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, 2013Sofitel Hotel Washington, D.C. Lafayette Square

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

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

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

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

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www.ultragenyx.com 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

Wk 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70dose 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

A 48 wk 1 mg/kg 4 mg/kg 2 mg/kg

B placebo 40 wk 1 mg/kg 4 mg/kg 2 mg/kg

C placebo 32 wk 1 mg/kg 4 mg/kg 2 mg/kg

D placebo 24 wk 1 mg/kg 4 mg/kg 2 mg/kg

Blinded period Dose titration period

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

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

The End

Thanks to all the Sponsors

EveryLife Foundation

For Rare Diseases