Mitchell W. Krucoff, MD, FACC Collaboration, Cardiac Safety And Children: The Cardiac Safety Research Consortium (CSRC) View Mitchell W. Krucoff, MD, FACC Professor, Medicine/Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Co-Director, CSRC Duke Clinical Research Institute

Cardiac Safety Research Consoritum (CSRC) Mission, who we are, how we work

Addressing Therapeutic Innovation in the USA http://www.fda.gov/oc/initiatives/criticalpath/ 2004 R&D Spending & New Rx Applications 10 Year Trends

Cardiac Safety in Regulatory Science: Rare but catastrophic events 2006 FDA-Duke MOU Cardiac Safety Research Consortium

The CSRC Public-Private Partnership MODEL FDA INDUSTRY Mortara Instrument CRADA ACADEMIA PT. GROUPS DCRI MOU PUBLIC-PRIVATE CONSORTIUM PROFESSIONAL ORGANIZATIONS PPP STEERING COMMITTEES WORKING GROUPS NON-PROFIT STATE, OTHER NEUTRAL GROUND COMMITMENT ADM. INFRASTRUCTURE: HELP ESTABLISH WG/SC CONTRACTS MGNT COORDINATE MEETINGS FINANCIAL OVERSIGHT IDENTIFY MUTUAL PRORITIES POOL RESOURCES/EXPERTISE DEFINE ROLES/RESPONSIBILITIES GAP ANALYSES (WHAT’S KNOWN?) CO-DEVELOP PROPOSALS BUDGETS TIMELINES RFPs IMPLEMENT PROJECTS

Partnering Organizations DIA HESI ACC-NCDR ICOS NIH AHA FDA Health Canada PMDA Japan

Member Companies 2016 Abbott AbbVie AliveCor Amgen AMPS Astra Zeneca AlCor Bayer Bioclinica Biomedical Systems Boehringer Ingelheim Cardiocore CardioNet Celerion Chiesi Pharma CytoVas Dabi, Ltd Daiichi Duck Flats Pharma Eli Lilly Epidemico Gilead Sciences G.E. Health Care Global Instrumentation GlaxoSmithKline InVivo Sciences Johnson & Johnson Medifacts Medpace Medtronic Merck Monebo Mortara Insrument Merck Nabios GmbH OBS Medical Perspective Informatics Pfizer, Inc Portola Quintiles Roche Salix Sanofi Aventis Takeda Taylor Microtech Vince & Associates

CSRC Basics Regulatory mission: CV safety concerns Unique partnership of stakeholders Dialogue Collaboration & trust Consensus Thinktank/incubators: To talk and to listen To do….

CSRC Consensus White Papers

CSRC 2006-2016 Ten Year Report

Pediatric Drug & Device Safety: 2010 A Complex Equipoise

Complexities of Pediatric Safety: “Normal” from conception thru adolescence A matrix of change: Growth Metabolic Hormonal Psychosocial development Exercise and exertion Drugs and devices On-target and off-target effects Ethical considerations & research (consent)

NCAA Cardiac Task Force Meeting Indianapolis September 23-24, 2014

Technology use False positives False negatives Additional testing Developmental impact Quality Cost Maron B et al, Circulation. 2014;130:1303-1334 Lawless C et al, JACC. 2014;60:2146-71

CSRC Consensus Focus on Pediatric Safety: Unmet needs for screening & for therapeutic innovations Defining “normal” Most kids screened are normal variants Enhanced definition of normal enhance detection of abnormal (sensitivity & specificity) “Normal” kids is an information signature, not a single technology Understanding “normal” in kids requires follow-up

CSRC: Developing consensus in place of contention Start with what’s easiest: To agree upon To do Tolerate imperfection Listen for what we can do together that no one of us could do alone

Screening: what can we all easily agree to? Screening programs are active nationally: Private foundations Academic centers NCAA Primary “flaw” in national screening: inconsistency We can do better working together than any one can do separately What’s good for screening (normals) is good for regulatory We can get better without being perfect

What could we make better (not “perfect”)? Enhance consistency of data content/structure across actice screening efforts Define contemporary, age-related “normals” criteria Automate technology wherever possible Blood pressure ECG Echo Lower cost, higher consistency data Automate follow-up wherever possible I-phone apps EHR For insight into “healthy”

Mitchell W. Krucoff, MD, FACC Collaboration, Cardiac Safety And Children: The Cardiac Safety Research Consortium (CSRC) View Mitchell W. Krucoff, MD, FACC Professor, Medicine/Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Co-Director, CSRC Duke Clinical Research Institute