1. Let’s talk about Orphan Drugs Critical Path Institute February 15, 2011 Marlene E. Haffner, MD, MPH 1

2. 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 2

3. 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 3

4.  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 4

5. How Far Have We Come ?... 5

6. 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 6

7. 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 7

8. 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) 8

9. DrugDiscoveryAnimalTesting Approval PostMarketing Human Testing Phase I Phase II Phase III 2 - 5 years Preclinical Development 0.5 - 1 year 0.5 - 3 years 6 months - 1 year 4 - 10 years $1.2 Billion New Drug Development INDNDA 9

10. WHY DOES IT TAKE SO LONG? HOW CAN WE SHORTEN THE TIME? 10

11. 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 11

12. 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) 12

13. 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. 13

14. 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 14

15. 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 15

16. 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 16

17. 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 17

18. 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

19. 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

20. 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 20

21. “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 21

22. ? Marlene E. Haffner, MD, MPH mhaffner3@verizon.net 301 984 5729 22

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