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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.

W

Withdrawal (of consent and from a clinical trial)

Withdrawal, in clinical research, refers to two related but legally distinct acts. Withdrawal from a clinical trial is the participant's decision to stop taking part, which Art. 28(3) CTR 536/2014 guarantees may be exercised at any time, without any resulting detriment and without having to provide justification, by revoking informed consent. Withdrawal of consent in the GDPR sense is the data subject's revocation of consent given as a legal basis for processing, which Art. 7(3) states must be as easy as giving consent and takes effect for the future without affecting the lawfulness of processing before withdrawal.

The distinction matters because, in most EU trials, consent is not the legal basis for processing trial data. Following the EDPB Opinion 3/2019, sponsors rely on legal obligation and public health for safety and regulatory purposes and on public interest or legitimate interest with Art. 9(2)(j) for research. Art. 28(3) CTR itself provides that withdrawal shall not affect activities already carried out and the use of data obtained before withdrawal. A participant who withdraws therefore stops further data collection and, at their request, further contact, but data already collected is retained under the 25-year archiving rule of Art. 58 CTR and GCP integrity requirements, safety follow-up may continue where legally required, and the right to erasure does not apply (Art. 17(3)(b), (c) and (d)). Where the sponsor did rely on consent for optional elements such as biobanking, future research or genomic sub-studies, withdrawal of that consent stops those uses and may require destruction of unused samples.

Drafting the withdrawal section of the informed consent form honestly is one of the most frequent corrections in iliomad's ICF reviews: forms that promise "all your data will be deleted if you withdraw" create an obligation the sponsor cannot lawfully meet. Good practice is to distinguish withdrawal from treatment, from follow-up and from data use; to explain what is retained and why; to offer restriction and the exclusion of the participant's data from future analyses where feasible; and to align the wording with the protocol, the DPIA and the rights-handling procedure agreed with sites.