U.S. Food and Drug Administration
`Protecting and Promoting Your Health
`
`Frequently Asked Questions (FAQ)
`
`Does the contact person’s signature need to be on the cover letter? Do you need an original signature? Can a signature page be sent separately?
`
`• 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.
`• OOPD requires that the original signature page be submitted with the application.
`
`Can we submit the designation electronically? What is required? If so, how?
`
`• An electronic Orphan designation application can be submitted on a single CD-ROM disk with a signed cover letter.
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`What information concerning approved designations is publicly available?
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`• Public available information (sponsor’s name, address and contact information, name of drug, orphan designated use and date of designation) on orphan designated
`products are posted on the OOPD website. (http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanPro-
`ductDesignation/default.htm)
`• 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). (http://www.fda.gov/RegulatoryInformation/FOI/default.htm)
`
`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 3rd 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.
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`Are the written reviews conducted by OOPD staff publicly available?
`
`• 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). (http://www.fda.gov/RegulatoryInformation/FOI/HowtoMakeaFOIARequest/default.htm)
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`The regulations say that the sponsor is required to submit all relevant data about their drug, why doesn’t the sponsor have to submit animal toxicology data
`for orphan designation?
`
`• 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 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 is not useful in supporting the scientific rationale section of the orphan drug designation.
`
`Common application (EMEA & FDA). What are the prevalence differences? How do you complete the form? When is it necessary to use? What are main
`advantages and disadvantages? Will one approval/denial affect the other? Can a sponsor submit a designation request simultaneously to the EMEA and FDA
`from this workshop? Â How does the OOPD form differ from the EU designation application?
`
`• Common EMEA application (http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048361.pdf).
`• A sponsor can choose to use this application or use the content and format in the regulations (21 CFR 316.20).
`• 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
`(http://www.ema.europa.eu/ema/).
`
`(For international sponsors). What is needed from a US sponsor/contact? What are they responsible for? If the sponsor is from a foreign country, is a US
`agent required in order to file a designation application?
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`• 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.
`• OOPD requires that all correspondence related to international sponsors to and from the Office of Orphan Products Development go through the US agent.
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`What if the sponsor has difficulty finding data on prevalence? What if data is 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 from other countries only)?
`
`CFAD Exhibit 1069
`CFAD v. NPS
`IPR2015-01093
`http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/ucm240819.htm
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`• 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 (http://www.cen-
`sus.gov/).
`• The National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program (http://seer.cancer.gov/) is another resource for determining
`cancer statistics in the United States.
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`In the case of a product used for an “acute” condition, should incidence of < 200,000 be used instead of prevalence?
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`• If a disease is an acute condition (i.e., less than one year duration) incidence may be used as an estimate of the target population.
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`If a drug is used for transplant to “prevent” rejection (solid organ tumors versus separate kidney & heart transplant indications). If a drug is used for
`“prevention” of rejection versus for “treatment” of rejection would prevalence or incidence be used in each case?
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`• If the drug is being used as a preventative, the target population is the number of people to whom the drug will be administered annually.
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`Is there a general list (besides OP database) of specific conditions considered to have prevalence of <200,000?
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`• The NIH Office of Rare Disease Research (ORDR) (http://rarediseases.info.nih.gov/site-search?q=rare%20disease%20list) 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.
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`How does OOPD define what constitutes “Pediatric” patient population for Orphan product designations, given the wide range of pediatric ages across the
`various Centers at FDA?
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`Given that OOPD designates products that are subsequently regulated by different Centers across the agency, OOPD will adhere to the pediatric age definitions used by
`each center as listed below:
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`• 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.
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`If a product with an Active Pharmaceutical Ingredient (API) is already approved for a rare disease indication, but a different formulation is believed to have a
`greater efficacy for the same rare disease indication, can an orphan designation be requested?
`
`• 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.
`• Â 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.
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`What does OOPD need to determine clinical superiority? Explain “major contribution to patient care.”
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`• 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).
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`Please explain “Orphan Subset.” Specific orphan subset questions (need to make case for why drug would be used only for this subset).
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`• 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, for example, 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
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`http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/ucm240819.htm
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`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.
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`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 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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`http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/ucm240819.htm