Food and Drug Administration Center for Drug Evaluation and Research

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Food and Drug Administration
Center for Drug Evaluation and Research
Summary Minutes of the Endocrinologic and Metabolic Drugs Advisory Committee
Meeting
December 12, 2013
Location: FDA White Oak Campus, Building 31, The Great Room (Rm. 1503), White Oak
Conference Center, 10903 New Hampshire Avenue, Silver Spring, Maryland
Issue: The committee discussed the efficacy and safety of new drug application (NDA)
202293, dapagliflozin tablet, submitted by Bristol-Myers Squibb. Dapagliflozin is a
sodium-glucose cotransporter 2 inhibitor developed as an adjunct to diet and
exercise to improve glycemic control in adults with type 2 diabetes mellitus.
These summary minutes for the December 12, 2013 Endocrinologic and Metabolic Drugs
Advisory Committee meeting were approved on January 17, 2014.
I certify that I attended the December 12, 2013 meeting of the Endocrinologic and Metabolic
Drugs Advisory Committee meeting and that these minutes accurately reflect what transpired.
___________/S/________________ ____________/S/______________
Karen Abraham-Burrell, PharmD Robert J. Smith, MD
Designated Federal Officer, AVDAC Acting Chairperson, EMDAC

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The Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) meeting of the Food and
Drug Administration (FDA), Center for Drug Evaluation and Research met on December 12, 2013,
at the FDA White Oak Campus, Building 31, The Great Room (Rm. 1503), White Oak Conference
Center, 10903 New Hampshire Avenue, Silver Spring, Maryland. Prior to the meeting, members
and temporary voting members were provided copies of the background materials from the FDA
and Bristol-Myers Squibb. The meeting was called to order by Robert J. Smith, MD (Acting
Chairperson); the conflict of interest statement was read into the record by Karen Abraham-Burrell,
PharmD (Designated Federal Officer). There were approximately 150 persons in attendance. There
were four Open Public Hearing speakers.
Issue: The committee discussed the efficacy and safety of new drug application (NDA) 202293,
dapagliflozin tablet, submitted by Bristol-Myers Squibb. Dapagliflozin is a sodium-glucose
cotransporter 2 inhibitor developed as an adjunct to diet and exercise to improve glycemic
control in adults with type 2 diabetes mellitus.
Attendance:
EMDAC Members Present (Voting): Erica H. Brittain, PhD; Diana Hallare, MPH (Consumer
Representative); William Hiatt, MD, FACP; Robert J. Smith, MD (Acting Chairperson)
EMDAC Members Not Present (Voting): Vera Bittner, MD, MSPH; David Cooke, MD;
Edward Gregg, PhD; Ed Hendricks, MD; Ellen Seely, MD; Charles Stanley, MD
EMDAC Member Present (Non-Voting): Mads F. Rasmussen, MD, PhD
Temporary Members (Voting): Barbara Berney; Antonio Tito Fojo, MD, PhD; Julia Lewis,
MD; Kevin McBryde, MD; Milton Packer, MD; Abraham Thomas, MD, MPH, FACP; Peter
Savage, MD; Miriam Vos, MD, MSPH; Peter Wilson, MD; Wyndham Wilson, MD
FDA Participants (Non-Voting): Curtis Rosebraugh, MD; Jean-Marc Guettier, MDCM; Frank
Pucino, PharmD, MPH; Eugenio Andraca-Carrera, PhD
Designated Federal Officer (Non-Voting): Karen Abraham-Burrell, PharmD

