Webinar sponsored by The Weinberg Group on Orphan Drugs, covering these topics:
The Basics of the Orphan Drug Act
Benefits of Orphan Drug status
Exclusivity
Protocol assistance, tax credits, and research grants
When is an indication is “rare”?
Orphan Drug Designation Requests – ensuring yours robust and persuasive
Approval criteria for orphan products – how they compare to non-orphan products
Challenges in the Orphan Drug Process

1. Orphan Drugs – the Challenges and Benefits of
Navigating FDA’s Regime Governing Therapies for Rare
Diseases
Presented by:
Michael A. Swit, Esq., Vice President
Moderated by:
Jeff Antos, Vice President
February 23, 2011

2. Michael A. Swit, Esq.
Vice President
Cardiff by the Sea, CA
+1 760.452.6568
+1 760.454.2979 (fax)
michael.swit@weinberggroup.com
Mr. Swit has been addressing critical FDA legal and
regulatory issues since 1984. His expertise includes product
development strategies, compliance and enforcement
initiatives, recalls and crisis management, FDA regulatory
activities, labeling and advertising, and clinical research
efforts. Mr. Swit develops and ensures the execution of a
broad array of regulatory and other services to clients, both
directly and through outside counsel.
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Today’s Presenter

3. What We Will Cover
The Basics of the Orphan Drug Act
Benefits of Orphan Drug status
Exclusivity
Protocol assistance, tax credits, and research grants
When is an indication is “rare”?
Orphan Drug Designation Requests – ensuring yours
robust and persuasive
Approval criteria for orphan products – how they
compare to non-orphan products
Challenges in the Orphan Drug Process
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4. 4
ADOPTING ORPHANS –
The Orphan Drug Act
Enacted – 1983
Goal -- create incentives for pharmaceutical companies
to adopt "orphan" drugs for uses for rare disorders.
“Orphan" -- many drugs were known as potentially
effective for rare diseases, but had been orphaned --
abandoned for developmental purposes -- by the
pharmaceutical industry due lack of profitability
associated with small patient population (aka “buyers”)

5. As many as 7,000 rare diseases in U.S.
Afflicting as many as 25 Million Americans – one in 10
American
Prior to 1983 – only 10 drugs approved in decade prior
to enactment
Since 1983 –
360 Orphan drug approvals
± 2,500 Orphan designations
How Many Orphans Are There?
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6. 6
Orphans . . .
Orphan Drug Act -- created four key incentives to
facilitate drug development for rare diseases:
Seven years marketing exclusivity during which time no
other company can secure approval for the same drug for the
orphan indication
Protocol assistance
Tax credits
Research Grants

7. 7
How Does a Drug Become an
Adoptable Orphan?
To qualify for benefits under the Orphan Drug Act, a drug
must serve a patient population:
< 200,000 people in the United States; or
if > 200,000, orphan drug applicant must show it cannot reasonably
recoup its commercial investment in the research and development
of the product –
rarely used (to the best of my knowledge, never been used).
Key question for orphan drug status is patient population --
the indication sought must be “medically plausible”
not just a "salami sliced" indication of a greater patient population
that might be otherwise over 200,000.

8. 8
Orphan Designation
To get orphan drug benefits, a sponsor must apply for
orphan drug designation.
Process -- sponsor-specific
21 CFR 316.20 requires that, among other things, the
sponsor show:
patient population proposed -- less than 200,000 people per
year.
is a confidential process with the designation application not
being one subject to public disclosure until after it is approved,
if it is approved.

9. Adequate demonstration of a medical plausibility for
the drug’s expected benefit also is required
Once approved, the designation will appear in a
quarterly cumulative list that the Agency publishes and
makes available on its website.
Orphan Designation …
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10. 10
Designation Issues – or May Identical Twins
Be Adopted by Two Different Families?
Clinical superiority – FDA may regard – for Orphan
Drug Act purposes -- as different, drugs that are
chemically the same and identically labeled if the second
drug is clinically superior to the first drug.
Types of superiority:
Efficacy
Safety
Major contribution to patient care (MC-PC)
Skirts Orphan Drug Act's restrictions on approving same drug by ruling
second drug is clinically superior and, therefore, essentially is not the same
drug as that one which enjoys exclusivity.
Example: Rebif® > Avonex®

11. “Molecular differentiation” (my term) -- in other
cases, FDA has gone to some length to differentiate a
product on the basis of its molecular structure differs
from an approved orphan drug.
Example – Human Growth Hormone case
Can There Be Identical Orphans? …
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12. 12
Designation -- Timing Considerations
When viewed relative to ODA exclusivity provisions,
timing of designation process is KEY…
Remember -- process is confidential until drug designated; then
published in FED REG.
Consider not seeking the OD designation until you have
done one or more of the following:
Confirmed the stability of their proposed formulation;
Validated that the formulation can be produced on a commercial
scale-up basis;
or, even more conservatively,
File to study the product pursuant to an IND.
Why – once in FED REG, anyone else can seek same OD
Designation and then … race to approval & Exclusivity!

