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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.

S

Software as a Medical Device (SaMD)

Software as a Medical Device (SaMD) is software intended to be used for one or more medical purposes that performs these purposes without being part of a hardware medical device, as defined by the International Medical Device Regulators Forum (IMDRF). Examples include apps that calculate insulin doses, algorithms analysing radiology images to detect lesions, digital therapeutics delivering cognitive behavioural therapy, and clinical decision support that recommends treatment. Software that merely stores, communicates or displays data, or supports lifestyle and wellness without a medical claim, is not a medical device, although the boundary is often contested.

In the EU, software with a medical purpose is a medical device under the MDR or an IVD under the IVDR; MDCG 2019-11 provides qualification guidance and MDR Annex VIII Rule 11 classifies most diagnostic or therapeutic decision-support software in Class IIa or higher, requiring notified body assessment, clinical evaluation and post-market surveillance. Cybersecurity requirements derive from the General Safety and Performance Requirements and MDCG 2019-16. In the United States the FDA regulates SaMD through the 510(k), De Novo and PMA pathways, with specific guidance on clinical decision support, cybersecurity and predetermined change control plans for AI-enabled software.

SaMD almost always processes health data and often runs on patients' own devices or in the cloud, so the manufacturer or the deploying healthcare provider is a controller under the GDPR requiring a DPIA, data protection by design, security measures and, for cloud hosting outside the EEA, transfer mechanisms. Where the software uses machine learning and requires notified body assessment, it is also a high-risk AI system under the AI Act, with integrated conformity assessment from August 2027, and the manufacturer is within scope of the NIS2 Directive. Companion apps for clinical trials (eCOA, eConsent) are usually not SaMD but face the same data protection questions. See iliomad's health apps and medical devices pages.