Emil D. Kakkis, M.D., Ph.D. President and Founder EveryLife Foundation for Rare Diseases

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 StudiesEthical 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

6. UX003-CL201: Blinded Start Design • 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

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 EndThanks to all the Sponsors EveryLife Foundation For Rare Diseases