FDA: More information needed on nesiritide
FDA: More information needed on nesiritide
Rejection sends investigators back to more trials
A bid to put a new acute care drug for hospitalized CHF patients into use by this summer hit a snag April 27, when the Food and Drug Administration (FDA) rejected a new drug application for nesiritide.
Investigators had been rallying on the drug’s earlier successes. In January, the FDA’s Cardio-vascular and Renal Drugs Advisory Committee recommended the formal panel approve the biologically engineered natriuretic peptide.
In March, researchers presented their results at the scientific meeting of the American Heart Association, demonstrating how the drug can reduce CHF symptoms as well as improve hemodynamic values such as capillary wedge pressure and cardiac index. (See CHF Disease Management, May 1999, p. 56, for more on the optimism for nesiritide.)
But in making the recent decision, the FDA noted there were important data still unknown such as the specifics relating to the risk of hypotension.
"My impression is that this is an approvable drug," says William T. Abraham, MD, researcher and director of the heart failure and cardiac transplantation section at the University of Cincinnati College of Medicine. He notes, however, the FDA wants more data on the ratio between benefit and risk.
Right up to the application, regulators had plenty of proof about the benefits. "They said unequivocally the drug is effective," Abraham says, adding that now it’s time to widen the database on how blood pressure can drop in some patients.
Defining the parameters
He notes the researchers now have to be more specific on defining the parameters of hypotension. At the time of the FDA decision, the researchers had learned that generally:
• At a dose of 0.015 mcg/kg/min, 8% of the subjects suffered hypotension.
• At a dose of .03 mcg/kg/min, 14% of the patients became hypotensive.
Abraham says these trials did not standardize when hypotension was clinically significant. If one patient, for example, reported feeling dizzy or lightheaded, it would probably prompt the doctor to check the blood pressure to note if it was low.
But it’s possible to have another patient not feel dizzy at the same blood pressure reading. In this instance, there would not be the complaint present to signal a blood pressure check in the second patient. So not every instance of hypotension was recorded.
At press time for this issue of CHF Disease Management, Abraham says he has been talking with other investigators by phone, designing new clinical trials that would record the blood pressure symptoms and readings in the new subjects treated with the drug.
"My expectation is it probably will take one or two additional moderately sized multicenter studies." The new project should take about a year, he says, which should provide the FDA with the information needed to approve the drug and make it available to U.S. hospitals.
A need for a nesiritide
Abraham says he still is optimistic about the drug. Although the FDA rejected the first attempt at getting it approved, it should not be difficult to provide what is still needed.
"They could have set the pole very high if they did not want it approved," he says.
Today, when CHF patients can’t keep the disease under control and need to go to the hospital, they often need drugs, which carry their own risks, says David S. Roffman, PharmD, BCPS. Roffman is associate professor at University of Maryland’s School of Pharmacy in Baltimore and a therapeutic consultant for the cardiac care unit in the University of Maryland’s Medical System.
He says patients in this situation often need to be given dobutamine or milrinone. These inotropic agents have a potential to create tachycardia. (Rhythm disorders also can result, but they are less common.)
"The newer agents, which are not inotropics, may give us a safer way to manage patients," he says.
An added benefit to the drug is that although it is a vasodilator, it has properties of a diuretic. That can be helpful, Roffman says, as CHF patients often have become resistant to traditional loop diuretics. Because the natriuretic peptides work on a different level of diuresis, it gives new opportunity to help hospitalized patients shed some fluid.
Seeing the hypotension associated with nesiritide use is no surprise, he says, since nesiritide is a vasodilator. But doctors need to know the specifics about how a drug may drop the blood pressure in CHF patients. Many times, he says, a CHF patient already has low blood pressure, but it is fairly stable and usually doesn’t go down significantly on its own.
Another drug to titrate
"The issue of titration is a practical one," Roffman continues. Doctors have to know how to gradually work patients up to effective levels of medications without bringing on too many symptoms that outweigh the benefit they are trying to get with the drug.
Research also had to work out the specifics of titrating established CHF drugs like beta-blockers. "Don’t forget that beta-blocker research has been going on for 15 years," he says. And once doctors knew how to titrate it, they could then change their goal to demonstrating how it could improve the survival of these patients.
Roffman says he suspects the learning curve will be easier than the one doctors experienced with beta-blockers. He notes the natriuretic peptides are being developed specifically for treating heart failure. Other types of drugs — like the beta-blockers — were developed for treating different types of disease such as hypertension, and doctors had to learn how to make the transition to using them to treat CHF patients.
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