Orphan Drugs – 2011 What’s Happening?

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

2. LOTS! Haffner Associates, LLC

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, LLC

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

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

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, LLC

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

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, LLC

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

10. 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 Haffner Associates, LLC

11. 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 Haffner Associates, LLC

12. 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 Haffner Associates, LLC

13. 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 Haffner Associates, LLC

14. 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 Haffner Associates, LLC

15. 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 Haffner Associates, LLC

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

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

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

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, LLC

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, LLC

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, LLC

22. A New Day in OOPD • Appointment of new Acting OOPD Director – GayatriRao, 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, LLC

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