November 14, 2000-Case Study: The Diet Drug Redux
Lisa Wiehard wasn't paying attention to concerns over the safety of a hot new diet drug when she began swallowing the pills in 1997. Spring was approaching, and the 34-year-old nurse was intent on dropping a few pounds in time for beach weather. Almost immediately, Wieghard suffered coughing fits and had trouble breathing. But she had also shed 7 pounds in a single week, and that was enough to make her forget about the side effects.
Wieghard was among the 2 million Americans who clamored for Redux after it was approved by the Food and Drug Administration in April, 1996. At the peak, doctors were writing 85,000 new prescriptions a week. But a little more than a year after the drug's debut, the Redux craze collapsed, as patients began showing up in doctors' offices short of breath and with hidden damage to their hearts and lungs.
The FDA forced the drug off the market in September, 1997. Blame was heaped on over-eager company officials, on compliant FDA officials, on careless physicians.
But largely overlooked is the critical role played by prominent academic scientists with financial links to the manufacturer.
Benefits were hyped; risks minimized. From the beginning, university researchers helped the company navigate a gauntlet of regulatory and marketing obstacles with a message remarkably in step with the drug maker's mission.
Douglas Petkus, a spokesman for Wyeth-Ayerst, the U.S. distributor of Redux, said that industry ties to academia are commonplace and that there was nothing unusual about Wyeth's relationships with obesity experts.
"It's common, it's good practice and it's good science. From our perspective, none of this is out of bounds."
But company documents, court records and interviews offer insight into the danger posed by growing ties between academic science and private industry.
"This is anything but science," said Lynn McAfee, director of the Council on Size and Weight Discrimination, an advocacy group based in Philadelphia. "It's not so much that individual researchers are throwing the game; it's more that it creates an atmosphere that does not foster looking critically at research."
Redux had powerful voices on its side in the fall of 1995, when corporate backers and obesity experts descended on Rockville, Md., for the first of two FDA hearings.
The crowd was a Who's Who of obesity research. There was JoAnn Manson of Harvard, who just that month had a major article published in the New England Journal of Medicine; Theodore Van Itallie of Columbia University, who was introduced as one of the country's leading obesity researchers; George Bray of Louisiana State University, the editor in chief of Obesity Research.
There was Gerald Faich of the University of Pennsylvania, a former FDA official and expert in epidemiology; Theodore Cicero of Washington University, an expert on drug addiction who spent six years heading an FDA advisory committee; Louis Lasagna of Tufts, a consultant to the National Institutes of Health and the FDA.
They were all there as paid consultants to Wyeth-Ayerst or the other companies involved in making and selling Redux. Faich's task, at this hearing and a subsequent one, was to persuade the FDA that the benefits of Redux outweighed any potential risk.
The FDA had originally insisted that to win approval, Redux would have to produce an average weight loss of 10 percent. After disappointing early results, the agency dropped the bar to 5 percent, the equivalent of a 240- pound person losing 12 pounds.
When the drug couldn't reach that goal either, the agency indicated it would look favorably on Redux if a significant number of patients hit the 5 percent mark.
But even that wouldn't fly if the company couldn't show Redux was safe. And they faced a serious obstacle in the form of a rare and often-deadly lung ailment called primary pulmonary hypertension, or PPH. Some studies, the FDA was told, had shown an increase in PPH among patients in Europe who took a drug identical to Redux.
Faich said his research showed Redux would prevent many more health problems than it would create. Patients who lost even a modest amount of weight, he said, would be less likely to suffer diabetes, heart disease and other ailments. But when Faich calculated the benefits of losing weight with Redux, he included the effect of strict diet and exercise - which accounted for two-thirds of the lost pounds. Faich said that was fair because patients would never lose that much weight without the discipline that would come with a physician-supervised prescription-drug therapy.
Panel member Jose Francisco Cara, a pediatrician at Henry Ford Hospital in Detroit, suspected just the opposite - that patients were less likely to be serious about diet and exercise if they were taking a drug. "People will see this as a quote-unquote 'magic pill' that will substitute for behavioral changes," he said. Other panel members agreed. "With all due respect to Dr. Faich," Cathy Critchlow of the University of Washington said during the hearing, "I think the benefit-to-risk ratio was probably vastly overstated in his presentation."
