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Advisory Council February 2014 Meeting Presentation: FDA Update

Monday, February 3, 2014

NAPA Scientific Advisory Council

FDA Update

Nicholas A. Kozauer, MD
Clinical Team Lead
Division of Neurology Products (DNP)
Center for Drug Evaluation and Research (CDER)


  • Commitment to AD Drug Development
    • Drug Development Tool Qualification
    • Expedited regulatory mechanisms
    • External engagement
  • Draft Guidance: Developing Drugs for Early AD
    • Response to paradigm shift in AD drug development (uncharted territory)
    • Published February 2013
  • Drug Development Tool (DDT) -- Qualification Process
    • Development of publically available drug development tools that can be widely employed
      • Biomarkers, clinical outcome assessments (COAs), and animal models
    • Facilitate work in the pre-competitive space
    • Several submissions by the Coalition Against Major Diseases (CAMD) are ongoing
      • Biomarkers
      • Prodromal AD clinical assessment scale
  • Endorsed AD Clinical Trial Simulation Tool
  • Expedited Regulatory Mechanisms for Serious Diseases
    • Fast Track Designation
      • Frequent interactions with FDA
    • Breakthrough Therapy Designation
      • New with FDASIA (2012)
      • Fast Track plus…
    • Accelerated Approval
      • Surrogate endpoint or intermediate clinical endpoint
      • FDASIA clarified (very relevant to AD Guidance)
  • External engagement
    • Meetings/conferences
      • Industry
      • Academia
      • Advocacy Groups
    • Public/private partnerships
      • Coalition Against Major Diseases (CAMD)
      • Accelerating Medicines Partnership (AMP)

Alzheimer's Disease: Developing Drugs for the Treatment of Early Stage Disease

AD Progression Model

  • AD Dementia trials disappointing
  • Move to Early AD trials
  • Novel regulatory framework required

Draft Guidance: Early AD

  • Early AD defined as symptomatic but pre-dementia

Early AD Diagnosis

  • Diagnostic criteria under development:
    • National Institute on Aging -- Alzheimer’s Association (NIA-AA)
    • International Working Group for New Research Criteria for the Diagnosis of AD
  • Combine clinical/biomarker findings
    • Amyloid -- PET, CSF levels of amyloid and/or tau, brain volume (vMRI)
  • Guidance supports enrichment

Clinical Endpoints

  • Dementia Trials
    • Co-primary outcome measures
      • Cognition
      • Function or Global Rating
  • Early AD Trials
    • Co-primary approach more challenging
    • Should still apply in principle
  • Closest to overt dementia
    • Some detectable functional impairment
    • Single endpoint that integrates cognition/function (e.g., Clinical Dementia Rating -- Sum of Boxes)
  • Earliest symptoms
    • No detectable functional impairment
    • Most to gain (potentially)
    • Isolated cognitive measure
  • Accelerated Approval (21 CFR 314.510)
    • Associated with an effect on a surrogate endpoint (e.g. viral load in HIV)
    • Effect on an intermediate clinical endpoint that is reasonably likely to predict ultimate clinical benefit (i.e., irreversible morbidity)
    • Requires further post-marketing evaluation to ensure the ultimate relationship to the ultimate clinical outcome
  • Requires accurate identification of patients
  • State of the science will be critical
    • e.g., Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Surrogate Biomarkers

  • Data do not yet support use of a biomarker as a single primary outcome measures
  • Potentially support a disease modification claim along with a clinical endpoint


  • AD drug development has proven extremely challenging
  • FDA is committed to AD on several fronts
  • Field is moving to early-stage trials that pose novel regulatory challenges
  • Draft Guidance attempts to suggest pathways forward