CHICAGO, March 31-- E-mails made public today described outrage more than a year ago by the ENHANCE trial's principal investigator because he perceived that a drugmaker was withholding bad results about ezetimibe/simvastatin (Vytorin) for non-scientific reasons.
The full ENHANCE results were released at the American College of Cardiology meeting here yesterday, two years after data collection ended. The study found that patients randomized to ezetimibe/simvastatin (Vytorin) had no significant benefit in atherosclerosis progression over simvastatin alone.
It was a heavy blow to Merck and Schering-Plough, the drugmakers. The emails from John Kastelein, M.D., of the Academic Medical Center in Amsterdam in Holland, lead investigator of the ENHANCE study, to a Schering-Plough executive outlined his concern about the lengthy lockdown on the data.
He warned the Schering-Plough executive in an email that if the company followed though with plans to introduce new endpoints in analyzing ENHANCE it would be viewed as trying to hide something, and Dr. Kastelein would be seen as being a party to the duplicity.
According to the emails, made public by Sen. Chuck Grassley (R-Iowa), Dr. Kastelein was seriously embarrassed because he had been assured, and had announced at various meetings for six months, that he could present the ENHANCE results at the American Heart Association meeting last November.
Then the rug was pulled out from under Dr. Kastelein. According to Grassley, more than a year after ENHANCE closed the data base for the trial, Dr. Kastelein wrote in July 2007 in an email to a Schering-Plough executive:
"Is it correct that SP has decided not to present at AHA, but to await the other, completely unvalidated, endpoints, which analysis is going to take us straight into 2008??!!?? [sic]"
Other endpoints involved ultrasound scans of femoral arteries and Dr. Kastelein said there was no reason to include that information.
"There is no reason whatsoever to include femoral," Dr. Kastelein wrote to the Schering-Plough executive. "You will be seen as a company that tries to hide something and I will be perceived as being in bed with you!"
Dr. Kastelein wrote that if it was true that Schering-Plough had decided to withhold the data, the company "must have taken this decision without even the semblance of decency to consult me as PI of the study. I can tell you that if this is the case, our collaboration is over … This starts smelling like extending the publication for no other [than] political reasons and I cannot live with that."
Rosemarie Yancosek, executive director of global communications at Schering-Plough, acknowledged receipt of a letter from Grassley recounting these emails. This, she said, was "one of a series of letters we have received from Senator Grassley. The selectively excerpted emails concern an issue that Merck/Schering-Plough -- and we believe Dr. Kastelein -- consider long resolved."
In an interview in the Wall Street Journal today, Dr. Kastelein called ENHANCE "the trial out of hell." It taught him two lessons.
"First, I'm never going to do another trial on my own," he said. "I would really have loved to have had a steering committee next to me."
"Second, it's never good to wait too long for the results of trial," he said. "From all points of view, it's always better once the last patient is out (and evaluated) that the results are rapidly known."
At a Merck/Schering-Plough press conference Dr. Kastelein said there was really no delay in the release of the trial findings. As captured by ľֱ in an exclusive video, he said there was a scientific disagreement between the investigators and the company.
Grassley concluded that Merck and Schering-Plough had been "placing marketing interests above science. For instance, in [a Merck and Schering-Plough] marketing review done just last December, it appears that advancing sales, not science was the priority."
Grassley alleged that internal emails from Merck and Schering-Plough urged drug sales and marketing people to "incorporate lower is better' into message flow." The company also urged sales staff to push the SNAG message, an acronym for "simvastatin not at goal."
Grassley also reported that Merck/Schering-Plough spent $3.5 million for the "49 plan," a wine-and-dine marketing blitz of physicians to increase the volume of ezetimibe/simvastatin (Vytorin) prescriptions.
The senator also chided the ACC because it issued a statement urging calm after the ENHANCE data were unveiled in a company press release last January. The ACC statement urged physicians to follow guidelines (guidelines recommend statins as the first line of medical treatment), but included an acknowledgement that ezetimibe was an effective agent for lowering LDL.
Jack Lewin, M.D., executive vice president of the ACC, said the group got pulled into the controversy because Merck/Schering-Plough "reprinted our statement and sent it to every member of Congress, which wasn't very nice."
The distribution to Congress, Dr. Lewin said, gave the impression that the ACC was endorsing ezetimibe, "which was completely wrong. We endorse the guidelines. The guidelines don't even mention ezetimibe."
Nonetheless, Grassley said he decided to make public an itemized list of Merck contributions to ACC that totaled $5 million since 2003 (the year after ezetimibe was approved). For example, in 2004 Merck donated $60,000 to the ACC to pay for cups used at the college's annual meeting.
Dr. Lewin said he opened the ACC books to Grassley "just to be completely transparent."
The American Heart Association said that "If the allegations are shown to be true that Merck/Schering Plough delayed the release of the ENHANCE data for reasons that were not motivated by science and the public interest, this would be an issue of serious concern to the American Heart Association and to the American public."
There is "no room for compromise when it comes to reporting on new research data," said Raymond Gibbons, M.D., of the Mayo Clinic. Dr. Gibbons, who is a former AHA president, said that once in his career a trial sponsor threatened to block publication of data. "I was appalled and I am happy to say that within six hours that company had a signed letter from the legal department at the Mayo Clinic and the issue was resolved."
Dr. Gibbons said that in his opinion delay of data is as serious an issue as outright blocking of scientific presentation or publication.
Steven Nissen, M.D., of the Cleveland Clinic, said the revelations from Grassley point out the danger of conducting clinical trials when the investigator does not control the data. "That's the case in 99% of clinical trials," he said.
Exceptions, he said are the TIMI investigators at Harvard, the Duke University researchers and Cleveland Clinic researchers because in each case they will not do trials unless they maintain control of the data and the right to publish.
Dr. Nissen also said that he and several other "physician researchers went to the company (Schering-Plough and Merck) and requested that they do a large clinical outcomes trial because they were concerned about clinical effects of cholesterol lowering with ezetimibe. The company said they would think about it."
But Dr. Nissen praised Dr. Kastelein for threatening to resign as principal investigator when the companies stalled on publication, which demonstrated that Dr. Kastelein was an ethical investigator.