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Open Public Hearing Speakers: Sidney Wolfe, MD (statement read by Sammy Almashat, MD, MPH-
Public Citizen Health Research Group); Robert Ratner, MD, FACP, FACE (American Diabetes
Association); Bennet Dunlap (Diabetes Advocates); Diana Zuckerman, PhD (Cancer Prevention and
Treatment Fund)
The agenda proceeded as follows:
Call to Order and Introduction of
Committee
Robert J. Smith, MD
Acting Chairperson, EMDAC
Conflict of Interest Statement
Karen Abraham-Burrell, PharmD
Designated Federal Officer, EMDAC
FDA Introductory Remarks
Jean-Marc Guettier, MDCM
Acting Division Director
Division of Metabolism and Endocrinology
Products (DMEP)
Office of Drug Evaluation (ODE-II)
Office of New Drugs (OND), CDER, FDA
S
PONSOR
P
RESENTATIONS
Bristol-Myers Squibb
Introduction
Amy Jennings, PhD
Group Director, Cardiovascular/Metabolics
Global Regulatory & Safety Sciences - US
Bristol-Myers Squibb
Medical Need for New
Anti-Diabetic Treatments
Harold E. Bays MD, FTOS, FACE, FNLA
Medical Director/President
Louisville Metabolic and Atherosclerosis Research
Center Inc. (L-MARC Research Center)
Louisville, Kentucky
Dapagliflozin: Overview of Mode of
Action and Introduction to Development
Program
James List, MD, PhD
Vice President, Development Lead –Dapagliflozin
Bristol-Myers Squibb
Clinical Efficacy
Shamik Parikh, MD
Vice President, Global Medical Diabetes &
Metabolism
AstraZeneca

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Safety
James List, MD, PhD
Dean F. Bajorin, MD
Professor of Medicine
Weill Cornell Medical College
Attending Physician
Genitourinary Oncology Service
Division of Solid Tumor Oncology
Memorial Sloan-Kettering Cancer Center
New York, New York
Clinical Perspective
John Wilding, DM, FRCP
Professor of Medicine & Honorary Consultant
Physician
Head of Department of Obesity and Endocrinology
Institute of Ageing & Chronic Disease
Clinical Sciences Centre
University Hospital Aintree
Liverpool, United Kingdom
Dapagliflozin Post-Approval
James List, MD, PhD
Clarifying Questions
B
REAK
FDA
P
RESENTATIONS
Statistical Assessment of Cardiovascular
Safety
Eugenio Andraca-Carrera, PhD
Mathematical Statistician
Division of Biometrics VII
Office of Biostatistics
Office of Translational Sciences, CDER, FDA
Clinical Efficacy and Noncardiovascular
Safety
Frank Pucino, PharmD, MPH
Clinical Reviewer
DMEP, ODE-II, OND, CDER, FDA
Clarifying Questions
L
UNCH
Open Public Hearing
Questions to the Committee/Committee Discussion

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B
REAK
Questions to the Committee/Committee Discussion (cont.)
ADJOURNMENT
Questions to the Committee:
Cardiovascular Risk Evaluation:
1) DISCUSSION: Based on the information provided in the briefing package and the
presentations at today’s meeting, please address the following with regard to the
cardiovascular risk assessment for dapagliflozin.
a. Comment on which data (i.e., overall population, enriched population) best inform the
cardiovascular risk associated with dapagliflozin use and discuss the weight you place on
the evidence provided by the subgroup of patients specifically recruited on the basis of
established cardiovascular disease in Trials 18 and 19.
b. Discuss whether you believe the updated cardiovascular risk data derived from Trials 18
and 19 are consistent with the overall findings reported for the pool of 21 clinical trials.
c. Discuss the clinical importance you place on the observed changes in blood pressure,
weight, glycemic control and lipid parameters in informing overall cardiovascular risk of
dapagliflozin.
d. Discuss additional concerns, if any, you may have with regard to dapagliflozin and
cardiovascular risk.
Committee Discussion: Some committee members commented that there was not a
convincing signal for increased cardiovascular events with the use of dapagliflozin. The
committee also commented that the conclusions of the studies do not fundamentally change
as different individual studies, in particular studies 18 and 19 versus the overall pool of
studies, are considered. With regard to the future trials, the committee agreed that data from
short-term trials are less informative than data from long-term trials and consideration
should be given to longer trials.
The committee also made the following comments related to the overall trials presented:
• There was a concern related to the overall role of censoring
• There was a lack of diversity in the studies with regards to Blacks and Hispanics
• Changes in blood pressure, weight, glycemic control and lipid parameters were
modest
Please see the transcript for details of the committee discussion.