Evelyn Pringle January 31, 2006
Let there be no mistake, Johnson & Johnson, and its subsidiary Scois, knew all about the dangers associated with its heart failure drug Natrecor, but threw caution to the wind in promoting its off-label use in pursuit of profits.
Natrecor was FDA approved in August 2001 for the sole purpose of treating patients for the most acute from of congestive heart failure to be administered intravenously to patients during hospitalization under close medical supervision.
However, the company's aggressive off-label marketing campaign has allowed the drug to be administered in outpatient clinics at a much greater dose and for longer periods of time than recommended.
The off-label prescribing of drugs is wreaking havoc on unsuspecting patients. Guessing at drug dosage levels, medical conditions, and treatment duration for uses that were never approved is proving deadly. This is especially true with life-and-death drugs like heart medications.
As a consequence of Natrecor's off-label use, patients have suffered serious injuries, including kidney failure, congestive heart failure, stroke, and death.
In this country, doctors are permitted to prescribe drugs to treat a condition even after the FDA has denied approval for a specific condition. Although a drug maker cannot directly promote a drug for an off-label use, a doctor can prescribe it for that use. If a company can orchestrate a doctor-backed marketing scheme, it can turn a restricted drug into a billion-dollar blockbuster.
A point has been reached, where many doctors are acting more like marketing agents than health care professionals. Doctors can spread the word of an off-label and create an exaggerated demand for a drug far and beyond its FDA approved market.
Health officials began investigating the off-label use of Natrecor in May 2005 after the New York Times published an article reporting how tens of thousands of patients were undergoing "tune-ups" at outpatient clinics by receiving weekly infusions over a period of months.
Albeit unfortunate, it is within the law for a drug company to send information to doctors about a drug's off-label uses, as long as it is for educational purposes only. In the case of Natrecor, this loophole proved to be as wide as a barn door.
Company sales representatives were actually distributing brochures to teach doctors how to set up outpatient clinics to provide regular off-label Natrecor treatments to patients. The company then recruited doctors and nurses with experience in administering outpatient infusions to deliver presentations at medical seminars and meetings.
Some outpatient clinics went so far as to establish programs to administer Natrecor to patients twice a week for up to 12 weeks with full knowledge that there had been no study conducted to determine whether long-term treatment was safe.
Operating a Natrecor clinic was very profitable. The vast majority of patients who received the drug were 65 or older, and eligible for Medicare which covered Natrecor treatment specifically because it was an infusion therapy.
An editorial in the July 14, 2005, New England Journal of Medicine by Dr. Eric Topol, the chairman of cardiovascular medicine at the Cleveland Clinic, objected to the company's encouragement of doctors to open clinics for Netracor infusions. Dr. Topol, noted that company documents instructed doctors to bill Medicare for a $172 observation fee for the first hour, and $408 for eight hours of observation during the treatment, above and beyond the actual cost of the drug.
The reimbursement guide told doctors to use Medicare codes that treat Natrecor like chemotherapy and allowed them to bill for larger reimbursement payments. As for Natrecor's $500-$700 per infusion price tag, Dr Topel explained that a dose of other equally effective medications cost less than $10.
"Natrecor was never shown to be superior for reducing death or reducing the need for repeat hospitalizations," Dr. Topol said. "How could this happen? All of a sudden we have 600,000 people using this drug."
The good Doctor is correct, there is no logical explanation for the situation. Natrecor has not only been proven to be no better than older drugs, infusion of the drug is often lethal.
A study that appeared in the April 20, 2005 issue of the Journal of the American Medical Association, found patients treated with Natrecor were 80% more likely to die in the 30 days following the treatment than patients given a placebo. And one trial found kidney problems were occurring at a rate three times that found in patients taking a placebo, according to a June 13, 2005 report by Health Day News.
The study was conducted by researchers Dr. Jonathan Sackner-Bernstein, of the North Shore University Hospital in Manhasset, N.Y; Drs. Marcin Kowalski and Marshal Fox, of St. Luke's-Roosevelt Hospital Center in New York; and Dr. Keith Aaronson, of the University of Michigan.
In their study, the team collected data on 1,269 heart failure patients who participated in five clinical trials comparing Natrecor with other drugs. "We found that there is a 40 to 50 percent higher risk of worsening kidney function when people are treated with nesiritide than when people are treated with other medications," Sackner-Bernstein said, according to a March 21, 2005 article by Health Day News.
In attempt to discount this damaging analyses, in April 2005, Johnson & Johnson appointed renowned heart specialist, Dr Eugene Braunwald, to form a committee to review the drug studies. Dr Braunwald's committee reached the same conclusion, that it was inappropriate to use Natrecor, except in acutely ill hospitalized patients.
Specifically, the panel recommended that Natreor should be used only in patients who show up at the hospital with an acute heart failure; that it should not replace diuretics, the front-line heart failure treatment; and that it should not be used for outpatients, where patients scheduled appointments to receive the drug ahead of time. The committee made the following verbatim recommendations:
1) The use of Natrecor should be strictly limited to patients presenting to the hospital with acutely decompensated congestive heart failure who have dyspnea at rest, as were the patients in the largest trial that led to approval of the drug (VMAC). Physicians considering the use of nesiritide should consider its efficacy in reducing dyspnea, the possible risks of the drug summarized above, and the availability of alternate therapies to relieve the symptoms of congestive heart failure.
