The debate over potential bias at the Duke Clinical Research Institute emerging fro this morning’s Avandia hearing inspired a trip to the archives. This story looked at many of the same issues, which came up when the Duke clinical trials operation was young.
By Tinker Ready
from The Raleigh News & Observer
Genentech and university researchers wanted to ensure that a study of the comparative effectiveness of tPA was definitive. Critics say they failed.
By TINKER READY and TRISH WILSON
THE NEWS & OBSERVER
All corporate research spending on campus isn’t aimed at inventions. Sometimes the goal is to torpedo a competitor.
That was the hope of Genentech, a San Francisco biotechnology company. It paid $55 million for a study comparing its heart attack drug to a far cheaper drug cornering the market for thrombolytics. The drugs dissolve blood clots and reopen arteries after a heart attack.
The study — completed last year — was coordinated at Duke University, where researchers said their goal was to determine which method of using the two drugs would save more lives.
Genentech’s sponsorship of the massive study raised eyebrows, but the company tried to reassure the medical community that the study would be unbiased. A previous tPA study had been dogged by charges of conflict of interest, and Genentech wanted to avoid a replay.
The company chose Duke University to coordinate the research because it had a relationship with Duke scientists and their collaborators, who had worked with tPA in the past.
“If Genentech was forking over the money, they wanted someone to run the study who they trusted, ” said Robert Califf, a Duke cardiologist and the study’s clinical director.
The company also had reason to trust Ralph Snyderman, the top administrator at Duke’s medical center and former Genentech executive. Snyderman left Duke to join Genentech in 1987 as director of research and development. While there, he successfully ushered tPA through a long and contentious Food and Drug Administration approval process before returning to Duke in 1989.
In the end, Genentech’s study paid off. After examining medical records of 41,000 heart attack patients in 15 countries, researchers announced that Genentech’s tPA (about $2,200 a dose) was superior to streptokinase (about $300 a dose). They concluded that the prompt use of tPA could reduce by 14 percent the number of people who died from heart attacks.
Eric J. Topol — a cardiologist at the Cleveland Clinic Foundation and chairman of the study — claimed victory for tPA.
“We have to put to rest this battle of the thrombolytics, ” Topol said at an April 1993 news conference in Washington. “Accelerated tPA was significantly better.”
That day, the price of Genentech stock jumped $4.75 a share to $37.50.
Not everyone shared the stock market’s optimism. Some doctors thought the results were ambiguous and failed to reflect tPA’s risks, particularly a higher incidence of stroke among users.
One member of the steering committee — streptokinase advocate Victor Marder — said Genentech had generated what it wanted.
“On the face of it, Genentech was not part of the decision-making apparatus, ” said Marder, the chief of hematology at the University of Rochester medical school.
On the other hand, he said, the test was not a fair comparison. It compared a hyped-up dose of tPA to a standard dose of streptokinase, Marder said. In addition, he said, he did not think the study properly accounted for the disproportionate number of tPA patients who might have done better because they had undergone heart bypass operations.
When he tried to raise these issues to the steering committee, “everybody got really angry, ” Marder said.
Marder thinks the study fails to prove that tPA is better.
“I don’t think it’s dishonest, he said. “I think it was an exaggerated conclusion made to influence people.”
Califf said that Marder is off the mark. The comparison between the two drugs was valid, he said, and the study accounted for the bypass operations.
Soon, Marder and other critics will be able to see that for themselves, because all the data is about to be published in 40 manuscripts.
“Anyone can look at it and draw their own conclusions, ” Califf said.
Califf doesn’t deny that Genentech had a huge stake in the outcome. But he vehemently denies that the study was designed with a foregone conclusion.
The project began when Califf and Topol — who had done research with tPA — began talking to Genentech about a larger study. At the time, the company was trying to cope with 1990 Italian study that found no significant difference in tPA and streptokinase.
By the time a second damaging European study came out in 1992, Genentech was ready. The company promised that a new, bigger study would definitively prove whether tPA was safer and more effective than its low-cost rival.
That study — know as GUSTO for Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries — was headed by Topol. Duke, with its massive cardiac computer data bases, served as a data clearinghouse.
“They needed to do this study, ” Califf said. “They were losing market share. We were very concerned that the European studies had missed the point.”
Both the company and the researchers wanted to make sure the findings were above question, he said.
The company had good reason to expect skepticism. In 1989, a congressional investigation found that 11 of the researchers involved in the original, federally sponsored studies of tPA owned Genentech stock. That stock became much more valuable when the FDA approved the drug.
So, when GUSTO trials came along, Genentech set up an independent steering committee to run them. None of the researchers could own Genentech stock, nor could they consult for the company until at least a year after release of the final results.
Genentech staff say that Snyderman played no role in bringing the study to Duke. Snyderman said in a recent interview that he still consults for Genentech and will continue to do so for the next couple of months.
“There was absolutely no conflict of interest, ” Snyderman said.
Califf called GUSTO’s ethical precautions “draconian.” Genentech staff saw none of the data and had no role in running the study, he said.
“The risk that Genentech had to take is that they had no control over this trial, ” he said.
Califf said his goal was not to compare the clot busters — it was to find out if a doctor can save more lives if he moves faster to open arteries after a heart attack.
Still, if the study also proved that Genentech makes a better drug, and its corporate fortunes turned around, more power to the company.
“I will not make apologies for industry being involved, ” Califf said. “That’s the American way.”