Any potential changes to Pfizer's antihypertensive therapy Cardura (doxazosin) labeling should await additional data from NIH's ALLHAT study, FDA's Cardiovascular & Renal Drugs Advisory Committee said May 24.

"The sense of the committee is that you need some additional data before it's appropriate to provide information to doctors," Acting Committee Chair Jeffrey Borer, MD, Cornell University, told FDA. "That information should be available within the foreseeable future, not years, but months."

The committee met to consider whether labeling changes should be made to reflect preliminary data from the ALLHAT trial that suggest Cardura patients were twice as likely to be hospitalized for congestive heart failure as the control group. The risk of CHF in the doxazosin group was 8.1% compared to 4.5% in the chlorthalidone group.

If additional data continue to "show the strong suggestion of something that's not being done by one drug that is being done by the other, the doctors probably ought to know about [it]," Borer said.

He added that the committee would be willing to provide additional comments to FDA in the future when more data are available.

Labeling changes to increase physician awareness of the ALLHAT data were among the requests in a Jan. 9 citizen petition filed by the New York City law firm Milberg, Weiss, Bershad, Bynes & Lerach, which is representing plaintiffs in a class action consumer fraud suit against Pfizer (¹ Also see "Cardura Advisory Cmte. To Discuss Limiting Hypertension Use To Second-Line" - Pink Sheet, 9 April, 2001.).

Several committee members expressed the difficulty in reaching any definitive conclusions based only on publication of interim data from the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial conducted by NIH's National Heart, Lung & Blood Institute.

"It's not just that we don't have all the results of the trial. It's that we have missing data from the interim analysis that resulted in this ending of the trial: things that I would consider to be very basic like what the mean doses were...what were the kinds of heart failure events [and] what was the distribution of kinds of heart failure events, "committee member Steven Nissen, MD, Ohio State University, said.

"It's really hard because not only do we not know about the other arms of the trial, we don't know very much about this arm of the trial at this point. We have one relatively express-type publication and that's all we have," Nissen continued.

Preliminary results of the ALLHAT trial were published in the April 4, 2000 issue of the Journal of the American Medical Association.

NHLBI's Clinical Application & Prevention Program Director Jeffrey Cutler, MD, noted that further analysis of ALLHAT data will be available in the near future in an upcoming publication.

ALLHAT is a practice-based, randomized, multi-center cardiovascular outcomes trial that is comparing the diuretic chlorthalidone (active control), the calcium channel-blocker amlodipine, the alpha-blocker doxazosin and the ACE-inhibitor lisinopril. The trial is expected to end in 2002.

NHBLI halted the doxazosin arm of the study on Jan. 24, 2000 based on a very low probability of doxazosin demonstrating superior efficacy for the primary coronary heart disease endpoints compared to chlorthalidone at trial-end, and a higher rate of CHF for the doxazosin arm compared to chlorthalidone.

FDA Cardio-Renal Drug Products Division Director Raymond Lipicky, MD, noted that this was the first time the committee was asked to review a product without the benefit of an FDA review of the data. FDA did not review ALLHAT data on Cardura since it was such an unusual case.

"We've been asked to make a decision from published materials. You have all the information we have....We have not reviewed the subject because it's not the usual stuff that we have to review," Lipicky told the committee.

"What we want is an evaluation of the data that is available and whether or not you can draw conclusions...in order to take some action. As you know we're so evidence-oriented and we don't like to take actions when we don't know what action we should take nor what the basis for that action is," Lipicky said.

In Pfizer's response to the ALLHAT data, the company told the advisory committee that the increased incidence of congestive heart failure attributed to Cardura in ALLHAT is likely due to the decreased risk of CHF in patients taking chlorthalidone.

Pfizer said that although its 271 clinical trials were not designed to examine the cardiovascular endpoints of CHF, myocardial infarction or stroke, the company reviewed its database to determine whether there were data that supported the ALLHAT findings.

"Review of the data from these 271 studies combined indicated a very low incidence (( .11%) of each of the selected cardiovascular events (CHF, MI and stroke)," the company concluded.

"Because the active control in ALLHAT is a diuretic that is a recognized effective treatment for CHF, it is possible that the emergence of CHF during the conduct of the study is masked in the chlorthalidone group, thereby increasing the observed difference in incidence between the groups," Pfizer said.

"One would expect a significant number of the ALLHAT patients, who were elderly and high-risk hypertensives, to develop CHF during the course of the study." Since chlorthalidone is used as a treatment for CHF, patients in the chlorthalidone arm would be expected to have a lower rate of CHF, Pfizer said.

Pfizer contended that the ALLHAT results could have also been affected by the study's use of an off-label dosing regimen.

"It is important to note that doxazosin was not used in ALLHAT according to labeled recommendations. Patients were titrated more slowly, with dosage increases at monthly intervals rather than the two week intervals recommended in the labeling. In addition, the maximum dose used in the study was 8 mg, rather than the recommended maximum of 16 mg," Pfizer said.

Lawrence Krakoff, MD, Englewood Hospital, observed during the open public hearing that Cardura, in practice, is dosed differently. "My impression is that there are very few physicians who use anything above 4 mg of Cardura before they add or change."

"The 8 mg even then is not somewhat unusual for treating hypertension and many physicians are looking at charts and just figure that if you didn't get much of a response by the time you get to 4 mg to 8 mg once a day, you were going to add or switch," Krakoff said.

"You may see information that is so compelling that you'll choose to say something without demanding to analyze the primary data. You may, however, find the data less compelling and then we'd be happy to provide an additional opinion," Borer said.

Pfizer also pointed out that a large percentage of patients were not taking their assigned study drug. At four years, 25% of patients in the doxazosin arm and 14% of patients in the chlorthalidone arm were not taking their respective drugs.

"Information is required as to how many events occurred in patients actually on their assigned treatment, how these events relate to blood pressure control, and how blood pressure control related to therapy and dose," Pfizer said.

Office of Drug Evaluation I Director Robert Temple, MD, said the agency would seek out data in the areas of uncertainty that troubled the committee.

"I'm positive we can find out what the approximate dose was, either in the form of a distribution or the average. I actually don't see how that makes too much of a difference because we know it was well below the 16 mg that you can go to," Temple said.

"I gather there is an analysis close to being born -whether we can get more details of it remains to be seen - that will look at whether...the people who did have adequate control also showed an increased rate of heart failure, in which case you would not really attribute it to not using the drug properly," he noted.

"That seems to me to be the area that people are most nervous about because it makes you ask whether the entire thing is due to the blood pressure. If you saw it in all levels of blood pressure control you would no longer believe that. I think there's a fair sentiment that people would like us to get that information before we did much," Temple concluded.

The committee also suggested that a firmer diagnosis of CHF would be useful to define the magnitude of the problem. Temple informed the committee that the efforts to better define CHF would take more time.

Borer suggested to FDA that the decision to change labeling would depend on the additional data from ALLHAT.

Pfizer Cardura Potential Labeling Changes Should Await More Data - Cmte.

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