FDA Releases Draft Guidance Document on Natural History Studies for Rare Diseases

Last week, the FDA released a draft guidance document titled, “Rare Diseases: Natural History Studies for Drug Development” with the intention of informing both the design and implementation of natural history studies that can be used to support the development of safe and effective treatments for rare diseases.

“Despite a recent wave of medical progress, most rare diseases still have no approved therapies. This presents a significant unmet public health need. It remains a top priority for the FDA to provide tools and clear advice to drug developers so that they can advance innovations that can help address these significant unmet medical needs,” said FDA Commissioner Scott Gottlieb, MD, in a prepared statement.

The FDA defines a rare disease as a disease or condition that “affects less than 200,000 persons in the United States.” The number of recognized rare diseases is estimated to be nearly 7000, most without any approved therapies.

In order to gain more understanding of a rare disease, researchers often conduct a natural history study. The natural history of a disease defines the course it takes in the absence of intervention in people with the disease. To study this, investigators employ and enroll participants in an observational study designed to track the course of the disease from onset to death. “Its purpose is to identify demographic, genetic, environmental, and other variables (eg, treatment modalities, concomitant medications) that correlate with the disease’s development and outcomes.” The FDA notes that data found in natural history studies can play an important role in drug development.

“One of the challenges we know innovators encounter developing therapies for rare diseases is the lack of natural history data to guide the design of successful clinical trials. Such data comes from observational studies that track how rare diseases develop and progress over time. Sometimes rigorous natural history models can help inform development programs, and even serve as comparator arms for studies where it may be impractical to randomize patients to placebo,” said Gottlieb.

The guidance document offered specific advice on how to approach natural history studies, which can take 1 of 2 forms, either retrospective or prospective. In retrospective studies, the patient evaluations have already occurred, whereas in prospective studies, the evaluations will happen at a later date according to a prespecified data collection plan. The guidance also included an outline of what would be expected in terms of study protocol and design, data elements, research plans, and how to relay this information and interact with the FDA.

“Because the natural history of many rare diseases remains relatively unknown, investing in rigorous models can help advance the development of treatments for these conditions. Information obtained from a natural history study can play an important role at every stage of drug development, from drug discovery to the design of clinical studies intended to support a drug’s marketing approval,” said Gottlieb.