Healthy Skepticism Library item: 16538
Warning: This library includes all items relevant to health product marketing that we are aware of regardless of quality. Often we do not agree with all or part of the contents.
Publication type: news
Hundley K
Researcher who saved countless lives takes on big pharma — and pays the price
St Petersburg Times 2009 Sep 26
http://www.tampabay.com/news/health/article1039179.ece
Full text:
For two decades, Dr. Dennis Mangano has collected data on patient care from nearly 300 medical research facilities around the world. His goal: discover ways to prevent heart attacks and strokes during and after surgery.
It has often put him on a collision course with major drug companies.
He found that taking low-cost aspirin after bypass surgery reduces the risk of heart attack. He sounded the alarm about the deadly risks of using Bayer’s drug Trasylol to control bleeding during bypass surgery – nearly two years before the FDA suspended marketing of the drug.
And he warned that Pfizer’s painkiller, Bextra, raised the risk of heart attack and stroke in bypass patients. Bextra was pulled from the market in 2005.
“He’s made a series of unique, important observations that appear to be seminal,” said Dr. Eric Topol, a cardiologist who wrote the editorial accompanying Mangano’s ground-breaking article on aspirin. “No one is doing the same thing he is with his perioperative database.”
Now Mangano is embroiled in his biggest fight against pharma, having accused Pfizer of stealing information from his database.
Mangano won the battle – but lost the war. The blow has been so devastating that the future of his independent, data-driven drug research, which has saved thousands of lives, is in serious jeopardy.
• • •
An anesthesiologist who had directed intensive care units and operating rooms, Mangano was well aware of the incidence of surgery-related heart attacks and strokes.
In 1987, he started the Ischemia Research and Education Foundation south of San Francisco. By collecting data on tens of thousands of patients worldwide, his nonprofit foundation hoped to identify which therapies helped and which hurt.
Dr. Zak Hillel, director of cardiac anesthesia at St. Luke’s-Roosevelt Hospital in New York City, said the collaboration was unique among cardiologists and anesthesiologists.
“It was driven by intellectual curiosity to look at what goes on with these patients who have risk for ischemia, or a lack of oxygen to the heart; how they fare when they go to surgery and what factors influence the outcome,” Hillel said. “It’s a very noble endeavor.”
Mangano and his colleagues spent more than a decade tracking Trasylol, a drug the FDA approved in 1993 for reducing blood loss during bypass surgery. Comparing the outcomes of more than 4,000 patients treated with Trasylol versus two different agents and a placebo, Mangano concluded that the Bayer drug increased the risk of renal failure and heart attack.
In January 2006, the New England Journal of Medicine published Mangano’s paper, which said the alternatives were as effective, safer and cheaper – as little as $11 a dose compared with $1,400 for Trasylol.
Nine months later, Mangano defended his findings before an FDA advisory committee. The panelists said he had not accounted for the high-risk condition of patients receiving the drug, while Bayer defended its safety. The FDA panel voted unanimously in support of Trasylol.
Days later, a researcher called the FDA with startling news: Bayer had conducted its own review of 67,000 bypass cases, and its findings matched Mangano’s.
Bayer executives apologized, saying they had mistakenly neglected to mention the study to FDA advisers. But it wasn’t until more than a year later, after a Canadian Trasylol study was halted because of increased risk of death, that the FDA stopped sales of the drug.
Mangano estimated that about 22,000 Trasylol-related deaths occurred between the time he first warned about the drug and the date it was removed from the U.S. market – about 1,000 deaths for each month of delay.
• • •
Because Mangano’s foundation, the IREF, collected a unique set of data, drug companies found it a valuable resource for studies. Using the proceeds to fund the IREF’s independent research, Mangano sold access to the data with one caveat: He retained the right to publish safety results from their investigations. That way, a drug company could not study its drug, find that it was unsafe and hide the results.
In 1999, Pfizer paid the IREF $4 million for help designing a study on the effectiveness of Bextra after bypass surgery. The study of 450 patients found that Bextra increased the risk of heart attacks, strokes, gastrointestinal problems and wound infections. Mangano wrote an article detailing the findings.
The FDA approved Bextra in late 2001 for limited use for pain related to arthritis and menstrual cramps. Pfizer, eager to expand the drug’s use for acute pain, embarked on a larger study of bypass patients.
Mangano offered Pfizer access to bigger databases for $15- to $20 million. Pfizer declined.
