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 ? . . .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 marketing-
starting 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 ActThalidomide induced congenital defects
Establishment of effectiveness as a pre-market requirement
1976 Medical Device AmendmentsFormalized device authorities
Established tiered risk based system
1983 Orphan Drug Act
1997 FDA Modernization Act
2007 FDA Amendments Act (FDAAA)
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DrugDrugDiscoveryDiscovery
AnimalAnimalTestingTesting ApprovalApproval PostPost
MarketingMarketingHuman TestingHuman Testing
Phase Phase II
Phase Phase IIII
Phase Phase IIIIII
2 - 5 years
PreclinicalDevelopment
0.5 - 1 year
0.5 - 3 years
6 months - 1 year
4 - 10 years4 - 10 years$1.2 Billion$1.2 Billion
New Drug DevelopmentNew Drug Development
INDIND NDANDA
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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
“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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