Rehnquist Warns Drug Makers _Marketing Actimune for Unapproved Use_NYT

Mon, 28 Apr 2003

1. The New York Times reports that Janet Rehnquist, the Inspector General of the Department of Health and Human Services, has issued “a compliance guide for drug manufacturers” in which they are waned that many of their marketing techniques “run a high risk of violating federal fraud and abuse laws.”

Monetary payments (kick backs) to doctors, hospitals, insurerers or pharmacists, as well as arrangements under which drug companies pay doctors for the time they spend listening to sales pitches, “are highly suspect under the antikickback statute, are highly susceptible to fraud and abuse and should be strongly discouraged,” the guide says.

The outgoing Inspector General is to be commended for spelling out some of the illegal sales practices by the pharmaceutical industry, practices that the Food and Drug Administration has bee evading.

See: U.S. Warns Drug Makers on Illegal Sales Practices By ROBERT PEAR

http://www.nytimes.com/2003/04/28/politics/28DRUG.html?pagewanted=print&position=

April 28, 2003.

2. In the Sunday NYT Times Business section, a report describes some of the practices that are listed in the guide. It describes about how IntermUne has generated $106 million in sales from a drug approved for a disease that afflicts only 800 Americans. Actimune is being promoted off-label to patients with idiopathic pulmonary fibrosis, a severe, ultimately fatal lung disease affecting 50,000 to 75,000 Americans.

The case is similar to Pfizer’s marketing of Neurontin, a drug approved for epilepsy–but whose sales for off-label uses reached $2.3 billion. The marketing of Actimune provides yet additional insight into the aggressive, but ethically questionable, promotional marketing practices, that bear little, if any, relation to scientific proof that a drug benefits the patients’ condition, can nevertheless succeed in garnering company profits. This is primarily so, because the Food and Drug Administration fails to enforce federal “truth in marketing” rules– the FDA looks the other way.

The case also demonstrates the marketing value of an article in The New England Journal of Medicine, and the drug industry’s propensity to disseminate partial–ie. positive findings–while suppressing negative findings. The NEJM published the positive findings of a clinical trial on just 18 patients. The NEJM article provided the company with an invaluable marketing tool upon which to base an aggressive marketing campaign for a drug it charges $50,000 a year.

Although the company denies it markets the drug for pulmonary fibrosis, the Times reports that company officials told an investors’ conference in September that “its sales force included 60 pulmonary specialists to call on every lung doctor in the country.” Company officials claim that this is “all in the context of our education and awareness program.”

In addition to contracting pulmonary physicians to “educate” colleagues at dinners convened for that purpose, InterMune set up a patient “Advocacy Coalition”—according to the Times, $187,000 was provided by InterMune to the "advocacy coalition," of which $170,000 was used to pay InterMune’s public relations firm. InterMune also set up a hot line for doctors and patients to order the drug, and to help them win reimbursement from many insurers. Despite the $50,000 price, the Times reports, they have no problem getting reimbursement fees.

A placebo controlled clinical trial that included 330 patients with pulmonary fibrosis did not show that the lungs of patients taking Actimune improved more than in those taking a placebo. The company seized upon an observation that some patients taking Actimune lived longer. However, the company’s claims about that trial’s findings are disputed by a data safety monitoring committee that observed the trial. The Times reports that committee members “accused the company of exaggerating the drug’s benefits while playing down side effects, like a greater incidence of nonfatal pneumonia.”

The Times notes that “Skeptics also wonder how the drug could prolong life if it did not improve lung function.” This case also reveals the pharmaceutical industry’s influence on the culture of American medicine: “Some doctors say that even if the drug does not work, it is worth trying because it is generally safe.”

But that assumption may be based on "positive" thinking, not evidence. Indeed, “French doctors reported recently that four patients who took the drug had deteriorated rapidly and died.”

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http://www.nytimes.com/2003/04/27/business/yourmoney/27DRUG.html
THE NEW YORK TIMES
April 27, 2003
Talking Up a Drug for This (and That)
By ANDREW POLLACK

EXCERPT:
THE drug Actimmune would not appear to have great sales potential. It is approved to treat only two rare diseases that together afflict just 800 Americans.

Yet sales nearly tripled last year, to $106 million, and its manufacturer expects them to exceed $160 million this year. Virtually all those sales are for an unapproved use: to treat idiopathic pulmonary fibrosis, a scarring of the lungs that afflicts 50,000 to 75,000 Americans and is often fatal.

The sales have stirred controversy about the drug and its maker, a small company called InterMune. Some doctors and patients hail the drug because most patients have no other treatments available and face death from the disease. Critics, however, say the company has been overselling an unproven remedy at a cost to each patient of about $50,000 a year, for injections three times a week.

“We’ve had patients who have been desperate enough to question mortgaging their house or giving up their life savings to get this treatment,” said Dr. Jonathan B. Orens, medical director for lung transplants at Johns Hopkins Hospital in Baltimore. “It’s our responsibility, ethically, to make sure patients aren’t given treatments and false hopes that cost a lot of money.”

A clinical trial completed last year suggested that Actimmune can prolong the lives of some patients with pulmonary fibrosis. But the company concedes that the results of the trial were not strong enough for the drug to be approved to treat that disease. Still, when the trial’s results were announced, the company predicted that sales of Actimmune would reach $400 million to $500 million a year, even without approval.

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“We don’t market it” for pulmonary fibrosis, said W. Scott Harkonen, InterMune’s chief executive, in an interview. “There’s been a lot of interest in the medical community, and we’ve responded to those requests.”

But there is evidence that the company has actively stirred interest. At an investors’ conference in September, it said its sales force included 60 pulmonary specialists to call on every lung doctor in the country — “all in the context of our education and awareness program,” a company executive said. Its annual report for 2002 said profits on Actimmune were low because of royalties and “direct costs of marketing.”

