Cardiovascular Safety in Drug Development: QT, Arrhythmias, Thrombosis, and Bleeding

April 19-21,12-13, 20102010 Tutorial: Tutorials: April April 11 18, 2010 SheratonMarriott Bethesda National North Hotel, Hotel Arlington, & Conference VA, USA Center, Bethesda, MD, USA

Co-sponsored by the FDA and the Heart Rhythm Society PROGRAM CHAIRPERSON Philip T. Sager, MD, FACC, FAHA Vice President, Clinical Research Head, CV/Metabolic Clinical Development Gilead Sciences, Inc.

PROGRAM COMMITTEE Norman Stockbridge, MD, PhD Director, Division of Cardiovascular and Renal New Directions, Practical Challenges, Possible Products, Offi ce of Drug Evaluation I Offi ce of New Drugs, CDER, FDA Solutions, and Regulatory Approaches in the Peter Kowey, MD, FACC Development of Pharmaceutical Agents. Chief of Cardiology, Main Line Health System Professor of Medicine and Clinical Pharmacology This conference, co-sponsored by the FDA and the Heart Rhythm Jeff erson Medical College Society, will bring together FDA, PMDA, industry, academic, and global regulatory speakers in an open forum. The sessions will include in- FEATURED REGULATORY SPEAKERS depth discussion of the evolution of drug development, cardiac QT issues, cardiovascular safety, and strategies for analyzing and mitigating Norman Stockbridge, MD, PhD potential risks to improve cardiac safety analysis during drug develop- Director, Offi ce of Drug Evaluation, Offi ce of New Drugs, CDER, FDA ment. Featuring close interaction with FDA policy-makers and industry Robert J. Temple, MD and academic experts, this has become the premier conference for Deputy Center Director for Clinical Science, CDER, FDA keeping current in this ﬁ eld. Suchitra Balakrishnan, MD, PhD, Medical Offi cer, Division of Cardiovascular and Renal Products, CDER, FDA FEATURED SESSION TOPICS: Albert De Felice • Preclinical Testing and QT/Torsade de Pointes Assessment Supervisory Pharmacologist, CDER, FDA • Thorough QT Study – Key Issues Michael Pacanowski, PharmD, MPH • ICH E14 Issues Under Consideration Clinical Pharmacologist, Offi ce of Clinical Pharmacology, • CV Safety Unrelated to QT Offi ce of Translational Sciences, CDER, FDA • Debate: Automatic QT Assessment Will Replace Manual and Semi- Kaori Shinagawa, MD, PhD Automatic QT Techniques for the Thorough QT Study Deputy Review Director, Offi ce of New Drugs Evaluation II Pharmaceuticals and Medical Devices Agency (PMDA), • Abstract Presentations Japan Yoshiaki Uyama, PhD Review Director, Pharmaceuticals and Medical Devices WHO SHOULD ATTEND Agency, Japan • Academic scientists Joanne Zhang, PhD, MS Mathematical Statistician, Offi ce of Translational Sciences, • Industry management OB, CDER, FDA • Clinical project physicians Hao Zhu, PhD • Quality assurance directors QT-IRT Scientiﬁ c Lead, Offi ce of Pharmacology, CDER, FDA • Preclinical/discovery scientists • ECG safety data managers Worldwide Headquarters • ECG lab and equipment vendors Drug Information Association, Inc. 800 Enterprise Road, Suite 200 • Regulatory specialists Horsham, PA 19044, USA • Clinical project management Regional Offi ces Basel, Switzerland Tokyo, Japan Mumbai, India Beijing, China • Safety assessment personnel 2

