Congress continues to ask questions about the ENHANCE trial

February 14, 2008

Washington, DC - Vytorin and the results of the Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial have been in the news for a month now, but the fallout from the much-publicized trial shows no sign of slowing down.

For clinicians tired of reading about the study in the media as well as reading about the back-and-forth between Merck and Co and Schering-Plough Pharmaceuticals, the two companies who market the drug together, and a US Congress that continues to ask questions of the companies, relief is on the way. The full ENHANCE data are expected to be presented and discussed on Sunday, March 30, 2008 at the American College of Cardiology (ACC) 2008 Scientific Sessions, in Chicago, IL.

In January 2008, the companies submitted a "late-breaker place-holder abstract," a shell abstract without the trial results, to the ACC to reserve a spot for the March 2008 meeting. Amy Murphy, associate director of media relations at the ACC, told heart wire that the study will now be part of an opening session with ACC president Dr James Dove. In additional to Dove's remarks, this opening session will include a presentation of the ENHANCE data, as well as a discussion of the findings. The session begins at 11:30 am and runs until 1:00 pm and will likely include other discussions/presentations on statin therapy. ENHANCE will be presented around 12:30 pm.

While ENHANCE was expected to be part of the late-breaking trials session, selection for that session occurred after the release of the ENHANCE data in January, and as a result, the study was not selected as a late-breaker. Because the ACC program committee wanted the data to be presented and discussed in a scientific forum, said Murphy, the investigators were offered the chance to present the data in another forum.

Still, despite the expected full release of the data, things appear to be intensifying for Merck and Schering-Plough. Congress sent yet more letters to the companies asking for further information about the trial and the release of the results and, specifically, "who knew what and when" about the study's findings, the Wall Street Journal reports [1][2].

Two days ago, Reps John Dingell (D-MI) and Bart Stupak (D-MI), the leaders of the House Committee on Energy and Commerce, sent the companies letters asking about various posts on Café Pharma, a pharmaceutical message board frequented by drug reps. The anonymous postings, first reported by Dr Peter Rost on BrandweekNRX, a drug marketing website, later reported by heart wire , suggest that the results of the ENHANCE study were known as early as March 13, 2007, and not in January 2008, as the company insists. In posts dating back as far as March, a series of anonymous messages suggested that ENHANCE was a failed trial and that this was the reason for the delayed presentation of results at the ACC annual meeting in 2007.

According to Dingell and Stupak, "these website entries are obviously troubling and raise again the question of whether anyone within Merck or Schering-Plough knew the results of the ENHANCE trial prior to the official release of data in the January 14, 2008 press release."

The committee has also sent a letter requesting information about the anonymous messages [3], including all records, names, and IP addresses, to Café Pharma, but at this point it is unclear whether Congress will get much help clearing up the anonymous nature of the posts. In a posting on Café Pharma just two days ago, webmaster Sarah Palmer writes that the site does not collect user information with anonymous messages and "does not believe we will have any information to provide regarding these posts."

Merck/Schering-Plough, who came under fire for taking nearly two years to release the results of ENHANCE after its completion in April 2006, called Café Pharma a "rumor mill" and an "unreliable source" and earlier told heart wire the company "stands by its previous statements and its SEC filing, which make clear that it was unblinded as to the study results only on December 31, 2007."

Senator wants more answers

Another letter written to Fred Hassan, chief executive officer of Schering-Plough, also pertains to the delayed release of the ENHANCE trial. This letter, from Sen Charles Grassley (R-IA), ranking member of the US Committee on Finance, zeroes in on the Watergate-like question of "who knew what and when."

Grassley questions whether or not officials at Schering-Plough would have been able to deduce the results of the ENHANCE trial before the data were unblinded. Even though the treatment arms were blinded, the treatment effect on the primary end point—change in mean carotid intima-media thickness (CIMT) after two years—was similar in the simvastatin-alone and ezetimibe/simvastatin-combination groups, and some experts, and now it appears Grassley, believe that unblinding the results might have been unnecessary to know the treatment effect was neutral.

"The ENHANCE trial is a noninferiority study," writes Grassley. "These studies try to detect a statistically significant difference between treatment groups on the primary end point. Once the results are recorded, the study is then unblinded to determine which drug is the better performer. However, if the drugs performed the same, meaning there is no statistically significant difference in the treatments, then this information is apparent before the study has been unblinded."

The gist of Grassley's letter, however, has been denied by Schering-Plough. Spokesperson Lee Davies told heart wire last month that it was "simply not possible" to know the results of the trial before the data were unblinded on December 31, 2007. He said that company officials did not have access to the carotid IMT images nor did they see the blinded end-point data in the 18-month interval between trial completion and release of the results.

In his letter to the company, Grassley has asked Schering-Plough for details on how the ENHANCE data were transferred between labs and to name all employees who had access to the data during or after completion of the trial. He also wants all emails and communication between the company and ENHANCE lead investigator Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands).

How's the market for Vytorin?

Vytorin, the combination of ezetimibe and simvastatin, and Zetia, ezetimibe alone, had a rough go when the results of ENHANCE were released, with sales for the drugs each falling in the weeks after the release of the data. New research, however, surveying pharmacy and medical executives at managed healthcare companies, suggests that most anticipate little change in how their companies reimburse for the drugs.

The study, conducted by a private healthcare research and consulting firm, included respondents who said there is likely to be little change to reimbursement, as most are awaiting the full ENHANCE results. Most formularies already promote generic simvastatin as the first-line drug for cholesterol reduction anyway.

Still, while drugs are viewed as having a place in the clinical armamentarium, 64% of pharmacy executives said they expected prescribing patterns to change, mainly because physicians will think twice about prescribing a drug that has been in the spotlight, and not in a particularly positive manner, for the past 30 days. Many medical executives were less sure how prescribing patterns would change.

Those findings appear to be supported by further research showing that physicians, especially general or family practitioners, expect to decrease their use of Vytorin as a first- and second-line treatment option in patients with hypercholesterolemia.

The data, from GfK Market Measures, a research firm that questioned 150 physicians about the ENHANCE trial and their expected prescribing habits in light of the findings, showed that family practitioners are cutting back on prescribing Vytorin as a first-line therapy, as are cardiologists and internists, although to a lesser extent. Vytorin as second-line therapy is anticipated to decrease among all the specialties surveyed, although it is expected to increase as a third-line option, says GfK.

The survey also showed that approximately 40% of general practitioners surveyed planned to switch patients from Vytorin or Zetia to another drug. An anticipated switch was less likely to occur with internists and cardiologists (25% to 30% expected to make the switch).

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