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

2. 2 Background

3. 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. 4 Orphan Drug Designation: Process Issues

5. 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. 6 For Complete FDA Organizational Chart see: http://www.fda.gov/downloads/AboutFDA/CentersOffices /OrganizationCharts/UCM288864.pdf Office of the Commissioner (OC) Office of Medical Products and Tobacco OMPT CDER Center for Drug Evaluation and Research CBER Center for Biologics Evaluation and Research OOPD Office of Orphan Products Development OSMP Office of Special Medical Programs Step 1: Orphan Designation Step 2: NDA or BLA

7. 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. 8 When to Submit an Orphan Designation Request No IND is required SUBMISSION OF NDA/BLA Pre-Clinical DevelopmentClinical Development CAN SUBMIT DESIGNATION REQUEST

9. 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. 10 Orphan Drug Designation: Substantive Issues

11. 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. 12 Review of a Designation Request 1.What is the disease/condition? 2.Is the disease rare (prevalence) 3.Is there sufficient scientific rationale that demonstrates “ promise ” that the drug/biologic will treat, diagnose or prevent the disease/condition at issue?

13. 13 #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 Non-Hodgkins’ Lymphoma Lymphoma Hodgkins’ Disease Non-Hodgkins’ B- Cell Lymphoma Non-Hodgkins’ T- Cell Lymphoma Non-Hodgkins’ null- cell Lymphoma Follow the WHO classification so each subtype of each of these 3 categories is treated as a distinct disease/ condition

14. 14 #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 EXAMPLE Malaria EXAMPLE Prevention of ischemia reperfusion injury associated with solid organ transplantation

15. 15 #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 EXAMPLE Myasthenia gravis Prevalence: ~ 43,500 – 63,500

16. 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 Severe preeclampsia due to toxicity of product Preeclamps ia EXAMPLE

17. 17 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 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.

18. 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. 19 Recent Publication by Lev et al., 2012- Drug Discovery Today Lev et al. 2012 Drug Discovery Today

20. 20 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 EXAMPLES Small molecule with same active moiety as approved drug but different ester or salt 2 proteins with minor differences in amino acid sequences

21. 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. 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 Designation Indication covered by orphan exclusivity

23. 23 Valuable Resources SourceCitation 1991 Proposed Rule56 Fed. Reg. 3338 (Jan.29, 1991) 1992 Final Rule57 Fed. Reg. 62076 (Dec. 29, 2992) 2011 Proposed Rule 76 Fed. Reg. 64868 (Oct. 19, 2011)

24. 24 Orphan Designation Highlights: 1983-2011 ~3740 Designation requests ~2600 Products have received Orphan Designation (~70%) 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 Number of Designation Requests Number of Orphan Designations

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

26. 26 OOPD – What Else We Do

27. 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. 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 ORorphan@fda.hhs.gov Call us at 301-796-8660