Avandia FDA Mole - Defends Off-Label Marketing of Natrecor

August 12, 2007, 7:15AM. By Evelyn Pringle

Washington, DCIt looks like that Mafia guy, Dr. Steven Nissen, leader of the Cleveland Clinic gang, who blew the whistle on the diabetes drug Avandia and before that Vioxx, was on to something when he voted against the FDA's approval of the heart failure drug Natrecor in 2001.

Giving once- or twice-weekly outpatient injections of Natrecor does not reduce the risk of death or hospitalization for heart or kidney problems, according to research presented at the American College of Cardiology meeting in New Orleans in March 2007.

In fact, the study of 920 patients found that outpatient use of Natrecor provided absolutely no benefit. The finding should halt the practice of giving once- or twice-weekly Natrecor to outpatients, said researcher Dr Clyde Yancy, medical director of the Baylor Heart and Vascular Institute in Dallas, Health Day reported on March 26, 2007.

Of course, the revelation that Dr Nissen was running the Cleveland Clinic Mafia and that they were out to get GlaxoSmithKline by publishing a study that showed Avandia increased the risk of heart attacks and deaths came in an email to reporters from FDA spokesman Douglas Arbesfeld, which included the warning to other drug companies, "if you don't hire the Cleveland Clinic for your big trials then you face the firing squad from Nissen and Company."

Mr Arbesfeld left his position as a highly-paid spokesperson for Johnson & Johnson to become a dedicated public servant at the FDA, if his supporters are to be believed.

When his conduct of sending the email came under scrutiny, Peter Pitts, who co-authored a June 6, 2007, critical commentary in the Washington Times about the Avandia study and fondly referred to Dr Nissen as a "Patron Saint of Drug Safety" and "Saint Steven the Pure," put out a statement on the internet saying that, by sending the email, Mr Arbesfeld was just defending the FDA and praised his selfless work, stating:
"I know Doug Arbesfeld," he wrote, "and he is a guy devoted to advancing the public health," he wrote.

"He is also a guy who took a pretty significant pay cut to put in some time in public service," Mr Pitts pointed out.

In response to that assertion, it could certainly be argued that a mole at the FDA would be in a position to earn far more money by selling invaluable insider information to all the drug companies than as media person working for one company.

It should be noted that in his email to reporters, Mr Arbesfeld also referred to Dr Nissen as St Steven - surely just by coincidence.

For the record, the Cleveland Clinic is rated as the top cardiac center in the country by US News and World Report, and Dr Nissen holds the number 72 position on Time Magazine's list of the 100 most influential people in our world.

An effort that included at least 50 different google searches on the internet over a period of several days found no similar praise listed for Mr Arbesfeld other than Mr Pitts' recent two-liner that showed up on about every search.

At the end of his Times commentary, Mr Pitts listed himself as the president of the Center for Medicine in the Public Interest and a former FDA associate commissioner, but a little checking revealed that he is also a Senior Vice President at the public relations firm of Manning, Selvage & Lee.

A review of the Manning website shows that the firm's clients have included Pfizer, Eli Lilly, AstraZeneca, Sanofi-Aventis, Johnson & Johnson, Genentech, Novartis, Amgen and Hoffmann La-Roche.

A review of Mr Pitts' articles on the internet clearly shows that he is in lockstep with his industry clients against: (1) allowing Americans to import drugs from other countries to cut costs; (2) allowing the government to negotiate lower drug prices; (3) barring drug makers from promoting their drugs for uses not approved by the FDA; (4) cutting back on direct-to-consumer advertising, and (5) adding black box warnings to product labels.

As luck would have it, a bit more checking found a December 16, 1999, press release by the Healthcare Marketing & Communications Council which reported that Mr Arbesfeld had joined Manning, Selvage & Lee as Senior Vice President.

The list of pharmaceutical companies that Mr Arbesfeld has worked for over the years includes Ciba-Geigy in 1994, and Rhone Poulenc Rorer Pharmaceuticals in 1998, the same year the company announced that it would merge with Hoechst AG to become Aventis, which merged with Sanofi-Synthelabo in 2004 to become Sanofi-Aventis.

In 1999, Mr Arbesfeld would have been working for the Manning clients listed above, and on August 5, 2002, he identified himself to Reuters as promoting a prescription drug card program called "Together Rx" for 7 drug companies that included Bristol-Myers, Aventis, GlaxoSmithKline, Johnson & Johnson, AstraZeneca, Abbott Laboratories and Novartis.