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InterMune’s supporters say its activities help patients and raise awareness of a disease that is hard to diagnose. If that indirectly helps the company, they add, so be it. The supporters include many leading pulmonary fibrosis experts who are advisers to InterMune.

“The company, in my opinion, has done a tremendous service for the disease,” said Dr. Paul W. Noble, an associate professor of medicine at Yale who has given speeches sponsored by InterMune.

Dr. King of San Francisco General, who is also a professor at the University of California at San Francisco and an adviser to InterMune, said, “I’ve always had the feeling the company put the right information out there.” Actimmune is “not a miracle drug, but it does appear to prolong life in a subset of patients.”

One pulmonary fibrosis patient, Alan Raff, 74, of Coral Gables, Fla., says the drug has halted the progression of his disease for three years. Speaking of InterMune’s activities, he said, “I don’t know what’s not to like, because in some cases it’s saving lives.”

Patients with idiopathic pulmonary fibrosis face a grim death, usually two to five years after diagnosis. The scarring of the lungs makes it harder and harder for them to breathe, until they essentially suffocate. The only proven treatment is a lung transplant, but donated lungs are scarce. Steroids are often used — also off label — but many doctors say they do not work and have side effects. The comedian Jerry Lewis, who has pulmonary fibrosis, has become bloated from the steroids.

InterMune, based in Brisbane, Calif., south of San Francisco, is one of a new breed of companies that do not invent drugs but instead license neglected drugs from bigger companies. Though the company has two other drugs on the market, Actimmune accounts for the vast bulk of its sales.

Actimmune is a protein called gamma interferon developed by Genentech, the biotechnology pioneer, which licensed it to Connetics, a small drug company. Dr. Harkonen, who worked at Connetics, persuaded it to license the drug to InterMune, which he formed in 1998.

Though InterMune initially envisioned using the drug to treat infectious disease or cancer, its plans changed in 1999, when a paper published in The New England Journal of Medicine reported striking results from a small trial for pulmonary fibrosis. The trial had only 18 patients, but the 9 who received the drug all had improved lung function, while those in the control group worsened.

SO InterMune organized a big trial, winning praise from doctors and patients. It also began to sell the drug based on the small trial.

The company also started the Coalition for Pulmonary Fibrosis, the advocacy group. As first reported by TheStreet.com, the executive director, Mark Shreve, worked for Edelman Public Relations, which represented InterMune, and the coalition at first was based in Edelman’s San Francisco office. The Internal Revenue Service filing for 2001 from the coalition reports only one donation — $187,000 from InterMune — with $170,000 of it being paid to Edelman.

In an interview, Mr. Shreve said that he had quit Edelman and now ran the coalition from his home near Scottsdale, Ariz. He said that there were now many other donors.

The coalition’s chairman, Dr. Marvin Schwarz of the University of Colorado, also an InterMune adviser, said the group was not a marketing front. “The coalition has never made a statement about the drug that I’m aware of,” he said.

The big trial, involving 330 patients, ended last year and was intended to see whether the drug improved lung function. But the lungs of those who took Actimmune were not significantly better than the lungs of patients who received a placebo.

Somewhat unexpectedly, however, patients who took Actimmune often lived longer. That result was not statistically significant over all. But in a subset of patients with milder disease, there was a large and statistically significant difference: only six who got the drug died, compared with 21 who got a placebo.

The company trumpeted the results in a news release in August. The stock soared, nearly doubling by the end of October.

A committee of independent doctors who had monitored the trial to assure patient safety quickly accused the company of exaggerating the drug’s benefits while playing down side effects, like a greater incidence of nonfatal pneumonia, doctors involved in the trial say.

Dr. Thomas R. Fleming, a biostatistician at the University of Washington and the chairman of the committee, said that he was bound by a confidentiality agreement. But he said, “I do think the subsequent reports the company has given do provide a much more detailed perspective of what was learned at the trial.”

The results have led to a quandary for doctors and patients. Some doctors say it is dangerous to jump to conclusions about survival because the trial was not designed to measure that. Skeptics also wonder how the drug could prolong life if it did not improve lung function.

“It’s not clear what to make of the mortality data,” said Dr. Fernando J. Martinez of the University of Michigan, an adviser to InterMune. He said he suspected that the drug did have some effect, but he has concerns that company marketing officials continue to provide snippets of data before complete results have been published.

Still, some doctors say the hint of a survival benefit is too strong to ignore. “We’re talking about a population that has no shot,” said Dr. Richard Miller, chief of pulmonology at St. Michael’s Medical Center in Newark. “Something is better than nothing.”

InterMune has said that 3,000 patients were being treated with Actimmune at the end of 2002, up from 2,500 three months earlier.

Some doctors say that even if the drug does not work, it is worth trying because it is generally safe. But French doctors reported recently that four patients who took the drug had deteriorated rapidly and died. Those patients, however, were far sicker than the ones in InterMune’s trial.

Karen Burnard of Finesville, N.J., said she thought Actimmune had contributed to the death in March of her brother, Jack Dwyer, a 64-year-old middle-school teacher who lived in Alloway, N.J.

Actimmune made him sick and unable to eat, Ms. Burnard said. “Food tasted like metal, and by the end he had lost 57 pounds,” she said. He stopped taking the drug, she said, but by then was too sick to qualify for a lung transplant.

Recent developments have dimmed Wall Street’s view of the company’s prospects. In January, InterMune announced that the survival benefit conferred by the drug on patients with milder disease had diminished somewhat when they were followed for three to five additional months, though the difference was still statistically significant.

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Copyright 2003 The New York Times Company

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