Accelerated Approval AA in Rare Diseases Review of a White Paper Proposal Emil D Kakkis MD PhD President and Founder EveryLife Foundation for Rare Diseases May 15 2013 Sofitel Hotel Washington DC Lafayette Square ID: 919034
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Slide1
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
Slide2Pivotal 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
Slide3Randomized, placebo-controlled studies: More plausible using a biomarker primaryPower often increased, allow small randomized controlled studiesNeed 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
Slide4Alternative Clinical Study DesignsWhen reasonable and feasible, should do randomized controlled studiesWhat 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
Slide5Blinded 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
5
Slide66
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
Slide7Natural history control strategiesExtremely challenging to provide comparable non-parallel controlVariations in patients, ancillary treatment, differences in observation
Need to control patient comparability
Difficult to use in pre-marketing setting and requires consultation and preparation
Slide8Clinical study section in the White PaperFocused on high-level recommendationsNot 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
Slide9The EndThanks to all the Sponsors
EveryLife
Foundation
For Rare Diseases