For Industry

Frequently Asked Questions (FAQ) About Designating an Orphan Product

1.  Does the contact person’s signature need to be on the cover letter of the orphan drug designation request? Do you need an original signature? Can a signature page be sent separately?

  • 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. 
2.  Can the orphan drug designation request be submitted electronically? What is required? If so, how?
  • 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
 3.   What information about orphan drug designations is publicly available?  What if the sponsor does not provide a generic and trade name of the drug?
  • 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). 
 4.  What is the review process like once the orphan drug designation request is received in OOPD? 
  • 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 seconds 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.
5.  The regulations say that the sponsor is required to submit all relevant data about their drug in the orphan drug designation request. Why doesn’t the sponsor have to submit animal toxicology data in the orphan drug designation request?
  • In order to designate a product as an orphan drug, the scientific rationale portion of the designation request must include enough information to establish a medically plausible basis for expecting the drug to be effective in the rare disease. This is best supported by clinical trials of the drug in the rare disease or condition. However, in absence of human data, the request for orphan drug designation may be satisfactorily supported with preclinical data that uses the active moiety or principal molecular structure of the proposed orphan drug in a relevant animal model for the rare human disease.  Animal toxicology data, which describes the safety of the drug in animals, does not provide efficacy data, so it is not generally relevant in supporting the scientific rationale section of the orphan drug designation.
6.   What information is required for an orphan drug designation request? How should the request be formatted? 
 7.  If the sponsor is from a foreign country, is a U.S. agent required in order to file a designation request? What is needed from a U.S. agent?  What are they responsible for?
  • A foreign sponsor is required to have a U.S. permanent-resident agent in order to file a request for an orphan drug designation.  See 21CFR 316.22 for full details.
  • 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. 
  • 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.
8.  What if the sponsor has difficulty finding data on prevalence? What if data are not available? What are the best prevalence estimate resources? What should a sponsor do if the best resource they can find is 10-20 years old (or only from other countries)?
  • 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.
  • The National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program is one recommended resource for determining cancer statistics in the United States.
9.   In the case of a product used for an “acute” condition, should incidence of < 200,000 be used  instead of prevalence?  
  • 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, if the disease is a relapsing/remitting disease where each episode is acute in duration, a prevalence estimate may still be required. 
10.  If the intended designated use of a drug is for “prevention” versus for “treatment”, how is the population estimated in each case?
  • 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.
11.  Is there a general list (besides OOPD database) of specific conditions considered to have prevalence of <200,000?
  • 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.
12. Under what conditions will OOPD designate an orphan drug and recognize orphan drug exclusivity for a new formulation of a drug that is otherwise the same drug as an already approved drug for the same rare disease or condition?
  • 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.
13.  What does OOPD consider a “major contribution to patient care?”
  • 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).
14.  Please explain “Orphan Subset.”
  • An orphan subset means the use of the drug in a subset of persons with a non-rare disease or condition may be appropriate but use of the drug outside of that subset (in the remaining persons with the non-rare disease or condition) would be inappropriate owing to some property(ies) of the drug (e.g.,  drug toxicity, mechanism of action, or previous clinical experience with the drug).
  • An example of an orphan subset is that it might not be appropriate to treat all persons with a non-rare disease or condition with a drug that is highly toxic. Those patients who are refractory to, or intolerant of, other less toxic drugs might be reasonable candidates for treatment with the drug and 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.
15.  If changes are made to the product formulation (such as solution form instead of emulsion versus intravenous, subcutaneous, intrathecal, intranasal or oral or a different concentration is formulated) after receiving orphan designation and prior to NDA  submission, will the approved NDA still qualify for exclusivity?
  • 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.


Page Last Updated: 09/26/2018
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