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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.

E

Explicit consent

Explicit consent is the qualified form of consent that the GDPR requires in three situations: as an exception allowing processing of special categories of personal data (Art. 9(2)(a)); as a basis for solely automated decision-making with legal or similarly significant effects (Art. 22(2)(c)); and as a derogation for occasional international transfers to a third country without adequacy or appropriate safeguards, after the individual has been informed of the risks (Art. 49(1)(a)). All ordinary conditions of Art. 4(11) and Art. 7 apply: consent must be freely given, specific, informed, unambiguous, demonstrable and as easy to withdraw as to give.

The EDPB Guidelines 05/2020 explain that "explicit" refers to the way consent is expressed: the data subject must give an express statement of consent, for example by signing a written declaration, ticking a box next to a specific statement, sending an email or completing a two-stage verification. Consent inferred from conduct or from a clear affirmative action that is not an express statement (scrolling, continuing to use a service) does not qualify. The statement should identify the sensitive data and the specific purpose, and where several purposes are pursued, granular options should be offered. Member State law may exclude the use of explicit consent for certain sensitive processing altogether (Art. 9(2)(a) final clause), as some do for genetic or employee health data.

In life sciences, explicit consent is the appropriate basis for optional processing where the individual has a genuine choice: participation in a biobank or genomic sub-study, use of a health app's optional features, enrolment in a patient support programme, or sharing data with a commercial partner. It is generally not the right basis for core clinical trial data processing, where the EDPB (Opinion 3/2019) points to legal obligation, public interest or legitimate interest with the Art. 9(2)(i) or (j) exceptions, because withdrawal would compromise data integrity and the power imbalance undermines freedom. Where explicit consent is used, the informed consent form or app flow should separate it visibly from consent to participate and from other information, and withdrawal should trigger a documented process.