Friday, January 11, 2008

Ezetimibe - where are our medical journals?

The BMJ EzetimibeThe huge ethical and scientific problems with the drug Ezetimibe have been discussed widely in the lay press (especially in the New York Times and some excellent reporting in Forbes). The problems have been discussed by patients, on the internet and in the blogsphere. However as of today, a search of our key medical journals reveals no hint of any ethical discussion. No discussion of the principles of good science. Not even a worthy news report. Nothing at all.
  • The British medical Journal : No discussion
  • The Lancet: On 24 November 2007 in the midst of the saga, the Lancet published a review entitled "The safety of statins in clinical practice" Jane Armitage, Vol. 370, Issue 9601 Pages 1781-1790. There was no relevant discussion or associated editorial in that issue or in any subsequent issue.
  • NEJM: No discussion
  • JAMA: No discussion
And the multitude was silent, not a voice, not a sound was heard upon the hillsides, across the valleys where they stood.'
Richard Bach, Illusions
One wonders how long our key medical journals will retain any credibility as honest impartial portals for discussion of science and the principles of good medicine. For the record, here is some of the discussion on the top 100 medical blogs collated in date order. Some have called for a boycott of Ezetimibe.Earlier|Later|Main Page


Anonymous said...

Here's another one that isn't on your list:

November 26, 2007
Even gold can be tarnished

Aubrey Blumsohn said...

Thank you - I have now added it

Anonymous said...

Here's the latest on this:Inside Schering And Merck's Secret PanelMatthew Herper, 01.11.08, 6:00 AM ET Details on how a controversial change was made in a study of their cholesterol drugs Zetia and Vytorin. When Schering-Plough (nyse: SGP - news - people ) and Merck (nyse: MRK - news - people ) announced Nov. 19 they had been advised to change the scientific goal of a long-delayed clinical trial comparing the effectiveness of their blockbuster cholesterol Vytorin to a generic, the decision drew press scrutiny, criticism and a Congressional investigation. More controversy: Forbes has learned that the lead investigator charged with conducting the study, John J. P. Kastelein of the University of Amsterdam, was not even present when the companies made the controversial decision to change its goals, an unusual circumstance in such situations. It's "shocking" that Kastelein would not be party to discussion of the ENHANCE trial, says Harlan Krumholz, a cardiologist at Yale University. "There should be a scientific committee that's independent running a study. He should be taking a leadership role." Asked about Kastelein not being present, Lee Davies, a Schering-Plough spokesman, said only, "I will confirm that this was an independent expert panel." Kastelein could not be reached for comment Wednesday or Thursday, but in the past he has said he disagreed with the company's decision to change the endpoint of the trial. In an interview with The Wall Street Journal in December, he said he breathed a "sigh of relief" when it was changed back.It's just the latest issue involving the study. ENHANCE, as the study is known, tests whether the cholesterol drugs Zetia and Vytorin, which together generate $5 billion annually, do a better job than a cheap generic at clearing plaque out of the arteries. For more than two years, the company delayed releasing the results of the study. Then, on Nov. 19, after Forbes questioned Merck and Schering about the delays, the companies said they would present the study in March, but would change its main goal. On Dec. 11, the companies backtracked, saying they would not make the change after all. That same day, the House Committee on Energy and Commerce expressed concern about "the delay in releasing the results of the study, the timing of ENHANCE trial registration and the apparent manipulation of trial data.""You just don't change a primary endpoint in a major important trial partway through," says Bruce Psaty, a drug safety expert at the University of Washington. Schering-Plough and Merck insist the ENHANCE study, though troubled, is only one trial testing their cholesterol drugs. Other trials to see if the drugs reduce heart attacks, strokes and deaths better than older treatments are under way. New techniques used in the study, such as using ultrasound to measure artery plaque, are generally difficult, and not as well understood as cholesterol lowering, they say. They say they have only had the best intentions toward answering the scientific questions posed by the study. "We pull together panels and seek expert advice on an ongoing basis," says Schering-Plough spokesman Davies. "There wasn't anything unusual about seeking expert comment. The point was to get information out about a recommendation that was very relevant at the time."The list of those on the panel, obtained by Forbes, is filled with well-regarded experts in the field and should satisfy critics left wondering who was behind the recommendation to change the goals. It's not a wide-ranging committee of experts on clinical trials, but instead a group with expertise on studying the arteries with imaging technology. Four are top experts in the field of using ultrasound to take pictures of artery plaque. David Orloff, as a former Food and Drug Administration official, has expertise in exactly what regulatory challenges might be posed by changes to a clinical trial. The panel: J. Robin Crouse and Gregory W. Evans of Wake Forest University, who conducted a study using Crestor, a rival cholesterol drug from AstraZeneca (nyse: AZN - news - people ); David G. Orloff, medical director of Medpace, a company that conducts clinical trials for drug firms and the former head of the FDA division that handled the approvals of Zetia and Vytorin; Michiel L. Bots of the Julius Center for Health Sciences and Primary Care University Medical Center Utrecht, Netherlands, who has worked on similar studies and James H. Stein of the University of Wisconsin, who has conducted studies on the treatment of heart disease in patients with HIV and how various substances affect artery walls.

