Frequently Asked Questions (FAQ)

• An original signature of an individual associated with the sponsor is required on one copy of the orphan designation application. 
• The original signature does not have to be the contact person. For example, the sponsor’s CEO may sign the application cover letter but the individual listed as the contact person is the head of regulatory affairs. 

• An electronic Orphan designation application can be submitted on a single CD-ROM disk with a signed cover letter. 

• Public available information (sponsor’s name, address and contact information, name of drug, proposed indication and date of designation) on orphan designated products are posted on the OOPD website.  
• After the designated Orphan product receives NDA or BLA marketing approval additional information about the drug and application including a copy of the written designation review, may be released through the Freedom of Information Act (FOIA).  

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What is the review process like once application is received in OOPD? How is a designation application reviewed in OOPD?  Please describe the review process for a designation application.

• Following receipt of the Orphan designation application, the OOPD review process is as follows: The application is assigned a designation application number and logged into OOPD database and an acknowledgement letter is sent to the sponsor. The assigned OOPD reviewer completes the review of the application by preparing a review. The review is forwarded to the OOPD Team Leader for a second level review and concurrence. The review is forwarded for a 3^rd level review by the OOPD Office Director. Following the OOPD Director’s concurrence, a designation letter, a letter requesting additional information, or a denial letter is prepared for the Director’s signature and the letter is issued to the sponsor.

• Once the designated orphan product achieves FDA marketing approval under an NDA or BLA, a copy of the written designation review can be requested through the Freedom of Information Act (FOIA).

• The party of interest refers to anyone who acknowledges they are actively interested in pursuing the development of the drug for the rare disease. 
• Anyone who is interested in developing the product may submit an application for orphan drug designation, even if they do not own the drug. 
• Each successful application for orphan drug designation must contain adequate scientific rationale and prevalence data to support the designation.
• There is no need for permission of the product’s owner or manufacturer to submit a designation request. Orphan designation does not obligate the owner or manufacturing company in any way.

• 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. This is best supported by clinical trials of the drug in the rare disease or condition
• However, in absence of human data, the application for orphan drug designation may be satisfactorily supported with compelling preclinical data that uses the active moiety of the proposed orphan drug in a relevant animal model for the rare human disease. Pharmtox data, which describes the safety of the drug in animals, does not provide efficacy data, so is not useful in supporting the scientific rationale section of the orphan drug designation.

• Common EMEA application.

•  A sponsor can choose to use this application or use the content and format in the regulations (21 CFR 316.20). When filled out and properly appended, both formats provide the same information to adequately support an application for orphan drug designation to OOPD. 
• However, the common form includes items on pages 6 to 8 that are specific to EMEA. If a sponsor is going to apply for orphan drug designation to both the EMEA and FDA, the sponsor may want to consider using the common form.  
• EMEA requirements are slightly different. Guidance for filing an orphan drug designation application with the EMA may be found on the EMEA webpage.

• A foreign sponsor must have a US resident agent in order to file an application for orphan drug designation.  
• A US agent can be anyone residing in the US who is responsible for the paperwork involved with the designation application and if designation is granted to the application, will serve as the contact person. Generally a US sponsor is associated with a regulatory affairs firm or a contact person at a US university.

• 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 application. If the reference source is from the Internet, 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 is available, the sponsor should explain this in the application.
• If data is old, the sponsor should explain why the data is still pertinent and, if from a foreign source, why data with that country’s population could also be representative of US 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 US population data available from the US Census Bureau.

• The NIH Office of Rare Disease Research (ORDR) 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 be supportive for an application for 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. 

• For the purposes of a drug or biologic designation, the OOPD will define pediatric as encompassing up to and including age 16. {Source: CDER 21 CFR 201.57 (c)(9)(iv)]; CBER 1996 Guidance for Industry “The Content and Format for Pediatric use Supplements” [59 FR 64242]}
• For purposes of a HUD designation, the OOPD will define a pediatric device as one designed for individuals up to the age of 22. [Source: Pediatric Medical Device Safety and Improvement Act of 2007 303 (a) (6) (E) (i)]
• For foods or special dietary use designation, OOPD defines pediatric as persons from birth to less than 12 years old. [Source: 21 CFR 105.3 (e)   Foods for Special Dietary Use]
• In cases of combination products, the OOPD will follow the age associated with the primary classification of the product as determined by the Office of Combination Products. 

• The public policy objective of the Orphan Drug Act is to further the testing and marketing of products for rare diseases in which no current therapy exists or where the product will significantly improve the existing therapy.
•  If a product has received marketing approval in the United States for use in the proposed orphan indication, the only way the proposed product can be designated as an orphan drug is if the sponsor provides a reasonable hypothesis that their product is “clinically superior” to the approved product by means of greater effectiveness, greater safety, or that it provides a major contribution to patient care (MC–to-PC).  
• Further, if orphan drug designation is ultimately granted, in order for the product to receive orphan drug exclusive approval for this indication, the sponsor must actually demonstrate the superiority claim by showing their product is significantly more effective than the approved product in a clinical trial, is safer in a substantial portion of the target population, or can provide a major contribution to patient care.  
• Any claim for clinical superiority could require a head-to–head trial. 

• A claim that a proposed orphan product may be clinically superior to an approved orphan product by a measure of major contribution to patient care MC-to-PC is intended to constitute a narrow category and its use is not intended to open the flood gates to FDA approval for every drug in which a minor convenience over and above that attributed to an already approved drug can be demonstrated.   Historically, the only situation which FDA has identified as a MC-to-PC is the development of an oral dosage form where the first drug was available only as 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. 
• What cannot be used for a MC-to-PC hypothesis: 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 needs to be based on a measure of greater safety or efficacy). 

• A medically plausible subset of a more common disease has been defined only in terms of a characteristic of the drug that would limit its use to just a segment of those afflicted.
• An example of a medically plausible subset is of a drug so toxic that only the most severely ill patients would use it (e.g. stage IV cancer); there would be too many risks for a less ill patient to use that therapy.

• Orphan drug designation is conferred to the active moiety rather than the product formulation; therefore, changes to the product formulation should not 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 exclusivity upon approval of the changed formulation unless the sponsor can demonstrate that the changed formulation is clinically superior to the original approved product.

   

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