Antihypertensive Cardio Labeling Should Be Applied To New Classes – Cmte.

Class labeling for reduction of cardiovascular outcomes based on blood pressure lowering should be applied to new classes of antihypertensives, members of FDA's Cardiovascular & Renal Drugs Advisory Committee said.

"I am leaning towards" a generalized label that could be applied to new classes of antihypertensives "because I want to encourage industry to develop new classes for us that we desperately need," Committee Chair Steven Nissen (The Cleveland Clinic) said.

It "would be an incentive for people to develop additional drugs, if they knew that they could get" a claim for prevention of cardiovascular outcomes "right off the bat," Nissen said.

Cardiologists need "at least a couple of more classes" of antihypertensives, he said. "I have a clinic full of patients that are on four drugs, five drugs that are having trouble getting to the goals that I want for them."

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The committee recommended that FDA develop class labeling for antihypertensives describing the relationship between blood pressure lowering and cardiovascular outcomes.

Invited speaker Jay Cohn (University of Minnesota) said that he expects new classes of drugs which prevent hypertension outcomes will be developed in the future, but their mechanism of action is likely to be independent of lowering blood pressure.

"We will find drugs which influence the structural remodeling process without lowering blood pressure," he said.

As a result, "we'll be forced into a new carrot" beyond class labeling for the benefits of blood pressure reduction, he noted.

Cohn suggested that the discovery of such a class of drugs will require the development of biomarkers for structural changes associated with early cardiovascular disease.

"It will be almost impossible to find a new class of drug and prove that it actually does some good, unless we are willing to move earlier in the course of the disease," he said.

Changes in arterial stiffness or microalbumin could be two indicators of positive effects on vascular or cardiac structure, Cohn suggested.

"We have to become comfortable that there is a structural marker that in fact can predict for us that this is really going to be effective," Cohn emphasized.

Committee member Thomas Pickering (Columbia Presbyterian Hospital) said that measures of arterial structural changes are not "yet ready for prime time. It's a really interesting research project, but we really don't know how to interpret them," he added.

Some committee members expressed concern that if new products were given a claim based on blood pressure reduction, they would not be differentiated from antihypertensive classes with cardiovascular outcomes data.

The committee recommended that data on products that have shown cardiovascular outcomes in controlled trials should be included in labeling (² (Also see "Hypertension Rx Labels Should Include Product-Specific CV Data – Cmte." - Pink Sheet, 20 Jun, 2005.), p. 7).

"Initially those new classes won't have" outcomes data, Nissen noted. "We should be providing some distinction between classes where we have seen benefit and classes where we simply don't know."

"If a new class comes along...until it has some outcomes data, I think we need to tell people."

"How is the situation different than when the [angiotensin II receptor blockers] first came along?" FDA Office of Medical Policy Director Robert Temple asked.

"We approved them because they lowered blood pressure," had an established dose and had "a reasonable amount of long-term data," he said. However, "there were no outcomes studies" for ARBs, he noted.

Nissen said that he has been "troubled by the ARBs from the very beginning." In head-to-head trials between ARBs and angiotensin-converting enzyme inhibitors, "certainly there is no evidence of superiority for a lot of" cardiovascular endpoints, he said.

"What I tell people is that ARBs are drugs to be used exclusively in people that don't tolerate ACE inhibitors because, until proven otherwise, they are certainly not superior," Nissen said.

Nissen noted that it is virtually impossible for new classes of antihypertensives to conduct placebo-controlled outcomes studies because of the availability of effective therapy.

"People are assiduously looking at the possibility of non-inferiority studies" for cardiovascular outcomes claims, Temple noted. FDA is considering less conservative approaches to non-inferiority trial design, he said (see ³ (Also see "FDA Considering “Less Conservative” Approaches To Non-Inferiority Trials" - Pink Sheet, 27 Jun, 2005.)).

Committee consultant and biostatistician Thomas Fleming said that differentiation between classes with and without outcomes data in labeling is important because it provides "truth in advertising."

Panelists also questioned whether data from a drug within a specific class would be included in labeling for all members of the class.

"Current practice is that those other labels will be silent on" outcomes data for other products in their class, Temple said. "We don't take someone's ability to show something and then transfer it to other members of the class."

There is a "perception" that doing so would take away manufacturers incentive for conducting their own trials, Temple noted. However, FDA "might bring that issue to the committee sometime," he said.

Some committee members also recommended that labeling note that a product has been recently approved and may lack the same depth of safety and efficacy data as older products.

Nissen said that he would not use a newly approved agent first-line until it had some outcomes data available.

"What, if anything, should we say about how scared you should be when a drug hasn't been marketed for a long time is the subject of some discussion?" Temple asked.

"In a proposal for a labeling revision - I can't tell you about the final rule because I would have to kill you - there was a proposal to put the date of approval on."

FDA's physician labeling rule, which was expected to be finalized last fall, is currently being reviewed by the White House Office of Management & Budget (⁴ (Also see "Rx Labeling Rule Will Be Final Soon; Warnings & Precautions To Be Merged" - Pink Sheet, 22 Nov, 2004.), p. 11).

Committee consultant Jonathan Sackner-Burnstein (St. Luke's-Roosevelt Hospital Center) said that he is in favor of including "born on dating" in product labeling.

Committee members expressed concern about the effect of generalizing outcomes data to entire classes, citing the diuretics hydrochlorothiazide and chlorthalidone as an example of two products in a class with different efficacy levels.

The Antihypertensive & Lipid-Lowering to prevent Heart Attacks Trial (ALLHAT) found that the chlorthalidone was better than Pfizer's calcium channel blocker Norvasc (amlodipine) in preventing certain cardiovascular outcomes (⁵ , p. 11).

"I was a little uncomfortable with what happened with ALLHAT," Nissen said. The implication that chlorthalidone was superior "was transferred publicly to the entire" diuretic class. Cardiologists "translated the lesson from ALLHAT...to clinical practice into the use of hydrochlorothiazide."

"They went too far in promoting the results in ALLHAT given the fact that it was a specific diuretic at a specific dose and one that's very different from some of the diuretics that we use every day," Nissen asserted. Chlorthalidone is more potent and has a longer duration of action than other diuretics, he noted.

FDA also asked the committee whether antihypertensive class labeling should specifically note that diuretics can lead to hypokalemia when overdosed.

The question "reflects my obsession with early failure to have cardiovascular benefit when the whole world overdosed everybody with diuretics, which I consider the worst adverse reaction there has ever been," Temple explained.

"That makes me want to remind [that] you must control the dose of diuretics," he said. "But maybe I'm obsessed?"

"Yeah, I think you're obsessed," Nissen replied. "You've got lots of opportunities in warnings and other areas to comment about this, and I think that that's the place it belongs."