Congressional investigation into ENHANCE focusing on re-created expert panel minutes

April 14, 2008

Kenilworth and Whitehouse Station, NJ - The US House of Representatives Committee on Energy and Commerce has sent yet another letter to Merck & Co and Schering-Plough Corporation, reminding the companies, as if they could have forgotten, that they are still being investigated for delays in reporting the results of the controversial Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial.

ENHANCE was finally presented at the American College of Cardiology (ACC) 2008 Scientific Sessions and published simultaneously in the New England Journal of Medicine [1], but according to Congress, the investigation is "by no means concluded." On Friday, Congress released a letter sent to Fred Hassan and Richard Clark, the chief executive officers of Schering-Plough and Merck, respectively, asking specific questions about the independent expert panel that convened to review select data from the intima-media thickness (IMT) study.

Congress also released 70 pages of documents obtained through its investigation that show the companies playing catch-up, an attempt to re-create precisely what happened behind the scenes of that expert panel meeting. In addition to various corrections, amendments, and deletions to the panel minutes—including whether or not the panel voted to change the study's primary end point—the document reveals some of the frustration between the two companies working together to market Zetia and Vytorin, ezetimibe and the ezetimibe/simvastatin combination, in light of data from ENHANCE.

Congress zeroing in on why the results delayed so long

The first and foremost contentious issue for Congress, one the companies can't seem to explain sufficiently, is the extensive delay between when the trial was completed in April 2006 and when the results were presented—in the form of a press release—in January 2008. As previously reported by heart wire , Merck and Schering-Plough contend that poor image quality was the reason for the delay, and these concerns about missing data or implausible IMT data led the companies to convene an independent expert panel to review select images.

The investigation, according to Rep John Dingell (D-MI), chair of the Committee on Energy and Commerce, and Rep Bart Stupak (D-MI), chair of the subcommittee on oversight and investigations, "has uncovered some unusual circumstances related to the ENHANCE trial that raise new questions." Attention is now focused on the expert panel and the secretive manner in which the group of experts assembled. First reported by Forbes and confirmed independently by heart wire , no recording of the expert panel meeting exists and no minutes were taken. Merck and Schering-Plough re-created minutes only after the FDA asked to see them.

Dr James Stein (University of Wisconsin, Madison), who was part of the independent panel, confirmed to heart wire that he participated in the panel and that they were told no minutes would be taken. He said the panel, which included Drs Robin Crouse and Gregory Evans (Wake Forest University, Winston-Salem, NC), former FDA division director Dr David Orloff, and Dr Michiel Bots (University Medical Center, Utrecht, the Netherlands), was told that lead ENHANCE investigator Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands) had recommended them and recused himself from the proceedings.

Dr Richard Veltri (Schering-Plough Research Institute, Kenilworth, NJ) confirmed to heart wire that Kastelein endorsed the independent panel, recommended experts, and volunteered not to attend to prevent biasing their views. After a request from the FDA, Schering-Plough sent a summary of the meeting to the agency. The re-created summary was first sent to all those who participated in the meeting, including representatives from Merck and Schering-Plough, and then to the panel members, all of whom signed off on the minutes, said Veltri.

Documents obtained by Congress, however, show that re-creating the minutes was no easy task and that at least one member disagreed with many characterizations of what transpired during the November 16, 2007 meeting in Washington, DC. In reviewing the first draft of the re-created minutes, Stein took issue with many statements, expressing concern that some accounts did not fit his recollection and that others did not accurately reflect the divergence of opinions expressed at the meeting. Stein even expressed concern that the minutes were called "minutes," telling the companies that they are a recollection or, at best, an "incomplete summary of what transpired," because no audio or written transcription exists.

One discrepancy that existed in the minutes, noted Stein, was a sentence stating that the expert panel was "granted unrestricted access to the blinded image database." Stein previously told heart wire that the panel's recommendations were qualified by the fact that the group saw only a subset of images, between 50 and 75 at the most, and that there was no way to make a judgment about image quality. In addition, as outlined in two revisions of the minutes, Stein states that any decision to change the primary end point of the study was made by Merck and Schering-Plough, although panel opinions ranged from being completely comfortable with changing the primary IMT measurement—elevating the common carotid artery to the primary end point—to a "lukewarm feeling that it was reasonable."

"The first two drafts I reviewed did not completely reflect my recollection of what happened and made it seem as if changing the primary end point was a strong recommendation of the advisory panel," Stein said in an interview with heart wire . "It was not. We did not vote on it. We simply gave our individual opinions, and each of us had varying degrees of enthusiasm for it."

In reviewing the meeting summary, Stein commented to Schering-Plough's John Strony that "the overall tone of the minutes makes it seem as if the conclusions represent strong, unanimous, scientific recommendations of the panel, when they really were opinions with varying degrees of enthusiasm from panel members, varying degrees of scientific justification, and varying degrees of consensus."

Stein said he is puzzled about the company's contention that poor image quality or biologically implausible data delayed the presentation of the ENHANCE results. When the study was reported, the standard deviations and intraclass correlations of the repeat measurements were excellent, he said.

"Thus, the concerns about the imaging protocol were theoretical—the data did not bear them out," said Stein. "So for anyone to say the data in the study are bad, they either need to say that John Kastelein is a liar, which he is not, or they need to talk to the statisticians for the study and ask them what really were problems with the data and why we should not believe the results of ENHANCE are accurate.  If they can't tell us why, we need to believe the study results and move on."

Regarding the minutes, Schering-Plough said and Stein agreed that all panel members signed off on the version sent to the FDA. Stein told heart wire that a final "summary" provided "a reasonable reflection of the meeting deliberations."

Tensions evident

The newly released documents also reveal a tension between Merck and Schering-Plough as the companies sought to get a handle on the results. In one email exchange, Merck employee Soren Christiansen writes that Kastelein has not been updated about the fate of the expert panel meeting and questions whether or not the ENHANCE study is high enough on the Schering-Plough Research Institute's priority list. Veltri's response was abrupt and dismissive.

In its letter to Schering-Plough and Merck, Congress also wants to know whether the FDA informed the companies that their advertisements for Vytorin were misleading and whether they were suspended for this reason. Congress then asks if the companies plan to put the Vytorin "Food & Family" ads back on television in the near future.

And finally, the documents released by Congress show that Schering-Plough and Merck were required to make more prominent claims in their promotional materials that "no incremental benefit of Vytorin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established."

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