Several bloggers have been following the saga of Ezetimibe (Zetia, Vytorin), the hidden data, and the threats to science which have resulted from the way in which Merck and Schering-Plough have thrown the usual safeguards of science into the gutter.Earlier this week Schering-Plough CEO Fred Hassan spoke for 45 minutes at Morgan Stanley’s "Pharmaceutical CEOs Unplugged" conference. He tried to assert that the ENHANCE trial was unimportant anyway as it wasn't being counted on for anything. Also, it was a study conducted in a very rare population of patients and has no implications for the general population of patients with hypercholesterolemia.
Obviously, ENHANCE was THE study designed to demonstrate that ezetimibe has an impact on atherosclerosis. Any impact at all would be nice, since no clinically relevant benefit of Ezetimibe was demonstrated prior to licensing of the agent.
Scientific malfunction is fine when studies can be deemed (in retrospect) by important CEOs to "not matter anyway".
When individual scientists conduct themselves in such a way as to cause our understanding of science to be disturbed, then (unless they are very important people) they get thrown out of science, imprisoned, and their future "findings" are not believed. The rules of participation and believability are different for corporate "science".
Schering-Plough is of course the company that writes £10,000 checks to doctors in exchange for prescribing their drugs.
Schering-Plough clearly has a record, as does Merck. The examples are many. In 1999 it was reported that deaths in clinical trials involving gene therapy were being hidden on demand from companies who were worried that it would "have an impact on their business". The Washington post reported in that "Scientists and drug companies have failed to notify the National Institutes of Health about six deaths that occurred in gene therapy experiments in the past 19 months". Researcher Ronald Crystal "cited concerns about the impact on his business if the death were made public". "Schering-Plough also had demanded confidentiality for three recently filed reports of serious patient illness during gene therapy trials. The lead scientists in two of those studies determined that the complications "probably" were caused by the gene therapy; Schering-Plough officials had downgraded those assessments." It was then reported that Schering-Plough Corporation and the University of California had done preliminary trials in dying cancer patients, but "lowered the dose when two early participants experienced serious drops in blood pressure" (Nelson, Deborah, and Weiss, Rick. Hasty Decisions in the Race to a Cure? Gene Therapy Study Proceeded Despite Safety, Ethics Concerns. Washington Post November 21, 1999: A1, A26-A27 [Link]). These were not reported, and later trial participants were not informed.
Actual people died.
Wilson (the researcher) said: "If a mistake was made, we've got to own up to it and learn from it. Ultimately, the tragedy of Jesse's death would be if we don't learn anything."
What have we learned over 8 years Dr Hassan?
As Ben Goldacre writes in Bad Science, "the data belongs to the patients who gave it to you". Our patients deserve better Dr Hassan. Science deserves better.
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Here's the latest on this:
Inside Schering And Merck's Secret Panel
Matthew Herper, 01.11.08, 6:00 AM ET
Details on how a controversial change was made in a study of their cholesterol drugs Zetia and Vytorin.
When Schering-Plough (nyse: SGP - news - people ) and Merck (nyse: MRK - news - people ) announced Nov. 19 they had been advised to change the scientific goal of a long-delayed clinical trial comparing the effectiveness of their blockbuster cholesterol Vytorin to a generic, the decision drew press scrutiny, criticism and a Congressional investigation.
More controversy: Forbes has learned that the lead investigator charged with conducting the study, John J. P. Kastelein of the University of Amsterdam, was not even present when the companies made the controversial decision to change its goals, an unusual circumstance in such situations.
It's "shocking" that Kastelein would not be party to discussion of the ENHANCE trial, says Harlan Krumholz, a cardiologist at Yale University. "There should be a scientific committee that's independent running a study. He should be taking a leadership role."
Asked about Kastelein not being present, Lee Davies, a Schering-Plough spokesman, said only, "I will confirm that this was an independent expert panel." Kastelein could not be reached for comment Wednesday or Thursday, but in the past he has said he disagreed with the company's decision to change the endpoint of the trial. In an interview with The Wall Street Journal in December, he said he breathed a "sigh of relief" when it was changed back.
It's just the latest issue involving the study. ENHANCE, as the study is known, tests whether the cholesterol drugs Zetia and Vytorin, which together generate $5 billion annually, do a better job than a cheap generic at clearing plaque out of the arteries. For more than two years, the company delayed releasing the results of the study. Then, on Nov. 19, after Forbes questioned Merck and Schering about the delays, the companies said they would present the study in March, but would change its main goal.
On Dec. 11, the companies backtracked, saying they would not make the change after all. That same day, the House Committee on Energy and Commerce expressed concern about "the delay in releasing the results of the study, the timing of ENHANCE trial registration and the apparent manipulation of trial data."
"You just don't change a primary endpoint in a major important trial partway through," says Bruce Psaty, a drug safety expert at the University of Washington.
Schering-Plough and Merck insist the ENHANCE study, though troubled, is only one trial testing their cholesterol drugs. Other trials to see if the drugs reduce heart attacks, strokes and deaths better than older treatments are under way. New techniques used in the study, such as using ultrasound to measure artery plaque, are generally difficult, and not as well understood as cholesterol lowering, they say. They say they have only had the best intentions toward answering the scientific questions posed by the study.
"We pull together panels and seek expert advice on an ongoing basis," says Schering-Plough spokesman Davies. "There wasn't anything unusual about seeking expert comment. The point was to get information out about a recommendation that was very relevant at the time."
The list of those on the panel, obtained by Forbes, is filled with well-regarded experts in the field and should satisfy critics left wondering who was behind the recommendation to change the goals. It's not a wide-ranging committee of experts on clinical trials, but instead a group with expertise on studying the arteries with imaging technology. Four are top experts in the field of using ultrasound to take pictures of artery plaque. David Orloff, as a former Food and Drug Administration official, has expertise in exactly what regulatory challenges might be posed by changes to a clinical trial.
The panel: J. Robin Crouse and Gregory W. Evans of Wake Forest University, who conducted a study using Crestor, a rival cholesterol drug from AstraZeneca (nyse: AZN - news - people ); David G. Orloff, medical director of Medpace, a company that conducts clinical trials for drug firms and the former head of the FDA division that handled the approvals of Zetia and Vytorin; Michiel L. Bots of the Julius Center for Health Sciences and Primary Care University Medical Center Utrecht, Netherlands, who has worked on similar studies and James H. Stein of the University of Wisconsin, who has conducted studies on the treatment of heart disease in patients with HIV and how various substances affect artery walls.
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