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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.

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One-stop-shop mechanism and lead supervisory authority

The one-stop-shop mechanism is the system under which a controller or processor engaged in cross-border processing within the EU deals primarily with one supervisory authority, the lead supervisory authority, which is the authority of the Member State where the organisation has its main establishment or its single establishment (Art. 56(1) GDPR). The lead authority is the sole interlocutor for that processing and coordinates its decisions with the other authorities concerned under the cooperation procedure of Art. 60.

Concerned supervisory authorities are those in Member States where the organisation has other establishments, where data subjects are substantially affected, or where a complaint was lodged (Art. 4(22)). The lead authority prepares a draft decision, the concerned authorities may raise relevant and reasoned objections, and unresolved disputes are settled by a binding decision of the EDPB under the consistency mechanism (Art. 65), as in the Meta, WhatsApp and TikTok cases handled by the Irish Data Protection Commission. Exceptions allow a local authority to handle purely local cases (Art. 56(2)) and urgent measures (Art. 66). The 2025 GDPR procedural regulation aims to streamline cross-border enforcement.

The mechanism only benefits organisations with an establishment in the EU. A sponsor or HealthTech company established solely outside the Union, even one that has appointed an Art. 27 Data Protection Representative, has no lead authority and is subject to the jurisdiction of every supervisory authority in whose territory it processes data, which multiplies regulatory exposure across the Member States where it recruits patients or has users. Groups with an EU headquarters should therefore document their main establishment carefully, since the choice of lead authority determines the regulator, the language and the enforcement culture they will face. Note that the one-stop shop does not extend to the UK or Switzerland.