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FDA Orphan Drug Designation 101
Gayatri R. Rao MD, JD
Director
Office of Orphan Products Development (OOPD)
FDA
October 12, 2012
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Background
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The Orphan Drug Act (ODA)
• Decade prior to 1983 – only ~1
drug/year independently
developed by pharmaceutical
sponsors
• Legislation needed to promote
rare disease drug development
• The Orphan Drug Act signed into
law on Jan. 4, 1983
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Orphan Drug Designation:
Process Issues
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Orphan Designation vs. NDA/BLA
• Sponsors send request to the Office of Orphan Products
Development (OOPD) to grant orphan designation to their
drug or biological product to take advantage of financial
incentives available for further product development
• Sponsors then send NDA or BLA to the Center for Drug
Evaluation and Research (CDER) or the Center for Biologics
Evaluation and Research (CBER) to market their orphan drug
or biological product
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Office of the
Commissioner
(OC)
OSMP
OOPD
Office of Special
Medical Programs
OMPT
Office of Medical
Products and
Tobacco
Office of Orphan
Products
Development
Step 1: Orphan
Designation
CDER
Center for Drug Evaluation
and Research
Step 2: NDA or BLA
CBER
Center for Biologics
Evaluation and Research
For Complete FDA Organizational Chart see:
http://www.fda.gov/downloads/AboutFDA/CentersOffices
/OrganizationCharts/UCM288864.pdf
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Incentives Associated with Orphan Designation
• When OOPD designates a drug or biological product as an
orphan, certain financial incentives can flow:
– Tax Credits – 50% of clinical trials costs
– Waiver of User Fees - $1.9 M
– 7-year Marketing Exclusivity
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When to Submit an Orphan Designation Request
Pre-Clinical Development
Clinical Development
CAN SUBMIT DESIGNATION REQUEST
SUBMISSION
OF NDA/BLA
• No IND is required
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After Designation Request Is Submitted…
• Typical review cycle ~ 90 days (often less)
• Will either receive:
– Designation Letter OR
– Deficiency Letter
• Once designated, sponsor is required to submit annual
reports until drug is approved
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Orphan Drug Designation:
Substantive Issues
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Basic Definitions
• What is an orphan drug?
– Drug (or biological product) used for the prevention, diagnosis or
treatment of a rare disease in the US; OR
– Drug that will not be profitable within 7 years following approval by
the FDA
• What is a rare disease?
– Disease/condition that affects <200K people in the US
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Review of a Designation Request
1.
What is the disease/condition?
2.
Is the disease rare (prevalence)
3.
Is there sufficient scientific rationale that demonstrates
“promise” that the drug/biologic will treat, diagnose or
prevent the disease/condition at issue?
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#1 – What is the Disease or Condition?
• Determine the disease/condition that would be treated,
diagnosed or prevented by the drug/biologic
• Challenging and can evolve
Hodgkins’
Disease
Lymphoma
Non-Hodgkins’
Lymphoma
Non-Hodgkins’ BCell Lymphoma
Non-Hodgkins’ TCell Lymphoma
Non-Hodgkins’ nullcell Lymphoma
Follow the WHO
classification so
each subtype of
each of these 3
categories is treated
as a distinct disease/
condition
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#2 – Is the Disease Rare?
• Generally determined by prevalence of the disease in US, so
prevalence must be less than 200K
– Exception – For acute illnesses (duration < 1 year), use incidence
EXAMPLE
Malaria
• For prevention claims, everyone who is at risk of the disease is
counted
EXAMPLE
Prevention of ischemia reperfusion injury associated
with solid organ transplantation
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#2 – Is the Disease Rare? (cont.)
• Sponsor must demonstrate prevalence
– Must provide a specific number; not enough to say that the disease occurs in
<200K persons
• Sources to demonstrate prevalence:
–
–
–
–
Published literature
Registries
SEER database for rare cancers
3 Independent expert opinions (last option)
• If a range exists for the prevalence, apply the highest estimate
EXAMPLE
Myasthenia gravis
Prevalence: ~ 43,500 – 63,500
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#2 – Is the Disease Rare? (cont.)
