Overview of FDA’s Orphan Drug Designation Program and qualification criteria for drug and disease.

1. Devanand Jillapalli, MD
Office of Orphan Products Development (OOPD)
U.S. Food and Drug Administration

2. 2
OOPD Mission
To promote the development of products,
including drugs, devices, biologics, and
medical foods, for the treatment, diagnosis
and prevention of rare diseases and
conditions.
www.fda.gov

3. 3
Rare Diseases
• More than 6,800 rare diseases
• Affect an estimated 25-30 million
Americans
https://www.genome.gov/27531963/ Accessed August 3, 2016
www.fda.gov

4. 4
Orphan Drug Act
Created by the Congress
in 1983 to motivate
industry to develop
drugs and biologics for
rare diseases by
providing financial
incentives.
4www.fda.gov

5. 5
OOPD Designation Programs
• Orphan Drug Designation
• Rare Pediatric Disease Designation
• Humanitarian Use Device Designation*
*Not discussed in this presentation
www.fda.gov

6. 6
OOPD Grant Programs
• Orphan Products Clinical Trials Grants Program
• Orphan Products Natural History Grants
Program
• Pediatric Device Consortia Grant Program*
*Not discussed in this presentation
www.fda.gov

7. 7
Orphan Drug Designation Program
www.fda.gov

8. 8
Orphan Drug Designation Program
Provides orphan status to drugs and biologics*
which are defined as those intended for the safe
and effective treatment, diagnosis or prevention
of rare diseases/disorders.
*“Drugs” in this presentation includes both drugs and biological
products.
www.fda.gov

9. 9
Incentives Associated With Orphan
Drug Designation
• Tax Credits for 50% of Clinical Trial Costs
• Waiver of Marketing Application User Fee
(PDUFA): >$2M
• Eligibility for 7-Year Marketing Exclusivity
• Now associated with additional financial
“incentives” under the Affordable Care Act
(e.g., pharmaceutical fee, 340B pricing)
www.fda.gov

10. 10
www.fda.gov

11. 11
Orphan Drug Designation Process
Sponsor
CDER
Center for Drug
Evaluation and Research
CBER
Center for Biologics
Evaluation and Research
Step 2 : Submit
Marketing Application
(NDA or BLA)
Disapproval or
Complete
Response Letter
Approval to
Market
Product
Office of Orphan
Products Development
Step 1 : Submit
Orphan Drug
Designation
Issue
Deficiency or
Denial Letter
Grant
Designation
Receive
financial
incentives
OOPD
Step 3 : Orphan Exclusivity
Determination
www.fda.gov

12. 12
Review of a Designation Request
Orphan drug designation based on disease or
condition, not on indication.
• Five critical questions:
– What is the disease or condition the drug is treating,
diagnosing or preventing?
– Is this disease or condition rare?
– If this disease or condition is not rare, is there orphan
subset demonstration?
– Is there a description of the drug and scientific
rationale?
– Is it “same drug” as a previously approved drug for same
use?
www.fda.gov

13. 13
What is the Disease?
What is the disease or condition the drug is
treating, diagnosing or preventing?
• Challenging and can evolve
• Depends on a number of factors, assessed
cumulatively, including:
• pathogenesis of the disease or condition;
• course of the disease or condition;
• prognosis of the disease or condition;
• and resistance to treatment.
www.fda.gov

14. 14
Is the Disease Rare?
Is the disease or condition rare?
• “Rare disease” for drugs is generally* defined by the
Orphan Drug Act as:
– Disease or condition that affects <200,000 people in the US
• Therapeutic drugs: prevalence < 200,000
• Vaccines, diagnostic and preventative drugs: number
of persons drug will be administered to < 200,000 per
year
*Prevalence can be >200,000 (or if applicable incidence >200,000 per year) if no
reasonable expectation that the cost of drug development and marketing will be
recovered in future sales of the drug in the US.
www.fda.gov

15. 15
Orphan Subset
If disease or condition occurs in > 200,000 persons (non-
rare):
• A demonstration of an “orphan subset”: use of the
drug appropriate in orphan subset due to one or more
properties of the drug, but inappropriate in the
remaining persons with such disease or condition.
• “Orphan subset” meets the regulatory threshold of
200,000 in the US.
Note: orphan subset cannot be considered without
reference to the drug, specifically to the property(ies) of the
drug (next slide).
www.fda.gov

16. 16
Orphan Subset
Property(ies) of the drug that limit its use to the
orphan subset but preclude its use in the remaining
persons with the non-rare disease or condition:
• Mechanism of action: For example, use of targeted
therapy (e.g., antibody-specific or biomarker-based
drug)
• Toxicity of a drug limits its use to patients refractory to,
or intolerant of, other less toxic treatments
• Previous clinical experience may be used to identify an
appropriate orphan subset
www.fda.gov

17. 17
Orphan Subset
Examples of subsets of non-rare conditions arbitrarily
chosen without reference to the drug:
• Clinical trial eligibility: subset defined only on basis of
inclusion/exclusion criteria in a clinical trial to support a
specific indication for use of a drug
• Sponsor’s plan to study the drug for a select indication
within the non-rare disease
• Particular disease grade or stage
• Any clinically distinguishable subset of persons with a
particular disease or condition
• Price: high price of drug may render it unlikely to be used in
broader population with the disease
www.fda.gov

