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Imported item 10
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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.

A

Imported item 42

ALCOA+ is a set of principles used to describe trustworthy data throughout their lifecycle. The letters stand for attributable, legible, contemporaneous, original and accurate; the plus adds complete, consistent, enduring and available. In clinical research, these principles help teams assess whether records reliably show what happened, when and by whom.

Key takeaways

  • Integrity concerns the complete data lifecycle.
  • A readable export is not always a complete record.
  • Apply controls proportionately to data risk.

The Nine ALCOA+ Principles

The MHRA data integrity guidance explains the terminology. The TGA’s data integrity guidance also connects reliable records with the controls used to create, modify and retain them.

PrinciplePractical question
AttributableWho performed the activity?
LegibleCan the record be read?
ContemporaneousWas it recorded when it happened?
OriginalIs this the first record or a verified copy?
AccurateDoes it reflect the observation correctly?
CompleteAre relevant records and metadata retained?
ConsistentDo sequence and timing make sense?
EnduringWill the record remain usable?
AvailableCan authorised reviewers retrieve it?

Why It Matters for Data Protection

Our recommended approach is to assess integrity and confidentiality together. Preserve necessary audit information without granting every user access to identifiable participant records. Define account ownership, correction procedures and retrieval tests before deployment. ALCOA+ is a useful assessment vocabulary, not a substitute for evaluating applicable GCP requirements or electronic-record rules such as 21 CFR Part 11.

Hypothetical example: A site corrects an incorrectly entered visit date. Its process preserves the earlier value, records the person making the correction and explains the reason. The monitor can review that history without receiving unnecessary participant identifiers.

Frequently Asked Questions

Is ALCOA+ a certification?

It describes integrity principles, not a standalone product certification.

Does a PDF export prove integrity?

Not by itself. Consider context, metadata and the underlying record history.

How does it relate to ICH E6(R3)?

Use it alongside a study’s GCP data-governance assessment, rather than as a replacement checklist.

Related reading: source data verification, data quality, computerised system validation. For practical support, see quality assurance.

Updated: 27 October 2026