CONTINUING EDUCATION Physician Continuing Medical Education Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Postgraduate Institute for Medicine (PIM) and Drug Information Association (DIA). PIM is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Postgraduate Institute for Medicine designates this educational activity for a maximum of 13.75 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Day 1 Tutorial: 6.5 AMA PRA Category 1 Credit(s)™ Day 2 Meeting: 7.5 AMA PRA Category 1 Credit(s)™ Day 3 Meeting: 6.25 AMA PRA Category 1 Credit(s)™ The Drug Information Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. The Drug Information Association designates this activity as follows: Tutorial: 6.5 contact hours or .65 CEUs; 286-000-10-014-L04-P Meeting: 14.25 contact hours or 1.425 CEUs; 286-000-10-013-L04-P Type of Activity: Knowledge To receive a pharmacy statement of credit, participants must attend the program and complete the online credit request process through My Transcript at www.diahome.org. Participants will be able to download a statement of credit upon successful submission of the credit request. For all physician participants who would like to receive a statement of credit, please complete the PIM evaluation and credit request form and return it to the DIA registration desk or to Benjamin Zaitz via fax at +1 215.293.5937. Disclosure of Confl icts of Interest: Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers and other individuals who are in a position to control the content of this activity to disclose any real or apparent confl ict of interest they may have as related to the content of this activity. All identifi ed confl icts of interest are thoroughly vetted by PIM for fair balance, scientifi c objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

LEARNING OBJECTIVES At the conclusion of this meeting, participants should be able to: • Recognize the state-of–the-art approach to performing the thorough QT study, including novel trial designs, the statistical analysis of the positive control, the deﬁ nition of adequate assay sensitiv- ity, and issues of multiplicity • Describe how to evaluate drugs for CV risk • Explain how new preclinical or clinical biomarkers can gain regulatory acceptance; • Identify how to optimally use preclinical data to assess CV risk • Discuss the use of automatic QT Measurements • Explain the major issues in clinical CV safety evaluation.

DAY 1 | SUNDAY, APRIL 11

8:00 AM-5:00 PM TUTORIAL AND CONFERENCE REGISTRATION • Design, conduct, analyze and interpret data from a ‘thorough QT/QTc study’ •Deﬁ ne the strategy behind choosing the optimal timing of the thorough QT study 8:00 AM-9:00 AM TUTORIAL REGISTRATION • Recognize the underlying regulatory thinking in terms of QT prolongation and patient safety • Identify relevant clinical, technological and statistical issues in the assessment 9:00 AM-5:00 PM FULL DAY TUTORIAL (MORNING BREAK: 10:30-10:45AM, of QT/QTc prolongation in clinical trials LUNCHEON: 12:30-1:30PM, AFTERNOON BREAK: 3:00-3:15PM) An Introduction to Clinical Assessment of QT • Discuss emerging new concepts and technologies for QT assessment, such as highly automated measurement methods and their potential role Prolongation in Drug Development • Explain the epidemiology of drug-induced proarrhythmias and the role of TUTORIAL INSTRUCTOR observational studies in assessing the risk for marketed products Borje Darpo, MD, PhD Pharmaceutical Consultant, Sweden This workshop serves as an introduction to the area of drug-induced QT prolonga- 5:00 PM TUTORIAL CONCLUDES tion and proarrhythmias. It is intended to provide participants with a background to the topic and is focused on how to clinically assess the ‘QT liability’ of drugs in development and which expectations regulatory authorities in diff erent regions DAY 2 | MONDAY, APRIL 12 will have on development programs in this regard. LEARNING OBJECTIVES 7:00-8:00 AM REGISTRATION AND CONTINENTAL BREAKFAST At the conclusion of this conference, participants should be able to: • Discuss the basis for proarrhythmias related to prolonged cardiac repolarization 8:00-8:05 AM WELCOME AND OPENING REMARKS •Recognize basic concepts related to the collection, analysis and interpretation PROGRAM CHAIRPERSON of clinical ECG data, taking into consideration the eff ect of study design and Philip T. Sager, MD, FACC, FAHA conduct on these parameters Vice President, Clinical Research • Design a program for QT assessment in early as well as late stage clinical Head, CV/Metabolic Clinical Development trials Gilead Sciences, Inc. 3

