Natrecor found to worsen kidney function, hasten death – NYT
Tue, 17 May 2005
Natrecor, a drug approved by the FDA for treating patients with heart failure, is being widely prescribed off label for unapproved uses. The drug is prescribed for so-called “tune-ups” in outpatient clinics – although that use has not even been tested.
A controversy has ensued after the publication of two studies by Dr. Jonathan Sackner-Bernstein, a New York heart failure specialist whose analysis of the data submitted to the FDA revealed that Natrecor “worsened kidney function and hastened death.”
Physicians’ off-label prescribing of powerful drugs that are approved for specified limited conditions is itself posing a very serious life-safety risk. Given that physicians are so intimately under the influence of drug sales reps, it is time to reconsider the carte blanche that physicians in the US enjoy on the assumption that physicians’ judgment is based solely on the best interest of the patient
In economic terms, Natrecor infusions – without physician’s examination charges – is about $600 a session. Natrecor sales have brought Johnson & Johnson $400 million last year – projected to $600 million this year.
Most of the cost is billed to Medicare. Thus taxpayers are being bilked
Contact: Vera Hassner Sharav
THE NEW YORK TIMES
May 17, 2005
The Marketing and Success of Natrecor
By STEPHANIE SAUL
When the Food and Drug Administration approved an expensive treatment for heart failure patients in 2001, its maker hailed it as potentially useful to as many as a million Americans who show up every year in hospital emergency rooms gasping for air and barely able to walk.
But the drug, Natrecor, made by the Scios unit of Johnson & Johnson, has also become widely used by thousands of patients in outpatient clinics around the country, where heart failure patients receive regular infusions, sometimes weekly or more often, over several months.
Some of the clinics, where patients receive the drug intravenously, are run by hospitals and medical centers, like Marion General Hospital in Marion, Ohio. Others are set up by cardiologists, including Dr. Larry Altschul in West Islip, N.Y. In the outpatient settings, the bill for a four-hour infusion session can be $600 or more, not including any examination fee the doctor charges.
Many doctors say that the treatments help patients. The problem with the “tuneups,” as some doctors call them, is that, while legal, they are not a federally approved use of Natrecor, an F.D.A. official, Dr. Norman Stockbridge, said. While the tuneup treatment might warrant further study, “there’s inadequate evidence it’s useful at this time,” said Dr. Stockbridge, who oversees cardiovascular disease products for the F.D.A.
Some heart doctors, meanwhile, have raised questions about whether the drug, which some studies have linked to kidney problems and other potentially fatal effects, is safe enough to be used so frequently. Many of the questions have been fueled by articles in The Journal of the American Medical Association and another medical journal, Circulation.
What is beyond dispute is that, through Medicare, the taxpayers are footing most of the bill. Since Natrecor’s introduction in 2001, the drug has become a brisk seller, generating sales of $400 million last year and has been forecast by some analysts to top $600 million this year. Johnson & Johnson, which challenges the statistical significance of the safety problems cited in the journal articles, says it has asked a noted Harvard cardiologist, Dr. Eugene Braunwald, to form a team of outside doctors to evaluate Natrecor’s risks and benefits.
The company says that 85 percent of the drug use still occurs among hospitalized patients. But the story of Natrecor’s expansion beyond an emergency treatment to a once-a-week maintenance therapy is, in the view of some doctors, another example of the pharmaceutical industry’s inexorable search for broader markets once a medicine has been approved for a narrower use by the F.D.A.
Many other doctors contend that much cheaper alternatives to Natrecor – like nitroglycerin, as well as Lasix and its generic variants – can work just as well as an emergency treatment for heart failure.
Recent examples of other drugs benefiting from a promotional push into broader application include Celebrex and Vioxx, which were both approved as a new class of arthritis painkillers. They were heavily promoted and widely prescribed, despite little evidence that, for many patients, they worked any better on pain than older, much cheaper pills. They were also eventually shown to pose safety risks, with Vioxx, made by Merck, no longer on the market and Celebrex, a Pfizer drug, carrying a stringent warning label.
Doctors are allowed to use drugs for any “off label” purposes that they think will benefit patients. And while federal law forbids drug makers to actively promote off-label uses, the rules give companies considerable latitude in providing information to doctors about such uses – as long as their efforts can be defined as merely educational and not promotional.
Johnson & Johnson, for example, operates a Natrecor Reimbursement Support telephone line and provides sample sheets instructing doctors and their office staffs on how to submit claims to Medicare or other insurers for outpatient reimbursement. The company has denied any improprieties in Natrecor’s promotion and says it does not market the treatment for off-label use.
The F.D.A., though, has held informal talks with Johnson & Johnson, according to Dr. Stockbridge, over the agency’s concerns that the company might have been too aggressively promoting Natrecor for off-label use. He said the questionable activities involved the company’s distribution of materials interpreted as promoting the drug’s unapproved use for what he called “tuneups” in outpatient clinics.
Dr. Stockbridge said Johnson & Johnson had given the F.D.A. assurances that the company would engage in no inappropriate marketing.
A company spokesman, Mark Wolfe, denied that the F.D.A. had expressed any displeasure over Natrecor promotional activities, but he would not otherwise comment on Johnson & Johnson’s “ongoing discussions” with the agency.
