1. 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)

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,  -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. New technologies soon will broadened the list of cardiotoxicity biomarkers Ionic Metabolic Genomic Proteomic Metabonomic... »Validation is key to new biomarker acceptance Cardiotoxicity Biomarkers on the [Near] Horizon

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