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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.

M

Medical Device Regulation (MDR)

The Medical Device Regulation (MDR), Regulation (EU) 2017/745, is the EU framework governing the safety and performance of medical devices placed on the Union market. It replaced the Medical Devices Directive 93/42/EEC and the Active Implantable Medical Devices Directive, applies since 26 May 2021, and is accompanied by transitional periods, extended in 2023 to 2027 and 2028, for legacy devices certified under the Directives. In vitro diagnostics are covered separately by the IVDR.

A medical device is any instrument, apparatus, appliance, software, implant, reagent, material or other article intended by the manufacturer to be used for a medical purpose such as diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of disease (Art. 2(1)). Devices are classified into Classes I, IIa, IIb and III according to risk (Annex VIII), with Rule 11 specifically addressing software. Manufacturers must implement a quality management system, compile technical documentation, perform clinical evaluation based on clinical data (including clinical investigations governed by Art. 62 to 82 and ISO 14155), undergo conformity assessment by a notified body for all but Class I devices, affix the CE mark, register in EUDAMED with a Unique Device Identifier, and run post-market surveillance, post-market clinical follow-up and vigilance. Non-EU manufacturers must appoint an EU authorised representative, and every manufacturer needs a person responsible for regulatory compliance.

The MDR interacts closely with data protection: clinical investigations process health data under rules parallel to the CTR; connected devices and companion apps collect patient data continuously, requiring data protection by design and a DPIA; the General Safety and Performance Requirements (Annex I, section 17) and MDCG 2019-16 guidance impose cybersecurity obligations; and post-market surveillance relies on real-world data. AI-enabled devices requiring notified body assessment are also high-risk AI systems under the AI Act, with integrated conformity assessment. See iliomad's medical devices compliance services.