Transcript The FDA

Let’s talk about Orphan Drugs
Critical Path Institute
February 15, 2011
Marlene E. Haffner, MD, MPH
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2011
• We treat symptoms, but seldom cure – except
with antibiotics
• With the discovery of the Human Genome
sequence we may be closer to cures – treating root
cause - personalized medicine
•Many – probably most - diseases do not have
cures. Many have no definitive treatment
• Many diseases will “divide.” In the future will
describe a disease in genomic terms rather than in
terms of phenotype
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Goals and Objectives
1. Describe how FDA works – what they do and
do not do
2. Discuss a bit of the regulatory history of FDA
3. Discuss the coming to pass of the US Orphan
Drug Act (ODA)
4. What has occurred in the last almost 30 years
since passage of the ODA and the effect on
patients around the world
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
The FDA

Promotes and protects the public health by
ensuring consumers have access to safe foods and
safe and effective medical products, including
drugs, biologics and medical devices

It is one of the world‘s most admired consumer
protection agencies and is widely respected for its
leadership in science-based regulation.

FDA-regulated products account for almost 25
cents of every consumer dollar spent in the United
States
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How Far Have We Come ? . . .
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Selected History of Biologics and Drug Regulation
• 1902 Biologics Control Act – in response to the
death of 13 children in St Louis. Signed by President
Theodore Roosevelt
•1906 – Food and Drug Act – prohibited interstate
commerce of misbranded and adulterated food, drinks
and drugs
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Dawn of the Modern FD &C Act – 1938
•The result of elixir of sulanilimide used as a diluent 107 children died
•Extended control to cosmetics and therapeutic devices.
•Required new drugs to be shown safe before marketingstarting a new system of drug regulation.
•Provided that safe tolerances be set for unavoidable
poisonous substances.
•Authorized factory inspections.
Signed by FD Roosevelt
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1962 Federal Food, Drug & Cosmetic Act
Thalidomide induced congenital defects
Establishment of effectiveness as a pre-market requirement
1976 Medical Device Amendments
Formalized device authorities
Established tiered risk based system
1983 Orphan Drug Act
1997 FDA Modernization Act
2007 FDA Amendments Act (FDAAA)
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New Drug Development
IND
Drug
Discovery
Animal
Testing
Preclinical
Development
0.5 - 3
years
0.5 - 1
year
NDA
Human Testing
Phase
I
Phase
II
Approval
Post
Marketing
Phase
III
2 - 5 years
6 months - 1 year
4 - 10 years
$1.2 Billion
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WHY DOES IT TAKE SO LONG?
HOW CAN WE SHORTEN THE
TIME?
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Enter the US ODA
• Established incentives to the development of
products to treat rare disease - <200,000 in
the US
• Result of years of study as to the best
Incentives – “Significant Drugs of Limited
Commercial Value”
• Consumer Groups support/activism
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Incentives
• Designation of Drugs and biologics as orphan
products
• Tax credits for clinical development
• Grants to academia for clinical development
• Protocol Assistance
• Exclusivity
• Waiver of Prescription Drug User Fees ($1.4+ m
in 2011)
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Establishment of the Office of
Orphan Products Development
• Review products for designation as an orphan
drug
• Review devices for Humanitarian Devices
• Serve as ombudsman within FDA for the product
• Serve as translator for “FDA speak”
• Administer the Orphan Products Grants program
• Coordinate with CDER Orphan Drugs Assoc. Dir.
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What is an Orphan Disease
• Affects fewer than 200,000 in the US
• May affect a disease common in the developing world
• Examples
– Malaria
– Active TB
– Childhood leukemias
– PKU
– Many genetic diseases
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Characteristics of Orphan
Diseases
•
•
•
•
•
•
•
•
90% Severe or Life Threatening
~50% Occur in Children
> 90% have no therapy
Natural history of the disease is not well known
Heterogeneous
Patients hard to find
Few specialists
Diagnosis frequently takes years
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Since 1983
•
•
•
•
More than 2000 products designated as orphan products
Almost 400 products approved as orphan products
Grants program has seen 40+ products approved
Orphan products programs in EU, Japan, Taiwan,
Australia, and beyond
• Many firms-large and small built around orphan drugs
• Consumer groups increasingly proactive
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ISSUES
• Biotech products are expensive – many newer
orphan products are biotech.
• How does one calculate expense of drug/expense
of disease/value of treatment
• On approval have a very effective drug but little is
known of safety ---REMS to assure safety – adds
to cost
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Regulatory Issues
•
•
Development of products difficult due to small number of patients available
for clinical trials
Many clinical trial designs utilized in trials
– Randomized, placebo controlled, blinded
– Withdrawal trial
– N of 1
– Controlled but unblinded
– Patient serves as own control - ocular cytomegalovirus
– Historical controls
– Use of biomarkers
Regulatory Issues
• On approval much is known about efficacy – little of safety. Most if
not all will have REMS with post marketing commitements (PMC)
• Fast Track approval very frequent – only drug for serious and life
threatening condition
• Accelerated approval – hard to follow through with PMCs.
• Ad com – March 2 to look at regulatory issues of orphan drug
development, review and approval
The Whole Story
• More than 19 million in the US can have benefitted from an
orphan product approved by the US FDA
• Many technological breakthroughs have come via orphan
drug research and development
– Pegylation
– Liposomal encapsulation
• World wide acceptance of the orphan product paradigm
• “Rare Diseases are not Rare” estimated at 10 – 15% of the
population
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“Never doubt that a small
group of thoughtful, committed
citizens can change the world;
indeed, it is the only thing that
ever has.”
. . . .Margaret Meade
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Marlene E. Haffner, MD, MPH
[email protected]
301 984 5729
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