Despite concerns, the expert panel narrowly endorsed Redux, and in April, 1996, the FDA formally approved the drug. In an effort to find voices that would carry weight with practicing physicians, the company recruited academic researchers to aid in the campaign.
In 1994, Wyeth signed a $180,000 contract with a New Jersey medical publishing company called Excerpta Medica that offered pharmaceutical companies an invaluable tool: ready-made scientific articles, placed in leading medical journals, and carrying the imprimatur of influential academic leaders. According to company documents, Excerpta laid out for Wyeth a schedule of nine articles, each with a carefully crafted message aimed at a carefully targeted audience, from primary-care physicians to cardiologists to nurse practitioners to pharmacists.
The articles would have a "writer" and an "author." The writer was a freelancer who was paid $ 5,000 to actually research and write the articles. The author was often a top university scientist who was paid $ 1,500 to review the work and assign his or her name to it for publication. Both Excerpta Medica and American Home Products, now the parent company of Wyeth-Ayerst, have defended the practice, saying academic authors had final say over the manuscripts.
"I do believe that there is a perception that if a pharmaceutical company is involved in writing an article, it is automatically suspect," Jo Alene Dolan, who was medical monitor for Redux at Wyeth-Ayerst, testified in a deposition. "That is not necessarily the reality."
But company officials frequently tinkered with the text of the articles, removing unflattering references to the chemical compound in Redux - dexfenfluramine - or deleting positive references to other drugs. In one article, for example, an early draft read that a recent study " found that the use of anti-obesity drugs, including dexfenfluramine, was associated with an increased risk of primary pulmonary hypertension. The risk was especially great for long-term users."
After Wyeth reviewed the draft, the reference to dexfenfluramine and the sentence about long-term use were crossed out. Petkus, of Wyeth-Ayerst, said it was common practice in the pharmaceutical industry to have articles written by freelancers and signed by prominent scientists. When asked about the changes, Petkus said Wyeth employees reviewed the articles only for accuracy and said all changes were made objectively. And he said the scientists were always welcome to suggest revisions.
"The bottom line," Petkus said, "is that these medical professionals have the final editorial say." Lisa Wiehard was not a good candidate for diet drugs. The FDA had intended for Redux to be prescribed to only the truly obese, and at 5-foot-3 and 145 pounds, she was 25 pounds below the threshold. "Really, it was just vanity reasons. It wasn't for health reasons. That was the most stupid part of the whole thing," said Wieghard, who lives in Las Vegas. "I didn't have health problems. I didn't have heart disease. I was just a vain 34-year-old woman."
Wieghard had started on Fen-Phen, but switched to Redux after a few weeks because of breathing problems. But the problem only got worse. Still, as the pounds continued to disappear, Wieghard kept going back for more. But while Wieghard and other patients were lining up for Redux, Lucien Abenhaim, a Canadian researcher, was studying a cluster of cases of primary pulmonary hypertension among patients who took diet drugs - principally dexfenfluramine - in Britain, France, Belgium and the Netherlands.
Abenhaim concluded that patients who took anti-obesity drugs for three months or less were 1.8 times more likely to suffer primary pulmonary hypertension. But for patients who took the drug longer than three months, the risk of contracting the disease increased dramatically, to 23-fold. Abenhaim's research was powerful, but the editors of the New England Journal of Medicine felt it was important to put it in perspective. So they began looking for obesity experts - without industry ties - to write an editorial to accompany the new study.
"Sometimes we have to go down the list a couple of times in order to find somebody who does not have a financial conflict of interest, because financial conflicts of interest are pretty widespread in the academic community," said Jerome Kassirer, a former editor of the journal. And who was tapped to comment on Abenhaim's study? JoAnn Manson and Gerald Faich, who had both spoken on Wyeth's behalf at the FDA.
Their conclusion: "The possible risk of pulmonary hypertension associated with dexfenfluramine is small and appears to be outweighed by benefits when the drug is used appropriately."