Anonymous said...

See Mer om Ezitimibe-"studiet"

Anonymous said...

Meanwhile, speaking from a parallel universe is the CEO of Schering.

Anonymous said...

Did SP employees leak ENHANCE data on Cafe Pharma as early as
March 13, 2007?

You be the judge.

Anonymous said...

A Failed Attempt to Improve Misperceived Greatness: The ENHANCE Trial

While it seems that sponsors of clinical trials usually end up with results that clearly favor their meds studied in their trial, there are rare exceptions, and Merck and Schering proved that with their disappointing ENHANCE Trial, which many have heard about through the media not long ago.

The drug studied was Vytorin, comparing it with Zocor
Vytorin is a combination med for high cholesterol and contains Merck’s Zocor, which is now generic, and Schering’s Zetia, which works differently than Zocor, which is one of many statin drugs. Both Vytorin and Zetia are co-promoted by Merck and Schering.

So, several years ago, an outcomes study was initiated to prove superiority of Vytorin over Zocor as monotherapy. The trial was named the ENHANCE trial.
After several years passed, a disappointment arrived for the sponsors of this trial, which was first brought to the attention of Schering in March of 2007, yet the results existed since the spring of 2006, I believe.

The disappointment is that Vytorin lacked anticipated benefit or superiority over Zocor. Since about 1 million scripts were written for both Vytorin and Zetia every week in 2007, combined with what I believe was about 5 billion in revenue for these two drugs that year, this was a problem for the drug makers. Perhaps for Schering in particular, it was more of a calamity, since over half of their profits and earnings were from these two drugs.
Being the responsible corporations both companies are, of course, alterations occurred after such events that fractured numerous rules and regulations with clinical trials.

The trial sponsors delayed the release of the trial results for secrecy reasons, it has been speculated. Results from the trial existed, yet were not disclosed at the time of their discovery. After several months of possessing these trial results that were only known to the manufacturers, they created or implemented some atrocious tactics to improve the trial’s unimpressive results. At the end of 2007, the companies changed the primary endpoint of the trial, which is what the results were measured upon during the entire course of the trial. Since their deliberate concealment of these trial results was clearly wrong, to respond to those who asked where the results were actually while such trial manipulation was occurring and results were being kept secret, Schering stated that continued data analysis from the trial results was the etiology for the delay.

With clinical trials, case report forms are used to record data from the trials, and are created in a manner where further analysis is not normally necessary, as such forms are quite clear and often not subject to interpretation. So at the end of 2007, both Merck and Schering got the attention of relevant government officials who contacted both companies regarding this ENHANCE trial, and an investigation began into the activities of both companies regarding this trial at that point.

This became a catalyst for the ENHANCE trial results to be finally released at the beginning of 2008, which caught the attention of major media organizations. In the spring of 2008, a very large cardiology meeting was held, where the audience was told to stick with statins due to this trial’s lack of outcomes for Vytorin, when the ENHANCE trial was discussed at this meeting. Furthermore, a cardiologist at this meeting also suggested that a moratorium should occur with the utilization of Vytorin, since statins are much less expensive, and are highly regarded, as they have been available for a couple of decades. Of course and as expected, Merck and Schering were not pleased, nor were they surprised at the review of Vytorin at this particular meeting. The following month after this cardiology meeting, Schering’s earnings dropped by 48 percent, as I recall.

