1. Welcome to Workshop #5: Accelerated Approval (AA) in Rare Diseases: Review of a White Paper Proposal Emil D. Kakkis, M.D., Ph.D. President and Founder EveryLife Foundation for Rare Diseases May 15, 2013 Sofitel Hotel Washington, D.C. Lafayette Square

2. Pivotal Study Trial Design: Concepts for studies using a primary surrogate marker endpoint Randomized, controlled studies are preferred when feasible and appropriate – Should be conducted in most situations An adequate assessment of safety is required – Smaller size studies still requires sufficient “n” Accelerated approval should not require internal validation of the biomarker – Clinical endpoint was not feasible in first place

3. Randomized, placebo-controlled studies: More plausible using a biomarker primary Power often increased, allow small randomized controlled studies Need to assess safety optimally with placebo control when possible Can still conduct valid clinical assessments if underpowered Risk of conflict between biomarker and clinical results

4. Alternative Clinical Study Designs When reasonable and feasible, should do randomized controlled studies What about when not possible? –Too small, variable population –Ethical issues Randomized controlled, without placebo Cross over designs, single, double, N=1 Blinded observations but open label design

5. Blinded Observations in Open Label Studies Ethical or challenging clinical situations Example: late infantile Batten’s Disease Severe neurologic disease, onset 2-5 yrs Cannot ethically conduct intraventricular ERT therapy using placebo Study of a neurologic biomarker and imaging, neurologic scoring –Use blinded specimens for the biomarker –Blind and randomize sequence of MRI –Scoring behaviors by video if possible 5

6. 6 12 subjects randomized to one of four (A-D) groups to either start on 2 mg/kg UX003 (A) or start on placebo (B-D) and cross over to 2 mg/kg UX003 in blinded manner at different pre-defined timepoints Subjects and observers do not know when subjects cross onto drug Rx Dosed every other week for 48 weeks. All groups receive a minimum of 24 weeks of 2 mg/kg UX003 therapy UX003-CL201: Blinded Start Design

7. Natural history control strategies Extremely challenging to provide comparable non-parallel control –Variations in patients, ancillary treatment, differences in observation Need to control patient comparability Difficult to use in pre-marketing setting and requires consultation and preparation

8. Clinical study section in the White Paper Focused on high-level recommendations Not intended to provide specific study design recommendations Supporting the need for quality study designs to maximize information Safety evaluation still needed Consideration for how confirmation of clinical benefit will occur is important

9. The End Thanks to all the Sponsors EveryLife Foundation For Rare Diseases