Recommended Tips for Creating an Orphan 

Drug Designation Application

A Webinar by the Office of Orphan Products Development (OOPD)

2018 
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Objectives

• How to create a concise and thorough orphan drug 

designation application

• What needs to be included in the designation application

• Common issues encountered during the review of the 

designation application 

• General tips to consider prior to submitting an orphan 

drug designation application
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Introduction

• Intent of the Orphan Drug Act

• Orphan drug:

– Drugs (includes biologics) for the prevention, diagnosis, or treatment of diseases or 

conditions affecting fewer than 200,000 persons in the US

OR 

– Drugs that will not be profitable within 7 years following approval by the FDA (not discussed 

further in this webinar)

• What are the benefits of obtaining orphan designation:

– Tax credits for qualified clinical testing

– Waiver of NDA/BLA user fees

– Eligibility for 7-year marketing exclusivity ("orphan exclusivity") upon marketing approval

www.fda.gov
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Application Content

For a complete list of required elements refer to 21 CFR 

316.20(b)

• Sponsor Template

• Basic elements:

– Administrative information

– Explaining what is the disease or condition

– Providing sufficient scientific rationale

– Determining the population estimate to support that the disease is 

rare 

www.fda.gov
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Administrative Information

• Statement that sponsor is requesting orphan drug 

designation for a rare disease or condition which is 

identified with specificity

• Contact information as specified under 21 CFR 

316.20(b)(2)

• Descriptive name of the product

• Manufacturer for drug substance/drug product
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Explaining the Disease or Condition

• Directly affects the population estimate

• Designation given to a drug for a disease or condition, not an 

indication

• Designation granted is typically for a broad disease or 

condition and not a specific indication

• Factors not taken into consideration when determining the 

disease or condition:

• Presence of an unmet need

• Sponsor’s intent to study the drug only in a certain population

www.fda.gov
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Explaining the Disease or Condition

• Scientific understanding of what the disease is can evolve 

with new scientific findings

• Factors for determining a disease or condition include:

– Mechanism of Action (MOA) of drug

– Pathophysiology

– Etiology

– Treatment options

– Prognosis
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Explaining the Disease or Condition

• Key points:

– Pneumonia in cystic fibrosis is a different disease than community 

acquired pneumonia

– For lymphomas, the WHO classification stipulates the disease of record

– Systemic sclerosis or systemic scleroderma is a different disease than 

localized scleroderma

– The 5 groups of pulmonary hypertension in the WHO classification are 

different diseases

– Generally, for infections, the site of infection determines the disease
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Providing Sufficient Scientific Rationale

• Drug must demonstrate “promise” to treat, 

diagnose or prevent the disease/condition

• Provide:

– Drug description and MOA relevant to disease/condition

– Data: in vitro, in vivo, clinical studies relevant to drug 

and disease/condition

www.fda.gov
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Scientific Rationale: General Tips

• Clearly explain when study drug was administered in relation to onset 

of disease or condition

– Treatment: study drug administered after disease/condition developed

– Prevention: study drug administered before disease/condition developed

• Do not include:

– Safety/toxicology information

– Pharmtox data 

– Data from use of the drug in other diseases/conditions

– Data from use of a similar product in the disease/condition
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Scientific Rationale: 

Drug Description and MOA

• Drug description (brief paragraph): 

• active ingredient(s)

• drug class/type 

• structure 

• physical/chemical properties 

• route of administration/formulation

• MOA: Brief paragraph describing drug’s actions and its 

relevance to the disease/condition

www.fda.gov
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Scientific Rationale: Data

• Data should support the rationale for using the drug in 

the disease or condition

• Data may include clinical study data, in vivo animal 

data, and in vitro data

• Be concise, descriptive and clear in how the data 

findings relate to the disease
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Scientific Rationale: Clinical Data

• Provide strongest rationale for establishing medically plausible 

basis for expecting drug to be effective in disease/condition

– Two adequate and well-controlled studies are not required

– Provide details about the study (study design, treated population, 

inclusion/exclusion criteria, outcome measures, timing of treatment)

– Case reports may be acceptable if presented with sufficient detail
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Scientific Rationale: In Vivo Data

• If no clinical data, animal studies conducted in a 

relevant animal model of disease may be considered

• Animal model need not perfectly recapitulate disease seen in 

humans

• Provide details about the study (how the disease was 

created, symptom development timeframe, timing of 

treatment)
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Scientific Rationale: In Vitro Data

• Considered with supporting information if no relevant 

animal model exists for disease and when there is no 

clinical data

• Clearly explain what the data means and how it relates 

to the disease 
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Same Drug

• Refer to 21 CFR 316.3(b)(14) for detailed definitions 

of what constitutes a “same drug”

• Must include a plausible hypothesis for clinical 

superiority

• Note: The previously approved same drug need not have 

been granted orphan drug designation

www.fda.gov
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Same Drug 

• Examples of same drugs include:

– Two monoclonal antibodies with the same complementarity 

determining regions (CDRs) or with only minor amino acid 

differences

– Liposomal and non-liposomal preparations of the same active 

moiety

– Pegylated and unpegylated proteins

– Small molecules with the same active moiety but different salt 

or ester
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Plausible Hypothesis for Clinical 