The stated use on Natrecor’s label is for “acutely decompensated” heart failure – a life-threatening flare-up, which, with rare exceptions, is treated in hospital settings. Natrecor, a manufactured version of a human cardiac hormone, works by reducing the amount of blood pooling in the heart and lungs so patients can breathe easier.
An estimated five million Americans suffer from heart failure, a number that is growing as the baby boom generation reaches its 50’s and 60’s. While some people with the disease can function almost normally with medication and proper diet, those with advanced illness are prone to acute episodes that send them to the hospital.
Even if Natrecor were limited to such events, it is a drug with significant growth potential. But if widely used as a continuing treatment for chronic heart failure patients, its potential market is far greater.
After the F.D.A. approved Natrecor in August 2001, Scios introduced the drug in fall 2001, hiring a contract sales organization called Innovex, based in Research Triangle Park, N.C., to conduct its marketing. And a team of about 180 sales representatives fanned out, aiming at doctors who practice in about 2,200 coronary care centers and clinics across the country. (Johnson & Johnson bought Scios in 2003 for $2.4 billion, mainly to acquire Natrecor.)
Dr. Milton Packer, a cardiologist who was chairman of the F.D.A. advisory panel on Natrecor in 2001 and who voted for the drug’s approval, said in a recent interview that the drug was approved for use in only a very limited group of heart failure patients.
“We said this is a drug that should be approved for patients who are short of breath at rest, who are hospitalized,” said Dr. Packer, a professor of cardiology at the University of Texas Southwestern Medical Center in Dallas. Dr. Packer faulted the drug’s F.D.A.-approved label for not specifying that Natrecor was meant for hospital use.
In presentations to analysts and investors on July 25, 2002, according to an account published by FDCHeMedia, Scios said that the label wording was important because it “didn’t indicate place of treatment, but type of patient.” The company cited the large number of patients who might be suitable for outpatient use of the drug.
“We believe 125,000 patients are candidates for Natrecor infusion on an outpatient basis,” the company said. While the company took pains to note that it was not promoting the periodic, or “serial” use of Natrecor, it projected that in each serial outpatient case, the company would sell 24 vials of the drug. That would compare with 2.7 vials for a hospitalized patient.
Mr. Wolfe, the Johnson & Johnson spokesman, dismissed the discussion as projections made three years ago, based on assumptions that had not played out.
Operating a Natrecor infusion clinic can be lucrative. About 80 percent of patients who receive the drug are 65 or over, and therefore eligible for Medicare – which fully covers Natrecor in many states because it is an infusion therapy.
But in several states recently, including Pennsylvania, insurers that provide Medicare coverage have refused to pay for the drug’s outpatient use. “We had several physicians here coming in and arguing an outpatient scenario,” said Dr. Andrew Bloschichak, who oversees coverage decisions for Highmark, the Medicare carrier for Pennsylvania. “My reply to them was that if those are the indications you want, or Scios wants, then the patient population should have been studied and approved by the F.D.A.”
This week, Dr. Bloschichak said, a group representing a large number of state Medicare carriers, including Empire Medicare Services in New York, plan to ask the federal Medicare administration for a national ruling on whether and in what circumstances the government should pay for Natrecor for outpatient use.
The company says it has been conducting its own clinical trials in hopes of demonstrating the drug’s effectiveness in nonemergency settings.
Perhaps as controversial as outpatient use is the safety debate.
Johnson & Johnson has some of the nation’s most eminent heart failure physicians on its side, including the Cleveland Clinic’s medical chairman, Dr. James B. Young, who helped present the company’s case to the F.D.A. when it was approved.
Dr. Altschul, who operates the infusion clinic in West Islip, N.Y., said that hospital admissions had been reduced among his patients who underwent regular weekly infusions of Natrecor, often for several months. Some of his patients who were very ill, Dr. Altschul said, have been able to return to normal activities as a result of the Natrecor treatment.
But the drug’s prominent detractors include Dr. Steven Nissen of the Cleveland Clinic, the only member of the F.D.A. advisory panel to oppose the drug’s approval in 2001. “You can accept a few safety concerns when a drug shows compelling efficacy advantages,” Dr. Nissen said. “In this case, I saw limited evidence of efficacy, but troubling safety issues.”
The controversy over Natrecor follows two recently published studies by Dr. Jonathan Sackner-Bernstein, a heart failure specialist at North Shore University Hospital in Manhasset, N.Y. The analyses, based on patient studies submitted to the F.D.A., linked the drug to worsened kidney function and hastened death.
Dr. Sackner-Bernstein has said that additional study of the drug is needed. But he argues that in the meantime, Natrecor should be used only when other treatment options have failed.
Dr. Packer, despite supporting Natrecor’s approval in 2001, said developments since the treatment’s approval had raised new questions.
“There’s now additional mortality data that wasn’t available at the time,” Dr. Packer said. “And this is not a drug being used for a very small focus group of patients anymore. We felt comfortable for a focused group of patients. Now we’ve got a greater safety concern than we had then, and a greatly expanded use for patients for which we have no efficacy data.”
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