Schering's Buy of Organon Had to Happen

"And the moment is right here."

However, skeptics sensed that something was very wrong instead. Some of them began posting concerns about ENHANCE on Cafepharma.com, a Web site frequented by pharmaceutical sales representatives, right after news of the Organon deal first broke.

Lawmakers have since collected those anonymous posts as evidence for an ongoing investigation of the ENHANCE trial. The first of those messages appeared just one day after Schering-Plough announced plans to buy Organon:

"Have a buddy at [Schering-Plough Research Institute]. He says that the study is a bust," the message states. "Adding Zetia to maxed-out statin is useless."

By the time that message surfaced, Schering-Plough had spent months reviewing ENHANCE data. Notably, Schering-Plough's timeline shows, the company kept questioning the data even though outside experts found its quality "similar to that in other [imaging] trials."

Those independent experts rendered their judgment in January 2007. Schering-Plough insiders went on to sell millions of dollars worth of company stock in the months that followed.

Carrie Cox, president of the global pharmaceutical business, pulled off especially well-timed sales. In two options-related transactions, executed just weeks before the stock hit a multi-year peak, Cox sold roughly 900,000 shares of Schering-Plough stock -- or roughly 90% of her stake -- and pocketed $11.5 million in the process.

Schering-Plough has since stated that Cox followed proper procedures and sold the stock with the company's blessings. The company has also stressed that senior executives, including Cox, learned about the "unblinded" results of ENHANCE long after those stock sales.

But Sen. Charles Grassley, who is leading an investigation of Schering-Plough, has since suggested that company insiders may have recognized the bad news in advance.

"It has come to my attention that Schering-Plough and Merck would not need to unblind the data to understand that Vytorin performed no better than generic [Zocor]," Grassley wrote in a letter to Hassan earlier this year. "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."

Instead, Grassley suggested, Schering-Plough delayed the study by waiting for data that it didn't need. Urgent messages written last summer by John Kastelein, the lead investigator for ENHANCE, help support that view.

"There is no reason whatsoever to include femorals," Kastelein wrote in a July email exchange uncovered during Grassley's investigation. "You [Schering-Plough] will be seen as a company that tries to hide something, and I will be perceived as being in bed with you!" By then, those emails show, Kastelein had threatened to end his collaboration with the company. Kastelein ultimately stuck it out, with Schering-Plough later supplying a full email exchange showing its efforts to cooperate well (Click to view pdf), but other prominent researchers would go on to raise concerns about the study.

Harsh Review

A particular crushing blow was then delivered by Harlan Krumholz, a distinguished cardiology professor at Yale.

Krumholz served on the panel that formally reviewed ENHANCE's results during last month's meeting of the American College of Cardiology. There, before large crowds of his peers, Krumholz dominated the discussion with a harsh attack on Vytorin -- suggesting that it could be no more than "an expensive placebo" -- and left little room for debate.

In Journal Watch Cardiology, where he serves as editor-in-chief, Krumholz outlined his complaints. His criticism extended far beyond Vytorin to include possible shortcomings with the ENHANCE study itself.