NCS S Fact Finding Cardio toxicity Expert Working Group

1. NCSS Fact FindingCardiotoxicity 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)

2. 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!

3. EWG Charge • Identify opportunities for collaborations to identify & develop valid biomarkers that effectively predict drug-induced myocardial toxicity. • Develop plan of implementation • Define expected benefits • Identify needed resources

4. Biomarker Definition • Biomarker Categories • Susceptibility • Exposure • Effect • Integrity / wellness / homeostasis • Stress • Injury / damage • EWG will focus on biomarkers of effect

5. 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 species • Bridge pre-clinical & clinical • Non-invasive / accessible

6. Key Questions • What cardiotoxicity markers are already accepted? • FDA regulatory applications • toxicology ‘research’ • How can new biomarkers be quickly identified & validated? • ICCVAM • toxicologist consensus meetings • What could the FDA do to enable this process? • confidentiality • RFPs / directed research • What will the EWG do next?

7. 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

8. 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 acceptance

9. Identification & Validation of New Biomarkers - Interagency Coordinating Committee on Validation of Alternative Methods (ICCVAM) • 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

10. 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

11. 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

12. 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 sources • Industry / PharMA • akin to patent application fees? • NTP / NIEHS / NHLBI / NIH • NCTR / FDA

13. 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

14. 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 cardiotoxicity • Suggest that agency establish data generating agreement to further validate candidate biomarkers • Put out call for investigation and development of “new” biomarkers of cardiotoxicity