• If disease/condition is common (i.e., occurs in > 200K persons
in the US), can grant orphan designation for use in a medically
plausible subset (“orphan subset”)
– Subset of all persons with the disease or condition who would only be
expected to benefit from the drug
Common disease
Preeclampsia
EXAMPLE
Orphan subset
Severe preeclampsia due to
toxicity of product
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Orphan Subset
SCCHN
• Prevalence of SCCHN in 2004 ~
297,000
Ep-CAM Negative
Ep-CAM Positive
• Overexpression of Ep-CAM in
29% of SCCHN, ~86,000
• Proxinium™ targets Ep-CAM
– Designated for Ep-CAM
positive SCCHN
Image: Stoecklein NH, Siegmund A, Scheunemann P, et al. Ep-CAM expression
in squamous cell carcinoma of the esophagus: a potential therapeutic target and
prognostic marker. BMC Cancer. 2006 Jun 23;6:165.
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#3 – Is the Scientific Rationale Sufficient?
• Basis of evidence that the drug holds promise for being
effective in treating/preventing/diagnosing disease
• Includes data from:
– Clinical data, case study reports OR
– Animal models OR
– In vitro data (with proposed MOA and pathogenesis of disease
when no adequate animal model)
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Recent Publication by Lev et al., 2012Drug Discovery Today
Scientific Rationale Presented by Sponsors for Orphan Product Designations in 2009
Scientific Rationale
Number of designations (%)
Clinical Experience
Phase I
19 (17.92%)
Phase II
47 (44.34%)
Phase III
21 (19.81%)
Phase of study not reported or specified
19 (17.60%)
Total
106 (66.25%)
Animal Study
Primate
6 (12.24%)
Large mammal
7 (14.29%)
Rodent
38 (74.51%)
Total
51 (31.88%)
In-vitro Study
Total
Total designations
3 (1.88%)
160
Lev et al. 2012 Drug Discovery Today
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Clinical Superiority
• When seeking designation of a drug that is the “same”
as an already approved drug, sponsor must provide a
plausible hypothesis of clinical superiority
• “Same drug” defined in regulation
– Does not mean identical
Small molecule with same active moiety as
approved drug but different ester or salt
EXAMPLES
2 proteins with minor differences in amino acid
sequences
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Clinical Superiority
• Defined as:
– Greater safety
– Greater efficacy
– Major Contribution to Patient Care – Rare Instances
• Sponsor must demonstrate that the product is actually
clinical superior at the NDA or BLA stage in order to get
7-years of marketing exclusivity
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Designation vs. Labeled Indication
• Often the approved labeled indication is narrower than
the designation
EXAMPLE
Designation: Ofatumumab designated for the treatment of
chronic lymphocytic leukemia (CLL)
Approved Labeled Indication: Ofatumumab approved for the
treatment of CLL refractory to alemtuzumab and fludarabine
Approved
Labeled
Indication
Indication covered by orphan
exclusivity
Designation
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Valuable Resources
Source
Citation
1991 Proposed Rule
56 Fed. Reg. 3338 (Jan.29, 1991)
1992 Final Rule
57 Fed. Reg. 62076 (Dec. 29, 2992)
2011 Proposed Rule
76 Fed. Reg. 64868 (Oct. 19, 2011)
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Orphan Designation Highlights: 1983-2011
350
350
300
300
Number of Orphan Designations
Number of Designation Requests
~3740 Designation requests
~2600 Products have received Orphan Designation (~70%)
250
200
150
100
50
0
250
200
150
100
50
0
83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11
83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11
Year
Year
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Range of Designated Orphan Drugs*
2%
2% 2%
Oncologic
Metabolic
1%
2%
2%
2%
3%
4%
36%
4%
Hematologic-immunologic
Neurologic
Infectious/parasitic
Cardiovascular
Transplantation
Gastrointestinal
Respiratory
4%
5%
6%
7%
7%
11%
Endocrinologic
Dermatologic
Ophthalmic
Musculoskeletal
Injury/poisoning
Perinatal
Congenital abnormalities
Others
* Represents orphan drug designations through 2006
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OOPD – What Else We Do
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What Else Does OOPD Do?
• Humanitarian Use Device (HUD) Designations
• Orphan Products Grants Program
• Pediatric Device Consortia Grants Program
• Outreach
– Science of Small Clinical Trials Workshop – Nov. 27-28, 2012 at
FDA
• Cross-agency coordination of rare disease efforts
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Questions?
For more information on OOPD’s programs, check out
www.fda.gov/orphan
Still have questions?
• Email us at orphan@fda.hhs.gov OR
• Call us at 301-796-8660
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