13. Request Process – 21 CFR 316.20 – content
Two copies
Orphan drug, orphan indication and “reasons why such therapy
is needed” [316.20(b)(3)]
a discussion of the scientific rationale for the use of the drug
for the rare disease or condition, including:
all data from nonclinical laboratory studies, clinical investigations, and
other relevant data that are available to the sponsor, whether positive,
negative, or inconclusive.
Copies of pertinent unpublished and published papers -- required.
If indication is a subset, info on why medically plausible
If vaccine, must show less than 200,000 per year will receive
Designation – The Request Process
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14. Request process …
Summary of the regulatory status and marketing history of
the drug in the United States and in foreign countries, e.g.,
IND and marketing application status and
Internal OOPD handling
Application -- assigned a designation application number and
logged into OOPD database
Acknowledgement letter -- sent to the sponsor.
Assigned OOPD reviewer completes the review of the
application and prepares a written review.
Designation Process …
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15. Internal OOPD handling …
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. Options – a letter:
Designation approval
Requesting Additional information,
Denial
Designation Process …
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16. Joint submission with EMEA -- FORM FDA 3671
(2/09)
Submitting electronically – is allowed – see
Providing Regulatory Submissions in Electronic Format — Orphan-
Drug and Humanitarian Use Device Designation Requests and Related
Submissions – Draft Guidance – Feb. 2006
Designation Process …
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17. Orphan Indications where drug also can treat non-
rare condition:
FDA will no longer approve as an orphan – even if there is a
unique rare disease – if the drug also would be effective
against a very similar indication that is not rare
Example:
Recent Designation Issue
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18. 18
Orphan Drug Exclusivity
Protects the orphan drug for the orphan indication
7 years
The most powerful incentive under Orphan Drug Act
Distinction from other types of exclusivity – can’t
“remake wheel”
Waxman-Hatch exclusivity -- does not bar a full NDA for a
drug with W-H exclusivity
Beware – less incentive to study approved drugs for
orphan uses – generics may come in and be used off-
label
Unless change in dosage form/strength, etc.

19. 19
Tax Credits
Only helpful to a company that is actually enjoying
taxable income that needs to be offset.
For startups, this may not occur any time in the short
term when the needs of the tax cut might be most
useful.
See a tax professional may be able to give you more
advice as to whether any losses can be carried forward
and for how long so as to be able to take advantage of
the tax cut provisions
Most observers -- low utility

20. 20
Protocol Assistance
Orphan Drug sponsors are eligible for significant
additional assistance from FDA in the design of its
clinical study protocols (caveat: nature of that aid is not
stated very clearly anywhere)
LINK any assistance to a clear written agreement with
FDA as to the nature of the clinical studies to be
performed

21. 21
Research Grants
Awarded by FDA per criteria articulated by Agency
Must be for a clinical study – safety or efficacy
Funding
Dependent on Congressional appropriations
Early on -- rarely exceeded $2 million;
Recently -- about $14 million annually; ± $10 mil. for
continuing studies; ± $4 mil. for new studies
Length of funding – 3 to 4 years
60 to 85 grants at any one time
Individual grants –
Phase 1 study – up to $200,000
Phase 2 or 3 – up to $400,000

22. Office of Orphan Product Development (OOPD)
Within Commissioner’s Office
Administers Orphan Drug program
Designations
Grants
Coordinates with reviewing divisions on issues relating to Orphan
Drug process
Director: Tim Coté, M.D.
Reports to Office of Special Medical Programs (OSMP)
FDA – Structure for Handling Orphan Drugs
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23. Feb. 2010 –Associate Director for Rare Disease – in
CDER – Anne Pariser
Goals
Help develop scientific and regulatory innovations to develop
and evaluate new treatments for rare diseases
Planning series of scientific workshops to address important
and difficult rare disease research issues –
Next one – end of February in California
Developing a “rare disease database” to establish the natural
history of rare diseases to assist with planning trials to test
rare disease therapies.
Part of FDA’s 2011-2015 Priorities
FDA – Orphan Drug Structure …
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24. FDA – Orphan Drug Structure
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25. FDA – “Repurposing Databases”
Table 1. Orphan-designated products with at least
one marketing approval for a common disease
indication (XLS - 102KB)
Table 2. Orphan-designated products with at least
one marketing approval for a rare disease
indication (XLS - 172KB)
Table 3. Orphan-designated products with marketing
approvals for both common and rare disease
indication (XLS - 156KB)
Orphan Drug – Resources
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26. No difference in standards for approval – still must
prove “substantial evidence” of safety and effectiveness
using adequate and well-controlled investigations and
clinical benefit
Clinical study hurdles
Small patient populations
Hard to recruit
Clinical investigators – more likely to be “naïve” as to Good Clinical
Practices (GCP)
Poorly understood disease processes
Many orphan diseases are genetically based – thus, can be very
heterogeneous populations – confounding study predictability
Challenges in Orphan Drug Development
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27. Clinical study hurdles …
Often chronic, progressive, serious, life-limiting and life-
threatening with unmet medical needs
Endpoints, outcome measures, tools, instruments, biomarkers
usually lacking
Clinical study differences – examples:
Carglumic acid – for NAGS deficiency – approved with just
one study – an open label, historically controlled, retrospective
cases series of 23 subjects
Dalfampiridine – to improve walking in patients with multiple
sclerosis – two randomized, placebo controlled studies with
540 subjects
Orphan Drug Development Challenges …
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28. Federal Food, Drug, and Cosmetic Act
Section 525 -- Protocol Assistance
Section 526 -- Designation
Section 527 – Exclusivity
Section 528 – Open Protocols
Regulations – 21 CFR Part 316
Guidances (not mentioned previously)
Interpreting Sameness of Monoclonal Antibody Products Under the
Orphan Drug Regulations – July 1999
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianc
eRegulatoryInformation/Guidances/Blood/UCM170111.pdf
Key References
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