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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.

C

Clinical Trials Regulation (CTR) 536/2014

The Clinical Trials Regulation (CTR), Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use, is the EU framework governing the authorisation, conduct, safety reporting and transparency of clinical trials of medicinal products. It repealed Directive 2001/20/EC, became applicable on 31 January 2022 with a three-year transition, and since 31 January 2025 governs all ongoing and new trials in the EU and EEA. Its stated aims are to streamline and harmonise trial authorisation while maintaining the highest standards of participant protection and data reliability.

Key features include a single application through the Clinical Trials Information System with a coordinated assessment by Member States (Part I, scientific and product aspects, led by a reporting Member State; Part II, national ethical aspects including informed consent and data protection compliance); one decision per Member State within defined timelines; a tacit approval mechanism; rules on the protection of subjects including incapacitated subjects, minors and emergency situations (Chapter V); safety reporting of serious adverse events and SUSARs through EudraVigilance (Chapter VII); IMP manufacturing and labelling (Chapters IX and X); a 25-year archiving obligation for the trial master file (Art. 58); mandatory publication of results and lay summaries; and the requirement for a non-EU sponsor to appoint an EU legal representative (Art. 74). Low-intervention trials benefit from lighter rules.

The CTR and the GDPR apply cumulatively. Art. 93 CTR refers to the data protection framework, and the EDPB Opinion 3/2019 explains that trial data processing rests on legal obligation and public health for safety and reliability purposes, and on public interest or legitimate interest with the Art. 9(2)(j) research exception for other purposes, rather than on consent. CTR informed consent, EU legal representation and GCP confidentiality do not satisfy GDPR requirements for a Data Protection Representative, DPIA, processor contracts or transfer mechanisms, which sponsors must handle separately. Clinical investigations of medical devices follow the parallel regime of the MDR. See iliomad's drugs clinical trials services.