Standard End Point Definitions in Cardiovascular TrialsKaren A. Hicks, M.D.Medical OfficerDivision of Cardiovascular and Renal Products (DCRP), Center for Drug Evaluation and Research (CDER),Food & Drug AdministrationOn behalf of the Standardized Data Collection for Cardiovascular Trials InitiativeCDISC WebinarFriday, November 19, 20101:00 p.m. –2:00 p.m.Key Events Leading to the Need for Standards in Cardiovascular Trials z Endocrinologic and Metabolic Drugs Advisory Committee (July 2008)z Diabetes Cardiovascular Guidance (December 2008)z Advisory Committee Meetings (April 2009)2July 2008 Endocrinologic and Metabolic Drugs Advisory Committeez Discussed the role of cardiovascular assessment in the premarketing and postmarketing settingsz Recommended requiring sponsors to conduct a long-term cardiovascular trial (VOTE: 14 “YES”, 2 “NO”)z If an anti-diabetic therapy demonstrated a concerning cardiovascular (CV) safety signal during Phase 2/3developmentORz If no signal existed (and sponsor could not provide other equivalent evidence to rule out unacceptable cardiovascular risk)3Diabetes Cardiovascular Guidance z Final guidance published in December 2008 z Guidance for Industry: “Diabetes Mellitus—Evaluating Cardiovascular Risk in NewAntidiabetic Therapies to Treat Type 2 Diabetes”z Identifies HbA1c as the primary efficacy end point for glucose reductionz Asks sponsors to demonstrate that new type 2 diabetes agents do not unacceptably increase cardiovascular risk4March 2009z Draft proposal for cardiovascular end points, definitions, and case report formsz Internal and external discussion on best path forward5Advisory Committee Meetings(April 2009)z Cardiovascular adverse events were not prespecified or predefinedz Missing data (key data elements never collected)z Limitations of retrospective analysis (Broad SMQ MACE, Custom MACE)z Cardiovascular adverse event rates appeared to be low (low risk populations)6Why Data Standards?z To improve the quality and efficiency of cardiovascular trialsz To provide end point definitions so that events are clearly characterized by objective criteria and reported uniformlyz To standardize data collection to capture key data elementsz To simplify analysis of events in drug development programs or among different clinical trials and to more easily identify trends and other safety signals7Standardized Data Collection for Cardiovascular Trials Initiative: Goals z Standardized Definitionsz Standardized Data Collection/Case ReportFormsz Integrate withz CDISC (Clinical Data Interchange StandardsConsortium)z SDTM: Study Data Tabulation Modelz HL7 (Health Level 7, Inc.)z FDA Data Warehouse of CardiovascularTrials8Stakeholders -1z FDA (CDER, CDRH, Office of Women’s Health)z CDER Data Standards (Jay Levine,Ana Szarfman)z Critical Path Initiative (Leonard Sacks)z Academiaz American College of Cardiology (ACC) (James Tcheng, Dan Roman, Maria Isler, Susan Fitzgerald)z Association of Clinical Research Organizations (ACRO) (Doug Peddicord, Christine Clark, Jean Morgan, Barbara Tardiff)9Stakeholders -2z Clinical Data Interchange Standards Consortium (CDISC) (Bron Kisler, Rebecca Kush, Chris Tolk, Brian McCourt (DCRI))z Clinical Trials Transformation Initiative (CTTI) (Judith Kramer, Martin Landray)z Health Level 7, Inc. (HL7) (Charles Jaffe)z NHLBI (Mike Domanski)z Pharmaceutical Research and Manufacturers of America (PhRMA) (Alan Goldhammer)z Pharmaceutical Industry Representatives (Paul Burton (J & J), and Yale Mitchel (Merck)10Academiaz Cleveland Clinic (Drs. Steve Nissen, Mike Lincoff)z Duke Clinical Research Institute (Drs. Ken Mahaffey, Chris O’Connor, James Tcheng)z Mount Sinai School of Medicine (Dr. Roxana Mehran) z Harvard Clinical Research Institute (Drs. Don Cutlip, Laura Mauri)z Harvard Medical School (Dr. Michael Jaff)z TIMI (Drs. Steve Wiviott, David Morrow, Ben Scirica) z Brigham and Women’s Hospital (Drs. Scott Solomon, Akshay Desai, Eldrin Foster Lewis, Marc Pfeffer,John McMurray (Glasgow,Scotland))z St. Louis University (Dr. Bernard Chaitman)z Yale