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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

Imported item 47

An investigator site file, or ISF, is the investigator-held collection of essential records documenting a clinical trial at a particular site. It forms the investigator’s part of the trial master file structure. Its purpose is to support evaluation of trial conduct and data quality while preserving the records for which the investigator is responsible.

Key takeaways

  • The ISF is not simply a copy of the sponsor’s file.
  • Keep responsibilities and record locations clear.
  • Protect identifiers during access and archiving.

ISF and Sponsor Records

The Danish Medicines Agency’s filing guidance explains the investigator and sponsor parts of the trial master file. Essential records can include relevant correspondence and decisions, not only documents listed in a filing index.

CollectionPractical focus
Investigator site fileSite-held evidence of conduct and investigator responsibilities.
Sponsor fileSponsor-held evidence of management and oversight.
Medical recordsClinical records with their own access and retention rules.

Why It Matters for Data Protection

Our recommended filing approach is to identify the authoritative location for each record, who may access it and whether an identifiable copy is actually needed elsewhere. Document access for monitors and inspectors without making unrestricted sharing the default. Keep an archive retrieval process and test whether electronic records remain readable after systems change.

Hypothetical example: A site prepares for closure. Its coordinator checks the index, resolves missing essential correspondence and confirms who will manage archive requests. Participant identification records are not copied into a general sponsor workspace merely to make the closure checklist appear complete.

Frequently Asked Questions

How long must an ISF be retained?

For trials governed by the EU Clinical Trials Regulation, essential TMF content is generally retained for at least 25 years after trial end, subject to longer applicable requirements.

Does the same rule always cover medical files?

No. Patient medical-file retention depends on applicable national law.

Can the sponsor and investigator use identical files?

Their holdings may overlap, but their responsibilities and necessary contents differ; avoid assuming identical copies are appropriate.

Related reading: trial master file, clinical trial site. For practical support, see clinical trial data protection support.

Updated: 27 October 2026