Food and Drug Administration
Center for Drug Evaluation and Research
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.
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):
Industry Representative (non-voting):
John Neylan, MD
Robert Temple, MD
Norman Stockbridge, MD
Cathy A. Groupe, RN, BSN
summary minutes for the
certify that I attended the
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.
Cardiovascular and Renal Drugs Advisory Committee
Welcome and Comments Norman Stockbridge, M.D., Acting Director
Division of Cardiovascular and Renal Drug Products
Regulatory Overview Cindy Lancaster, M.S., M.B.A, J.D.
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.
Benefit/Risk Summary James B. Young, M.D.
Discussion Marc A. Pfeffer, M.D., Ph.D.
Brigham and Women’s Hospital Boston
Questions from the Committee
Open Public Hearing
Committee Discussion and Questions
Committee Discussion and Questions (continued)
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
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