Now, these cholesterol drugs promoted by Merck and Schering, Zetia and Vytorin, were aggressively marketed in a number of ways, including investing I believe about 200million dollars in 2007 for DTC ads for these products. To add to this, and soon after both meds were launched, reps from both companies made inferences to doctors about outcomes regarding plaque accumulation and how Vytorin was superior in that area, which, of course, this ENHANCE trial proved it is in fact not the case whatsoever. It did not matter, apparently, to both Merck and Schering that such a claim is entirely void of proof, which Is not unique to any pharma rep, in my opinion. Yet what is known now is that these companies performed junk science with their deliberate manipulation of this ENHANCE trial. Last year, Zetia and Vytorin had about 20 percent of the cholesterol lowering market. It does not seem that there will be an increase of this percentage because of this scandal.

Worst of all is the harm caused to both doctors and patients. The ENHANCE trial concerned and confused both of these participants in the health care system. Furthermore, it’s likely they were devastated by being so clearly misled by the marketing of both Merck and Schering regarding the false benefits of Vytorin they were led to believe by the companies that promoted them.
This whole situation is another example of the corruption of the scientific method by placing profits over the well-being of patients. Most were shocked by Merck behaving in such a way in particular because of what use to be their excellent reputation as an ethical pharmaceutical company. And this alone shows the progression and infiltration of such damaging corruption that desperately needs to be stopped and corrected for the sake of others.

Don’t just say something. Have something to say- to the right people, with conviction and with others who share your views.

“Waste no more time arguing what a good man should be. Be one.” --- Marcus Aurelius

Dan Abshear

Greg Pawelski said...

The New England Journal of Medicine (NEJM) editorial blasted the analysis by Oxford University statistician, Richard Peto that dismissed Vytorin's possible link to cancer. The SEAS study found that Vytorin patients had higher rates of cancer and cancer deaths. The results for cancer incidence was clearly significant, as well as the results for cancer death.

The NEJM editorial on ezatimibe accompanied the publication of the SEAS trial and a statistical analysis of cancer incidence and deaths in SEAS and two other ezetimibe trials conducted by Richard Peto and the Clinical Trials Service Unit of Oxford University.

Vytorin is a combination of cholesterol-lowering Zetia (ezetimibe) and the statin Zocor (simvastin). As mentioned in the NEJM editorial, some have theorized that Zetia could cause cancer because it blocks chemicals called plant sterols, which may cause heart disease but could also have some anti-cancer effect.

Plant sterols (phytosterols) resemble cholesterol in structure but are found exclusively in plant-based foods like fruits, vegetables, nuts and whole grains. A number of tissue culture studies have exposed various types of human cancer cells to plant sterols and have found a slowing of the progression of cells from one stage to another, something that is abnormal in cancer cells.

In addition, plant sterols have been found to cause apoptosis and shown to inhibit changes in cells that take place when tumor cells metastasize. Also, it has been shown an increase in growth of cells that are part of the human immune system, such as natural killer cells, which could be protective against cancer.

Ezetimibe inhibits cholesterol absorption, as opposed to removing cholesterol from the blood like statins. But ezetimibe also inhibits absorpotion of dietary plant sterols and there is a plausible theory that the reduction in sterol absorption in patients in the SEAS trial may have increased risk of contracting cancer.

The SEAS trial found an increase in cancer cases and deaths in the group that received ezetimibe. The Peto analysis of two ongoing ezetimibe trials found no increase in cancer cases, but did find more cancer deaths (97 vs. 72 in the control group), although the increase in cancer deaths did not reach statistical significance (p = .07).

When all three trials (SEAS, IMPROVE-IT and SHARP) were combined, there was a significant excess of cancer deaths among the patients assigned to ezetimibe (134 vs. 92; risk ratio, 1.45; p = 0.007). The Oxford group believes this is a statistical fluke, noting that there was no trend in the relative risk of death from cancer over time in SHARP and IMPROVE-IT alone or in all three trials combined.

Several lines of evidence suggest that plant sterols may have anti-cancer effects. The New York Tiimes interviewed Peter Bradford, a pharmacologist at SUNY Buffalo who has extensively studied plant sterols. Bradford explained that in laboratory tests plant sterols promote cell death in a way that could make them valuable anti-cancer agents as weapons against tumors. But by blocking plant sterol absorption, ezetimibe could be promoting cancer, he said.

More data is urgently needed before patients can again feel comfortable taking ezetimibe. It would be useful for the SEAS investigators to test the levels of plant sterols and carotenoids in blood samples from participants in the SEAS trial.

Until more information is available, ezetimibe use should be limited to patients in clinical trials. Zetia should not be used in clinical medicine until the justifiable and substantial cloud of uncertainty over it is resolved.