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Transfer impact assessment (TIA)
T
Trial master file (TMF)
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UK GDPR
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Unexpected serious adverse reaction (SUSAR)
V
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Zero trust architecture
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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.

C

Contract research organisation (CRO)

A contract research organisation (CRO) is a company that provides clinical research services to pharmaceutical, biotech and medical device sponsors on a contractual basis. Services range from full-service management of a clinical trial (feasibility, regulatory submissions, site selection and monitoring, data management, biostatistics, pharmacovigilance, medical writing) to functional service provision of individual activities. Global CROs run hundreds of trials in parallel across dozens of countries; specialist CROs focus on a therapeutic area, a region or a service line such as imaging or eCOA.

Under Art. 71 CTR 536/2014 and ICH E6 GCP section 5.2, a sponsor may delegate any or all of its trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. Delegated tasks must be specified in writing, and the sponsor must oversee the CRO through governance meetings, key performance indicators, audits and review of the CRO's own quality system; ICH E6(R3) reinforces sponsor oversight of service providers. CROs are inspected by regulators alongside sponsors.

Under the GDPR a CRO is normally a processor, because it processes trial data on the sponsor's documented instructions as set out in the protocol and the service contract, and a data processing agreement under Art. 28 is required. A CRO becomes a controller where it decides on purposes and means for its own account, for example for its investigator databases, its own quality analytics or when it acts as regulatory sponsor in its own name, and it is a joint controller only in rare cases. CROs manage extensive chains of sub-processors, are frequently established outside the EEA (requiring SCCs and TIAs) and must appoint their own DPO and, if non-EU, an Art. 27 representative. iliomad supports both sponsors assessing CROs and CROs building their own compliance frameworks; see vendor assessment services.