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Executive Summary

DuPont Critical Care's short-acting beta blocker Brevibloc (esmolol) should be approved for prophylactic treatment in an as yet undefined group of high risk perioperative patients, FDA's Cardio-Renal Drugs Advisory Committee recommended by a four-to-three vote on Sept. 29. Speaking for the majority, Committee Chairman Jeffrey Borer, MD, Cornell Medical Center, stated: "The company has defined a way of giving the drug that appears to me to be safe and achieve the endpoint and effect that I want to achieve. . . . Therefore, I believe that they have sufficient data to approve the drug in very well-circumscribed subgroups of patients." The committee unanimously concurred that in order to support a general prophylactic claim for perioperative uses, DuPont Critical Care should submit study data supporting the anti-ischemic effect of I.V. esmolol in patients at lower risk. The committee also recommended that DuPont develop data supporting a therapeutic claim. The NDA had originally been submitted by American Critical Care, which was acquired by DuPont in September ("The Pink Sheet" Aug. 11, p. 13). The panel's vote in support of an approval recommendation reversed an earlier vote during the meeting in support of requiring objective data from DuPont that demonstrated Brevibloc's anti-ischemic activity. The committee considered whether the company had to submit large mortality/morbidity surgical outcome trial data for approval of the prophylactic claim or just demonstrate anti-ischemic activity in perioperataive situations. The panel also discussed whether the drug's proven beta adrenergic blocking trait was enough evidence to support a panel recommendation that the drug was anti-ischemic. However, because ethical considerations would not allow studies in high risk groups that might benefit from the drug, four panel members supported approval of the drug for prophylaxis in those patients with a "definable and unacceptably high risk under operation." Panel suggestions of subgroups where esmolol pre-treatment might be appropriate included patients undergoing surgery with left ventricular lesions, Class III and Class IV heart patients undergoing coronary bypass surgery, and neural aneurism patients undergoing surgery. Borer suggested that DuPont Critical Care should submit to FDA a proposal on those "specific subgroups for whom we could accept that esmolol is approvable without additional evidence." Reflecting a fundamental disagreement with the panel majority view, FDA Cardio-Renal Drug Division Director Raymond Lipicky, MD, suggested that the company send its proposal to the committee, instead -- indicating that Brevibloc will likely reappear at a future advisory committee meeting. "There is data here that says the drug is a beta blocker and that a dosing regimen has been worked out that allows it to manifest its action as a beta blocker and the rest of the data that is required to build a logical, coherent story is absent, except for general knowledge and a discipline's clinical practice," Lipicky stated. "The question is -- do we want to go beyond the data that exists?" DuPont Critical Care Pharmaceutical Research Director W. L. Matier, PhD, noted in his presentation that esmolol is "very similar" chemically to metoprolol (Ciba-Geigy's Lopressor) except for an ester group that gives the drug its fast-acting characteristic. Matier reported that the drug has a distribution half-life of two minutes and an elimination half-life of nine minutes. DuPont Critical Care also discussed two pivotal double blind studies -- a placebo comparison study in 84 coronary artery bypass surgery (CABG) patients from six centers; and a seven center placebo control study in 74 patients undergoing surgery with serious heart problems (ASA Class III or IV). The primary endpoints in both studies were reduction in heart rate and blood pressure -- and whether a fast acting I.V. nitrate or beta blocker was required to stabilize the patient. In the CABG study, only 14% of the 43 esmolol patients required nitroprusside to control hypertension versus 32% of the placebo group; 15% of the placebo heart rate required treatment for tachycardia while only one patient in the treatment group needed more beta blocker; and (3) only 3% of the esmolol group developed heart rate over 100, while 21% of the placebo group went over 100. "The data that has been presented indicated that this drug is an effective beta blocker. In fact, it prevents a heart rate rise and to some extent it prevents a rise in systolic blood pressure that is caused by known stimulus," Borer said in explaining his position in support of approval. "I believe there are sufficient reasons, because of my understanding of cardiac physiology and pathophysiology and my extrapolation of what happens in other clinical situations, that there is a group of patients going to operation in whom [blocking heart rate and blood pressure response] can be a beneficial thing to do." Therefore, Borer stated, "I believe it is reasonable for this drug to be made available for that purpose in certain very well circumscribed groups of patients, and I'm not suggesting that it should be given to all of them." To determine prophylactic effectiveness the committee shied away from surgery outcome studies because of difficulties in design and their prohibitive expense. The committee did agree that FDA should require some objective evidence of ischemia reduction. However, except for one suggestion on holter monitoring in 200 surgical patients, the panel did not provide advice on the appropriate methods for such a study. On the subject of a treatment indication for perioperative patients, the committee recommended that DuPont present data about a "defined administration regimen that will affect the heart rate and blood pressure significantly as therapy after induction." Borer suggested that such a regimen that "could be written into a label so that people would know how to give it . . . would be the basis for approval of the drug." While the committee had not yet seen such data, Borer continued, "Those data undoubtably exist and could be submitted to the FDA for review." On Brevibloc use in treating supraventricular tachycardias, the panel recommended: (1) that the claim be limited to ventricular fibrillation and flutter, based on the data submitted; and (2) that the company submit existing data on anti-arrhythmic drug crossover results because of the likely use of Brevibloc as a short term stabilizing therapy. Following the company presentations, four outside consultants for FDA, all anesthesiologists, were in agreement in recommending the drug be approved for the prophylaxis indication in perioperative situations. Robert Merin, MD, University of Texas Medical School at Houston, highlighted esmolol's "titratable" characteristic. "This drug is the most uniquely titratable beta adrenergic blocker that has been presented to us thus far in a surgical situation," Merin told the committee. "In my opinion, this drug is very useful to us for a number of indictions." Merin added that it was his opinion that the benefits of beta blockade for myocardial ischemia were "unquestionable" and that efficacy studies looking at surgical outcome were "practically impossible in the settings that we're talking about."

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