University School of Medicine (Dr. Alexandra Lansky)z Beth-Israel Deaconess Medical Center (Dr. C. Michael Gibson)11Neurology Working Groupz FDA Stroke Teamz Drs. Billy Dunn, John Marler,Heather Fitter, and Kachikwu Illohz Cathy Sila, M.D. (Case Medical Center)12Standardized Data Collection forCardiovascular Trialsz July 22, 2009: Draft definitions releasedz September 11, 2009: Meeting of Major Stakeholdersz February 5, 2010: Internal Working Group Meetingz March 26, 2010: Meeting of Major Stakeholdersz Multiple meetings with FDA Senior Managementz Ongoing communication with the Universal Definition of MI Working Group14Standardized Data Collection forCardiovascular Trials –Next Stepsz Posting of Definitions on CDISC website (November 17, 2010) for 30 days of public commentz Links to definitions provided to professionalsocieties to facilitate commentsz Formal testing of Definitions (Drs. Roxana Mehran and Stephen Wiviott)z Creation of Standardized Case Report Forms for Cardiovascular End Point Eventsz Integration with CDISC / HL715Standardized Data Collection for Cardiovascular Trials –Other Stepsz FDA is working with ACC and other professional societies to harmonize ACC and CDISC data elements(Dr. Chris Cannon)z Goal is for data to be CDISC ready forsubmissionz Sentinel Initiative16Acknowledgementsz Robert Temple, M.D. (CDER)z Norman Stockbridge, M.D., Ph.D. (DCRP)z Shari Targum, M.D. (DCRP)z Ellis Unger, M.D. (DCRP)z Steve Grant, M.D. (DCRP)z Jim Hung (Director, Division of Biometrics I)z Andrew Farb, M.D., Bram Zuckerman, M.D., Steve Brooks, M.D., Ken Cavanaugh, M.D. (CDRH)z Mary Parks, M.D. , Hylton Joffe, M.D., M.M.Sc, Ilan Irony, M.D.(DMEP)z Rachel Hartford, RPM (DMEP)/Lori Wachter, RN, BSN, OCN Project Manager (DCRP)/ Anna Park, R.Ph Project Manager(DCRP))z Chuck Cooper, M.D. (OTS/OB/DBVI)z FDA Stroke Team (Billy Dunn, M.D., John Marler, M.D., Heather Fitter, M.D., Kachikwu Illoh, M.D.)17Next StepsBrian McCourtAssociate Director, Clinical Research InformaticsClinical Data IntegrationDuke Clinical Research Institute1819Standardized Data Collection for Cardiovascular Trials Initiative: Goals z Standardized Definitions z Standardized Data Collection/Case Report Forms z Integrate withz CDISC (Clinical Data Interchange Standards Consortium)z SDTM: Study Data Tabulation Modelz HL7 (Health Level 7, Inc.)z FDA Data Warehouse of Cardiovascular Trials9Sept2011Key Considerationsz Standard end point definitions are critical, but not sufficient to meet the quality, efficiency or analysis objectivesz End point data is clinical data, standardize at the sourcez Coordinate various cardiology standards efforts to collaboratively produce a single set of work products20Collect Once, Repurpose ManyTimesClinical DataResearch Clinical Decision Support Public & Population HealthQualityMeasurement& PatientSafety Business,Operations/AdministrationDon Mon, AHIMACollaborating Organizationsz American College of Cardiology Foundation (ACC)z Clinical Data Standards Interchange Consortium (CDISC) z Duke Clinical Research Institute (DCRI)z Duke Translational Medicine Institute (DTMI)z US Food and Drug Administration (FDA)z Health Level Seven (HL7)z National Cancer Institute (NCI)z National Cardiovascular Research Infrastructure (NCRI) Partial funding provided by NHLBI Award 1RC2HL101512-01Work ProductsHealthcareResearch Use cases and patient scenariosCardiovascular Domain Analysis Model Data elements and clinicaldefinitionsActivity diagramsInformation modelHealthcare (HL7 RIM)representationHL7Sample data collection formsCDISC CDISC (CDASH, SDTM)representationsCDISC Electronic metadata publication(NCI EVS/caDSR)HL7 and CDISCProcess & Milestonesz Identification and development of common data elementsz CV CDASH Domains, Related artifactsz Preparatory work started, growing CDISC & HL7activityz CDISC Public Commentz Target: 2nd Quarter 2011z HL7 Ballot (Cardiology DAM, R2)z Target: September 2011 Ballot Cyclez Publish Metadata (NCI EVS/caDSR)24Standardized Data Collection for Cardiovascular TrialsComing Soon25。