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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.

T

Third country

A third country, in the sense of Chapter V GDPR, is any country that is not a Member State of the European Union or of the European Economic Area (the 27 EU Member States plus Iceland, Liechtenstein and Norway, which apply the GDPR through the EEA Agreement). The United Kingdom has been a third country since 1 January 2021; Switzerland, the United States, Canada, Japan, China, India, Australia and every other non-EEA jurisdiction are third countries, whatever the quality of their data protection law.

The consequence is that any disclosure of personal data to a recipient in a third country, or remote access from one, is an international data transfer that requires a Chapter V mechanism: an adequacy decision under Art. 45, appropriate safeguards such as SCCs or BCRs under Art. 46 (with a transfer impact assessment), or a derogation under Art. 49. Third countries recognised as adequate include the UK, Switzerland, Japan, Korea, Canada (commercial organisations), Israel, Argentina, Uruguay, Brazil, New Zealand and, for certified organisations, the US under the Data Privacy Framework; transfers to them require no further safeguards. Adequacy decisions are subject to periodic review and to challenge before the Court of Justice.

For a European clinical trial, third-country recipients typically include a US or Swiss sponsor parent, a global CRO, central laboratories, cloud-hosted EDC and eCOA platforms, safety database providers and non-EU regulators such as the FDA. Each should be mapped in the DPIA with its mechanism, disclosed in the informed consent form and recorded in the RoPA. Note that the UK GDPR and the Swiss FADP treat EU Member States as third countries from their perspective, though both recognise the EU as adequate.

Does being a third country mean a destination is prohibited for data transfers?

No. A third-country destination is not automatically a prohibited destination. Assess whether an applicable adequacy decision covers the transfer or whether another lawful transfer route is available. Check the actual recipient and arrangement, not merely the country name, and continue to apply minimisation, security and other processing requirements.