Friday, August 01, 2008

Shut Up, They Explained (to Ezetimibe Critics)

One of our scouts alerted me to a remarkable editorial just published by Harrison, Brown and Raggi on the ezetimibe controversy [Harrison DG, Brown WV, Raggi P. Enhanced hype. Am J Cardiol 2008; 102: 368-369. Link here, requires subscription.]

We have posted before (as have many others,) about problems with the ENHANCE trial of ezetimibe (Zetia, by Schering-Plough, and one component of Vytorin, by Merck), and how the trial seemed to be designed and implemented so as 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, (later reversed after it was publicized.) It also turned out that the supposedly "independent" panel responsible for that decision included a majority of members who had previous financial ties to Merck and/or Schering-Plough.

The ENHANCE trial was not meant to determine whether ezetimibe had any effects on clinical outcomes, that is, whether it made patients feel or function better, avoid morbid events, or live longer. Its focus was on whether the drug reduced the thickness of arterial walls in patients with very high cholesterol levels. The study failed to show even this effect.

Since no previous study had shown that ezetimibe leads to symptom reduction, functional improvement, prevention of morbidity, or extension of life, it was surprising that the American College of Cardiology and the American Heart Association rushed to the drug's defense, counseling physicians not to take patients off it. Why continue to give patients a drug that has never been shown to provide clinical benefit? In this post, we wondered whether this enthusiasm unsupported by clinical research evidence had to do with undisclosed conflicts of interest affecting the defenders of ezetimibe.

Since then, in the continuing absence of evidence about the benefits of ezetimibe, there has been continuing controversy over its use. Harrison, Brown and Raggi continued in this vein. They clearly sided with the American College of Cardiology's statement that physicians should not take patients off ezetimibe, which they contrasted with what they characterized as

hysterical coverage from Web sites, news organizations, and cardiologists who seem to seek high visibility.
So the "hype" and hysteria, according to Harrison, Brown and Raggi, were criticisms of attempts to manipulate the ENHANCE trial, and observations about the lack of clinical evidence supporting the use of ezetimibe. What made their article remarkable, however, was its suggestion that purveyors of "hype" and "hysteria" as defined by Harrison, Brown, and Raggi, should just shut up. First the three authors wrote,

Strong statements regarding guidelines or policy in the use of this drug by cardiologists (with little background in lipid research and atherosclerosis biology) are inappropriate and certainly premature.
unsupported premature claims regarding a drug’s effectiveness or lack thereof should be conveyed properly, as in the case of the American College of Cardiology’s official statement. There seems to be a recent love affair with the issuance of headline-grabbing statements to the press, and this should be discouraged. When done in haste without proper study and thought, they appear to be self-aggrandizing, and at worse, they are very misleading.

So this editorial is noteworthy not because it defended ezetimibe, or belittled its critics, but because it seemed to question the right to criticize the established dogma.

Obviously, the authors of the editorial have no legal authority to censor those whose views offend them. But even veiled questioning of the right to express dissent are contrary to the core values of science and medicine. For science to advance, open discussion and criticism of methods, results and interpretations is vital. For physicians to take the best possible care of patients, they must have access to the best possible evidence from clinical research, even if that evidence offends the powers that be or those with vested interests.

A clue as to why the authors took such an extreme position may be found in the last sentence of their article,

In the case of ezetimibe, we are concerned that this drug or its makers will be eliminated on the basis of hyperbole, misinformation....

Why would they be so worried as to raise the hyperbolic concern that the controversy over ENHANCE could cause ezetimibe, and even Merck and Schering-Plough to be "eliminated?" A quick Google search revealed disclosed that the authors collectively have multiple relevant financial relationships that they did not disclose.

Perhaps the authors' financial identification with Merck and Merck Schering-Plough, and with the pharmaceutical and biotechnology industries in general lead to such exaggerated concern. In any case, the authors should have revealed these financial relationships, and allowed readers to decide whether they might have affected their views. Nonetheless, while conceivably such relationships could have somewhat explained the authors' partiality to censorship, it does not excuse it.

