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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.

K

k-anonymity

k-anonymity is a formal privacy model, introduced by Latanya Sweeney in 2002, under which a dataset is said to be k-anonymous if every combination of quasi-identifier values (attributes such as age, sex, postcode or diagnosis date that could be linked to external sources) is shared by at least k records. Any individual is therefore indistinguishable from at least k-1 others, which reduces the risk of re-identification by linkage. It is achieved through generalisation (replacing exact ages with bands, postcodes with regions) and suppression (removing outlier records).

k-anonymity addresses the "singling out" risk identified in the Article 29 Working Party Opinion 05/2014 on anonymisation techniques, but not the risks of inference: if all k records in a group share the same sensitive value (for example the same diagnosis), the attribute is disclosed. Refinements such as l-diversity (requiring diverse sensitive values within each group) and t-closeness (requiring the distribution of sensitive values in each group to be close to the overall distribution) were developed to close these gaps, and differential privacy offers a fundamentally different, probabilistic guarantee.

In health research, k-anonymity is widely used when releasing datasets for secondary use, preparing clinical study reports for EMA Policy 0070 publication, or sharing trial data through platforms. A k of 5 to 11 is common in practice, but the appropriate value depends on context. Applying k-anonymity is itself a processing operation on personal data, and the resulting dataset should be assessed and documented as anonymous or pseudonymised before it is treated as outside the GDPR.

Does achieving k-anonymity prove that a clinical dataset is anonymous?

No. K-anonymity addresses particular identification risks but does not remove every risk of inference or linkage. People in the same group may still share a sensitive characteristic, and other available information can change the assessment. Evaluate the release context and residual risks rather than using a chosen k value as a universal anonymity certificate.