Release of Clinical Drug Trial Study Data

Editor's Note: For additional information on this topic please see our article "Disclosure of New Clinical Drugs to the Community" ; Clinical Drug Trials and Risks

(4/17/08)- The FDA has issued a stern warning letter to GlaxoSmihKline PLC, saying the drug maker failed to file regular reports to the agency about clinical trials that it was carrying out on its diabetes drug Avandia, as required by the law. The agency said it requires companies to report regularly on clinical trials so that it can spot potential safety problems with drugs.

The FDA uncovered the violations during an inspection last year of the company's records. The letter stated that the company failed to tell the agency about the initiation of nine clinical studies, and failed to update the FDA about the progress of more than a dozen other studies done between 2001 and 2007.

Avandia has been under scrutiny since last year, when a study concluded that patients taking the drug had a higher risk of suffering a heart attack than those taking other oral diabetes medicines or placebo pills. The FDA required the company to add a "black box" warning to Avandia's label describing the study's finding.

If a company fails to comply with a warning letter's demands, it can be fined or even slapped with other penalties.

(4/7/08)- John P.Kastelein, the lead investigator in the Enhance study of Vytorin said in an e-mail message last July that Merck and Schering-Plough, the manufacturers of the drug, were deliberately delaying the release of the trial results "to hide something". For additional details on this matter see our items dated 1/26/08, 1/22/08, 12/27/07, 12/23/07,12/19/07 and 12/4/07 below.

The companies did not release the preliminary results of the Enhance trial until January 2007, which was almost 2 years after the trial was finished.

Senator Charles E. Grassley (Rep-Io) the ranking Republican on the Senate Finance Committee released the e-mail and other information supplied to the committee by Merck and Schering along with a copy of a letter that he had sent to the chief executives of each of the companies.

In the e-mail that Dr. Kastelein sent on July 6, he indicated that he was quite upset to learn that the companies had decided against having the data ready for him to analyze and present at the meeting of the American Heart Association in November 2007.

The next day in another e-mail to Schering, Dr. Kastelein indicated that as a result of the delay, "you will be seen as a company that tries to hide something and I will be perceived as being in bed with you."

The FDA intitially approved Zetia in 2002 on the basis of trials that lasted no more than 12 weeks and covered only 3,900 patients. As we indicate in our item dated 12/27/07 there are some indications that when Zetia is combined with Zocor, there may be an increased risk of damage to the liver.

A panel of 4 cardiologists at the recent meeting of the American College of Cardiologists called on physicians to sharply curtail their use Vytorin. One of the panelists, Yale University cardiologist Harlan Krumholz stated, "You've seen a negative trial, that should change practice, especially the way we in this country have prescribed" the drugs. He urged doctors to stick with plain old statins.

The panel of 4 cardiologists was chosen by the College to interpret the results of the Enhance trial, which was formally presented at their recent meeting. The results of the trial were published in the recent edition of the New England Journal of Medicine. The articles in the journal urged doctors to consider the drugs only for patients who have failed to reach cholesterol goals on high doses of statin drugs or who are not able to tolerate them and other remedies that have been shown to prevent cardiovascular events.

A large trial investigating Vytorin's impact on death and heart attack rates had been scheduled to finish in 2011, but researchers announced that they are expanding the number of patients to as many as 18,000 from 12,500, because there have been fewer events than expected. The estimate now is that the study will be done in 2012.

(1/26/08)- The ramifications of the Vytorin/Zetia controversy that we discussed in our item dated 1/22/08 below continue to swirl and expand, so that now an issue of conflict of interest has now entered into the plot. The Enhance end-point study of Vytorin, which is made as a joint venture between Merck & Co. and Schering-Plough determined that it was no better than the statin drug Zocor (also made by Merck) working alone at reducing arterial plaque.

The issue that initially caused consternation was the delayed release of the results of the study.

On January 15th, the day after the results of the study was released, the American Heart Association came out with a statement saying that the announced result was too limited to draw conclusions about Vytorin's ability to reduce heart attacks or deaths compared to Zocor alone. The association advised patients to consult with their physicians before discontinuing usage of the drug.

At no time did the association reveal that it receives nearly $2 million a year from the joint venture

Merck and Schering-Plough have suspended all television ads for Vytorin and Zetia, but print ads, defending the drug have been appearing as full page ads in newspapers such as the NY Times and the Wall St. Journal. .

Total U.S. prescriptions written for Vytorin in the week ended January 18th fell about 9.5% to 359,659 from 397,533 in the week ended January 11th, according to Verispan, a Yardley, Pa., drug-data firm. Prescriptions for Zetia, which the Merck/Schering-Plough joint venture also markets, fell 12% to 258,619 from 294,405 the week before according to Verispan.