As documented on the FIRE web-site, it is now commonplace for academic administrators to try to silence those who disagree with the prevailing campus dogma. This impulse to censor those who provide inconvenient opinions or facts now seems to be extending to the scholarly medical literature. It is ironic that those calling for censorship simultaneously seem loathe to reveal their financial relationships with those with vested interests in maintaining the status quo.

The inconvenient truths that we censor or hide surely will return to afflict us.

ADDENDUM (3 August, 2008) - See also comments by anonymous blogger "PM" on Gooznews.


Daniel Carlat said...

Great post. These researchers are lashing out in anger at those who are critical of Schering-Plough and the company's handling of Zetia. They are getting personal, and that's never a good strategy.

InformaticsMD said...

unsupported premature claims regarding a drug’s effectiveness or lack thereof should be conveyed properly

How the biomedical bullies hate free dissemination of information, a domain in which they cannot compete. Used to power and the success of backroom character assassination and logical fallacy, usually unchallenged due to position of power, the new media has leveled the playing field to some extent.

The comment on my post "On a Clinical IT Abomination" that stated:

"This post is unnecessary shrill and quoting crackpot editorializing masking as journalism does not help"

is an example.

Anonymous said...

In the July issue of the Cleveland Clinic Journal of Medicine, there are two editorials on ezetimibe, one by Allen Taylor and one by Michael Davidson. Dr. Taylor was co-author of one of the editorials that appeared in the NEJM at the time ENHANCE was published and is an ezetimibe skeptic. Dr. Davidson supports ezetimibe's continued use as an add-on to a statin or for people who cannot tolerate statins (i.e., second-line therapy after statins) based on its ability to lower LDL. Here are the urls:

These editorials are well worth reading for their discussion of the scientific issues. In addition, the last paragraph of Davidson's editorial is particularly striking for its apocalyptic warning about the prospects for the pharmaceutical industry:

"Enormous challenges are on the horizon for the pharmaceutical industry, with a shrinking pipeline of potential new drugs, increasing regulatory hurdles, greater liability risk, political pressure for price controls, enhanced scrutiny of sales practices, and a growing media bias. As a cardiologist and clinical researcher whose father died at age 47 of a myocardial infarction, I am concerned that, unless change occurs, a vibrant pharmaceutical industry with the financial and intellectual capital to find and develop new, more effective treatments will cease to exist."

His father's early death from heart disease is a tragedy, but it seems irrelevant to the topic at hand (i.e., the extent, if any, to which ezetimibe should still be used post-ENHANCE). Likewise, the warning about the possible demise of the pharmaceutical industry seems overblown and irrelevant to the topic of his editorial. It's as if he's saying that people who criticize pharmaceutical company practices, or even particular drugs, are endangering public health. Give me a break. Could it be that many of the problems of the pharmaceutical industry are self-inflicted?

Marilyn Mann

InformaticsMD said...

Give me a break. Could it be that many of the problems of the pharmaceutical industry are self-inflicted?

Yes, and partly through generic leadership and a culture of mediocrity.

This starts at the top.

Andrew Witty, GSK CEO: has a BA in Economics as sole degree. No discernible formal clinical or biomedical background.

Ray Gilmartin, ex-Merck CEO: BS in electrical engineering and MBA. No discernible formal clinical or biomedical background.

Richard Clark, current Merck CEO: BA in liberal arts, MBA; no discernible formal clinical or biomedical background.

Jeffrey Kindler, Pfizer CEO: lawyer for McDonald's just before entering pharma, no discernible formal clinical or biomedical background.

Bernard Poussot, Wyeth CEO: graduated from Ecole Supérieure de Commerce de Paris in 1975. No discernible formal clinical or biomedical background.

Need I go on?

Anonymous said...

Here's a bio for Dr. Brown:

He's a former president of the AHA.

Dr. Harrison's first name is David.

Anonymous said...

unsupported premature claims regarding a drug’s effectiveness or lack thereof should be conveyed properly

Business speak translation:

Inconvenient information should only be disclosed properly, that is, in a manner in which it can be easily buried and ignored.