Delays in drug’s test fuel debate

In January, Merck & Co. and Schering-Plough Corp. disclosed surprising news: A long-overdue study of their blockbuster cholesterol drug Vytorin found it was no better at fighting heart disease than a far-cheaper generic.

Doctors and public officials questioned whether the companies had delayed the results for more than a year to protect billion of dollars in sales.

The firms said they had merely been trying to correct irregular data. But by late 2005, company officials overseeing the study already had spotted a threat to Vytorin. They noticed, they now say in interviews, that patients being studied were healthier than expected – which could make it harder to demonstrate Vytorin’s superiority at slowing disease.

The Vytorin study has fueled two broad controversies, both likely to be stoked this week as the findings are formally presented for the first time. Its handling has sharpened the debate over how much control sponsors should wield in clinical trials that influence doctors and regulators. And the study’s results have led some skeptical doctors to question the value of cholesterol-lowering drugs that have become the front-line medical weapon against heart disease, the Western world’s leading killer.

The management of the Vytorin trial, known as Enhance, was unusual in a number of ways. The companies have previously acknowledged that they kept the study under wraps for more than a year amid a prolonged effort to address their concerns about the data. They didn’t provide for an independent steering committee to oversee scientific issues, as is typically – though not always – done.

The companies brought in a second lab to compete to produce more accurate results than the original research team. In another unusual step, they proposed changing the primary way the data would be analyzed after it had already been collected. Company officials began publicly minimizing the significance of the study as too narrow. Finally, the companies compiled the results themselves, without the participation of the outside academic scientist they had hired to lead the study, and announced the findings in a news release in January, rather than wait for the researcher’s report.

Dutch researcher John Kastelein, the outside scientist who led the study, has called it ”a trial from hell.” In an interview in December, he said he wished he had stood up to the companies before they announced they planned to change how the data would be analyzed. They later abandoned that move amid a blitz of criticism. ”This is an unusual case history of clinical research,” says Jerry Avorn, a drug-policy researcher at Harvard Medical School not connected with the study.

Merck and Schering-Plough say they were acting with integrity. The companies say they didn’t peek at the results or know Vytorin had failed in the study until very recently. ”What we were trying to do was to improve … the precision and the accuracy of the data so that at the end, the results would be credible,” says Enrico Veltri, Schering-Plough group vice president of global clinical development and a leader of the companies’ joint venture. He says no independent steering panel was needed because the study was ostensibly simple, seeking only additional information about drugs that were already on the market. ”There was nothing to steer,” he says.