(1/22/08)- The theory that lowering bad cholesterol levels (LDLs) is beneficial has been an accepted fact for decades now. The results of the Enhance clinical trial of Merck and Schering's combined drug Vytorin, and the disappointing results of the Illuminate study for Pfizer's drug torcetrapib (increasing the good HDLs drug) may be bringing into question that whole theory. For more on the abandonment of pursuing its selling of torcetrapib, please see our article dated 12/19/06 below.

The Enhance clinical trial was a 2-year study evaluating whether Merck's statin drug Zocor (80mgs) which when combined with Schering-Plough's Zetia (10mgs) to form the drug Vytorin was more effective in reducing atherosclerosis than was Zocor when taken alone.

The results of the study as released by Merck and Schering-Plough showed that the study failed to meet the primary as well as the secondary end points. As a matter of fact not only did Zetia fail to slow the accumulation of fatty plaque in the arteries, it actually seemed to contribute to plaque formation, although by such a small amount that the finding could have been a result of chance.

Dr.Steven E. Nissen, the chairman of cardiology at the Cleveland Clinic said, "This is as bad a result for the drug as anybody could have feared." Dr. Eric J. Topol, a cardiologist and director of the Scripps Translational Science Institute in La Jolla, Calif said, "The idea that you're just going to lower LDL and people are going to get better, that's too simplistic, much too simplistic."

The Enhance trial covered 720 patients and lasted two years. It was completed in April 2006. In November 2007, the companies announced plans to change the trial's primary measure of effectiveness to "expedite their analysis", but they reversed course last month after a large outcry of criticism about the ethical matter in changing the primary measure of a trial.

Merck and Schering recently began a large study intended to test whether the combination of Zeia and statin drugs actually reduces heart attacks and strokes when compared with statins alone. The study involves doctors at Harvard and Duke Universities and is called Impove-It, but it will not be available until at least 2011.

Because the link between excessive LDL cholesterol levels and cardiovascular disease has been so widely accepted, the FDA generally has not required drug companies to prove that cholesterol medicines actually reduce heart attacks before approval.

They have not had to conduct so-called outcome or event trials beforehand, which are expensive studies that involve thousands of patients and track whether episodes like heart attacks are reduced.

(12/27/07)- Partial results of studies that had been conducted by Merck and Schering-Plough, showed the possibility that Schering-Plough's cholesterol medication Zetia, when combined with statin drugs might cause damage to the liver, and that this risk had not been revealed by the companies. The discovery of the unpublished research adds more fuel to the controversy involved in the failure of Schering and Merck to make a timely disclosure of the results of the Enhance study that we discuss in the items below.

A Schering executive, Dr. Robert J. Spiegel, when queried about the unpublished studies confirmed their existence. Dr. Spiegel went on to explain that Merck and Schering did not consider the studies scientifically important enough to publish the findings.

Before Zetia was approved in 2002, one FDA reviewer said it should not be cleared for use with statins, because the combination had caused liver damage in animals. In the last two years, scattered case reports of severe liver damage in patients taking Zetia in combination with statins have appeared in medical journals.

The label for Zetia contains only mild warnings about the drug's potential for liver damage. Regulators in Australia and Canada have warned since 2005 about the drug's potential to cause hepatitis, pancreatitis and depression. Most of the studies for which Merck and Schering have published results for Zetia covering only 12 weeks, which is not enough time for liver problems to develop in most patients.

The unpublished studies were conducted from 2000 to 2003 according to FDA documents but were not listed on the industry Web sites where campaniles are supposed to register the results of all drug trials that were ongoing after October 2002. When the FDA approved Zetia in 2002 it relied on trials that covered only 3,900 patients and lasted no more than 12 weeks.

The data from those trials indicated that Zetia might be dangerous when it is combined with a statin.

Reversing course once again, Merck & Co., and Schering-Plough announced that they would present the full results of the Enhance study at the American College of Cardiology's conference in Chicago in March 2008. Please see our items on this topic dated 12/19/07 and 12/4/07 below.

The lead researcher for the study, Dr. John P.Kastelein, a cardiologist at the Academic Medical Center, said that he regretted not standing up to the companies when they announced on November 19 that they would announce only limited primary endpoints for the study, and not the full primary endpoints. The study was completed in April 2006.

