FDA Orphan Drug Designation 101

1. FDA Orphan Drug Designation 101 Gayatri R. Rao MD, JD Director Office of Orphan Products Development (OOPD) FDA October 12, 2012

2. Background

3. The Orphan Drug Act (ODA) • Decade prior to 1983 – only ~1 drug/year independently developed by pharmaceutical sponsors • Legislation needed to promote rare disease drug development • The Orphan Drug Act signed into law on Jan. 4, 1983

4. Orphan Drug Designation: Process Issues

5. Orphan Designation vs. NDA/BLA • Sponsors send request to the Office of Orphan Products Development (OOPD) to grant orphan designation to their drug or biological product to take advantage of financial incentives available for further product development • Sponsors then send NDA or BLA to the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER) to market their orphan drug or biological product

6. Office of the Commissioner (OC) OMPT Office of Medical Products and Tobacco OOPD Office of Orphan Products Development OSMP Step 1: Orphan Designation Office of Special Medical Programs CDER Center for Drug Evaluation and Research Step 2: NDA or BLA CBER Center for Biologics Evaluation and Research For Complete FDA Organizational Chart see: http://www.fda.gov/downloads/AboutFDA/CentersOffices/OrganizationCharts/UCM288864.pdf

7. Incentives Associated with Orphan Designation • When OOPD designates a drug or biological product as an orphan, certain financial incentives can flow: • Tax Credits – 50% of clinical trials costs • Waiver of User Fees - $1.9 M • 7-year Marketing Exclusivity

8. Pre-Clinical Development Clinical Development SUBMISSION OF NDA/BLA CAN SUBMIT DESIGNATION REQUEST When to Submit an Orphan Designation Request • No IND is required

9. After Designation Request Is Submitted… • Typical review cycle ~ 90 days (often less) • Will either receive: • Designation Letter OR • Deficiency Letter • Once designated, sponsor is required to submit annual reports until drug is approved

10. Orphan Drug Designation: Substantive Issues

11. Basic Definitions • What is an orphan drug? • Drug (or biological product) used for the prevention, diagnosis or treatment of a rare disease in the US; OR • Drug that will not be profitable within 7 years following approval by the FDA • What is a rare disease? • Disease/condition that affects <200K people in the US

12. Review of a Designation Request • What is the disease/condition? • Is the disease rare (prevalence) • Is there sufficient scientific rationale that demonstrates “promise” that the drug/biologic will treat, diagnose or prevent the disease/condition at issue?

13. Non-Hodgkins’ B-Cell Lymphoma Follow the WHO classification so each subtype of each of these 3 categories is treated as a distinct disease/ condition Hodgkins’ Disease Lymphoma Non-Hodgkins’ T-Cell Lymphoma Non-Hodgkins’ Lymphoma Non-Hodgkins’ null-cell Lymphoma #1 – What is the Disease or Condition? • Determine the disease/condition that would be treated, diagnosed or prevented by the drug/biologic • Challenging and can evolve

14. EXAMPLE EXAMPLE Prevention of ischemia reperfusion injury associated with solid organ transplantation #2 – Is the Disease Rare? • Generally determined by prevalence of the disease in US, so prevalence must be less than 200K • Exception– For acute illnesses (duration < 1 year), use incidence • For prevention claims, everyone who is at risk of the disease is counted Malaria

15. EXAMPLE #2 – Is the Disease Rare? (cont.) • Sponsor must demonstrate prevalence • Must provide a specific number; not enough to say that the disease occurs in <200K persons • Sources to demonstrate prevalence: • Published literature • Registries • SEER database for rare cancers • 3 Independent expert opinions (last option) • If a range exists for the prevalence, apply the highest estimate • Myasthenia gravis • Prevalence: ~ 43,500 – 63,500

16. #2 – Is the Disease Rare? (cont.) • If disease/condition is common (i.e., occurs in > 200K persons in the US), can grant orphan designation for use in a medically plausible subset (“orphan subset”) • Subset of all persons with the disease or condition who would only be expected to benefit from the drug Common disease Orphan subset Preeclampsia EXAMPLE Severe preeclampsia due to toxicity of product

17. SCCHN Ep-CAM Negative Ep-CAM Positive Image: Stoecklein NH, Siegmund A, Scheunemann P, et al. Ep-CAM expression in squamous cell carcinoma of the esophagus: a potential therapeutic target and prognostic marker. BMC Cancer. 2006 Jun 23;6:165. Orphan Subset • Prevalence of SCCHN in 2004 ~ 297,000 • Overexpression of Ep-CAM in 29% of SCCHN, ~86,000 • Proxinium™ targets Ep-CAM • Designated for Ep-CAM positive SCCHN

18. #3 – Is the Scientific Rationale Sufficient? • Basis of evidence that the drug holds promise for being effective in treating/preventing/diagnosing disease • Includes data from: • Clinical data, case study reports OR • Animal models OR • In vitro data (with proposed MOA and pathogenesis of disease when no adequate animal model)

19. Recent Publication by Lev et al., 2012-Drug Discovery Today Lev et al. 2012 Drug Discovery Today

20. Small molecule with same active moiety as approved drug but different ester or salt EXAMPLES 2 proteins with minor differences in amino acid sequences Clinical Superiority • When seeking designation of a drug that is the “same” as an already approved drug, sponsor must provide a plausible hypothesis of clinical superiority • “Same drug” defined in regulation • Does not mean identical

21. Clinical Superiority • Defined as: • Greater safety • Greater efficacy • Major Contribution to Patient Care – Rare Instances • Sponsor must demonstrate that the product is actually clinical superior at the NDA or BLA stage in order to get 7-years of marketing exclusivity

22. Designation vs. Labeled Indication • Often the approved labeled indication is narrower than the designation Designation: Ofatumumab designated for the treatment of chronic lymphocytic leukemia (CLL) Approved Labeled Indication: Ofatumumab approved for the treatment of CLL refractory to alemtuzumab and fludarabine EXAMPLE Approved Labeled Indication Indication covered by orphan exclusivity Designation

23. Valuable Resources

24. Orphan Designation Highlights: 1983-2011 ~3740 Designation requests ~2600 Products have received Orphan Designation (~70%) Number ofDesignation Requests Number ofOrphanDesignations 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 Year Year

25. Range of Designated Orphan Drugs* * Represents orphan drug designations through 2006

26. OOPD – What Else We Do

27. What Else Does OOPD Do? • Humanitarian Use Device (HUD) Designations • Orphan Products Grants Program • Pediatric Device Consortia Grants Program • Outreach • Science of Small Clinical Trials Workshop – Nov. 27-28, 2012 at FDA • Cross-agency coordination of rare disease efforts

28. Questions? For more information on OOPD’s programs, check out www.fda.gov/orphan Still have questions? • Email us at orphan@fda.hhs.gov OR • Call us at 301-796-8660