Monday, December 17, 2007

Manipulation of ENHANCE Reversed

We, and many others have written about problems with the ENHANCE trial of ezetimibe (Zetia, by Schering-Plough, and one component of Vytorin, by Merck), and how aspects of it seemed meant to increase the likelihood of a favorable result for the sponsors' interests. Particularly controversial was the sponsors' decision to change the definition of the trial's outcome variable after the data was collected. After considerable public discussion, and the threat of a US congressional investigation, things have changed, as Ron Winslow reported in the Wall Street Journal,

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.

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.

We have posted frequently about cases in which a sponsor manipulated the design, implementation, analysis, or dissemination of clinical research to increase the likelihood that the results would favor the sponsor's product (e.g., recently here and here). One important study showed the contractual basis for such manipulation when studies are done in academic medical environments (see post here). In extreme cases, sponsors have attempted to suppress the research results entirely when they turn out to be unfavorable to their interests (e.g., see recent post here). Such manipulaton, of course, is bad for patients and doctors, since it impedes their ability to make decisions about tests, treatments etc based on the best clinical evidence. It also betrays the trust of people who volunteer to participate in research thinking that the goal is to improve health care and advance science.

So this case is unusual, in that an early public outcry resulted in at least some of the clinical research manipulation being reversed. There may be hope yet.


Anonymous said...

Wow, I cannot believe that this actually happened, though it is interesting to note that the investigators conducting the study (conveniently?) ex post facto observe how opposed to the alteration they were. As Brody and others have documented repeatedly, this kind of conduct was more the rule than the exception in years past, so one has to wonder how many past investigators opposed such conduct for it to become so relatively widespread.

Still, it is refreshing to see the pressure that critics can bring to bear.

--Daniel Goldberg

Anonymous said...

While admittedly limited to my experience, and antidotal, I have noticed the promotion of the BP med Tarka along with Vytorin. Tarka has a known side effect of constipation, while Vytorin's Zetia can have some unsettling effects in reverse. Both drugs are combo pills that contain drugs with generic equivalents.

In an effort to extend patient protection; are we now seeing drugs with generic components, marketed with known side effects, only to be countered by other drugs with generic components, marketed with known counter side effects?

This would be the ultimate breach of trust.

Steve Lucas