8:05-9:00 AM SESSION 1 CON Argument Preclinical Testing and QT/Torsade de Pointes Joel Morganroth MD FACC Assessment Chief Scientist and Chairman ERT SESSION CHAIRPERSON Philip T. Sager, MD, FACC, FAHA FDA Commentary (10 min) Vice President, Clinical Research Norman Stockbridge, MD, PhD Head, CV/Metabolic Clinical Development Director, Division of Cardiovascular and Renal Gilead Sciences, Inc. Products, Offi ce of Drug Evaluation I Offi ce of New Drugs, CDER The Use of Preclinical Data to Impact Early Clinical Development — FDA QT, QRS, and AV Conduction (25 min) What Would It Take To Replace the Thorough QT Study Part II (15 min) Matthew Skinner, PhD Associate Principal Scientist, Safety Pharmacology Ignacio Rodriguez, MD AstraZeneca R&D, UK Director Drug Safety Risk Management Roche Preclinical Testing, Arrhythmogenic Risk, and Clinical Validation: Panel Discussion (40 min) Case Study of Ranolazine (20 min) All Session Speakers and John C. Shryock, PhD Senior Director, Biology Eric L. Michelson, MD Gilead Sciences, Inc. Senior Director Clinical Research AstraZeneca Panel Discussion (10 min) Robert J. Temple, MD All Session Speakers Deputy Center Director for Clinical Science, CDER FDA

9:00-10:15 AM SESSION 2

Thorough QT Study - Key Issues 12:45-1:45 PM LUNCH SESSION CHAIRPERSON Peter Kowey, MD, FACC Chief of Cardiology, Main Line Health System 1:45-2:45 PM SESSION 3 Professor of Medicine and Clinical Pharmacology Abstract Presentations Jeff erson Medical College SESSION CHAIRPERSON The Thorough QT Study Optimal and Novel Designs (25 min) Philip T. Sager, MD, FACC, FAHA Joanne Zhang, PhD, MS Vice President, Clinical Research Mathematical Statistician, Offi ce of Translational Sciences, CDER Head, CV/Metabolic Clinical Development FDA Gilead Sciences, Inc. The Thorough QT Study without a Positive Control — Alternative Electrocardiographic Markers Associated with Sotalol-induced Torsades Innovative Approaches (25 min) de Pointes Marek Malik, MD, PhD Jean-Philippe Couderc, PhD Professor of Cardiac Electrophysiology Associate Professor of Medicine/Electrical and Computer St. Paul’s Cardiac Electrophysiology, UK Engineering, University of Rochester Medical Center Thorough QT Study Results — How do They Translate into Product Novel Three-dimensional Markers in Assessment of Proarrhythmic Labeling (25 min) Cardiotoxicity (Beyond QT/QTc) Suchitra Balakrishnan, MD, PhD Ihor Gussak, MD, PhD, FACC Medical Offi cer Chief Medical Offi cer and Vice President, NewCardio, Inc. Division of Cardiovascular and Renal Products Clinical Professor of Medicine, UMDNJ-RWJ Medical School CDER, FDA ECG Morphology Changes with Diff erent Type of Repolarization Dispersions Joel Xue, PhD 10:15-10:45 AM REFRESHMENT BREAK Principal Scientist, GE Healthcare QT Beat-to-beat and Restitution (QT-TQ) Analysis During Drug-induced Changes in Autonomic Tone and Heart Rate 10:45AM-12:45PM SESSION 2 CONTINUED Anthony Fossa, PhD Debate: Automatic QT Assessment Will Replace Manual Vice President/Consultant, Cardiovascular Safety, iCardiac and Semi-Automatic QT Techniques for the Thorough Technologies QT Study (40min) PRO Argument Borje Darpo, MD, PhD Pharmaceutical Consultant, Sweden 4