Finally, Mr Arbesfeld is listed as the contact person for Johnson and Johnson subsidiaries Janssen Pharmaceutica, Ortho-McNeil Pharmaceutical and Ortho Biotech Products in the 2005 Reporters Handbook.

While his supporters say Mr Arbesfeld's email to reporters was justified, lawmakers on Capitol Hill see it differently and have launched an investigation into what they refer to as a smear campaign against Dr Nissen. At a June 6, 2007, hearing before the US House Oversight Government Reform Committee, in response to questions about Mr Arbesfeld email stunt, FDA Commissioner Andrew von Eschenbach claimed that he did not approve of the email and told the lawmakers, "I completely concur with you that it was inappropriate and unacceptable."

"It was an inappropriate and unfortunate act on the part of an individual," he said, "which has been addressed through disciplinary procedures."

In a letter to the FDA Commissioner, the lawmakers said they found it troubling that Mr Arbesfeld might be trying to settle old scores with Dr Nissen because he cast the lone vote against the approval of the heart drug Natrecor (nesiritide) and later spoke out against the off-label use of the drug in a New York Times article in which Mr Arbesfeld spoke on behalf of the drug's maker J&J subsidiary Scios.

The fact is, a review of the regulatory history behind Natrecor proves that Dr Nissen was right then, just as he is now about Avandia.

The drug was approved for limited use by hospitalized patients with acute congestive heart failure, to be administered intravenously under close supervision. However, due to a massive off-label marketing campaign, the drug was soon being administered in outpatient settings at a much greater dose and for longer periods of time than recommended.

In May 2005, the New York Times reported that tens of thousands of patients were undergoing "tune-ups" at outpatient clinics by receiving weekly infusions of Natrecor over a period of months.

In the July 14, 2005, New England Journal of Medicine, apparently another Mafia guy from the Cleveland Clinic gang, Dr Eric Topol, was out to get J&J because he reported that the company was encouraging physicians to open their own infusion centers to bill Medicare for Natrecor treatment and that company documents instructed doctors to bill Medicare $408 for eight hours of observation during the infusion, above and beyond the actual cost of the drug, which was around $500 per vial, he said.

In addition, the company set up a toll-free telephone hotline for "Natrecor Reimbursement Support" and published a 46-page reimbursement and billing guide to provide doctors with specific Medicare billing codes.

"Natrecor was never shown to be superior for reducing death or reducing the need for repeat hospitalizations," Dr Topol said, and asked: "How could this happen? All of a sudden we have 600,000 people using this drug."

He also pointed out that other drugs, costing less than $10 a dose, were equally effective.

The Natrecor infusion-for-profit scheme was indeed on a roll. J&J had recruited doctors and nurses with experience in administering infusions to deliver presentations at medical seminars, and some clinics had programs set up to administer Natrecor to patients twice a week for up to 12 weeks. In 2004, Natrecor brought in about $400 million for J&J, and sales were projected to be $700 million for 2005.

However, the profiteers were hit with a ton of bricks on April 20, 2005, when a study appeared in the Journal of the American Medical Association that reported patients treated with Natrecor were 80% more likely to die in the 30 days following the treatment than patients given a placebo, by Dr Jonathan Sackner-Bernstein of the North Shore University Hospital in Manhasset, NY; Drs Marcin Kowalski and Marshal Fox, of St Luke's-Roosevelt Hospital Center in NY; and Dr Keith Aaronson of the University of Michigan.

On April 26, 2005, in response to the findings of the study, Mr Arbesfeld told HeartWire, "We take any question about the safety of Natrecor seriously."

"At the same time," he said, "a review of Scios's full clinical study data set does not show a statistically significant difference in mortality."

Although the collective data from the studies reflects a 23% higher death rate for those taking Natrecor, Mr Arbesfeld said, the number of patients in the studies was too small to produce conclusive results of death risk, in a Reuters article on April 25, 2007.

In response to comments about Natrecor not being approved for outpatient use, Mr Arbesfeld told the Times that the FDA label did not specify where the drug could be administered, so giving it in an outpatient setting did not run counter to its approved use.

However, that Mafia guy from the Cleveland Clinic, Dr Nissen, told the Times that treating patients in ambulatory settings was "inappropriate and cannot be recommended."

