What is a natural history study and why is it important in rare disease research?
UpdatedNovember 14, 2019

For rare diseases, it’s critical to learn more about a condition before effective trials can be developed. That’s where a “natural history study” comes in.

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Natural history studies track diseases over time

A natural history study is a medical research study that focuses on the disease progression and patient population. The name “natural history” refers to how a disease develops without any treatment.

The goal of a natural history study is to get a big picture view of how a disease develops, to improve understanding of that condition. RDMD can help organizations create high-quality natural history studies that can feed research for years to come.

Researchers aim to capture a variety of patient experiences

When a natural history study is conducted, a range of information on the patient experience is collected. This can include symptoms, test results, physical signs, imaging, patient age, genetics and quality of life, as well as on any other factor relevant to the disease and its development.

Differences between groups of patients within one condition may emerge from a natural history study. This can help researchers identify important disease subtypes and better understand the patient population.

Natural history studies can be retrospective or prospective

  • A retrospective natural history study uses pre-existing data on patients with the disease, for instance from medical records.
  • Prospective natural history studies use new data collected for the study at specified times after the study has begun.

Depending on the disease, the period of time covered in a natural history study may start before the disease begins, through a period when symptoms have not developed yet, then through the different stages of disease.

Knowledge gained from a natural history study can lead to improvements in treatment

Natural history studies are particularly important in rare disease research because so little is known about so many rare diseases. Without this information, doctors and patients may find themselves unprepared to manage the disease and unsure of what to expect as the disease progresses.

Natural history studies document the current standard of care for patients and may uncover ways it can be improved. Patient subgroups once recognized may benefit from subgroup specific management or treatment. Centers of excellence specializing in the disease may be located through the study.

Natural history studies can also identity new, or confirm the importance of known, disease markers such as genetic variants, or molecules in body tissues and fluids. These findings may be used to help diagnose the disease, provide a prognosis or as a basis for drug development.

Clinical trials are informed by natural history studies

Natural history studies help researchers design clinical trials well suited to the patient population and disease.

The information they provide allows researchers to determine the appropriate entry criteria, time intervals for data collection and duration of the trial. It also helps them decide which variables or outcomes they should measure to assess whether a drug or treatment has been successful. An in-depth understanding of the disease can be useful for choosing the drug dose and early recognition of safety issues.

‘Historically controlled trials’ often depend on data from natural history studies

In a clinical trial patients are usually divided into two groups: one that receives the trial drug or treatment and another, called the control group, that receives a placebo.

This can raise ethical concerns when the disease is serious and has no effective treatment other than potentially that in the trial. In special circumstances where the course of the disease is predictable and the effect of the treatment is dramatic a natural history study may be used to provide the control group.

This is known as a historically controlled trial and in this type of trial all patients receive the drug or treatment being investigated.

Disease registries are a frequent source of data for natural history studies, but often the information in a registry is exclusively patient-reported and is not audit-trailed in the way it would need to be in order to be considered research-grade or FDA-grade. RDMD collects records on behalf of patients, for free, enabling us to audit trail everything and set a patient community up for future uses of that important natural history information, such as in lew of a placebo group.

Reliable high quality data is essential in research

Natural history studies provide a foundation for further research. When designing and conducting a natural history study it is important to consider possible future uses for the study information.

Data reliability can be compromised by inconsistent measurement procedures, irregularly recorded data, missing data and inconsistent use of medical terminology. In multinational natural history studies it is also important to take into account the impact of language and cultural differences. If the data collected is not of sufficient quality its potential uses will be limited.

At RDMD we are focused on creating a foundation of knowledge about rare diseases and one of the primary ways to achieve this is through a high-quality natural history study. If you represent an organization interested in conducting a natural history study, please email us at community@rdmd.com for more information.


U.S. Department of Health and Human Services, Food and Drug Administration (2019) Rare Diseases: Natural History Studies for Drug Development, Guidance for Industry, Draft Guidance, available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/rare-diseases-natural-history-studies-drug-development [Accessed 1 Sept 2019]

U.S. Department of Health and Human Services, Food and Drug Administration (2019) Rare Diseases Common Issues in Drug Development Guidance for Industry, Draft Guidance

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ALS Association. “Natural history studies.” 2019. http://www.alsa.org/research/focus-areas/natural-history-studies/

Friedreich’s Ataxia News. “FDA revising ‘draft guidance’ on developing treatments for rare diseases.” January 2019. https://friedreichsataxianews.com/2019/01/31/fda-revising-draft-guidance-on-developing-treatments-for-rare-diseases/

National Organization for Rare Diseases. “Rare disease facts.” 2019. https://rarediseases.org/wp-content/uploads/2019/02/nord-rareinsights-rd-facts-2019.pdf

National Organization for Rare Diseases. “Research grant program.” 2019. https://rarediseases.org/for-clinicians-and-researchers/research-opportunities/research-grant-program/

Originally posted at November 14, 2019

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