Summary Minutes of the
Cardiovascular and Renal Drugs Advisory Committee
July 29, 2010
Location: The Marriott Inn and Conference Center,
University of Maryland University College,
3501 University Blvd. East, Adelphi, MD.
All external requests for the meeting transcripts should be submitted to the CDER, Freedom of
These summary minutes for the July 29, 2010 Meeting of the Cardiovascular and Renal Drugs
Advisory Committee of the Food and Drug Administration were approved on August 26, 2010.
I certify that I attended the July 29, 2010 meeting of the Cardiovascular and Renal Drugs Advisory
Committee of the Food and Drug Administration and that these minutes accurately reflect what
Elaine Ferguson Sanjay Kaul, M.D.
Designated Federal Official Acting Committee Chair
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Meeting of the Cardiovascular and Renal Drugs Advisory Committee
July 29, 2010
The Cardiovascular and Renal Drugs Advisory Committee of the Food and Drug Administration, Center for Drug
Evaluation and Research met on July 29, 2010 at The Marriott Inn and Conference Center, University of Maryland
University College, 3501 University Blvd. East, Adelphi, MD. Prior to the meeting, members and invited consultants
were provided copies of the background material from the FDA and the sponsor. The meeting was called to order by
Sanjay Kaul, M.D. (Acting Committee Chair); the conflict of interest statement was read into the record by Elaine
Ferguson (Designated Federal Official). There were approximately 100 persons in attendance. There were 2 speakers
for the Open Public Hearing session.
Issue: The committee discussed Revatio (sildenafil) for the treatment of pediatric pulmonary arterial hypertension
(PAH) and whether to amend the clinical trials section of the written request, issued by FDA to Pfizer, to include
assessment of a hemodynamic endpoint. An area of particular interest was what the appropriate study endpoint should
be in patients with PAH unable to perform exercise testing. The discussion was to help the agency determine what
studies to request for products intended to treat pediatric PAH.
Cardiovascular and Renal Drug Advisory Committee Members Present (Voting):
Sanjay Kaul, M.D. (Acting Committee Chair), James Neaton, Ph.D., Mori Krantz, M.D., Jonathan L. Halperin, M.D.,
Henry Black, M.D., Darren K. McGuire, M.D., M.H.Sc.
Special Government Employee Consultants (Voting):
Allan Coukell, BscPharm. (Acting Consumer Representative), Ralph D’Agostino, Ph.D., Steven Kawut, M.D., M.S.,
John Newman, M.D., Stuart Rich, M.D., Geoffrey Rosenthal, M.D., Ph.D., Jürgen Venitz, M.D., Ph.D.
Industry Representative (Non-Voting):
Enrico Veltri, M.D. (acting)
FDA Participants (Non-Voting):
Norman Stockbridge, M.D., Robert Temple, M.D.
Designated Federal Official:
Open Public Hearing Speakers:
Simon Anthony Beardsworth M.D., Eli Lilly & Company
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The agenda was as follows:
Call to Order Sanjay Kaul M.D.
Introduction of Committee Acting Chair, CRDAC
Conflict of Interest Statement Elaine Ferguson
Designated Federal Official, CRDAC
Opening Remarks Norman Stockbridge, M.D., Ph.D. Director,
Division of Cardiovascular and Renal
FDA presentations Elizabeth Durmowicz, M.D.
Pediatric Drug Development and the Best Medical Officer
Pharmaceuticals for Children Act Pediatric and Maternal Health Staff, Office
of New Drugs, CDER
Sildenafil Written Request Norman Stockbridge, M.D., Ph.D.
Questions from the Committee
Sponsor presentation Robyn Barst, M.D.
"Clinical Perspective on Pulmonary Arterial Emeritus of Pediatrics (in Medicine) at the
Hypertension (PAH) in Children and Adults" College of Physicians and Surgeons at
Questions from the Committee
FDA presentation Satjit Brar, Pharm.D., Ph.D.
"Use of Change in PVRI for Dosing Recommendations of Adult- Division of Pharmacometrics
Approved Drugs in Pediatric PAH Patients" Office of Clinical Pharmacology
Questions from the Committee
Sponsor presentations Nancy McKay
"Introduction and Regulatory History" Director
Worldwide Regulatory Strategy
"The Sildenafil Adult and Pediatric Pulmonary Arterial Colin Ewen, Ph.D.
Hypertension (PAH) Development Program" Executive Director
Speciality Care Business Unit
Sponsor presentation Lutz Harnisch, M.D.
"Integration of Adult and Pediatric Sildenafil Data" Senior Director
Clinical Pharmacology, Pharmacometrics
Sponsor presentation Colin Ewen, Ph.D.
