One day after the full ENHANCE data were presented at the ACC meeting, Sen. Chuck Grassley sent Merck & Co. and Schering-Plough Corp. executives a letter asking for the names of “key opinion leaders” who advised the companies on development and marketing of their cholesterol-lowering drug ezetimibe/simvastatin (Vytorin). The letter also called for a full accounting of payments made to these medical professionals and of how much was spent in total on advertising and marketing for Vytorin and/or ezetimibe (Zetia).
Sen. Grassley (R-Iowa) is the ranking minority member on the Senate Finance Committee, which has been investigating an alleged delay of the release of pivotal data from the ENHANCE study.
“Delaying the release of the results from the ENHANCE trial not only affected medical decisions, but also imposed financial burdens on patients as well as the federal government,” Sen. Grassley said in his letter, adding that since the trial's completion in 2006, the federal government has paid “hundreds of millions of dollars for Vytorin,” a drug which now seems to be of limited utility.
ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) showed that in patients with heterozygous familial hypercholesterolemia, a combination of ezetimibe and simvastatin was substantially more potent than simvastatin alone for reducing levels of LDL cholesterol and high-sensitivity C-reactive protein. But the combination had absolutely no advantage over the statin alone for slowing the progression of carotid atherosclerosis during 2 years of follow-up.
According to Sen. Grassley's letter, the Finance Committee staff has unearthed e-mail correspondence between Schering-Plough and Dr. John Kastelein, the ENHANCE primary investigator.
In July 2007, Dr. Kastelein wrote to a Schering-Plough executive, saying, “Is it correct that SP has decided not to present at AHA [the American Heart Association annual meeting], but to await the two other, completely unvalidated, endpoints, which analysis is going to take us straight into 2008??!!??” Dr. Kastelein added, “If this is true, SP 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.”
Just a day later, Dr. Kastelein wrote again to a Schering-Plough executive that he had been “cleared to say that ENHANCE would be presented at AHA” when he was presenting ezetimibe data at meetings he attended on behalf of the company over 6 months. “There is no reason whatsoever to include femorals; you will be seen as a company that tries to hide something and I will be perceived as being in bed with you!”
Sen. Grassley also said he was disturbed by a Merck/Schering-Plough public relations campaign, the “49 plan,” which was “designed to wine and dine doctors and convince them to prescribe Vytorin.” The campaign budget was at least $3.5 million, said Sen. Grassley, adding, “This seems like a great deal of money for free lunches and dinners.”
A Schering-Plough spokeswoman said that the letter from Sen. Grassley is one of a series the company has received from the committee. “We are cooperating fully with the committee, and we stand behind our products, as we have done nothing wrong,” Rosemarie Yancosek said in an interview.
The Iowa senator also wrote to the American College of Cardiology, saying that he was hopeful that the college was hewing to its own conflicts-of-interest policies but that he was concerned, noting that ACC had received $5 million from Merck since 2003, $1 million from Schering-Plough, and $5 million from the joint venture.
Soon after the ENHANCE data were released in January, ACC issued a statement saying that “there is no reason for patients to panic” and advising concerned patients to talk to their health care professional. ACC also said that further research was needed to determine Vytorin's usefulness. Sen. Grassley noted that in internal e-mails, both Merck and Schering-Plough officials had pointed to the ACC statement as evidence of Vytorin's effectiveness.
“It would not be unreasonable for an independent third party to conclude that the Merck and Schering-Plough payments to ACC influenced ACC's comments about Vytorin, especially now that experts are calling for doctors to use this drug only as a last resort,” Sen. Grassley said in his letter.