2) Nesiritide should not be used to replace diuretics. Furthermore, because sufficient evidence is not currently available to demonstrate benefit for the applications listed below, nesiritide should not be used:
For intermittent outpatient infusion
For scheduled repetitive use
To improve renal function
To enhance diuresis.
3) Scios should immediately undertake a pro-active educational program to inform physicians regarding the conditions and circumstances in which nesiritide should and should not be used, as described above. Sponsor supported communications, including review articles of nesiritide, should reflect the above recommendations. Scios should ensure that current and future marketing and sales activities related to nesiritide are consistent with this educational program.
Although Scios spokespersons have argued that they can not control how doctors prescribe Natrecor, Scios itself created the problem by encouraging and praising off-label use right from the start.
Back on April 2, 2002, Scios issued a Press Release to announce that "net sales for its flagship product Natrecor(R) (nesiritide) were $15.4 million in the first quarter of 2002, a 60 percent increase over the prior quarter ended December 31, 2001."
The company could not have been more enthusiastic about the drug's off-label use. The press release bragged about the profits from off-label use. "We achieved better than expected sales due to greater than expected physician prescribing of Natrecor for their patients suffering from acute heart failure," said Richard Brewer, President and CEO of Scios at the time. "Our market research shows physicians are increasingly interested in using Natrecor in a variety of clinical settings," said Thomas Feldman, Vice President of Sales and Marketing at Scios at the time.
The company also noted that Natrecor had received a pass-through code from the Centers for Medicare & Medicaid Services that allowed reimbursement for patients treated in an outpatient setting, and said that the issuance of a code was a further indication of the growing therapeutic importance of Natrecor and would help increase use of it in outpatient settings.
"We believe this is a significant step toward making Natrecor more widely available to the physicians and patients who need it, and creates a bigger market for the product," the Press Release said.
The code makes the economics of prescribing the product more attractive for physicians interested in using it for their patients in the outpatient setting, "an area in which Natrecor is particularly well-suited because it is easy to use, has a good safety profile and makes patients feel better," the release said.
Doctors seeking reimbursements for off-label outpatient treatment were directed to call a toll-free hotline to obtain billing codes and forms.
Reputable doctors consider it ethically irresponsible for a drug company to promote the possibly harmful use of a drug for financial gain. The hotline prompted allegations from some of the country's leading cardiologists that the company was improperly promoting Natrecor's off-label use.
Doctors began speaking out against its frequent use, noting the lack of clinical trials to support outpatient treatment, and the drug's link to kidney problems and death.
Dr Milton Packer, a cardiologist who was chairman of the FDA advisory panel that approved Natrecor in 2001, said the drug was approved for a very limited group of 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. He faulted the drug's FDA-approved label for not specifying that Natrecor was meant for hospital use, according to the May 17, 2005 New York Times.
"The fact that the FDA doesn't have much enforcement capability is a problem," Dr Sackner-Bernstein told Health Day Reporter. "Then again," he said, "where are the ethics? The people involved at Scios and others who knew about this data should be hanging their heads."
"What is wrong with everybody," Dr Sacker-Bernstein continued, "that you've got a drug that increases renal dysfunction and death, and costs 50 times as much as a regular treatment, and yet it's given to hundreds of thousands of people?"
Whether Natrecor has been illegally marketed for off-label use, is the subject of an investigation by the Justice Department. On July 20, 2005, Johnson & Johnson acknowledged receiving a subpoena from the US Attorney's office in Boston, MA requesting documents related to the sales and marketing of Natrecor.
The entrance of Sullivan on the scene is no doubt unwelcome news for Johnson & Johnson. He earned a reputation as the pharmaceutical industry's adversary last year, when he secured a $430 million penalty against Warner-Lambert, with the help of an employee turned whistleblower, involving the off-label sale of Neurontin, a drug approved for epilepsy, but promoted for various other uses. By the time of the settlement, Pfizer had acquired Warner-Lambert.
As if the death rate with Natrecor listed above is not high enough, as it turns out, Johnson & Johnson did not report 2 patient deaths from the study, according to news reports in early January 2006. In addition, to not telling the FDA, the deaths were not included in the results of the study published in the October 2005 Journal of Emergency Medicine.
The October article reported five deaths of patients within 30 days of using Natrecor in hospital emergency rooms in 2001 and early 2002. Of the 237 patient covered in the study, the two new deaths raises the total number of Natrecor deaths to seven.
According to Matthew Herper, in Forbes.com, Johnson & Johnson hired private detectives from Pinkerton Consulting & Investigations, the famous gumshoe agency and the detectives found the two deaths that were not accounted for in the published study.
There seems to be a changing of the guard for Scois. After all the commotion over the hotline, since July 29, 2005, the new message recorded advises callers about the "lack of clinical data" regarding off-label use and warns that Scios "does not recommend Natrecor for this use."
"As a result," the message states, "the support line does not maintain or provide information regarding the physician office or hospital infusion clinic use of Natrecor." The recording clearly seeks to discourage the off-label use of the drug.
And last but not least, on December 5, 2005, officials from the Centers for Medicare and Medicaid Services, announced that Medicare will no longer cover outpatient costs of Natrecor.