The Enhance study was intended to determine whether the combination treatment of Schering's Zetia and Merck's Zocor works better than Zocor alone. Vytorin is a combination pill of both Zetia and Zocor. Zetia is not a statin drug. The study was initially designed to measure changes in the thickness of the carotid artery walls after two years of treatment.

That measurement was taken at 6 points-3 different locations- in carotid artery and would serve as the primary endpoint of the study.

(12/23/08)- Representative Bart Stupak (D.-Mich.) chairman of the House's subcommittee on Oversight Investigation said, "In light of today's results, which were released nearly two years after the Enhance trial ended, it is easy to conclude that Merck and Schering-Plough intentionally sought to delay the release of this data, ". Represenative John Dingell (D.-Mich.) said, "We will continue our investigation until these questions are answered."

Dr. Harlan M. Krumholz, a cardiologist at Yale-New Haven Hospital, said drug companies had a responsibility to release all their trial finding, positive or negative, as quickly as possible- even if the results might hurt sales.

The makers of antidepressants, like Prozac and Paxil, never published the results of about a third of the drug trials that they conducted about the drug's true effectiveness. In a study, a team of researchers identified all antidepressant trials submitted to the FDA to win approval from 1987 to 2004. The studies involved 12,554 adult patients testing drugs like Lilly's Prozac, Zoloft from Pfizer and Effexor from Wyeth.

The researchers found that 37 of 38 trials that the FDA viewed as having positive results were published in professional journals. Of 36 other trials that the agency found to be failures or unconvincing, only 14 made it to the professional journals.

Eleven of the 14 journal articles however were "conveyed a positive outcome" that was not justified by the underlying FDA review, said the study's lead author, Dr. Erik H. Turner, a psychiatrist and former FDA reviewer who now works at Oregon Health and Sciences University and the Portland Veterans Affairs Medical Center.

His co-authors included researchers at Kent State University and the University of California Riverside.

(12/19/07)- The House Committee on Energy and Commerce Chairman John D.Dingell (Dem.-Mich.) and Bart Stupak, the chairman of the committee's subcommittee on oversight and investigations sent a letter to Merck and Schering Plough regarding that "we are concerned with the delay in releasing the results of the study (Enhanced)" that we discuss in our item dated 12/4/07 below.

Vytorin accounts for more than 50% of Schering-Plough's earnings per share, and about 20% of Merck's earnings per share. As we note in the item below the companies completed the study in early 2006 of the drug, and announced that they would reveal the results of the study in 2007. On November 16th they announced that after consulting with an independent panel of clinical biostatistical experts, that they had decided to change the primary endpoint of the ENHANCE trial. It is very unusual to change the endpoint of a study.

(12/4//07)- Nearly two years after the completion of a clinical study of the cholesterol lowering drugs Zetia and Vytorin in combination, the results have still not been published. Even though there are 800,000 prescriptions written each week, at a cost of about $4 billion, the results of the trial, called Enhance are still unknown.

The two drug manufacturers of the drugs recently announced that they would release the results of one of the three original end-points of the study in March 2008 at the American College of Cardiology's conference in Chicago. The results of a larger clinical study of the drugs are not due to be released until at least the year 2010.

The companies originally said that they would measure the thickness of plaque in two arteries. The first artery would be the carotid artery, which runs through the neck and supplies the brain with blood. The second artery would be the femoral, which runs through the hips and supplies blood to the legs. The primary endpoint of the study was supposed to be the amount of plaque at three points in the carotid artery.

The companies announced however that they would announce only the endpoint of the study at the meeting to releasing only the measurement of the thickness at just one point in the carotid artery. At the same time they announced that they do not expect to release any results from the femoral artery study.

Dr. John Kastelein, a Dutch cardiologist who oversaw the study stated that he believed that the trial should still be considered valid.

The Enhance trial was supposed to show that Zetia and Vytorin (simvastatin) when used together would reduce the growth of plaque in blood vessel walls more than if simvastatin were used alone.

Zetitia works differently than does the statin medications such as Prizer's Lipitor or Merck's Zocor. The FDA approved Zetia in 2002 on the basis of trials that showed it could lower LDL, or so-called bad cholesterol, by 15% to 20%. It is the brand name medication for a cholesterol-lowering medication known as ezetimibe.

It can be taken with any of the statin medications. Vytorin is a pill that combines Zetia with simvastatin, the active ingredient in Merck's Zocor medication. Zetia and Vytorin both cost about $3 a day.

Dr. Eric J. Topol, a cardiologist and director of the Scripps Transitional Science Institute in La Jolla, California stated: " There has yet to be a clinical trial to show that ezetimibe improves clinical outcomes."


Allan Rubin
updated April 17, 2008

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