Image: JoNel Aleccia
By JoNel Aleccia Health writer
msnbc.com
updated 4/15/2008 4:14:43 PM ET 2008-04-15T20:14:43

Questions of scientific integrity and deliberate deception have dogged Merck & Co., manufacturer of the painkiller Vioxx, through courtroom trials and into a $4.85 billion settlement with more than 44,000 of some 47,000 people who claimed they suffered heart attacks or strokes caused by the recalled drug.

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Critics have charged that the drug company withheld crucial data that showed increased deaths and injuries caused by Vioxx in order to boost prescriptions that reached some 20 million users and led to sales of $2.5 billion a year.

Two new studies in this week’s Journal of the American Medical Association dig deeper into information made public during the Vioxx trials.

In one study, scientists examined 20,000 pages of court documents. Dr. Joseph S. Ross, a researcher at the Mount Sinai School of Medicine in New York City, and colleagues revealed that manuscripts of clinical trials on Vioxx’s effects on Alzheimer’s disease were written by Merck scientists, but then attributed to academic scientists who lent their names for final publication.

The collusion between so-called “ghostwriters” and guest authors failed to disclose Merck’s financial ties to the trials, the study concluded.

The second study, co-authored by Dr. Bruce M. Psaty, a professor of medicine and epidemiology at the University of Washington in Seattle, also reviewed court documents related to clinical trials of Vioxx. Psaty and his co-author, Richard A. Kronmal, a professor of biostatistics at the same school, found that Merck officials either hid or misrepresented results of trials that showed more deaths among people taking Vioxx than those taking placebos.

Psaty, who writes frequently about drug safety issues, testified as an independent public health scientist about the risks of Vioxx before a Senate panel in 2004. He discussed the implications of the new studies for future medical research with msnbc.com health reporter JoNel Aleccia. Questions and answers have been condensed and edited for clarity and length.

MSNBC.com: Throughout the lengthy trials, consumers heard so much about the allegedly deceptive practices of Merck regarding Vioxx. How does your study fit into that larger conversation?

Bruce Psaty: I think that what may be new or different here is that the use of new internal company documents provided during the Vioxx litigation provided a window into what Merck knew and when Merck knew about the mortality findings in the Alzheimer’s trial.

The issue here is the selective reporting of the results of these trials. Can you describe how Merck represented the risk-benefit profile of Vioxx?

In April 2001, Merck conducted high-quality analyses that identified a three-fold increase in the risk of deaths for patients taking Vioxx compared to those taking placebo. These analyses were not submitted to the FDA or made public. When Merck submitted data to the FDA in July 2001, they used a counting method that minimized the appearance of any risk.

The FDA looked at the data that was submitted in July and it was still of concern. In December, the FDA raised questions about the mortality findings. Merck simply dismissed the FDA concerns and was unable to discern any “compelling or clear safety issue” here.

What does that mean for consumers?

By conventional scientific standards, a three-fold increase in death is a major safety issue. And failure of a sponsor to inform participants, investigators, the subjects of the study, the FDA, of the mortality findings violates the trust of the human subjects. 

This information may well have been important to thousands of patients in April of 2001 who were taking Vioxx. They may have decided not to take it.

How did you and Richard Kronmal come to pursue this particular investigation?

Well, we’ve worked together for 15 years, so we talk about issues, problems, drug safety matters, and it was out of our ongoing collaborations that this work emerged.

He is still serving as a guest expert for plaintiffs who have continuing litigation against Merck. Is there any ethical problem with him doing this analysis now?

Ethical problem? I’m not sure …

He’s still being compensated for his work as the plaintiff’s expert, is that right?

Yes. These are all public documents, however, so I don’t see a problem with our working on this. I don’t have a financial conflict of interest here.

This questionable data comes from Merck, but is there reason to believe that other drug companies engage in similar practices? Do you have any idea how common such data manipulation may be?

That’s an interesting question. The litigation provided a window here so we could see what was happening. This sort of representation of the mortality findings, as opposed to a kind of forthright, scientific, disinterested reporting of the results is really quite troubling.

... We don’t know the extent to which similar sorts of issues may have arisen for other drugs and other problems. Presumably it’s rare, but in the absence of access to internal documents, I don’t know how we know.

The integrity of medical research is based largely on trust, and it’s not well designed to control manipulations by a company that has major financial interests.

The other issue that has been raised is the issue of ghostwriting. Have you ever been offered a guest authorship?

I have not worked with (drug) companies in many, many years.  I just don’t work with them, so it’s not likely they would contact me. It may have happened that 10 years ago or so I was offered that, but I have no specific recollection.

The editors of JAMA have concluded that this couldn’t have happened without the active and tacit cooperation of the scientific community. Do you agree?

I think the word “tacit” sounds reasonable. I expect that it may become easy for some people to see this as appropriate behavior. 

Certain scientists have told me that working with the drug companies is the only way to get funding for research to advance medical knowledge.

Well, I do studies all the time. Many of us obtain funding from the National Institutes of Health, from the American Heart Association.  There are many investigators who obtain funding from pharmaceutical companies and maintain high standards, conduct independent studies and don’t let companies interfere with scientific quality or the publication process.

... I'm not sure the claim that it's impossible to get funding is verifiable.

Do you think that FDA Amendment Act, which requires registration of clinical trials of most drugs, biologics and devices, is going to solve this problem?

Well, no, actually.

... I guess, with the FDA Amendment Act, there are penalties for misrepresenting the results, but how are you going to know that happened?

Do you have a solution in mind? Or do you think drugmakers will find a way to subvert any requirement?

They have a lot of resources and they are quite clever. It’s probably not possible to come up with a solution. It’s like an evolving problem ...

Our study, however, raises question about the wisdom of allowing the sponsor to control the data and the analyses.

... A system where the sponsors simply fund the studies conducted by independent investigators would provide additional protection. I’m not commenting on the practicality, but that would seem to me to help.

Is this simply a situation in which scientists need to police their own ranks?

The medical research enterprise was not set up to regulate quality of the science that shows up in the peer-reviewed journals.

... So when you have a sponsor and they have a major financial conflict and they start trying to manipulate the literature, not publish certain studies, or not publish certain findings in certain studies, or write a lot of favorable reviews, it poisons the literature.

Finally, do you think that the problem is that the incidence of this deception is increasing, or has there simply been more exposure?

We cannot know that with the current data. You know, this comes to light through the litigation process, so we don’t have a large enough denominator and a large enough experience to know.

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