The controversy over long-delayed and unflattering data from a clinical trial of Merck & Co and Schering-Plough’s combination cholesterol treatment Vytorin continues to gather pace, with lawyers circling and the US House Committee on Energy and Commerce stepping up its investigation of the blockbuster drug.

The results of the ENHANCE trial were finally released last week following a good deal of speculation over possible data manipulation and a U-turn on the study’s primary endpoint. The results showed that Vytorin (10mg ezetimibe + 80mg simvastatin) was no more effective at slowing the progression of atherosclerosis than 80mg simvastatin (the now genericised Zocor) alone.

The House Committee on Energy and Commerce has been looking into the ENHANCE trial since Merck/Schering-Plough announced last November that they were narrowing the study’s primary endpoint – a decision on which the joint venture partners subsequently reneged, fuelling suspicions that Vytorin was not what it claimed to be. Now, John Dingell, chairman of the House Committee, and Bart Stupak, chairman of the Subcommittee and Oversight and Investigations, are looking at “misleading statements” in direct-to-consumer (DTC) advertising for Vytorin.

Letters have been sent to Fred Hassan, chairman and chief executive officer of Schering-Plough, and Richard Clark, chairman, president and chief executive officer of Merck & Co, as well as to Dr Andrew von Eschenbach, commissioner of the US Food and Drug Administration (FDA), with requests for all documentation relating to adverts for Vytorin (print, radio, television and internet), as well as records of communications between Dr John Kastelein, principal investigator in the ENHANCE trial, and Schering-Plough/Merck or any members of the outside advisory panel created to address the ENHANCE data.

Troubling questions
The congressmen also want to see records relating to the 14 January press release announcing the ENHANCE trial results. Declaring themselves “dismayed at the pace of the release”, they said the results raise “a number of troubling questions related to apparent manipulation of the study’s endpoints”.

Given Vytorin’s “large market share, we believe that the vast number of patients who have been using Vytorin could have learned of its insignificant benefits earlier than January 2008”, the letter to Schering-Plough and Merck & Co continued. “In addition, given the frequency of Vytorin advertisements, it concerns us that a study showing that Vytorin provides no increased benefit was not issued for nearly two years while direct-to-consumer advertisements were carried on the airways. This situation raises concerns that the drug companies and their advertisement agencies profited at the significant expense of patients’ health.”

According to the letter, the congressmen have also discovered “that the outside advisory panel created to provide expertise in dealing with the ENHANCE data did not include the study’s primary investigator, Dr John Kastelein. Not only was Dr Kastelein not a member of the advisory panel, but apparently he was not even present at the meeting in which the panel recommended altering the study’s endpoints.”

The House Committee on Energy and Commerce is planning to hold hearings on Vytorin in the coming weeks. In an interview with Newsweek, Stupak commented: “Do I think they knew about it [the unfavourable trial data] and attempted to put lipstick on the pig, so to speak? Yes. They knew about it. This was their blockbuster drug. Take away $5 billion or more from these companies, and man … These allegations are very serious though.”

On top of this, reports that Carrie Cox, Schering-Plough’s executive vice president and president, Global Pharmaceuticals, sold US$28 million worth of company stock last spring after the ENHANCE study was completed, but well before the results were made public, have attracted the Committee’s scrutiny. Schering-Plough insists that Cox followed all the correct procedures before offloading the stock.

Class action looms
In this climate, it comes as little surprise that a class action over Vytorin is also brewing. Six law firms, including Parker Waichman Alonso, Douglas & London, and Bailey Perrin Bailey, have filed a lawsuit against Merck & Co. and Schering-Plough in the Federal District Court for the Eastern District of New York seeking, inter alia, refunds for patients who were prescribed Vytorin.

The class action suit alleges that the joint venture partners “made misrepresentations and withheld significant information” in their approval submissions and filings with the FDA for Vytorin, the law firms said. It also claims that “misrepresentations were made to the general public through marketing efforts as to the effectiveness of the drug”.