Food and Drug Administration
Center for Drug Evaluation
and Research
Advisory Committee
Conference Room, Rm. 1066,
Summary
Minutes of the Cardiovascular and Renal Drugs Advisory Committee Meeting
The committee discussed
supplemental applications (sNDAs) S-022, S-024 and S-025 to approved new drug
application (NDA) 20-838, ATACAND® (candesartan cilexetil) Tablets (4 mg, 8 mg,
16 mg and 32 mg), AstraZeneca, for the use in the treatment of patients with
congestive heart failure.
Attendance:
Cardiovascular and Renal Drugs Advisory Committee
Members Present (voting):
Steven Nissen, MD (Committee Chair)
Blasé Carabello, MD
Susanna Cunningham, PhD
William Hiatt, MD
Frederick Kaskel MD, PhD
Thomas Pickering, MD, DPhil
Ronald Portman, MD
John Teerlink, MD
Cardio-Renal Advisory Committee Members Absent:
Beverly Lorell, MD
David Demets, PhD
Lynn Warner Stevenson, MD
Cardiovascular and
Renal Drugs Advisory Committee Consultants (voting):
Jonathan Sackner-Bernstein, MD
Ralph D’Agostino, PhD
Patient
Representative (voting):
None Present
Industry Representative (non-voting):
John Neylan, MD
FDA Participants:
Robert Temple, MD
Norman Stockbridge, MD
Executive Secretary:
Cathy A. Groupe, RN, BSN
These
summary minutes for the
I
certify that I attended the
_________//S//___________________ ______//S//______________________
Cathy
A. Groupe, R.N., B.S.N. Steven
E. Nissen, M.D.
Executive
Secretary Chair
Open Public Hearing Speakers:
There were no registered speakers
for the open public hearing.
Prior to the meeting, the members and the invited consultants had been provided the background material from the FDA and from the sponsors. The meeting was called to order by Steven Nissen, M.D. (Committee chair); the conflict of interest statement was read into the record by Cathy Groupe, RN, BSN (Executive Secretary). There were approximately 65 persons in attendance. There were no speakers for the Open Public Hearing sessions.
Issue: The committee discussed
supplemental new drug applications (sNDAs) S-022, S-024, S-025 to approved new
drug application (NDA) 20-838, ATACAND® (candesartan cilexetil) Tablets (4 mg,
8 mg, 16 mg, and 32 mg), AstraZeneca LP, for the use in the treatment of patients
with congestive heart failure.
The agenda was as follows:
Call to Order and Introductions Steven E. Nissen, M.D. (Chair)
Conflict of Interest Statement LT Cathy Groupe, B.S.N.
Executive Secretary
Cardiovascular and Renal Drugs Advisory Committee
Welcome and Comments Norman Stockbridge, M.D., Acting Director
Division of Cardiovascular and Renal Drug Products
Sponsor Presentation
Regulatory Overview Cindy Lancaster, M.S., M.B.A, J.D.
AstraZeneca LP
Sponsor Presentation (continued)
Background and Rationale James B. Young, M.D.
John J.V. McMurray, M.D.
Efficacy Mark A. Pfeffer, M.D., Ph.D
Brigham and Women’s Hospital Boston
Safety James Hainer, M.D., M.P.H.
AstraZeneca LP
Benefit/Risk Summary James B. Young, M.D.
Discussion Marc A. Pfeffer, M.D., Ph.D.
Brigham and Women’s Hospital Boston
Break
Questions from the Committee
Lunch
Open Public Hearing
Agenda (continued):
Committee Discussion and Questions
Break
Committee Discussion and Questions (continued)
Adjournment
Questions to the Committee:
The Cardiovascular and Renal
Drugs Advisory Committee is asked to opine on the candesartan development
program in heart failure, a series of three studies enrolling a total of 7601
subjects.
The Division expects to
approve use of candesartan in patients with heart failure who are not, for
whatever reason, taking an ACE inhibitor. CHARM-Alternative shows candesartan
is effective in patients intolerant of ACE inhibitors and, at least,
CHARM-Added is supportive of this use. The question for the Advisory Committee
is whether CHARM-Added provides compelling evidence that candesartan should,
under some circumstances, be recommended for use in patients on an ACE
inhibitor.
The questions address three
possible bases for approval. Once there is general agreement on a possible
basis for approval, the Committee is invited to skip directly to question 7 and
address the strength of evidence for this claim.
1.
When two drugs
are presumed to operate by sufficiently distinct mechanisms, one generally does
not worry whether therapy with the older one has been optimized before testing
the addition of the newer one.
1.1.
Should one, in
fact, test a new drug against optimized background therapy?
1.2.
What are the
implications if such optimization is not done?
1.3.
Did CHARM-Added
have adequate optimization of background therapy with respect to …
1.3.1.
…ACE inhibitor
use?
1.3.2.
…other treatments
for heart failure?
1.3.3.