2:45-3:50 PM SESSION 4 DAY 3 | TUESDAY, APRIL 13, 2010 ICH E14 Issues Under Consideration SESSION CHAIRPERSON Norman Stockbridge, MD, PhD 7:00-8:00 AM REGISTRATION AND CONTINENTAL BREAKFAST Director, Division of Cardiovascular and Renal Products, Offi ce of Drug Evaluation I Offi ce of New Drugs, CDER, FDA 8:00-9:00 AM SESSION 5 The Extrapolation of Foreign TQT Data into Japanese Subjects and Abstract Presentations Populations (10min) SESSION CHAIRPERSON Boaz Mendzelevski, MD Philip T. Sager, MD, FACC, FAHA Vice President of Cardiology Vice President, Clinical Research Medifacts International, UK Head, CV/Metabolic Clinical Development Overview of the New ICH E14 Questions and the Process (10 min) Gilead Sciences, Inc. Daniel Bloomﬁ eld, MD Simulation of Cross-over TQT Studies with Drug-induced Heart-rate Vice President, Cardiovascular Franchise Integration Eff ects; Methodological Comparisons Among Diff erent Methods to Merck & Company Inc. Analyze QT Data in the Presence of Heart-rate Changes Validation of Novel ECG Methodologies — Is Regulatory Guidance David Svensson, PhD Needed? (15 min) Principal Statistician, QT SKG/ECG Centre Statistician, Adel Nada, MD, MS AstraZeneca R&D, Sweden Director, Clinical Pharmacology Medical Department and Frequency and Accuracy of Limb Lead Interchange in Thorough QT Cardiac Safety Clinical Systems Studies Abbott Laboratories Snehal Kothari, MD, DM, DNB, FISE, FACC How to Characterize the QT Eff ect in the Targeted Patient Population Senior Medical Director, Quintiles Cardiac Safety Services, India When a TQT Study is Positive (15 min) Optimization of Assessment of QT/QTc Interval Prolongation: Charles M. Beasley, Jr., MD Exploration of ‘Thorough’ QT Trial Design Distinguished Lilly Scholar Chief Scientiﬁ c Offi cer, Global Patient Safety Charles Benson, MD, PhD Eli Lilly and Company Medical Fellow, Eli Lilly and Company Automated QT Interval Measurements in 12-lead Digital Holter ECGs: A Comparison of Devices Sampling at 180 Hz and 1000 Hz 3:50-4:20 PM REFRESHMENT BREAK Dilip Karnad, MD, FACP, FRCP, FCP Head, Research and Reports, Quintiles Cardiac Safety Services

4:20-5:30 PM SESSION 4 CONTINUED Impact of Hysteresis Between QT/QTc Interval and Drug Concentration Implementation of the Thorough QT Study in Japan (15 min) — on Concluding QT/QTc Interval Prolongation: Moxifl oxacin Example James Li, PhD Via Webinar Senior Principal Scientist, Director of Clinical Pharmacology, Kaori Shinagawa, MD, PhD AstraZeneca R&D Deputy Review Director, Offi ce of New Drugs Evaluation II Pharmaceuticals and Medical Devices Agency (PMDA), Japan 9:00-10:40 AM SESSION 6 Yoshiaki Uyama, PhD Review Director, Offi ce of New Drug III CV Safety Unrelated to QT Leader for PMDA Omics Project (POP) SESSION CHAIRPERSON Pharmaceuticals & Medical Devices Agency, Japan Use of Concen- Philip T. Sager, MD, FACC, FAHA Vice President, Clinical Research tration-Response Modeling and Alternative Designs to Enhance the Data Head, CV/Metabolic Clinical Development Obtained from Phase 1 Studies (15 min) Gilead Sciences, Inc. Steve Riley, PharmD, PhD Director, Clinical Pharmacology Collaborative CV Safety Eff orts — CSRC Update Specialty Care Business Unit Mitchell W. Krucoff , MD, FACC, FAHA Pfi zer, Inc Professor, Medicine/Cardiology Director, Cardiovascular Devices Unit FDA Commentary on the Use of Concentration-Response Modeling and Director, eECG Core Laboratory Alternative Designs to Enhance the Data Obtained from Phase 1 Studies Duke University Medical Center/Duke Clinical Research Institute Hao Zhu, PhD QT-IRT Scientifi c Lead, Offi ce of Pharmacology, CDER, FDA Drug Eff ects on Heart Rate and Conduction Slowing — Is There a CV Safety Issue? (30 min) Panel Discussion (45 min) Jeremy N. Ruskin, MD All Session Speakers Associate Professor of Medicine, Harvard Medical School Director, Cardiac Arrhythmia Service Massachusetts General Hospital

