Obligatory Drug-Device Interactions-Why The Critical Path Obligatory Drug-Device Interactions-Why The Critical Path? An Academic View Mitchell W. Krucoff, MD, FACC Professor, Medicine/Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Duke Clinical Research Institute

Mitchell W. Krucoff, MD DISCLOSURES Consulting Fees Biosensors International, Terumo Medical Corporation Grants/Contracted Research Boston Scientific Corporation, Medtronic CardioVascular, Inc. Honoraria Abbott Vascular, Cordis, a Johnson & Johnson company

Critical Path Initiatives: March 2004 http://www.fda.gov/oc/initiatives/criticalpath/

2006 FDA – Duke/DCRI Memorandum Of Understanding (MOU) Establish Public/Private Partnership (PPP) Leverage resources / expertise Advance pre-competitive assessment tools Advance public health Cardiac Safety Research Consortium (CSRC) www.cardiac-safety.org

Discontinuation of Anti-platelet Therapy and Risk for ST Overall stent thrombosis = 1.3% (P=0.09, N=2229) Incidence (%) Premature discontinuation of antiplatelet therapy was a major significant univariate predictor of stent thrombosis. The cumulative incidence of thrombosis was 29% (5 of 17 patients), with a hazard ratio of 152 (95% Confidence interval; 52 to 442; P<0.001); clopidogrel was discontinued in one patient. Other significant univariate predictors included prior brachytherapy, renal failure, bifurcation with 2 stents, bifurcation lesions, and diabetes, with respective cumulative thrombosis rates of 8.7%, 6.2%, 3.9%, 3.6%, and 2.5% (P<0.05). Unstable angina, thrombus, and unprotected left main were not significant univariate predictors of thrombosis. Unstable angina Thrombus Diabetes Unprotected left main Bifurcation Renal failure Prior brachy Rx Premature antiplateletdiscont’d Iakovou et al. JAMA. 2005;293:2126. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293:2126-2130.

The Public Health Question 10,000,000 DES patients Permanent implants Linear hazard 0.3-0.6%: 50,000 death/MI per annum Growing every year

DES Thrombosis: A Novel Regulatory Domain: Obligatory Drug-Device Safety Interaction Combination drug-on-device (Medical Device Reg) Studied in de-novo 1-vessel PCI to reduce restenosis Clopidogrel/Prasugrel: Thienopyridines (Drug Reg) Studied in ACS patients Public health issue: Crossover of drug-device “cultures” No clear regulatory predicate Combinations of new DES and new DAP Post-market “real world” population

DES & Extended Dual Antiplatelet Therapy: What It Takes: Collaboration Regulatory FDA: CDER CDRH Off Comm E.U. Austria U.K. Sweden Japan: MHLW PMDA Societies ACC SCAI ESC Academia Duke Harvard Cleveland Clinic Columbia U of NM Wash Hrt Ctr London School of Hyg & Trop Med CVPath Industry Abbott Medtronic BSCI Cordis/J&J Biosensors OrbusNeich Eli Lilly (Daichi) Sanofi BMS Federal NIH AHRQ

Dual Antiplatelet Therapy (DAPT) RCT Initial Procedure – Enrollment Randomization (All Eligible Subjects) End of Treatment End of Follow Up 0 12 m 30 m 33 m 30 m DAPT arm Obs Double Blind Placebo Controlled RCT 12 vs 30m randomization in subjects clear and on treatment at 12m Stratified by lesion and clinical complexity Co primary endpoints: ST and MACCE, Safety endpoint: Major bleed 33 months follow up, to include 3 month “rebound period” Simultaneous RCT of 12 vs 30m DAPT in BMS Both clopidogrel and prasugrel R DES n = 12,196 BMS n = 4,320 DES n = 15,245 BMS n = 5,400 Open label DAPT Source patients denovo + PMS studies 12 m DAPT arm Obs

SAFARI April 2009

Trans-Radial Education, Assessment &Training The TREAT Registry Obligatory Device-Drug Interaction: Impact of device technique on drug safety (bleeding) profiles

Obligatory Drug-Device Safety Interactions: Critical Path Initiatives Collaborative, transparent PPP forum: Unique resource for combined expertise, including CDER, CDRH, OC Opportunity to focus on pre-competitive regulatory & public health issues Provides a “thinktank/incubator” environment to launch tangible programs Individual programs require tailored management and operations solutions

Obligatory Drug-Device Interactions-Why The Critical Path Obligatory Drug-Device Interactions-Why The Critical Path? An Academic View Mitchell W. Krucoff, MD, FACC Professor, Medicine/Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Duke Clinical Research Institute