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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.

L

Legitimate interest assessment (LIA)

A legitimate interest assessment (LIA) is the documented analysis a controller carries out to justify reliance on legitimate interest under Art. 6(1)(f) GDPR. Although the GDPR does not use the term, the accountability principle (Art. 5(2) and 24) requires the controller to be able to demonstrate that the balancing test was performed before processing started, and supervisory authorities routinely request the LIA in investigations and complaints.

An LIA follows the three-step test set out by the Court of Justice and the EDPB Guidelines 1/2024. The purpose test identifies the interest pursued, by the controller or a third party, and confirms it is lawful, real and sufficiently specific. The necessity test asks whether the processing is genuinely needed to achieve that interest and whether less intrusive alternatives, including processing less data or pseudonymised data, would suffice. The balancing test weighs the interest against the impact on data subjects, considering the nature of the data (with special category data weighing heavily), the reasonable expectations of individuals given the context of collection, the scale and consequences of processing, the status of the data subjects (patients, employees, children) and the safeguards and mitigations applied, such as minimisation, transparency, opt-outs and retention limits. The outcome, the reasoning and the mitigations are recorded and dated, and the interest is disclosed in the information notice.

An LIA differs from a DPIA: the DPIA assesses risks to rights and freedoms across all aspects of a high-risk processing, while the LIA justifies one legal basis. In practice the LIA is often annexed to the DPIA for clinical trials in which a private sponsor relies on legitimate interest for research processing, for secondary use of real-world data, for processing of investigator and key opinion leader data, and for B2B marketing. It should be revisited when the processing, the population or the context changes.