Glossary · Study designUpdated September 28, 2026

What is a natural history study?

A natural history study collects information about the course of a disease in people who are not receiving the investigational treatment, to understand how it develops, which outcomes matter and how to design trials for it.

  • Natural history studies in plain language
  • How it works in practice
  • Related terms

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Natural history study · 5-year follow-up
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Years

Enrolment and baseline
Annual clinical assessments
Quarterly ePRO
Endpoint selection for Phase 2

In short

  • Natural history studies are observational: no investigational intervention is assigned.
  • They can be retrospective (from existing records) or prospective, and cross-sectional or longitudinal.
  • In rare diseases they are often essential: they identify outcomes that change measurably, inform eligibility and trial duration, and can support external control comparisons.
  • FDA has published draft guidance on natural history studies for rare disease drug development.

Explained

Why rare disease programmes start with natural history

For common diseases, decades of trials and clinical experience show how the disease progresses and which endpoints work. For many rare diseases that knowledge does not exist. A natural history study fills the gap: it shows how fast the disease progresses, how variable it is between patients, which measures change meaningfully over a trial-length period and which patient subgroups progress fastest.

Good natural history data can shape every later decision, from the choice of primary endpoint to the sample size, and in some cases provide an external comparator where a concurrent control arm is not feasible. Because the data may later support regulatory decisions, collect it with the same attention to consistency, audit trail and definitions as trial data. See EDC for rare disease trials and EDC for registry studies.

FAQ

Common questions

Something not covered here? Ask us directly.

Is a natural history study a clinical trial?

It is a clinical study, but observational: participants are not assigned an investigational intervention.

Why are natural history studies important in rare diseases?

They provide the disease knowledge needed to select endpoints, size trials and sometimes serve as external controls.

Can natural history data be used as a control arm?

In some circumstances, as an external control. Its suitability depends on data quality and comparability, and should be discussed with regulators.

How long do natural history studies run?

Often years, because progression is slow. Long follow-up needs low-burden, consistent data collection.

Collect natural history data like trial data

Long schedules, ePRO and a full audit trail. Free sandbox.

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