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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.

I

Institutional Review Board (IRB)

An Institutional Review Board (IRB) is a committee formally designated by an institution to review, approve and monitor biomedical and behavioural research involving human subjects, to protect their rights and welfare. In the United States, IRBs are required for research supported by federal departments under the Common Rule (45 CFR Part 46, revised in 2018) and for clinical investigations regulated by the FDA under 21 CFR Parts 50 and 56. IRBs may be local (attached to a hospital or university) or independent commercial IRBs; since 2020 the Common Rule requires single IRB review for most US multi-site studies, and the FDA has proposed the same.

An IRB must have at least five members with varying backgrounds, including at least one scientist, one non-scientist and one member unaffiliated with the institution. It reviews the protocol, the informed consent documents, recruitment materials and investigator qualifications; approves research for a period not exceeding one year with continuing review; may use expedited review for minimal-risk research and exempt certain categories; and must be notified of unanticipated problems and serious non-compliance. Under HIPAA, an IRB or a separate privacy board may waive or alter the requirement for individual authorisation to use PHI in research, applying criteria of minimal privacy risk, impracticability and adequate protection.

IRBs are the US counterpart of EU ethics committees and of the broader category of human subjects protection review boards, but their remit and outlook differ. IRBs review privacy and confidentiality provisions and HIPAA authorisation language, but not GDPR compliance, and US-centric consent templates frequently describe coded data as "de-identified" or promise deletion on withdrawal in ways that conflict with EU rules. For a global trial, the sponsor should prepare a master consent with US (HIPAA, Common Rule) and EU/UK (GDPR Art. 13, CTR) data protection modules, and align IRB submissions with the DPIA so that the same data flows are described consistently to all reviewers. iliomad reviews US consent forms and HIPAA authorisations alongside EU ICF reviews.