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  5. Frequently Asked Questions (FAQ) About Designating an Orphan Product
  1. Designating an Orphan Product: Drugs and Biological Products

Frequently Asked Questions (FAQ) About Designating an Orphan Product

Frequently Asked Questions

Designation is given to a drug/biologic for the treatment, diagnosis or prevention of a rare disease or condition, not to proposed drug indication or how a sponsor may wish to study a drug.

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. 

An orphan drug designation can be submitted on a single compact disk (CD) with a signed cover letter attached.   It is preferred to be sent by regular or express mail.  An orphan drug designation request cannot be submitted by email or by any other physical media, such as a thumb drive.  Additional information and the address for sending the orphan drug designation request to the Office of Orphan Products Development (OOPD) can be found at Corresponding with OOPD Drug Designation Programs

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) about the orphan designated product is posted in the searchable database on the OOPD website.

Per 21CFR 316.28(b), 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 OOPD.

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

Following receipt of the orphan drug designation request at OOPD, the review process is as follows: the request is assigned a designation request number, logged into OOPD database, and an acknowledgement letter is sent to the sponsor (or sponsor’s agent). The assigned OOPD reviewer completes the review of the request, which may require consultation with an FDA Center.  The review is forwarded to the Director of the Orphan Drug Designation Program for a second level review and concurrence.  Following the OOPD Office Director's concurrence, a designation letter, a deficiency letter requesting additional information, or a denial letter is prepared for the OOPD Office Director's signature and the letter is then issued to the sponsor.

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 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 absence of human data and when a relevant animal model does not exist, the OOPD 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.

The content and format of a request for orphan drug designation is described in 21 CFR 316.20(b). The FDA Orphan Designation Request Form (FDA 4035) is designed to assist sponsors in providing the required content of the orphan drug designation request completely and succinctly.  A resource for sponsors in compiling the orphan drug request is the Recommended Tips for Creating an Orphan Drug Designation Application webinar and PowerPoint slides which can be found at  Education and Media Resources for Orphan Designation Program .

A foreign sponsor is required to have a U.S. permanent-resident agent to file a request for an orphan drug designation.  See 21CFR 316.22 for full details.

OOPD requires that all correspondence to and from OOPD related to international sponsors go through the U.S. agent. This includes submitting subsequent annual reports after a product is designated.

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 contact person afterwards. Generally, a U.S. sponsor is associated with a regulatory consulting firm or a contact person at a U.S. university. If the sponsor’s agent changes, then OOPD must be notified immediately. 

Besides referenced texts and journals, prevalence data for many rare diseases can be found on the internet at government and patient support group websites. Copies of all materials documenting how the prevalence estimate was made 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.

A sponsor is 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 with that country’s population could also be representative of U.S. population.

The sponsor should be reminded that 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.

Estimate should be current at the time of the submission of the orphan drug designation request. US 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 (i.e. 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 US population and the limitations of the data.

The National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program is one recommended resource for determining cancer statistics in the United States. A complete prevalence is required.

If the drug is being used as a preventative, the population estimate should be the number of people to whom the drug will be administered annually in the United States.

If the drug is being used for a treatment, the population is comprised of the number of persons in the United States who have been diagnosed as having the disease or condition at the time of the submission of the request for orphan drug designation.

The NIH Genetic and Rare Diseases Information Center (GARD) provides a Rare Disease list.  However, the purpose of the list is to distribute general information about rare diseases and on its own does not provide the current prevalence information that would support a request for an orphan drug designation.

OOPD will not accept the fact that a disease is listed as a rare disease on a website as evidence of prevalence of <200,000.

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 therapeutically superior drugs. Accordingly, the orphan drug regulations attempt to ensure that orphan drug exclusivity approval does not preclude significant improvements in treating rare diseases.

OOPD 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. 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 (MC-to-PC).

Further, if orphan drug designation is granted, and if the drug receives marketing approval for the designated use, in order for the drug to receive orphan drug exclusive approval for this use, the sponsor must demonstrate that the drug is actually clinically superior to any previously approved same drug for the same use.

Any claim for clinical superiority could require a head-to-head trial.

Major contribution to patient care (MC-to-PC) is a narrow category and is not intended to open the flood gates to orphan exclusive approval for every drug in which a minor convenience over and above that attributed to an already approved drug can be demonstrated. For example, FDA has identified as providing a MC-to-PC the development of an oral dosage form where the previously approved versions of the same drug for the same use are only available in a parenteral form.  However, each measure of MC-to-PC stands on its own and it could be possible that an oral dosage form is not superior to a parenteral form.

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 MC-to-PC: convenient treatment location; duration of treatment; patient comfort; reduced treatment burden; advances in ease and comfort of drug administration; longer periods between doses; and potential for self-administration.

Factors that FDA cannot consider when determining whether a drug makes a MC-to-PC include: cost of therapy (FDA has no authority on drug pricing or any authority to consider it in drug approval), and 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 (e.g., mechanism of action, toxicity profile, prior clinical experience) why the drug will be limited to use in the subset of question.  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 to OOPD that the drug could never be used in the disease or condition outside of the subset. 

For example, it might not be appropriate to treat all persons with a non-rare disease or condition with a drug that is highly toxic; however, those patients who are refractory to, or intolerant of, other less toxic drugs might be reasonable candidates for treatment with the drug. Therefore, those patients who are refractory to, or intolerant of, other less toxic drugs may be considered an appropriate orphan subset for purposes of orphan drug designation of the highly toxic drug. In addition, other inherent properties of a drug, such as its pharmacologic or biopharmaceutical characteristics, may provide a reasonable basis upon which to identify a subset of patients to whom it would be appropriate to limit treatment and who thus would qualify as an orphan subset of a non-rare disease or condition. Likewise, characteristics of the drug that have been demonstrated through previous clinical experiences may be used to identify an appropriate orphan subset. If you believe that your drug can only be used an orphan subset of the disease, we ask that you please describe the orphan subset and provide an estimate of this target population.

Orphan drug designation is generally conferred to the active moiety rather than the product formulation; therefore, changes to the product formulation should not generally affect orphan drug designation status.

The first sponsor to bring an active moiety to market receives the benefits of exclusivity if that sponsor has orphan designation. 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. But the sponsor will not receive a new term of exclusivity upon approval of the changed formulation unless the sponsor can demonstrate that the changed formulation is clinically superior to the original approved product.

Additional Resources:


For any other questions not listed here, please email orphan@fda.hhs.gov