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					NCSS Fact Finding
Cardiotoxicity Expert Working Group
     • Kendall B. Wallace (University of Minnesota)
        – Chair
     • Elizabeth Murphy (NIEHS, NIH)
     • I.Y. Rosenblum (Schering-Plough)
     • Gene Herman (CDER, FDA)
     • Alan L. Metz (Pfizer)
     • Michael R. Rosen (Columbia University)
     • Malcolm J. York (Glaxo SmithKline)
     • Gordon Holt (Oxford GlycoSciences)
     • James T. MacGregor (NCTR, FDA)
     • Elizabeth Hausner (CDER, FDA)
     • David M. Essayan (CBER, FDA)
Major points considered

      •   EWG charge
      •   Biomarker definition
      •   Characteristics of an „ideal‟ biomarker
      •   Key questions
      •   List of current cardiotoxicity biomarkers
      •   Novel reporters of cardiac stress
      •   Criteria for validation
      •   Enabling the process
          » Note: Work in progress!
EWG Charge

   • Identify opportunities for collaborations to
     identify & develop valid biomarkers that
     effectively predict drug-induced myocardial
   • Develop plan of implementation
   • Define expected benefits
   • Identify needed resources
Biomarker Definition

      • Biomarker Categories
         – Susceptibility
         – Exposure
         – Effect
            • Integrity / wellness / homeostasis
            • Stress
            • Injury / damage
                 » EWG will focus on
                   biomarkers of effect
Characteristics of an „ideal‟ biomarker
    • Specific
        – High myocardium/serum ratio
        – Not present in non-cardiac tissue, even pathologically
        – Differentiation of cardiac toxicity (acute versus chronic, necrosis,
           hypertrophy, rhythm)
    • Sensitive
        – Zero baseline
        – Marker of „early,‟ reversible cardiotoxicity
        – Immediate release with injury
    • Predictive
        – Long half-life in blood
             • Gives indication of reversibility
        – Release proportionate to extent of injury
    • Robust
        – Rapid, simple, accurate and inexpensive detection in all relevant
    • Bridge pre-clinical & clinical
    • Non-invasive / accessible
Key Questions

    • What cardiotoxicity markers are already accepted?
       – FDA regulatory applications
       – toxicology „research‟
    • How can new biomarkers be quickly identified &
       – ICCVAM
       – toxicologist consensus meetings
    • What could the FDA do to enable this process?
       – confidentiality
       – RFPs / directed research
    • What will the EWG do next?
List of Current Cardiotoxicity Biomarkers

   FDA regulatory acceptance
   • No current existing FDA guidelines for myocardial toxicity
      – [QTc not covered under EWG biomarker definition]
   Toxicology „research‟ acceptance
   • Many protein markers are associated with types and
     degrees of cardiac damage
      – LDH, CK isozymes, AST, SGOT, myoglobin, myosin,
         a-actin, cardiolipin, fatty acid binding protein, ANP,
         BNP, glycogen phosphorylase, calcium gene-related
         peptide, ECG, C-reactive protein, ...
   • Troponins (T, I, C) are the most widely implemented
      » Validation is key to new biomarker acceptance
Cardiotoxicity Biomarkers on the [Near] Horizon

         New technologies soon will broadened
         the list of cardiotoxicity biomarkers
            • Ionic
            • Metabolic
            • Genomic
            • Proteomic
            • Metabonomic
            • ...
            » Validation is key to new biomarker
Identification & Validation of New Biomarkers -
Interagency Coordinating Committee on Validation of Alternative Methods

      • Best available template for bringing new markers online
      • Investigator driven
      • Process tested across a wide variety of circumstances
         – Animal testing
                • multiple species
                • conditions anticipating clinical circumstances
         – Human testing
                • gender, ethnicity
                • likely disease / treatment background
                • across appropriate tissues
      • Process meets for regulatory acceptance
                 » explore EWG / ICCVAM interface
Identification & Validation of New Biomarkers -
Toxicologist Consensus

      • Driven by EWG, investigators, ...
      • Establish expert consensus on specific biomarkers
         – toxicology conferences as forums
               • speakers and platform discussions
               • plenary sessions as required / possible
         – mediated by EWG member(s)
      • report findings to NCSS
               » akin to NIH consensus conferences?
               » explore EWG / ICCVAM interface
How can the FDA enable this process?
  - Confidentiality

  • EWG needs info on newest markers
  • Many innovators / discoverers likely to require
    maintenance of non-disclosure
     – needed to insure market preservation
  • Multi-party confidentiality agreements may be too
    complex / restrictive to be useful
     – governmental, academic & industrial diligence
     – [EWG alone has 9 institutional members]
        » suggest forming EWG subgroup to receive and
          review data in confidential setting
How can the FDA enable this process?
  - Financial support

 • Lack of targeted support will slow biomarker emergence
    – I.D. of biomarkers for specific toxicity types
    – research by academic scientists
    – generation & maintenance of samples, standards
    – independent testing
 • Suggest agency organize multiple, integrated support
    – Industry / PharMA
        • akin to patent application fees?
    – NCTR / FDA
Next Steps in Fulfilling EWG‟s Charge
• Troponin workshop to meet at FDA on 29 July, 2001 [open to all]
   – Review existing data
   – Identify data gaps in validation as a biomarker of cardiotoxicity
   – Draft suggestions for further development
       • data sharing / data generating collaborations
• Conduct fall workshop at American College of Toxicology (Nov, 2001)
   – open to all conference attendees
   – Presentation of current candidate biomarkers of myocardial injury
       • particularly focus on troponins
   – Satellite EWG meeting at FDA to follow [open to all]
           – Review status of troponin initiative
           – Presentation of status of other existing biomarkers
                » Novel reporters
                » New technologies
Possible outcomes?

  • Suggest agency consider establishing a committee to monitor
    development of biomarkers over next several years
  • Identify candidate biomarkers for further pursuit:
     – Prioritize
     – Suggest that agency establish data sharing agreement
       regarding selected candidate biomarkers of
     – Suggest that agency establish data generating agreement
       to further validate candidate biomarkers
  • Put out call for investigation and development of “new”
    biomarkers of cardiotoxicity

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