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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.

D

Decentralised clinical trial (DCT)

A decentralised clinical trial (DCT) is a clinical trial in which some or all trial-related activities take place at locations other than a traditional investigator site, typically the participant's home or a local healthcare facility, using digital health technologies and mobile or local healthcare providers. Elements include remote recruitment and electronic informed consent, telemedicine visits, home nursing and phlebotomy, direct-to-participant shipment of the investigational medicinal product, eCOA and wearable sensors for endpoint capture, and local laboratories or imaging centres. Fully decentralised trials are rare; most are hybrid.

The COVID-19 pandemic accelerated adoption, and regulators have since issued frameworks: the European Commission, EMA and HMA "Recommendation paper on decentralised elements in clinical trials" (December 2022), the FDA guidance on decentralised clinical trials (final, September 2024) and ICH E6(R3), which explicitly accommodates technology-enabled and decentralised approaches. Key regulatory questions are the investigator's continued oversight and responsibility for participants they may never meet in person, the qualification of home nurses and local providers, the status of these providers as trial staff or service providers, the shipment and accountability of IMP, and the validation of digital tools. National rules on telemedicine, home nursing and direct shipment vary considerably across EU Member States.

Data protection is one of the main operational challenges of DCTs. Participants' health data is collected in their homes through devices and apps, often provided by technology vendors acting as processors; direct-to-patient shipment and home visits require the sponsor's vendors to hold participants' names and addresses, breaking the usual pseudonymisation boundary and requiring careful segregation from the trial dataset; telemedicine platforms, courier services and home-nursing agencies join the chain of recipients and sub-processors; and continuous sensor data tests the minimisation principle. A DCT DPIA should map each decentralised element, define who is controller for each data flow, address device security and bring-your-own-device policies, and ensure that the informed consent explains the additional recipients and the use of home-based technologies.