Mangano said money wasn’t the issue. “They didn’t want to deal with me because my mandate has always been, whatever I find, I publish, good, bad, indifferent.’‘
In 2004, Mangano says he discovered that Pfizer had found another way to gain access to the IREF’s database: pay an employee to steal it.
He filed a lawsuit alleging that Ping Hsu, an IREF statistician, “ravaged” the foundation’s databases and helped Pfizer gain critical information for its drug trial.
“Ping accessed our data to do more than 159 sophisticated analyses for Pfizer,” said Mangano, who fired Ping after finding incriminating e-mails on his computer. “This was a database that took us $70 million to accumulate, and big pharma was getting it for free.”
Before the case went to trial in California Superior Court late last year, Mangano said Pfizer offered $24 million to settle. “I refused,” he said. “I wanted a jury of peers to hear the case.”
The trial lasted six weeks. Hsu’s defense was that he exercised bad judgment but did not steal. Pfizer said it was unjustly caught in the crossfire of a dispute between the IREF and a former employee.
The jury found both Pfizer and Hsu guilty on all counts and awarded Mangano and his nonprofit nearly $39 million in damages, plus $19 million interest. Mangano’s gamble appeared to have paid off.
“It’s very risky going against a big company like Pfizer but the right thing has been done,” he said after the verdict on Dec. 22. “They were willing to profit at the expense of patient safety, something I have fought against my whole life.”
• • •
Mangano, whose accent still reflects his Brooklyn roots, is, by many accounts, monumentally stubborn and notoriously prickly. In 1997, the IREF paid $25 million to settle a lawsuit by his employer, the University of California at San Francisco, which said Mangano diverted drug company grants to his nonprofit foundation.
But Jay B. Hunt, a lawyer and businessman who headed the IREF’s board until last fall, said he agreed to contribute his time to the nonprofit foundation because of Mangano’s genius.
“Dennis is not the world’s easiest person to get along with because he’s absolutely committed to doing the right thing, the things that can save human lives,” he said. “People with that kind of passion can sometimes be difficult.”
Mangano’s longtime friend and research associate, Dr. Paul Barash, is more blunt.
“It’s torturous working with him (on studies) because he’s so demanding,” said Barash, professor of anesthesiology at Yale University. “He will do anything if he feels he’s right, particularly in an area where patient care is concerned.”
Which might explain why Mangano rejected Pfizer’s settlement offer of $24 million, against his board’s advice. For seven months, he got to revel in his triumph.
But two months ago, the trial judge threw out the jury verdict.
Though the jury decided that Pfizer was equally as guilty as Hsu for stealing the IREF’s trade secrets, Judge Gregory H. Ward ruled: “The weight of the evidence established that Hsu acted without the knowledge and consent of Pfizer,” Ward wrote. He granted the company a new trial.
Jury foreman Jeffrey Frenster said the jurors took the news as a slap in the face. “We were shocked and deflated,” he said. “We didn’t find the testimony of the vast majority of Pfizer witnesses to be credible.”
Said Pfizer spokesman Chris Loder: “We continue to believe that the allegations in this case have no merit.”
Mangano says he can’t afford another round with Pfizer, which had $44 billion in sales last year. At 66, with four young children, Mangano says he ransacked his retirement account and spent $15 million for the first trial.
His nonprofit foundation, which had 80 employees, is down to three; it’s running millions of dollars in the red.
“We’re out of money,” said Mangano, who was contacting a lawyer this week about filing bankruptcy for the nonprofit. “We had enormous legal fees and we have very little recourse. Maybe I was too headstrong.”
He has little faith the drug company contracts that funded the IREF’s independent work will return.
“Once you sue a pharmaceutical company, and you go on 60 Minutes as the whistle blower who cost Bayer Trasylol sales, you’re persona non grata,” he said. “No one wants to do business with you.”
• • •
Bextra, a Cox-2 inhibitor similar to Merck’s banned drug Vioxx, proved to be a major headache for Pfizer. The results of the company’s second trial of Bextra, the one for which Mangano said his nonprofit’s data was misappropriated, showed the same kinds of safety concerns as the initial, smaller study.
The FDA rejected the expansion of Bextra’s use for surgical pain and then removed the drug entirely from the market.
This month, Pfizer finalized a $2.3 billion settlement with the federal government on charges that it marketed several drugs for unapproved, off-label uses.
As part of the record-breaking fine, a Pfizer subsidiary pleaded guilty to a criminal charge related to its promotion of Bextra for unapproved uses, including surgical pain.
Bextra’s upside for Pfizer? In just over three years, the painkiller posted sales of nearly $2.5 billion.