18. 18
Drug Description & Scientific Rationale
• Description of the drug
– Active moiety
• Scientific rationale: to establish a medically
plausible basis for the use of the drug for the rare
disease or condition
• What is Scientific Rationale based on?
• Clinical data, case study reports
• Acceptable animal model(s) of human disease
• In vitro data (with proposed mechanism of action and
pathogenesis of disease when no adequate animal model of
human disease exists)
www.fda.gov

19. 19
Same Drug & Clinical Superiority
Is it “same drug” as a previously approved drug for same
use?
• “Same drug” defined in 21 CFR 316.3(b)(14); does not
mean identical.
• If composed of a small molecule, it contains same active
moiety as previously approved drug.
• If composed of macromolecules, it contains the same
principal molecular structural features of previously approved
drug. E.g.,: two protein drugs are same if the only differences
were due to post-translational events, minor differences in
amino acid sequences, different glycosylation patterns, etc.
• When seeking designation of a drug that is the “same” as
an already approved drug for the same use, must provide
a plausible hypothesis of clinical superiority
www.fda.gov

20. 20
Same Drug & Clinical Superiority
“Clinical superiority” demonstrated in one or
more of following ways:
• Greater effectiveness
• Greater safety
• Major contribution to patient care
To get 7-years of market exclusivity, regulations
require sponsors to demonstrate product is
actually clinically superior
www.fda.gov

21. 21
Rare Pediatric Disease
Designation Program
www.fda.gov

22. 22
Rare Pediatric Disease (RPD)
Designation Program
• Under Section 529 to the Federal Food, Drug,
and Cosmetic Act, and amended by the
Advancing Hope Act of 2016, FDA awards
priority review vouchers to sponsors of rare
pediatric disease product applications that meet
certain criteria.
• OOPD implements the “rare pediatric disease”
designation component of this authority.
www.fda.gov

23. 23
What is a Rare Pediatric Disease?
A rare pediatric disease is a disease that meets each
of the following criteria:
• The disease is a serious or life-threatening disease
in which the serious or life-threatening
manifestations primarily affect individuals aged
from birth to 18 years, including age groups often
called neonates, infants, children, and adolescents.
• The disease is a rare disease or condition, within
the meaning of Section 526.
www.fda.gov

24. 24
Eligibility Criteria for a Voucher
• RPD designation is not required, nor sufficient, to
receive a voucher.
• To receive a voucher, application for the drug must
meet all eligibility criteria. For additional
information:
– FDA OOPD website:
http://www.fda.gov/ForIndustry/DevelopingProductsfor
RareDiseasesConditions/ucm2005525.htm
– Draft guidance, Rare Pediatric Disease Priority Review
Vouchers Draft Guidance for Industry
www.fda.gov

25. 25
Orphan Products Clinical Trial Grants
Program
www.fda.gov

26. 26
Orphan Products Clinical Trial Grants
Program
Awards and administers grants for clinical studies of
drugs, biologics, devices, and medical foods
• Current fiscal year alone: 68 grant applications
received; awarded 21 research grants totaling more
than $23 million over the next four years
• Current funding levels:
• Phase 1 studies: up to $250, 000 per year for 3 years
• Phase 2 and 3 studies: up to $500,000 per year for 4 years
• For additional information, see OOPD’s website
www.fda.gov

27. 27
Orphan Products Natural History
Grants Program
www.fda.gov

28. 28
Orphan Products Natural History Grants
Program
NEW grant program to fund targeted natural
history studies for rare diseases
• Approximately $2M in FY 2017 to award 2-5 grants
• Funding levels:
• Prospective Natural History Studies: up to $400,000 per
year for up to 5 years
• Retrospective or Survey Natural History Studies: up to
$150,000 per year for up to 2 years
• For additional information, see OOPD’s website
www.fda.gov

29. 29
OOPD Resources and Contact
Information
www.fda.gov

30. 30
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
– 2013 Final Rule – 78 Fed. Reg. 35117 (Jun. 12, 2013)
– 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)
• Additional information available at:
http://www.fda.gov/ForIndustry/DevelopingProductsforRare
DiseasesConditions/HowtoapplyforOrphanProductDesignatio
n/default.htm
www.fda.gov

31. 31
OOPD Contact Information
OOPD Website: www.fda.gov/orphan
Program Contact
Orphan Drug Designations Jeff Fritsch (301-796-8682)
Jeff.Fritsch@fda.hhs.gov
Jim Bona (301-796-8673)
James.Bona@fda.hhs.gov
RPD Designations Jim Bona (301-796-8673)
James.Bona@fda.hhs.gov
HUD Designations Jim Bona (301-796-8673)
James.Bona@fda.hhs.gov
OPD Grants Mary Limon (301-796-8689)
Mary.Limon@fda.hhs.gov
PDC Grants Eric Chen (301-796-6327)
Linda.Ulrich@fda.hhs.gov
NHS Grants Mary Limon (301-796-8689)
Mary.Limon@fda.hhs.gov
Still have questions?
Email us at orphan@fda.hhs.gov | Call us at 301-796-8660
www.fda.gov