Merck & Co. and Schering-Plough Corp. offered a detailed accounting of why trial results for their cholesterol drug Vytorin were delayed more than a year, but in the process fueled more doubts about how the data were handled and how the study was managed.

The companies, responding to intensifying scrutiny of the trial, issued a chronology describing a two-year effort they say was aimed at ensuring the accuracy of imaging data collected in the study.

Delay and Doubts

  • Delayed Release: Results of a study for cholesterol drug Vytorin came out more than a year later than expected.
  • Marking the Trail: Merck and Schering-Plough released a chronology of events amid pressure to explain the delay.
  • Still Cloudy: Critics say they still don't understand why the companies spent so long working on the data.

But critics said that despite the recounting, they didn't fully understand why the companies spent so long working on the data. They said the affair shows the problems that can arise when corporate sponsors, rather than independent academic investigators, control how a study is run.

The study, called Enhance, cast doubt about whether Vytorin is better than a cheaper generic drug in halting the progression of cardiovascular disease, even though Vytorin was more effective in reducing LDL, the so-called bad cholesterol, which is a major risk factor for heart attacks.

The trial was completed in April 2006, but the companies didn't disclose the disappointing results until Jan. 14 of this year. During that time, combined annual sales of Vytorin and a sister drug, Zetia, grew to more than $5 billion.

In November, a firestorm erupted after the companies said they were changing the trial's primary measure of effectiveness to "expedite" analysis of data -- a move generally considered a violation of scientific protocol. That triggered complaints from cardiologists and a congressional inquiry. The companies have since said they went back to the primary endpoint.

The study collected images designed to measure the drugs' effect on the thickness of the wall of the carotid, or neck, arteries.

The companies' chronology indicates that questions about image quality surfaced in late 2005 during "routine data quality reviews." In subsequent months, the companies settled on a plan to reanalyze the images, ran a pilot study of this new approach, hired consultants to help evaluate quality control and convened at least two outside expert panels on the problem.

In January 2007, the chronology says, one consultant reported that the quality issues were similar to those experienced in other trials using the same imaging technique, but the companies continued their effort anyway. Throughout the process, the companies say the results of the study remained "blinded," meaning neither company officials nor people examining the images knew which patients got Vytorin and which got the generic.

"The timeline shows what an immense effort the companies went to work on the data," said Allen Taylor, chief of cardiology service at Walter Reed Army Medical Center in Washington. "The question is, why were you doing all that? People don't spend 18 months jumping through hoops for nothing."

Dr. Taylor said he wonders whether the companies knew all along that the study failed to show a benefit for the more-expensive Vytorin. Added Harlan Krumholz, a cardiologist at Yale University: "It's in their great interest to delay this study if there is any possibility that it doesn't come out positive."

A Schering-Plough spokesman said the companies didn't know whether the results were positive or negative until they first looked at them Dec. 31.

"While the Enhance trial was time consuming and took longer than originally anticipated to complete, our companies acted with integrity and good faith in connection with the trial," Merck and Schering-Plough said in a statement. Among other things, they said the delay resulted from their efforts to find missing or obscure data and re-examine measurements that seemed implausible.

The decisions to reanalyze the data were made by an internal group called the Cholesterol Development Committee, and were a significant departure from the original analysis plan as published in an article in the American Heart Journal in 2005. A steering committee independent of the corporate sponsor is commonly named before a study begins to oversee the scientific aspects.

In Enhance, no steering committee was named and the companies have controlled the data and the analysis. As a result, Dr. Krumholz said, "There is no way to determine that the decision [to re-analyze data] is being driven by science or the best interest of the company."

Schering-Plough said independent oversight boards were not named for Enhance because the study involved approved drugs at approved doses and unusual events weren't expected.

The Food and Drug Administration on Friday said it planned to review the study after the agency gets final results from the companies and will also look at whether it needs to make changes to its "current approach to drugs that lower LDL cholesterol."

The FDA expects it will need about six months to evaluate the Enhance findings. Depending on its analysis, it might require changes to the Vytorin label reflecting the findings.

FDA officials defended the agency's process for approving Vytorin and Zetia. They relied on the drugs' impact on LDL rather than insisting on evidence that the drugs prevented heart attacks or reversed the progression of cardiovascular disease.

Write to Ron Winslow at and Anna Wilde Mathews at