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By RON WINSLOW
December 17, 2007; Page B3

The lead researcher of a long-delayed drug study says he regrets not standing up to Merck & Co. and Schering-Plough Corp. when they first told him last month that they planned to alter the statistical analysis of their jointly sponsored trial.

Under mounting criticism, the companies last week reversed the earlier decision to change the primary measure to evaluate the drug. The study, called Enhance, tested 720 people to determine whether a combination of Schering-Plough's Zetia and Merck's now off-patent cholesterol fighter Zocor works better than Zocor alone.

The companies say the results will be ready to present in March, more than a year later than first expected.

The study's stakes are high. The results are crucial for Vytorin, a pill that combines Zetia and Zocor, and is sold through a joint venture between Merck and Schering-Plough. Vytorin and Zetia are major drugs, with combined sales expected to reach $5 billion this year, double their 2005 level.

A positive result would strengthen the case for the $3-a-day Vytorin in high-risk heart patients over the cheaper generic form of Zocor alone. A negative finding could, among other things, encourage insurers to reduce coverage for the more expensive drug.

A spokesman for Merck/Schering-Plough said the plan to change the analysis was based on recommendations of an expert panel to focus on a more reliable measure of the drug's effectiveness. But after considering other views, the companies decided to go back to the original plan.

John P. Kastelein, a cardiologist at Academic Medical Center, Amsterdam, and principal investigator of the study, said he breathed a "sigh of relief" when the companies told him last week they were reversing course.

"It's never, ever right to change the primary endpoint of a study," especially after all the data are in, he says. "It is statistically not good and it gives the wrong impression to the outside world." He says he initially went along with the plan but now regrets not firmly resisting it from the outset.

He says the episode was the culmination of a long-running battle over the conduct of the trial and the companies' worries that some deficiencies in the data would jeopardize a good result. He says the concerns were unnecessary.

The Enhance study is intended to determine whether the combination treatment outperforms Zocor in slowing or reducing the accumulation of fatty deposits in the carotid or neck arteries that carry blood to the brain. Such deposits are considered a strong predictor for heart attacks and strokes.

The study was initially designed to measure changes in the thickness of the carotid artery walls after two years of treatment. That measurement was taken at six points -- three different locations in each artery -- and would serve as the primary endpoint for the study.

The study was completed in April 2006, and results initially were expected by the end of last year. But Dr. Kastelein said new technology used to record the total of about 40,000 ultrasound images of the carotid arteries, changing regulatory demands, and other factors played a role in delaying reading of the tests. When the findings weren't on the agenda for last month's American Heart Association meeting, some cardiologists began to express concern that the companies were holding back on reporting negative results, according to accounts reported by Forbes.com. The companies say they don't know the outcome of the study.

Meantime, Dr. Kastelein says, as data were turned over in batches to the companies, Schering-Plough and Merck noticed that some images were missing; other data suggested patients had undergone changes in their carotids that were "biologically implausible." The companies worried that these images would undermine the results of the study, he said.

Dr. Kastelein says such issues are common in these types of trials and were anticipated in the design of the study. He says a disagreement between him and the sponsors over what to do about the problem went unresolved last summer.

The companies say that with Dr. Kastelein's agreement, they assembled a group of experts in both carotid imaging and statistics Nov. 16 to determine what course to take. The experts' advice was to focus the primary analysis on one spot in each carotid artery, instead of the original three. The single measurement would yield a more valid result, the experts said.

After the meeting, they told Dr. Kastelein of the plan to make that measure the primary endpoint, and they disclosed the decision in an evening press release Nov. 19. The new plan would "expedite" reporting of the trials findings, the announcement said.

The decision drew a wave of criticism, including the launch last week of a Congressional inquiry into the conduct of the study. The companies say their decision to go back to the original analysis plan was made before they heard from Congress. They say the data will be ready to present at a meeting of the American College of Cardiology in March in Chicago. The look at the single location, already intended to be part of a secondary analysis, will also be reported, the companies and Dr. Kastelein say.

--Sarah Rubenstein contributed to this article.

Write to Ron Winslow at ron.winslow@wsj.com