Before long, more doctors began speaking out. Cardiologist Dr Milton Packer, chairman of the advisory panel that voted to approve the drug, told the Times on May 17, 2005, that Natrecor was not intended for outpatient use. "We said this is a drug that should be approved for patients who are short of breath at rest, who are hospitalized," he said.
He also faulted the FDA's approval of a label that did not specify that Natrecor was for hospital use only.

Dr Sackner-Bernstein expressed outrage in the Health Day Report. "The people involved at Scios and others who knew about this data should be hanging their heads," he said.

"What is wrong with everybody," he 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?"

After the April study came out, J&J hired a heart specialist, Dr Eugene Braunwald, to form a committee to review the studies, and the committee reached the same conclusion, that it was inappropriate to use Natrecor except with acutely ill hospitalized patients.

Specifically, the panel said, Natrecor should be used only when patients show up at a hospital with acute heart failure; that it should not replace diuretics as the front-line treatment; and that it should not be used where patients schedule appointments to receive the drug ahead of time.

Their report also stated: "Scios should immediately undertake a proactive educational program to inform physicians regarding the conditions and circumstances in which [Natrecor] should and should not be used."

So what did J&J do in response? According to Dr Packer, who was a member of the panel, the committee members were shocked several weeks later when they received invitations from a mass mailing to enroll in a continuing medical education program, sponsored by Scios, that appeared to promote the outpatient use.

"We were flabbergasted," Dr Packer told the Times on August 1, 2005. "Scios was sponsoring meetings to discuss nesiritide and its potential use in outpatients."

As so often happens these days, this drugging-for-profit scheme caught the attention of lawmakers because about 80% of the patients receiving Natrecor were on Medicare.
D-Day came on December 5, 2005, when the Centers for Medicare and Medicaid Services announced that Medicare would no longer pay for outpatient infusions.

But the Natrecor story is far from over because, according to Johnson & Johnson's 2006 Annual Report, the company received a subpoena from the US Attorney's Office, District of Massachusetts, in July 2005, seeking documents related to the sales and marketing of Natrecor, and in August 2005, J&J was advised that the investigation would be handled by the US Attorney's Office for the Northern District of California in San Francisco.

The latest news came on March 12, 2007, when J&J revealed that it had received 3 new subpoenas from the US Attorneys' offices in Philadelphia, Boston and San Francisco wanting information for the investigation into the company's sales and marketing of Natrecor.

More recently, in an apparent repeat of the exact same scam, investigators have found that J&J and Amgen have been paying doctors to administer the anemia drugs Aranesp, Epogen and Procrit off label for profit. On May 9, 2007, the New York Times reported that drug makers are paying "hundreds of millions of dollars to doctors every year in return for giving their patients anemia medicines."

The Times cited documents obtained from a former employee of a group of 6 cancer doctors which showed that between them, the 6 doctors received $2.7 million from Amgen for prescribing $9 million worth of anemia drugs in 2006.

On May 10, 2007, the Wall Street Journal cited a document provided by a former J&J sales representative-turned-whistleblower which showed that a doctor who purchased nearly $1 million worth of Procrit over 15 months would receive $237,885.

In March 2007, the FDA ordered black box warnings on the drug's labels about an increased risk of numerous adverse events and issued a public health advisory warning health care providers to administer the lowest possible dose necessary to treat anemia.

According to the FDA, as of March 2007, there are five clinical trials that demonstrated decreased survival time in cancer patients receiving the drugs compared with those receiving transfusion support.

The agency also reported a higher rate of blood clots, strokes, heart failure, heart attacks and death were found in patients with chronic kidney failure when the drugs were given to raise hemoglobin levels higher than recommended.

The FDA advisory also noted a higher risk of blood clots in patients who were scheduled for major surgery and received the anemia drugs and also warned of an increased rate of tumor growth in patients with advanced head and neck cancer receiving radiation therapy and metastatic breast cancer patients receiving chemotherapy, when the drugs were given to maintain levels higher than recommended.

J&J is already facing several class-action lawsuits filed by shareholders as a result of the revelation of this latest drugging-for-profit scheme, and the company has also received a subpoena from New York's attorney general requesting information on the sales and promotional activities related to Procrit.

But then, why should J&J worry over a minor little investigation by the NY attorney general. The feds have been investigating the Natrecor fiasco for more than 2 years, and the J&J executives who reaped the benefits have probably not lost one wink of sleep.