FDA Revises Draft Guidance on Developing Drugs for Rare Diseases

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The FDA has issued an update to its 2015 draft guidance on developing drugs to treat rare diseases.

The FDA has issued an update to its 2015 draft guidance on developing drugs to treat rare diseases.

The new draft guidance, issued last month by the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research within the FDA, contains several updates to the original document, including the following added and revised sections:

Natural History Studies

While the FDA does not require natural history studies, it advises sponsors to investigate the depth and quality of existing knowledge to determine whether it is satisfactory to inform drug development. In some circumstances, a well-designed natural history study can provide an external control group in interventional trials. Regardless of the type of study, natural history studies should generally be sufficiently long to capture clinically meaningful outcomes and variability in the course of the disease, select data that includes symptoms that are important to patients, collect data from relevant sources that include standards of care and concomitant therapies, a wide spectrum of patients, and use standard collection methods and terminology.


Because knowledge about a disease’s pathophysiology and clinical manifestations over time are often incomplete for rare diseases, development of new treatments by identifying new biomarkers or modifying existing can be highly useful. Biomarkers may also serve as surrogate efficacy endpoints, but the use of such a surrogate endpoint requires demonstrate of analytical and clinical validation of the biomarker test.


Nonclinical Flexibility

In nonclinical studies, factors that the FDA will evaluate when determining areas of flexibility include the pharmacological and chemical characteristics of the drug, the design and objectives of the clinical program, anticipated risks to humans, and existing nonclinical toxicology and human data.

Historical Controls and Early Randomization

The use of historical (or external) controls is typically restricted to areas of unmet medical need where there is a well-document and predictable disease course and an expected drug effect that is large and self-evident. Early randomization helps to ensure that each patient’s contribution to the trial is interpretable, and stratified randomization may be helpful.


The goal of a safety evaluation is to characterize the drug’s safety profile in a reasonable number of patients over a reasonable duration. In the context of rare diseases, “reasonable” must be understood in light of the number of patients with the disease. Ultimately, says the FDA, what constitutes a feasible and sufficient safety assessment will be determined on a case-by-case basis. The FDA encourages sponsors to discuss their overall plans for maximizing the quantity and quality of their safety data with the agency in early meetings.

Changes to Drug Substance or Manufacturing Process

The FDA recommends careful assessment of any changes to the drug substance or manufacturing processes to determine whether changes could affect the safety or efficacy of the product. Assessments may include both clinical and nonclinical trials, and FDA may exercise some flexibility on the type of manufacturing information needed.

Additional Considerations

The FDA also adds material on additional considerations, such underscoring the fact that it encourages the participation of patients and advocates in the rare disease drug development process. It adds that sponsors should consider expedited programs for serious or life-threatening diseases with unmet needs, and adds that, given that half of those affected by rare diseases are children, sponsors are encouraged to study their drugs in all relevant pediatric populations.

The FDA will receive comments on the draft guidance via the Federal Register for 60 days.