When the manuscript first came in, Kassirer thought it was exactly the perspective he wanted. Paging through the article, he found it an intelligent evaluation of the risk of Redux against the risk of obesity. He jotted "interesting" in a margin and signed off on the piece. Soon after publication, however, editors at the journal learned that Manson and Faich both had financial ties to the companies involved in making and marketing Redux. Manson had been hired solely to speak at the FDA, while Faich had helped Wyeth-Ayerst and the European manufacturer of Redux develop methods for studying the link between the drug and PPH. The editors apologized for printing the article.
"I went back and read the editorial, and now I wasn't sure what to believe," Kassirer said. The episode touched off a controversy. The editors of the journal said the writers - particularly Faich, who had consulted for Wyeth the same month the article was written - had split hairs about what constituted the journal's strict prohibition on "regular" and "ongoing" financial ties for editorial writers. Manson and Faich said they told editors of their financial ties to Wyeth- Ayerst and the other companies involved in making Redux, but that editors misunderstood the nature of the consulting deals. Faich, who has since left academia, did not respond to telephone messages and to a list of questions faxed to his home at his request. But in the nasty aftermath, Manson says her scientific study - and her reputation - were unfairly smeared.
"It's not like I was consulting for this company and then did research on dexfenfluramine," Manson said. "I was doing no research on dexfenfluramine." Manson said she was paid a "very modest amount" to go to the FDA hearing and present the results of her research on the dangers of obesity. But she said her research was completed long before she was contacted by Wyeth-Ayerst.
"There is no way that anything that I said in that editorial would have been any different if I had never, ever had anything to do with them. I just wrote what I believed to be the science," she said. "Scientists are not going to sell their opinions for a few billable hours. That's just an outrageous concept." At the famed Mayo Clinic in Rochester, Minn., cardiologist Heidi Connolly was tracking a suspicious pattern. A patient who had undergone surgery to repair a rare problem in one of her heart valves had returned in the summer of 1996 for treatment of the same condition in a second valve.
Five months later, another patient came in with damaged heart valves, and soon after that, Connolly heard of a doctor in Fargo, N.D., who had seen several more cases. By March, the count was up to 24. Based on their medical histories, none of the women was at risk for developing heart-valve problems. But all had been taking the wildly popular diet-drug combination known as fen-phen. The drugs in the cocktail were phentermine and fenfluramine, a chemical cousin of the drug in Redux.
Connolly asked officials from American Home Products - which distributed both fenfluramine and Redux - to come to Minnesota, where she spent four hours walking company officials through case histories and echocardiograms. The company concluded that more study was needed. Connolly wrote up what she had seen and submitted it to the New England Journal. The story was scheduled to run Aug. 28, but given the urgency of the situation, editors at the journal invoked a rare exception to their rule that forbid the release of data before publication.
On July 8, 1997, Connolly leaned into a microphone at a Mayo Clinic conference room and calmly uttered a sentence that would spell the end of Redux. "Today," she began, "my colleagues and I from the Mayo Clinic report a new clinical observation of a possible relationship between heart valve disease and fen-phen." Later that day, the FDA rushed letters to 700,000 physicians warning of the potential dangers of both fen-phen and Redux. Wyeth-Ayerst said the new study was "inconclusive" and that further studies "must be conducted before any possible link can be confirmed."
But regulatory officials were seeing an epidemic of their own. By the end of July, as more reports of valve damage came in, the FDA forced American Home Products to add a warning to the Redux label about potentially serious side effects. Sales began to slip, while reports of heart damage and death continued to come into the FDA.
On Sept. 15, 1997, with 90 known cases of valvular heart disease, the agency asked Wyeth to pull the drug off the market. Sales stopped that day. In August, a federal judge approved a $ 3.75 billion settlement of class-action lawsuits filed against American Home Products by diet-drug patients. Wieghard, one of millions who will be entitled to money, is looking forward to having the legal settlement pay for medical tests to determine if there is lasting damage to her heart or lungs. She stayed on Redux for about two months before the side effects scared her off the medication. Soon after, her breathing problems subsided - and all the weight came back.
Today, Wieghard keeps to a strict low-fat diet and walks several miles a day to stay fit. "If I knew then what I know now, I wouldn't have put one single pill in my mouth," Wieghard said. "I'd rather be fat and alive, than thin and dead."
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