1. Haffner Associates, LLC1 Orphan Drugs – 2011 What’s Happening? Women in BIO Marlene E. Haffner, MD, MPH Mhaffner3@verizon.net 301 984 5729 - Office 301 641 4268 – cell November 1, 2011

2. LOTS! Haffner Associates, LLC2

3. INCENTIVES 7 Years Exclusive Marketing Waiver of PDUFA Filing Fee Assistance of OOPD Tax Credits – 50 % of clinical development costs  – one year fall back; 20 year carry forward Grant Support Recommendations from Brownback Brown Report Associate Director for Orphan Drugs - CDER Haffner Associates, LLC3

4. Accomplishments ~ 390 products approved > 2000 designations > 15,000,000 patients potentially treated > 45 products approved through the grants program Haffner Associates, LLC4

5. 2009 Emergence of Big PhRMA GSK Novartis Pfizer Genentech/Roche Sanofi Haffner Associates, LLC5

6. Biotech and Orphan Products Began with Genentech – hGH - and has progressed Now the emergence of “molecular medicine” Personalized medicine – genetic knowledge fits well with orphan drug development Haffner Associates, LLC6

7. 1992 Regulations 2011 NPRM 2011 NPRM released week of October 21 st Codifies practices already in place Medically plausible subsets vs the disease process Better defines the designation process Haffner Associates, LLC7

8. Review and Approval of Orphan Products Orphan Products must be Safe and Effective for their intended use Is that possible? FDA has demonstrated flexibility 90 of 135 non-oncology approvals approved with non standard approaches – NORD study  Smaller clinical trials  Historical controls  Single arm/non-randomized  Case-by-case Haffner Associates, LLC8

9. 9 Current Issues and Activities Safety concerns REMS Cost Reimbursement Large # of orphan programs and activities globally Increasing coordination with the EU

10. Haffner Associates, LLC10 Safety Orphan Products approved based on small clinical trials Infrequent adverse events will not be seen Until the last 3 – 4 years “there had been no safety concerns with orphan products”  That has changed – e.g. EPO – 25 years following initial approval; Botulinum toxin - black box warning  Virtually all new orphan approvals carry a REMS

11. Haffner Associates, LLC11 REMS – Risk Evaluation and Mitigation Strategy Orphan Products with REMS –  Nplate – no safety signals in clinical trials  Botulinum toxin – new findings  FDA (and Congress) erring on the side of safety  Allows FDA to approve some products which would not previously have been approved

12. Haffner Associates, LLC12 Cost of Orphan Drugs US expenditure for drugs - 2.2% of GDP in 2000; will be 5.6% in 2030 Newest products in the health care arena are Biotech Biotech products are expensive – whether they are orphan products or not Because of some high profile examples, orphan products are often sighted as expensive  Some orphan products are expensive; most are not  Economies of scale for a small population is not present – need to explain better to the public

13. Haffner Associates, LLC13 Reimbursement Must figure reimbursement strategies as drug development proceeds. This involves working with CMS and individual insurance companies Must explain to patient groups the rationale for cost of the product if high. Cost may by necessity be high Some EU member states very conservative in reimbursement Recent unfortunate examples

14. Haffner Associates, LLC14 Personalized Medicine Human genome allows more targeted therapies Many of these will subdivide larger diseases into smaller ones which may be orphan diseases – gene mutations NIH TRND program Repurposing of old drugs

15. Haffner Associates, LLC15 What does this mean for my company? What is your strategy? Orphan Products generally treat life threatening diseases – may mean faster approval Common application format in EU and US – saves money Tax incentives Exclusivity Waiver of PDUFA Filing Fee – $1.8 mil in 2011

16. Examples of Office of Orphan Products Assistance Haffner Associates, LLC16

17. Envenomation Envenomation – OOPD convinced review division to broaden thinking re indication – approved product in 2011 Other envenomation products being developed Haffner Associates, LLC17

18. Narcolepsy How should the product be DEA scheduled? Without the intervention of OOPD the product may not have been developed Haffner Associates, LLC18

19. Prevalence and # of clinical trials A disease with < 100 patients in the US Hard, if not impossible, to do TWO placebo controlled trials When to use historical controls How to develop phase 1,2,3 trials Inviting the OOPD to meetings with the division Need for Natural History studies Haffner Associates, LLC19

20. Toxicity testing The disease is lethal at a very young age What are the considerations Can toxicity testing be done following clinical trials in humans Need new methodologies for preclinical drug development Haffner Associates, LLC20

21. Roll of the Associate Director for Orphan Products in CDER Primarily policy/consistency Evaluating new science with regards to Orphan Product development Biomarkers Close collaboration with the OOPD Hopefully will grow in size Haffner Associates, LLC21

22. A New Day in OOPD Appointment of new Acting OOPD Director – Gayatri Rao, MD, JD NPRM issues 19 years following initial regulations Increasing # of companies join the drive toward rare disease therapies NIH efforts Commitment of FDA with Associate Director for Orphan Products Haffner Associates, LLC22

23. ? Marlene E. Haffner, MD, MPH Haffner Associates, LLC mhaffner3@verizon.net www.mhaffner.com 301-984-5729 301-641 4268 Haffner Associates, LLC23