The Natural History Studies of Orphan Products (R01) grant is a program from the FDA Office of Orphan Products Development (OOPD) that funds research to better understand the progression, presentation, and unmet needs of rare diseases. Because rare diseases lack the extensive clinical knowledge base of common conditions, natural history studies are critical to developing safe and effective medical products.

The program supports public and private entities conducting studies to characterize disease course, identify core unmet needs, and establish endpoints for future clinical trials. Grant amounts vary based on study scope and research design.

Natural History Studies Grants Program | FDA Skip to in this section menu Medical products for rare diseases and conditions Grant Programs to Support Development of Medical Products for Rare Diseases Orphan Products Grants Program Natural History Studies Grants Program Orphan Products Grants Program About the Natural History Studies Grants Program Unlike common diseases, there is little existing knowledge on the presentation, major limitations on day-to-day function, core unmet needs and course of most rare diseases which makes drug development challenging.

To address this, it is critical to study the natural history of rare diseases. The FDA has funded natural history studies since 2016, to help address significant unmet medical needs for patients with rare diseases where there is often little knowledge on the progression of many rare diseases which makes medical product development challenging.

The information obtained from a natural history study can play an essential role in addressing these challenges, such as identifying the patient population or developing clinical outcome assessments and biomarkers for a given disease. What is a natural history study? Natural history studies look closely at how specific diseases progress over time.

A natural history study is a preplanned, observational study intended to track the course of the disease. Its purpose is to identify demographic, genetic, environmental and other variables (e.g., treatment modalities, concomitant medications) that correlate with the disease’s development and outcomes.

Information obtained from a natural history study plays an essential role at every stage of product development, such as identifying the patient population, identifying or developing clinical outcome assessments and biomarkers and, when appropriate, serving as external controls. Natural history studies are observational and non-interventional in nature and may be retrospective or prospective.

More background and definitions The natural history of a disease is the natural course of a disease from the time immediately prior to its inception, progressing through its pre-symptomatic phase and different clinical stages to the point where the disease has ended without external intervention.

Natural history studies track the course of disease over time, identifying demographic, genetic, environmental, and other variables that correlate with its development and outcomes in the absence of treatment. Thorough understanding of disease natural history is the foundation upon which a clinical development program for drugs, biologics, medical foods or medical devices is built.

Rare diseases , as defined in the U.S. Orphan Drug Act (ODA), are diseases or conditions with a prevalence of fewer than 200,000 persons in the U.S. Though individually rare, together there are ~30 million Americans affected by 7,000 known rare diseases.

Unlike common diseases, there is little existing knowledge on the natural history of most rare diseases, which makes natural history studies of particular importance for rare diseases product development. For more information, see the draft guidance: Rare Diseases: Natural History Studies for Drug Development . Types of natural history studies Retrospective study : data have already been generated prior to study initiation.

Retrospective studies are most commonly reviews of medical records, such as patient charts. Prospective study: data are generated after study initiation. Prospective studies allow implementation of a predefined and consistent data collection, up-to-date medical terminology and standard of care and the flexibility to collect additional data as the study evolves.

Survey study: collects and analyzes natural history data through questionnaires answered by patients, primary caregivers, and/or others. Survey studies typically do not involve clinical visits and provide a quick overview of the disease population. This program is intended to fund well-designed, protocol-driven natural history studies that address knowledge gaps, support clinical trials and advance rare disease medical products.

OOPD currently awards new natural history study grants every two years. OOPD is focusing efforts to support efficient and innovative natural history studies that advance medical product development in rare diseases and conditions with unmet needs. For a list of grants awarded, see: Orphan Products Grants Awarded .

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