5:30 PM END OF DAY 1

5:30-6:30 PM NETWORKING RECEPTION 5

Cardiac Troponin as a Safety Biomarker in Drug Development (25 min) 1:15-3:20 PM SESSION 6 CONTINUED Borje Darpo, MD, PhD SESSION CHAIRPERSON Pharmaceutical Consultant, Sweden Norman Stockbridge, MD, PhD Drug Induced Cardiomyopathy — Phenomenology, How Should it Director, Division of Cardiovascular and Renal be Assessed, and Future Research Directions for Oncologic and Products, Offi ce of Drug Evaluation I Non-Oncologic Drugs (25 min) Offi ce of New Drugs, CDER, FDA Thomas Force, MD Frequent Safety Assessments — How Do We Handle the Occasional Professor of Medicine Transient Finding (eg., Troponin, Liver Function Test, A Few Beats of VT) Clinical Director, Center for Translational Medicine Without Doing Too Much — A Statistical Approach (25 Min) Thomas Jeff erson University Kerry L. Lee, PhD Professor of Biostatistics Duke University School of Medicine 10:40-11:00 AM REFRESHMENT BREAK Director of Faculty Biostatistics Duke Clinical Research Institute Data Standards for Assessing CV Events (20 Min) 11:00 AM-12:45 PM SESSION 6 CONTINUED Chris Tolk, BS MT (ASCP) Director, Terminology Pharmacogenomics in the Assessment of Drug Safety (30 Min) CDISC Michael Pacanowski, PharmD, MPH Clinical Pharmacologist, Offi ce of Clinical Pharmacology, Offi ce Assessment of Vascular Damage, Preclinical and Clinical Assessment, of Translational Sciences, CDER and Biomarker Use Versus Routine Outcome (20 Min) FDA Albert De Felice Pharmacogenomics of Plavix - Is There a Real Safety Issue? (20 Min) Supervisory Pharmacologist CDER, FDA Paul A. Gurbel, MD Director, Sinai Center for Thrombosis Research Panel Discussion (30 Min) Sinai Hospital of Baltimore All Session Speakers Associate Professor of Medicine Johns Hopkins University School of Medicine How Do We Make Drug Development Effi cient and Adequately Assess Risk — Does Every Chronically Administered Drug Need an Outcome How to Assess Safety of Anticoagulant Therapies and Appropriately Bal- Study? (30 Min) ance the Beneﬁ ts on CV Outcome vs. Bleeding Risks? (25 Min) Robert J. Temple, MD Michael D. Ezekowitz, MD, FRCP, FACC Deputy Center Director for Clinical Science Vice President, Lankenau Institute for Medical Research CDER, FDA Professor, Jeff erson Medical College Panel Discussion (30 Min)

All Session Speakers 3:20-3:30 PM FINAL COMMENTS

12:45-1:15 PM WORKING LUNCH (Boxed lunches will be provided) 3:30 PM CONFERENCE ADJOURNED