Are ACE
inhibitors and ARBs sufficiently different that CHARM-Added can support use of candesartan with ACE inhibitors? What
clinical data support your view?
Committee Vote on Question 1.4: Yes: 0 No:
10
If you conclude that ACE
inhibitors and ARBs are sufficiently different, skip to question 7. If
the mechanisms overlap, then optimization of ACE inhibitors matters more.
2.
The protocol for
CHARM-Added required subjects to be on an ACE inhibitor and the possible
choices were not limited to ones with established claims for heart failure. In
designing a trial for an add-on claim, …
2.1.
… should the ACE
inhibitors all be ones with an established claim in heart failure?
2.2.
… how does one
pick the target regimen for the ACE inhibitors?
3.
The CHARM-Added
protocol recommended that subjects be treated on “individualized optimum” doses
of ACE inhibitor, based on tolerability and “recommended target doses”.
3.1.
What is known
about the relationship between dose of ACE inhibitor and clinical benefits and
risks in heart failure?
3.2.
Were the choices
of ACE inhibitor in CHARM-Added reasonable?
3.3.
Were the target
regimens in CHARM-Added reasonable?
3.4.
What features of
the CHARM-Added ensured ACE inhibitor optimization?
3.5.
Was optimized
usage of ACE inhibitors realized? How do you know?
3.6.
Many subjects in
CHARM-Added were never on the target dose of ACE inhibitor. Does one know why?
3.7.
The protocol
permitted investigators to lower the dose of other antihypertensive drugs, including ACE inhibitor, in order to
achieve the target dose of candesartan.
3.7.1.
Was this a
potential problem?
3.7.2.
Was it an actual
problem?
4.
A second possible
claim would be that candesartan has effects one could not achieve with ACE
inhibitors, regardless of dose. What evidence does CHARM-Added provide that
candesartan has benefits in patients with full ACE inhibition?
4.1.
In analyses of
CHARM-Added that factored in ACE inhibitor dose, does it matter that subjects
were not randomized to ACE inhibitor dose?
4.2.
Compared with
full ACE inhibition, what loss of effect with candesartan has been excluded by
these analyses?
4.3.
Do the results of
CHARM-Added support a claim that candesartan has clinical benefits unachievable
with ACE inhibitors?
Committee Vote on Question 4.3: Yes: 0 No: 10
If CHARM-Added supports use
of candesartan by virtue of effects unachievable with an ACE inhibitor, skip to
question 7.
5.
A third possible
claim might result if one could not achieve a full effect on a system by one
drug, perhaps because of system-independent tolerance problems, but one could
achieve a larger effect with the addition of a second agent.
5.1.
Does one need to
establish that the original, poorly tolerated therapy is still needed in such a
trial?
5.2.
What would be
required to obtain such a claim?
5.3.
Does CHARM-Added have
these design features?
5.4.
Do the results of
CHARM-Added support a claim that candesartan should be used in patients unable
to take a full dose of ACE inhibitor?
Committee Discussion:
Although Question 5.4 was originally designated a ‘vote question’, the Division was satisfied,
after extensive discussion, that no vote was necessary based on comments
surrounding the fact that the trial design did not include a protocol
requirement to maximize the ACE inhibitor before starting candesartan therapy
for heart failure.
The committee considered trial design features
required, when adding a second agent due to the patient’s system-independent
tolerance problem. Again, discussion surrounded the lack of sufficient data to
answer this question as stated. There was general agreement amongst the
committee that for future clinical trials, it is important to establish that
the original therapy is needed prior to the addition of a second therapy. Most
committee members agreed that the CHARM-Added trial did not validate the need
for the original therapy nor did the trial address whether candasartan should
be used in patients unable to take a full dose of ACE inhibitor. The members discussed
various possibilities for this chosen design and offered suggestions to address
these issues with additional trials. That being said, the committee concluded
that at the doses of ACE inhibition reached, it was evident that the addition
of candasartan treatment appeared to reduce the risk of cardiovascular
mortality and congestive heart failure hospitalizations enough to support some
claim. (See transcripts for detailed
discussion)
If CHARM-Added supports a
claim for candesartan in patients on some dose of ACE inhibitor, skip to
question 7.
6.
Is there another
possible claim resulting from CHARM-Added?
7.
If you have
identified a possible pathway to approve candesartan based on questions 1, 4,
5, or 6, comment on the available strength of evidence.
7.1.
What are one’s
prior expectations based on mechanism of action?
7.2.
Are there
supportive findings in CHARM-Added? Are these findings covered by the statistical
analysis plan?
7.3.
Are there other
data on the use of candesartan added to ACE inhibitors in the treatment of
heart failure? If so, are these data supportive?
7.4.
Is it appropriate
to consider studies of other angiotensin receptor antagonists in this or some
related setting? If so, …
7.4.1.
… what are these
studies?
7.4.2.
… are these data
supportive?
8. Should candesartan be approved for use with an ACE inhibitor in the treatment of heart failure?
Committee Vote on Question 8: Yes: 10 No: 0