Vytorin and the ENHANCE Study

The news that the drug Vytorin' may not be very effective for its advertised purpose has created a crisis for its manufacturers. Critics claim the results of a clinical trial of the medication's efficacy were released months, if not years, after the drug companies knew their product was not what they had originally claimed. Now, government oversight agencies are investigating the possibility that the drug's manufacturers are guilty of insider trading, medical test manipulation and/or false advertising. In addition, shareholders are upset and consumers are suing.

Vytorin contains two medications: Zocor' (simvastatin), manufactured by Merck & Co.; and Zetia' (ezetimibe), manufactured by Merck and Schering-Plough Corp. It is indicated for some patients who need to reduce total cholesterol and LDL (bad) cholesterol, and raise HDL (good) cholesterol.

Because Vytorin is more expensive than its component parts, Zocor and Zetia, health-care providers, government entities, insurers and patients have an interest in knowing if they are spending money wisely to obtain the combination drug. However, by late last year it was widely known that the test had long-since been completed, but Vytorin's makers continued to keep the results from the medical community and the general public.

The Clinical Trial

The clinical trial of Vytorin that is causing the controversy is known as ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the atherosclerotic Process in Subjects With Heterozygous Familial Hyperchol-esterolemia). According to Merck, the study was designed as a 'multinational, randomized, double-blind, trial that examines the effects of the highest approved dose of VYTORIN/ INEGY (10 mg ezetimibe + 80 mg simvastatin) versus the highest approved dose of simvastatin 80 mg alone in patients with Heterozygous Familial Hypercholesterolemia (HeFH). Patients with this uncommon genetic condition usually have very high cholesterol levels.' Merck Product News, 11/19/07, http://www.merck.com/newsroom/press_releases/product/2007_1119.html (last accessed 1/25/08). The study, which involved the testing of more than 700 patients with hereditarily high cholesterol levels, began in 2002 and ended in April 2006.

Many were anxious to see the results, but they were not immediately forthcoming. Late in 2007, some doctors and news media outlets began asking publicly why a test that had been completed in the spring of 2006 was still under wraps. What were the makers of Vytorin trying to hide, they asked? Causing further suspicion was the fact that the manufacturers did not register the trial with the National Institutes of Health until 18 months after the study was completed.

In a November 2007 release, Merck attempted to answer its critics, stating that although the trial had been completed, the company was unready to release the results because of ongoing analysis of the data. Id. That analysis, Merck said, was going to take longer than originally anticipated, due to the need to examine more than 40,000 scans of arteries collected in 18 multi-national study locations. In addition, the manufacturers said they were going to need more time because they had ' just one day before issuing the release ' convened what Merck termed an 'independent panel of clinical and biostatistics experts.' That panel recommended altering the test's stated endpoint ' thus, according to skeptics, allowing for a more flattering assessment of the health attributes of Vytorin use. It was these trail results, altered in accordance with the 'independent panel's' recommendation, that Merck proposed it would report at a meeting of the American College of Cardiology, in March 2008.

Consumer Suits Follow News

In the period after the ENHANCE trial was completed, advertisements touting the superior benefits of Vytorin over less expensive generic cholesterol-lowering drugs continued ' and as of the end of January, still continue. You've undoubtedly seen some of them. A voice-over tells you that cholesterol comes from two sources: food and family. On one side of a split screen is a food item, such as a fancily decorated cake; on the other side, a 'family member' who dresses remarkably like that food ' in the case of the cake, it's a middle-aged woman in a cake-like hat. The voice-over tells you that Vytorin works both to reduce absorption of dietary cholesterol and to reduce genetically high cholesterol.

The problem with these advertisements, critics say, is that they don't tell the whole story. The ENHANCE trial results showed that Vytorin did indeed decrease cholesterol, but that the combination of the two drugs in Vytorin is no better at decreasing arterial plaque than Zocor alone. It is the buildup of arterial plaque that is believed to lead to coronary events, due to the plaque's blockage of the free-flow of blood. Keeping cholesterol levels low is considered important because lower cholesterol levels are associated with lower levels of arterial plaque. If the combination drug Vytorin has no added benefit over less expensive single drugs in decreasing arterial plaques, where is the added benefit?

On the heels of this news, consumers reacted swiftly.

Steve Berman at Hagens Berman Sobol Shapiro in Seattle was reading about the clinical trial results one day. Said Berman, 'I hadn't even finished reading the article when people were calling me, irate. They were paying out of pocket because they were told [Vytorin] would lower their plaque. They wouldn't have paid for it if the drug was truthfully marketed.” Berman's suit, filed on Jan. 17 in the U.S. District Court for the District of New Jersey, seeks the return of money to purchasers of Vytorin. Lionel Galperin v. Merck & Co. Inc., No. 08-cv-349.

Another suit, Rheingold v. Merck, No. 08-CV-00438, was filed on Jan. 17 in the U.S. District Court for the Southern District of New York. The plaintiff is a Vytorin user and the wife of David B. Rheingold of Rheingold, Valet, Rheingold, Shkolnik & McCartney. He said the filing of the suit was 'almost reflexive,” following his reading of newspaper articles about the study.