Unless otherwise disclosed, DIA acknowledges that the statements made by speakers are their own opinion and not necessarily that of the organization they represent, or that of the Drug Information Association. Speakers and agenda are subject to change without notice. Recording of any DIA tutorial/workshop information in any type of media, is prohibited without prior written consent from DIA. REGISTRATION FORM TRAVEL AND HOTEL The most convenient airports are Reagan National and Register online or fax this page to +1.215.442.6199 Washington-Dulles International Airport and attendees should make airline reservations as early as possible. The Sheraton National Hotel is holding a block DIA is a fi nancially independent nonprofi t, global, multidisciplinary association of rooms at the reduced rate below until March 19, 2010, for the DIA event at- that provides a neutral forum for sharing information that optimizes the develop- tendees. Room availability at this rate is guaranteed only until this date or until ment and lifecycle management of biopharmaceutical and related products. the block is fi lled. Single $215 Double $215 Cardiovascular Safety in Drug Development: QT, Arrhythmias, Attendees must make their own hotel reservations. Contact the Sheraton Na- Thrombosis, and Bleeding tional Hotel by telephone at +1.800.325.3535 and mention the DIA event. The Event #10009 • Tutorials: April 11 • Workshop: April 12-13, 2010 hotel is located at 900 South Orme Street, Arlington, VA 22204, USA. Sheraton National Hotel, Arlington, VA, USA CANCELLATION POLICY: On or before APRIL 4, 2010 Contact Information Administrative fee that will be withheld from refund amount: Event Information: Contact Ben Zaitz at the DIA offi ce by telephone Member or Nonmember = $200 215.293.5803, fax 215.442.6199 or email [email protected]. Government or Academia or Nonprofi t (Member or Nonmember) = $100 Tutorial (if applicable) = $50 Registration Fees Cancellations must be in writing and be received by the cancellation date Registration fee includes refreshment breaks, luncheons, and reception (if applicable), and above. Registrants who do not cancel by that date and do not attend will be will be accepted by mail, fax, or online. responsible for the full registration fee paid. Registrants are responsible for can- celling their own hotel and airline reservations. You may transfer your regis- Industry Fee US $1295 tration to a colleague at any time but membership is not transferable. Please Join DIA now to save on future events and MEMBERSHIP notify DIA of any such substitutions as soon as possible. Substitute registrants to receive all the benefi ts of membership US $140 will be responsible for nonmember fee, if applic able. www.diahome.org/Membership DIA reserves the right to alter the venue, if necessary. If an event is

Discount Fees cancelled, DIA is not responsible for any airfare, hotel or other costs incurred by registrants. Government (Full-time) US $390 Charitable Nonproﬁ t/Academia (Full-time) US $650 Participants with Disabilities: DIA event facilities and overnight accommoda- TUTORIAL: SUNDAY, APRIL 11 9:00 AM-5:00 PM US $710 tions are accessible to persons with disabilities. Services will be made available to sensory-impaired persons attending the event if requested at least 15 days prior to event. Contact the DIA offi ce to indicate your needs.

PAYMENT OPTIONS: Register online at www.diahome.org or check payment method. Please check the applicable category: CREDIT CARD number may be faxed to: +1.215.442.6199. You may prefer to pay by check or Academia Government Industry CSO Student bank transfer since non-U.S. credit card payment will be subject to the currency conversion (Call for registration information) rate at the time of the charge.

Visa MC AMEX Exp Date______Last Name

Card # ______First Name M.I. Name (printed) ______

Degrees Dr. Mr. Ms. Signature ______

Job Title

CHECK drawn on a US bank payable to and mailed along with this form to: Drug Information Association Inc, P.O. Box 95000-1240, Philadelphia, PA 19195-1240, USA. Please include a copy Company of this registration form to facilitate identiﬁ cation of attendee.

BANK TRANSFER When DIA completes your registration, an email will be sent to the Address (As required for postal delivery to your location) Mail Stop address on the registration form with instructions on how to complete the Bank Transfer. Payment should be made in US dollars. Your name and com pany, as well as the Event I.D. # must be included on the transfer document to ensure payment to your account. City State Zip/Postal Country

email Required for conﬁ rmation

Phone Number Fax Number Required for conﬁ rmation