refugees, minors and those incapable of giving consent. The EU Clinical Trials Regulation 536/2014 provides specific conditions for incapacitated subjects (Art. 31), minors (Art. 32), pregnant or breastfeeding women (Art. 33), other groups defined by national law such as persons deprived of liberty (Art. 34) and emergency situations (Art. 35), and Recital 31 recognises additional vulnerable populations.

Protections include consent by a legally designated representative with information adapted to the participant, respect for the participant's own refusal or wish to withdraw, prohibition of incentives beyond compensation for expenses, the requirement that the research be necessary for and directly related to the population's condition, a favourable benefit-risk assessment, and review by an ethics committee with relevant expertise. Trials excluding vulnerable groups without justification are increasingly challenged, since the resulting evidence gap is itself a harm; regulators now expect inclusion plans, for example for older adults and pregnant women, where safe.

The GDPR treats vulnerability as a risk factor rather than a category: Recital 75 cites processing of data of vulnerable natural persons, in particular children, among the situations creating risk to rights and freedoms, the EDPB DPIA guidelines list vulnerable data subjects as a criterion making a DPIA likely, and imbalance of power undermines the validity of consent as a legal basis (Recital 43). Trials in vulnerable populations therefore need heightened attention to minimisation, confidentiality of sensitive contextual data (capacity assessments, detention status, pregnancy), accessible information for participants and representatives, and clear procedures for exercising data protection rights through or alongside the representative. Children's data additionally attracts specific national rules on the age of digital consent and on information design.