Twenty-eight men and women were already dead while an expert panel of the US Food and Drug Administration (FDA) were huddled together to decide what government regulators should do about Warner-Lambert’s controversial diabetes drug Rezulin. They knew about reports that the risk of liver failure associated with the drug was perilously high. But nine prominent university researchers who testified before the committee, downplayed concerns that the drug was killing patients. The scientists, from Harvard, UCLA and other schools, all urged the Food and Drug Administration to keep Rezulin on the market. Interestingly, all the nine scientists had financial ties to the drug’s manufacturer. Another year would pass – and 33 more deaths would be reported – before Rezulin was pulled from the market in March 2000.
An estimated 2 million Americans got hooked on to Redux (dexfenfluramine), a new anti-obesity drug marketed in the US by Wyeth-Ayerst (now amalgamated in American Home Products), after it was approved by the US Food and Drug Administration in April 1996. At its peak popularity, doctors were writing 85,000 new prescriptions a week. But a little more than a year after the drug’s introduction, the craze for Redux collapsed, as patients began to exhibit symptoms of damage to their hearts and lungs. Fearing an epidemic, the FDA banned the drug in September 1997. Numerous lawsuits followed and blame was heaped on over-eager company officials, compliant FDA officials, and careless physicians.
But largely overlooked in these episodes is the critical role played by prominent academic scientists with financial links to the manufacturer. From the time approval was sought for Redux, university researchers helped the company negotiate regulatory and marketing obstacles with “evidence” remarkably in line with the drug company’s mission. Company documents, court records and interviews provide an insight into the danger posed by scientists having ties with industry. Redux received endorsements from a galaxy of scientists at the FDA hearings which were held to approve the drug. The hearings were attended by a crowd that was akin to a Who’s Who of obesity research. And they were all there as paid consultants to Wyeth-Ayerst or the other companies involved in manufacturing and marketing Redux.
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. When the drug couldn’t reach that milestone either, the agency indicated it would approve Redux if a significant number of patients hit the 5-percent mark. In addition, however, the company had to show that Redux was safe. It was known that Redux increased the risk of contracting a rare and often-deadly lung ailment called primary pulmonary hypertension. Despite such concerns, the expert panel narrowly endorsed Redux, largely due to positive endorsements by the specialists.
The Redux Story doesn’t stop here. 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 signature of influential academic leaders. 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 had a “writer” and an “author” – but they weren’t the same person. The writer was a free-lancer who was paid $5,000 to do the actually researching and writing 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. Company officials tinkered with the text of the articles, removing unflattering references to Redux, or deleting positive references to other drugs. In one proposed 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.
These incidents focus on the growing reliance of university scientists on corporate funding, which is threatening the basic tenets of openness, honesty and objectivity in academic medical research. As government grants continue to shrink, corporate money has produced a profound shift that has introduced the values of the marketplace to university science. The scientific community has responded by saying that industry cash fuels discovery and, moreover, that no amount of money can corrupt a researcher who is trained to seek the truth. But a review by Courant, a small newspaper in the US, of more than 40 recently developed drugs, as well as interviews with dozens of researchers across the nation, has found that scientists are getting answers in their research that neatly fit the agenda of their corporate sponsors.
Although the federal government remains the primary source of funding for academic medical research in the US, the amount and influence of corporate cash has grown dramatically over the last 20 years. The above study by Courant quotes Dr. Allen Arieff, of the University of California, who says, “The drug companies make it very clear what the results had better be if you want any more money from them.” Arieff had been hired to test a popular diabetes drug, but when he publicly presented research results showing the drug had dangerous side effects, his five-year grant was summarily stopped after only two years.
The infamous case of Betty Dong dramatically illustrates how the clash between the values of scientists looking for answers and corporations looking for sales can hurt consumers. When the maker of a popular thyroid drug wanted to find out if the drug was better than the less expensive generic drugs on the market, they turned to Dong, a prominent researcher at the University of California at San Francisco. Dong found that generic substitutes worked just as well in controlling people’s thyroid problems. The manufacturer, Knoll Pharmaceutical, challenged the results, attacked Dong’s work and told her she couldn’t publish the study. For more than five years Dong’s findings were suppressed, only surfacing in 1996 after details of the episode became public.
As the ties between academia and industry grow, researchers play the twin roles of objective evaluator and paid company spokesman. Virtually every pharmaceutical company has a scientific advisory committee made up of researchers who are paid to give talks at hospitals and scientific conferences.
A Closed Nexus
Growing links between researchers and pharmaceutical companies have made it difficult — often impossible — for doctors to get unbiased information on the safety and effectiveness of newly introduced drugs. There are instances where as high as 90 percent of the published information on a medication is sponsored by the very industry that designed the medication.
In spite of all these concerns, the scientific community still holds the notion that it is impossible to “doctor” the outcome of a well-designed study. But many studies that have examined whether scientific outcomes are influenced by financial ties, point to a problem.
One of the most comprehensive studies by a team of Canadian researchers examined the safety of a group of drugs called calcium-channel blockers, that are used to treat high blood pressure and cardiac pain. The team’s conclusions were published in the New England Journal of Medicine in 1998. After analyzing 70 studies, the researchers found that while 96 percent of authors who wrote favorably about calcium-channel blockers had links with manufacturers, only 37 percent of the critical scientists had relationships with the industry. Another survey in1996 looked at the increasing practice of releasing new information at scientific gatherings, rather than in peer-reviewed journals. The survey found that studies financed by drug companies were more likely to support the drug in question than were those without financial backing from the industry. Other studies have found that scientists who get money from private industry are more likely to keep secrets from their colleagues and wait longer to publish the results of their research — trends that run counter to the ideals of open and honest exchange of information.
Faculty researchers have long been expected to cover a portion — often a majority — of their salary through outside grants from public or private sources. As the US government budget tightened, industry-sponsored research took pressure off schools and faculty members to come up with funding for their sustenance. Corporations are famous for their generosity with contract money. When faculty members at Harvard do corporate-funded research, for example, the companies are charged an add-on fee as high as 69.5 percent to cover the university’s indirect costs. Also, drug companies pay for much more than the true direct and indirect costs of the sponsored research.
With universities under pressure, consumers look to the Food and Drug Administration for protection. But the FDA, long criticized for its slow pace in approving drugs (which often meant a rigorous approach to approval of new drugs), began facing pressure in the 1980s to approve new therapies. Over the last five years, the FDA has approved a record number of drugs at a record pace — with a record number of the new medicines later pulled off the market for safety issues. The FDA also relies heavily on the same academic researchers who have taken money from industry. The cycle is thus complete — a closed nexus between the manufacturer, the evaluator and the regulator.