Superiority

• Required if “same drug” is approved for the same use for which 

the sponsor is requesting orphan drug designation

• Hypothesis for superior effectiveness, safety or a major 

contribution to patient care (MC-to-PC) over previously approved 

same drug

• Only a hypothesis is required at the designation stage

• To be eligible for the 7-year marketing exclusivity upon approval, 

sponsor must demonstrate that their drug is clinically superior to 

the previously approved same drug(s)

www.fda.gov
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Plausible Hypothesis for Clinical 

Superiority: Common Pitfalls

• Inadequate detail to support the hypothesis

• Hypothesis must be more than just a theory
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Plausible Hypothesis for Clinical 

Superiority: MC-to-PC

• What constitutes a major contribution to patient care

• Only considered when neither greater safety nor greater effectiveness has 

been shown

– Example: IV to oral dosage form

– Example: once daily injectable to once a month injectable 

• Each request for a major contribution to patient care stands on its own

• Factors not accepted for a major contribution to patient care:

– cost of therapy or improved compliance
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Orphan Subset

• See 21 CFR 316.3(b)(13)

• Applies to diseases or conditions occurring in 200,000 

or more individuals 

• Based on a characteristic or feature of the drug (e.g., 

MOA, toxicity profile, prior clinical experience) which 

would limit its use to a subset of a non-rare 

disease/condition
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Orphan Subset 

• Not based on:

– Sponsor’s plan to study the drug for a select indication

– Cost of the drug

– Clinical trial eligibility 

– Disease grade or stage

• Note: Orphan subsets are not commonly granted
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Regulatory Status 

• Include:

– Pre-IND and IND numbers with respective indication(s) 

– NDA and BLA numbers with respective indication(s)

– EMA designation status and designated use, if applicable

– Brief regulatory history for drug both inside and outside of the US

– Relevant regulatory determinations for combination products 

– Any orphan drug designations held for the drug in other uses

• Self certification 

• Do not include listing of all orphan drug designations for the drug 

and/or use held by other sponsors
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Population Estimate

• See 21 CFR 316.20(b)(8)

• Prevalence vs Incidence:

– Prevalence: number of persons in the US diagnosed as having disease/condition

– Incidence: the number of new cases of the disease/condition

» Generally, only used for acute diseases with a duration of <1 year that are 

curable and do not recur

• If there is a prevalence or incidence range, generally use the highest estimate to 

provide the most conservative population estimate

• Do not:

• Average prevalence/incidence rates

• Simply note a prevalence/incidence rate

• Simply note that the disease is rare because it was noted on a website associated with 

rare diseases

www.fda.gov
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Population Estimate: 

Data Sources and General Tips

• Foreign, geographically restricted, or old data

• Registries, databases, literature searches

• Estimate must be current as of the time of 

application submission

• Include all calculations and references used to 

derive the population estimate
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Population Estimate: Methodology 

• Methodology for calculating size of target population is 

different for treatment, prevention, and diagnosis

• Treatment: use the highest incidence or prevalence rate and apply it 

to the most current US population 

(http://www.census.gov/popclock/)

– Alternatively may multiply incidence by the mean disease duration 

• Prevention: include the number of persons to whom the drug will be 

administered in a given year 

• Diagnosis (initial diagnosis): see prevention above

• Diagnosis (for management of disease/condition): see treatment 

above

www.fda.gov
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General Tips

• Use the sponsor template form, follow 21 CFR 316.20(b) 1-8 format, or the 

common application format

• Use page numbers

• Do not reiterate information in multiple sections

• Explain formulation or packaging for combination products

• Designation requests for prevention and treatment uses for the same drug for 

the same disease/condition generally must be submitted as two separate 

applications, each with its own scientific rationale and population estimate 

calculation

• Hard copy applications should be bound using a report cover or binder

• References – Include a copy of each cited reference

– Separate references

www.fda.gov
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General Tips

Suggested page limits:

• Entire application (excluding references): 20-30 pages

• Administrative information: 1-2 pages

• Explaining the disease/condition: 1-3 pages

• Scientific rationale: 3-5 pages

• Same drug: 2-3 pages

• Orphan subset: 2-3 pages

• Regulatory status: 1 page

• Population estimate: 2-3 pages
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Additional Website Links

• Office of Orphan Products Development

• Designating an Orphan Product

• Searchable Database for Designated Products

• Code of Federal Regulations
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Orphan Drug Regulations and Resources

• 21 Code of Federal Regulations (CFR) Part 316

– Subpart C – Designation of an Orphan Drug

– Subpart D – Orphan Drug Exclusive Approval

• Proposed and Final Rules

– 2012 Final Rule – 78 Fed. Reg. 35117 (Jun. 12, 2012)

– 2011 Proposed Rule - 76 Fed. Reg. 64868 (Oct. 19, 2011)

– 1992 Final Rule - 57 Fed. Reg. 62076 (Dec. 29, 1992)

– 1991 Proposed Rule - 56 Fed. Reg. 3338 (Jan.29, 1991)
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OOPD Contact Information

• Still have questions?

• Email us at orphan@fda.hhs.gov | Call us at 301-796-8660