Food and Drug Administration Center for Drug Evaluation and Research

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/________________
Karen Abraham-Burrell, PharmD
Designated Federal Officer, AVDAC
____________/S/______________
Robert J. Smith, MD
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, MPHPublic 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
SPONSOR PRESENTATIONS
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
BREAK
FDA PRESENTATIONS
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
LUNCH
Open Public Hearing
Questions to the Committee/Committee Discussion
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BREAK
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.
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Malignancy:
2) DISCUSSION: Based on the information provided in the briefing package and the
presentations at today’s meeting, discuss your level of concern with regard to the observed
association between dapagliflozin use and occurrence of cancer identified in the application.
Specifically, comment on whether you believe use of dapagliflozin is associated with an
increased risk of bladder cancer and explain your rationale.
Committee Discussion: The committee commented that, based on the data for dapagliflozin
use, the overall risk of any cancer had a relative risk of one (1) and that was reassuring that
dapagliflozin is not associated with an increased overall risk of cancer. In regards to
bladder cancer, the committee noted that there were ten cases of bladder cancer in the
various dapagliflozin studies presented and that the data represents a potential risk, but not
a convincing risk due to the small number of events. The committee members further noted
that five of the ten cases of bladder cancer occurred in the first six months of treatment with
dapagliflozin and this is a much shorter time than would be anticipated if tumorogenesis
were to occur due to use of this drug. In addition, it was noted that eight of the ten cases
were noninvasive; if dapagliflozin were a tumor promoter one would expect to see more
invasive cancers.
There was a consensus among the committee that the data presented do not warrant a
requirement for further studies on bladder cancer risk prior to approval; however, postmarketing studies are recommended.
Regarding breast cancer risk with the use of dapagliflozin; the committee agreed that an
evaluation of studies for breast cancer risk should be conducted in the post-marketing phase.
Please see the transcript for details of the committee discussion.
Liver Toxicity:
3) DISCUSSION: Based on the information provided in the briefing package and the
presentations at today’s meeting, discuss your level of concern with regard to dapagliflozin
use and drug-induced liver injury. Specifically comment on whether you believe use of
dapagliflozin is associated with an increased risk of drug-induced liver injury and explain
your rationale.
Committee Discussion: Overall, the committee did not have substantial concerns about liver
disease occurring with dapagliflozin use as the data presented did not appear to provide a
significant risk signal for liver disease. However, the committee recommended monitoring
for liver disease post-marketing. Please see the transcript for details of the committee
discussion.
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4) VOTE: In accordance with FDA’s Guidance for Industry titled “Diabetes Mellitus –
Evaluating Cardiovascular Risk in New Anti-diabetic Therapies to Treat Type 2 Diabetes”,
has the Applicant provided sufficient evidence that dapagliflozin, relative to comparators, has
an acceptable cardiovascular risk profile?
a. If you voted “Yes” to question #4, please provide your rationale.
b. If you voted “No” to question #4, please provide your rationale.
Vote:
Yes= 10
No =
4
Abstain = 0
Committee Discussion: The majority of the committee members agreed that the Applicant
provided sufficient evidence that dapagliflozin, relative to comparators, has an acceptable
cardiovascular risk profile. The committee members who voted “No” indicated that some of
the results from the subgroups raised concerns, and several noted that the data was not
sufficient. Please see the transcript for details of the committee discussion.
5) VOTE: Based on the information included in the briefing materials and presentations today,
do the benefits of dapagliflozin use outweigh identified risks and support marketing of
dapagliflozin as an adjunct to diet and exercise to improve glycemic control in adults with
type 2 diabetes mellitus?
a. If you voted “Yes” to question #5, please provide your rationale and whether you
recommend any additional studies post-approval.
b. If you voted “No” to question #5, please provide your rationale and discuss what
additional data are necessary to support approval.
Vote:
Yes= 13
No =
1
Abstain = 0
Committee Discussion: The majority of the committee members agreed that the benefits of
dapagliflozin use outweigh identified risks and support marketing of dapagliflozin as an
adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
mellitus. Some of the committee members who voted “Yes” commented that the cancer risk
does not rise to the level of non-approval. On the other hand, the committee member who
voted “No” commented that dapagliflozin does appear to increase the risk of cancer,
infections and cardiovascular events.
There was a consensus that post-marketing studies should be conducted and the committee
members made the following suggestions for long-term considerations:
• Monitor kidney function and drug-induced liver injury via post-marketing studies
• Monitor occurrence of bladder cancer via post-marketing studies
• Conduct follow-up studies to determine whether a lower dose might be appropriate in the
elderly
• Review the DECLARE study once it is complete
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•
Conduct studies that provide information on dapagliflozin use and diabetic neuropathy
with proteinuria
• Perform longer follow-up studies to evaluate breast cancer risk
Please see the transcript for details of the committee discussion.
The meeting was adjourned at approximately 4:47 p.m.
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