An original signature of an individual representing the sponsor organization is required on one copy of the orphan drug designation request (typically the cover letter.) The original signature does not have to be the contact person. For example, the sponsor’s CEO may sign the cover letter, but the individual listed as the contact person is the head of regulatory affairs. 

Yes. Orphan drug requests can be submitted by email to [email protected]. Please include a dated and signed cover letter, a bibliography and full copies (not abstracts) of all references cited. See Designating an Orphan Product: Drugs and Biological Products for more information. 

If a product receives an orphan drug designation, certain information (sponsor’s name, address and contact information, name of drug, orphan designated use and date of designation and status) about the orphan designated product will be available in the FDA’s searchable database.

FDA will post the generic and trade name of the drug, or if neither is available, the chemical name or a meaningful descriptive name of the drug provided by the sponsor and subject to approval by FDA. See 21CFR 316.28(b) for more information.  

If a designated product is approved by FDA for marketing, certain additional information is available on the website (approval date, approved indication and exclusivity status). 

The FDA will send an acknowledgement letter to the sponsor (or sponsor’s agent). The FDA conducts the review of the request, which may require agency-wide coordination. When FDA’s review of the request is complete, if FDA determines the drug is eligible for orphan drug designation, FDA will send the sponsor a designation letter. The sponsor may receive a deficiency letter requesting additional information or a denial letter as appropriate. 

In order to designate a product as an orphan drug, the scientific rationale portion of the designation application must include enough information to establish a medically plausible basis for expecting the drug to be effective in the rare disease. The scientific rationale is best supported by clinical data of the drug in treating, preventing or diagnosing the rare disease. However, in the absence of human data, the application for orphan drug designation may be satisfactorily supported with preclinical data using the drug in a relevant animal model for the human disease. 

In the absence of human data and when a relevant animal model does not exist, the FDA may consider a combination of alternative data that includes the pathogenesis of the disease, a clear description of the drug and its mechanism of action specific to the disease and supporting in vitro data.  

Animal toxicology data describing the safety of the drug in animals do not provide efficacy data and are not generally relevant in supporting the scientific rationale. Only in rare situations, where there is an absence of both human data and a relevant in vivo model, will FDA consider a combination of alternative data that include the pathogenesis of the disease, a clear description of the drug and its mechanism of action specific to the disease and supporting in vitro data.

See Recommended Tips for Creating an Orphan Drug Designation Application for information on compiling an orphan drug designation request.

A sponsor located outside the U.S. is required to have a U.S. permanent resident agent to file a request for an orphan drug designation. All correspondence to and from FDA related to international sponsors should go through the U.S. agent including submitting annual reports after a product is designated as an orphan drug. 

A U.S. agent can be anyone residing in the U.S. who is responsible for the paperwork involved with the designation request and, if a designation is granted, will serve as the primary contact going forward. If the sponsor’s U.S. agent changes, FDA must be notified.

Besides referenced texts and journals, prevalence data for many rare diseases can be found on the internet at government and patient support group websites. There is no general list of specific conditions considered to have prevalence of fewer than 200,000. Copies of all materials documenting how the prevalence estimate was determined should be provided in the designation request. If the reference source is from a website, a hard copy of the document should be included as well as the website address. The date each website was accessed should also be provided for all website sources referenced. 

Sponsors are expected to make a good faith effort in finding the most recent prevalence data that refers to a United States population. If only old and/or foreign data are available, the sponsor should explain this in the request. If data are old, the sponsor should explain why the data are still pertinent and, if from a foreign source, why data from that country’s population could also be representative of U.S. population.

The prevalence estimate must be current to reflect the prevalence at the time of submission of the request for orphan drug designation (21CFR 316.21 (b)). To update this estimate, the sponsor should use U.S. population data available from the U.S. Census Bureau.

Provide all calculations and cite references used to make the population estimate. The estimate should be current at the time of the submission of the orphan drug designation request. U.S. Census Bureau data can be used to update any population estimate.

When a range of estimates exists, FDA accepts only the largest estimate unless a justification is provided why another estimate is more accurate.

If the drug is intended for diagnosis or prevention of a rare disease or condition, provide the estimated number of people to whom the drug will be administered annually.

If a disease is an acute condition (e.g., less than one year duration) incidence may be used as an estimate of the population. However, note that if the disease is a relapsing/remitting disease where each episode is acute in duration, a prevalence estimate may still be required.

If using data from a claims database or foreign data, clearly explain how such data are generalizable to the U.S. population and the limitations of the data.

The National Cancer Institute’s Surveillance, Epidemiology and End Results Program is one recommended resource for determining cancer statistics in the United States.

If the drug is being used for prevention, the population estimate should be the number of people to whom the drug will be administered annually in the U.S. (21 CFR 316.21(b)(3).) 

The public policy objective of the Orphan Drug Act is to stimulate innovation in developing treatments for patients with rare diseases and conditions, and to foster the prompt availability of clinically superior drugs. Accordingly, FDA’s regulations help ensure orphan drug exclusivity does not preclude significant improvements in treating rare diseases.

FDA may grant orphan drug designation to a drug that is otherwise the same drug as a drug already approved in the U.S. for the same rare disease or condition only if the sponsor can present a plausible hypothesis that its drug may be clinically superior to the previously approved drug. See 21 CFR 316.20(a) for more information.

Clinical superiority may be established by means of greater effectiveness, greater safety in a substantial portion of the target populations, or in unusual cases a major contribution to patient care. (21 CFR 316.3(b)(3).)

If orphan drug designation is granted, and if the drug receives marketing approval for the designated use, in order for the drug to be eligible for orphan drug exclusivity, the sponsor must demonstrate that the drug is clinically superior to any previously approved same drug for the same use (21 CFR 316.34(c).) Any claim for clinical superiority could require a head-to-head trial.

The following factors, when applicable to severe or life-threatening diseases, may in appropriate cases be taken into consideration when determining whether a drug makes a major contribution to patient care:

• Convenient treatment location
• Duration of treatment
• Patient comfort
• Reduced treatment burden
• Advances in ease and comfort of drug administration
• Longer periods between doses
• Potential for self-administration

Factors that FDA cannot consider when determining whether a drug makes a major contribution to patient care include: 

• Cost of therapy
• Compliance to therapy (significantly improved compliance should be reflected by a measure of greater safety or efficacy)

Sponsors can receive orphan drug designation for the use of a drug in an orphan subset of a non-rare disease or condition when they can explain based on a characteristic or feature of the drug why the drug will be limited to use in an orphan subset of a non-rare disease. An orphan subset is not based on an unmet need, or how a sponsor may wish to study or indicate a drug. The explanation for the orphan subset must make it clear that the drug could never be used in the disease or condition outside of the subset. See 21 CFR 316.3(b)(13) for more information.

Orphan drug designation is generally granted to the active moiety rather than the product formulation so changes to the product formulation should not generally affect orphan drug designation status.
The first sponsor to bring an active moiety to market for a particular use or indication is generally eligible for orphan drug exclusivity if that sponsor has orphan designation for that drug. If the sponsor subsequently makes a change in formulation to the original product, which was designated and approved for marketing, we consider the sponsor to still have designation for the active moiety. The sponsor will not be eligible for a new term of orphan drug exclusivity upon approval of the changed formulation unless the sponsor can demonstrate that the changed formulation is clinically superior to the original approved product.