Pfizer Wrap-up Pfizer
Questions from the Committee
Open public hearing
Committee Discussion and Questions to the Committee
Questions to the Committee
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Questions to the committee: Please see the transcript for detailed discussions.
1. Does the FDA analysis show PVRI to be a reliable predictor of effects of vasodilator therapy on exercise
capacity in adults with PAH?
The Committee Members agreed that there seems to be a relationship between PVRI and exercise capacity in
adults with PAH; however, many questioned the extent and conditions under which it is reliable.
2. If a drug has been documented to improve exercise in adults with PAH, can PVRI be used to extend that
indication to another subpopulation of adults?
Overall the committee was not in favor of using PVRI to extend the indication (improved exercise in adults) to
another subpopulation of adults, stating that there are disparities in the type, etiology, pathogenesis and
pathophysiology of PAH in adults.
3. Is PAH in children sufficiently similar to the disease in adults to allow PVRI to be used to bridge the adult
indication to children? In particular, please comment on whether there are important differences between
adults and children with PAH with respect to …
3.1. … etiology of disease.
3.2. … symptoms of PAH. Similar
3.3. … clinical course of PAH. Less consistence
3.4. … hemodynamic effects of PAH. Very similar
Although the etiologies of PAH are different in children than adults, and the clinical course has some
inconsistencies, the committee agreed that they were similar enough, with the caveat of subgroups.
4. Please comment on the following aspects of studying hemodynamics in young children:
4.1. Is it technically feasible?
4.2. Do the risks of collection of hemodynamic data in children raise ethical concerns?
The committee members agreed that it is technically feasible. Most of the members did not feel that the risk of
collecting hemodynamic data in children raised ethical issues. Some members expressed that in children with
PAH the benefits could outweigh the risk.
5. VOTE: Does the Committee agree that, for a product with an approved indication in adults with PAH, a
treatment effect on PVRI can be used to demonstrate effectiveness and to derive dosing information in the
pediatric PAH population?
The committee voted: Yes 7, No 6 and Abstain 0
5.1. If you voted no, …
5.1.1. … what end point would be suitable for extending a claim to children?
Suggestions from the committee members included looking at: (1) concordance of 6 minute walk
data with peak oxygen consumption (VO2peak), (2) time to clinical worsening, and 3) a
combination of right atrial pressure and PVRI to determine a more suitable endpoint. In addition,
it was suggested that effort should be given to developing a physical performance measure for
children. One member suggested that there may be a class effect, and that one endpoint may not
be suitable for all agents.
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5.1.2. … what further validation would one need for PVRI?
The committee members agreed that more work is needed to validate the proposed hemodynamic
endpoint using the data available in adults. It was suggested that the available data be used to
determine if the result of a study could be predicted. Others stated that the validation model
under development is the right one to use, but that the information provided to the committee was
incomplete and needs more complete characterization.
5.2. If you voted yes, …
5.2.1. … would one need one study or two?
Committee Members agreed that one study would be sufficient.
5.2.2. … response to a single dose or after some weeks of treatment?
Committee members agreed that the evaluation should encompass some weeks of treatment (4 –
16 weeks), depending on the particular drug and experience with a particular class of drugs.
5.2.3. … assessment of PVRI at peak or trough?
The committee agreed upon assessment of PVRI at a trough drug level.
5.2.4. … would one also need exercise as a secondary end point in older children able to
perform the test?
Yes, the committee agreed.
5.2.5. … does the PVRI-exercise relationship for the adult data offer a way to set the size of the
required study? In particular, if one wanted to resolve an effect corresponding to a 10%
exercise improvement in adults, can one define the corresponding change in PVRI?
The committee members agreed that the data collected in adults could be used to set the size of
the required study.
The Committee is now asked to consider the application of PVRI in the pediatric development program for
6. What are the implications of the unsuccessful study targeting exercise?
6.1. Are the exercise data supportive of use in children?
6.2. What are the implications of a new statistical analysis plan at this point? In particular, …
6.2.1. … how do you view changing end points at this stage? Does it matter that the changes are
proposed by FDA and are based on data external to the sildenafil pediatric program?
6.2.2. … given that there are numerous ways in which the new end point might be analyzed,
how would one handle the establishment of a new specific statistical analysis plan?
6.2.3. … how should one handle missing data for PVRI?
The committee was not ready to respond to these questions given the suggestions for further analysis and
characterization of the data presented by the FDA and the need for the FDA to consider the totality of data,
including the results (not yet reviewed by the FDA) of the Sponsor’s study.
7. VOTE: Should the sildenafil Written Request be amended to utilize available data on hemodynamics in
It was determined that following the outcome of question 6, the committee should not vote on question 7.
Please see the transcript for detailed discussion.
The session adjourned @ approximately 4:00 p.m.
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