Congress Continues to Probe Merck and Schering-Plough: Angry Emails Highlight ENHANCE Controversy

April 01, 2008

April 1, 2008 (Chicago, IL) – Although the controversial Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) study has been published, presented, and debated [1], the back-and-forth between the US Senate Committee on Finance and Merck & Co and Schering-Plough Corporation, the two companies that market the drug together, continues unabated.

The finance committee once again is putting hard questions to the drug companies, asking them to explain their handling of the controversial trial that was finally presented here at the American College of Cardiology (ACC) 57th Annual Scientific Session this weekend. In a letter sent March 31, 2008, Sen Chuck Grassley (R-IA), ranking member of the finance committee, said he is troubled to learn that medical experts are now calling ezetimibe a drug of last resort, or, in the words of Dr Harlan Krumholz (Yale University School of Medicine, New Haven, CT), a panel discussant of the ENHANCE trial, an "expensive placebo."

The committee said it continues to be troubled by the delay in presenting the data. As previously reported by heartwire , experts have been highly critical of the 18-month delay between when the study was completed and when the results were presented. While the companies contend the delay was caused by problems with outliers in the carotid intima-media thickness (IMT) images and missing images, there has been concern the delay was deliberate so as to hold back negative results that affected the companies' financial bottom line. The companies deny deliberately delaying the results for marketing purposes.

Now, a number of angry emails between lead ENHANCE investigator Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands) and Schering-Plough uncovered by the Senate Finance Committee suggest that Kastelein was kept out of the loop of important decisions regarding when the data would be presented and what end point would ultimately see the light of day.

"Is it correct that SP [Schering-Plough] has decided not to present at AHA [American Heart Association] but to await the two other, completely unvalidated, end points, which analysis is going to take us straight into 2008??!!??," writes Kastelein in an email to Schering-Plough executives, including Dr Richard Veltri (Schering-Plough Research Institute, Kenilworth, NJ). "If this is true, SP must have taken this decision without even the semblance of decency to consult me as PI [primary investigator] 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."

The following day, Kastelein wrote again to Schering-Plough:

"I have been traveling half the globe in the past six months to a number of large and important meetings at the strong wish of Merck to chair them or to present ezetimibe data. At every single one of them I was cleared to say that ENHANCE would be presented at AHA." He adds that a decision to include IMT data on the femoral artery adds nothing to the analysis, a decision contemplated by the company, and that if included, the company will seen as hiding something and "I will be perceived as being in bed with you!"

In his letter to Merck and Schering-Plough, Grassley writes that the delay in releasing the results of the ENHANCE trial not only affect medical decisions but "impose financial burdens on patients as well as the federal government." Since the studywas completed in 2006, the federal government has paid the two companies hundreds of millions of dollars for Vytorin, the combination of ezetimibe and simvastatin studied in the controversial trial, he writes.

The ACC questioned, the ACC responds

The latest letter from the Senate Finance Committee also took aim at the ACC. Both the ACC and the AHA came under fire for statements issued in the wake of the release of the ENHANCE study findings, statements that urged patients not to panic about the findings and said that clinical decisions should not be made based on the data of this surrogate-end-point trial. Both urged patients to speak with their physicians.

In his letter to Dr James Dove, president of the ACC, Grassley said he is pleased that the ACC has policies to guard against undue influence from industry, but that he still has concerns that "monies from Merck and Schering Plough create the appearance of influence." Since 2003, the ACC has received nearly $5 million from Merck, $1 million from Schering-Plough, and more than $5 million from a joint venture that paid for seminars and advertising on cardiology and ezetimibe and Vytorin.

In an interview with a number of media outlets at the ACC, Dr Jack Lewin, chief executive officer of the ACC, said the organization does not let industry support or influence its educational content or its scientific policy decisions.

"It's a tough thing to protect ourselves from receiving the money, in terms of advertising and so forth, and then making sure it doesn't influence us," said Lewin. "But we have set up painstaking efforts over many years to protect our professionalism. That's an obligation to patients. Is it tough to do? Yes, it's very tough. It's requires an enormous amount of vigilance and a high level of scrutiny and professional ethics."

Their money at work . . . 

In his interesting letter to the ACC, one sent to facilitate complete transparency, Grassley points to some of the ways Merck and Schering-Plough have spent their money at the ACC annual meeting in Chicago, IL.

For example, $192 000 was spent to secure 6400 square feet of booth space and $270 000 on an HDL education initiative. Another $50 000 was spent on hotel "Do Not Disturb" door hangers.

Over the years, the companies have spent $60 000 for insulated coffee mugs and thousands more for promotional banners, action registries, and satellite symposia, according to documents released by Grassley's office.

Schering-Plough and the ACC statement

In addition to speaking with the media, Lewin, on behalf of the ACC, returned the congressional volley, sending a letter to the finance committee stating that he recognizes the concerns about the delayed release of data in the ENHANCE trial. He again pointed the committee to the ACC statement on ENHANCE, one that stated that the study reinforces the need to adhere to ACC/AHA guidelines, which recommend statins to maximally tolerated doses or to as close to goal as possible as first-line therapy for patients with coronary artery disease.

The ACC, Lewin points out, as did the AHA, got into their dilemma by trying to clarify the results of the ENHANCE trial. He said the organizations had to put a message out to tell patients not to stop their medications, especially the ezetimibe/simvastatin combination, where simvastatin has been proven to reduce clinical events. "We didn't want to see tens of thousands of people in the emergency room," said Lewin.

The problem with the statement, however, was that Merck and Schering-Plough liked it, too, so much so that they began forwarding the press release internally. In his latest letter to the ACC, Grassley notes that Merck and Schering-Plough felt the statement lined the ACC up as a credible supporter of the Vytorin brand and began advising colleagues to direct others to the ACC press release.

In his letter to the drug companies, Grassley also questions the "49 Plan," a public-relations campaign intended to "wine and dine" doctors after the disappointing results of ENHANCE. The budget of the campaign was $3.5 million, a "great deal of money for free lunches and dinners," writes Grassley.

  1. Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008; 358:1431-1443. Abstract

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.



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