David Krangle of Parker Waichman Alonso in Great Neck, NY, quickly assembled a team of firms to bring suit in the U.S. District Court for the Eastern District of New York after receiving calls from potential plaintiffs who purchased the drug in New York. The suit is Tomaszewski v Merck, No. CV 08-258. Krangle's firm is partnering with New York's Douglas & London; Becnel Law Firm of Reserve, La.; Levin Simes Kaiser & Gornick of San Francisco; Houston's Bailey Perrin Bailey; and Weitz & Luxenberg of New York. 'We like to team up to get everyone's resources to handle the case more effectively,” Krangle said. 'We moved quickly because there are certain advantages to getting started early. When the class counsel is appointed, one of the things a judge will look at it is who filed the case first, so that's why cases are filed quickly.”

Government Steps In

On Dec. 11, 2007, the co-chairmen of the Congressional Committee on Energy and Commerce, John D. Dingel (D-MI) and Bart Stupak (D-MI), sent letters to the Chairmen of the Boards of Schering-Plough and Merck, informing them that the Congressional Committee on Energy and Commerce and the Subcommittee on Oversight and Investigations were opening an investigation into the companies' alleged wrongful withholding of clinical trail data. In their letters to Merck and Schering-Plough, the Congressmen asked the manufacturers to make company representatives and some who conducted the study available for questioning, and to provide explanations for the failure to timely register the study, among other things.

Said Dingell in a release at the time of the opening of the congressional investigation: 'Today's announcement that the ENHANCE study failed to find any positive benefit from the addition of Zetia to a common, inexpensive, generic therapy raises concerns that attempts were made to mask the minimal value of this new drug. Additionally, Merck and Schering-Plough's delay in releasing study results, as well as their attempt to manipulate the data is, quite frankly, suspicious. Heart disease is a serious and growing national problem. American consumers and their doctors should not have had to wait nearly two years for this information. Why did Merck and Schering-Plough go to great lengths to delay the study results? Why did they attempt to manipulate the data? We will continue our investigation until these questions are answered.' News release 1/14/08, at: http://energycommerce.house.gov/Press_110/110nr171.shtml (last accessed 2/1/08).

On Jan. 14, the Merck and Schering-Plough issued a press release outlining the results of the ENHANCE trail, ahead of the scheduled March 2008 date. As we've noted, rather than quelling concerns, the trail's results caused an even bigger uproar because it appeared that Vytorin, while better at lowering bad cholesterol, was no more effective at reducing arterial plaque than generic versions of Zocor. Statistically, the drugs yielded like results, but the higher cost of Vytorin should have made it a less attractive alternative to generic Zocor.

Soon, the urgency of the government's investigations appeared to be stepped up. Congressmen Dingel and Stupak asked the Centers for Medicare and Medicaid Services (CMS) to provide the Energy and Commerce Committee with the dollar amount it had expended on Vytorin prescriptions since April 2006, presumably to discover how much money the government may have overpaid for a drug whose benefits over cheaper medications is questionable.

Insider trading questions also arose. Charles Grassley of the Senate Committee on Finance wrote to the Chairman of the Securities and Exchange Commission asking that that organization investigate the companies for this possibility. 'What disturbs me,' wrote Grassley, 'is that, according to news reports, while the Companies failed to release the ENHANCE trial results, several executives at Schering-Plough sold stock. This sequence of events raises serious questions about whether executives at the Companies sold stock because they knew that the results of ENHANCE were negative which in turn would negatively affect stock value.' Letter to SEC Chairman Cox, http://www.senate.gov/~finance/press/Gpress/2008/prg012408e.pdf (last accessed 1/27/08).

Merck and Schering-Plough Respond

In a joint release from the two drug manufacturers defending their companies' actions, Thomas Koestler, Ph.D., president of the Schering-Plough Research Institute, stated, 'While the ENHANCE trial was time consuming and took longer than originally anticipated to complete, our companies acted with integrity and good faith in connection with the trial. We took numerous actions to assure the quality of the reading of the ultrasound images.' Merck Product News, 1/25/08, www.merck.com/newsroom/press_releases/product/2008_0125.html (last accessed 1/27/08). The release went on to describe some of the causes for the delays in reporting the ENHANCE trial's results. Significantly, it also asserted that the study remained blinded ' with no one in the company, on the research team or among the study's participants knowing which study subjects received which drug treatment ' until at least Dec. 31, 2007. (The companies have provided the public with a timeline of events surrounding the Vytorin ENHANCE study. It can be accessed at: http://www.merck.com/newsroom/pdf/ENHANCE_Chronology_1-25-08.pdf.)

If these claims are true, the Merck and Schering-Plough employees suspected of insider trading may have had no reason to doubt Vytorin's value or to anticipate any drop in share prices upon publication of the study's results. Likewise, the manufacturers' advertised claims that Vytorin is superior to other drugs at reducing cholesterol could have been based on genuinely held beliefs.

In fact, many in the world of medical care are urging caution in the apparent rush to tar and feather Merck and Schering-Plough. Both the American Heart Association and the American College of Cardiology said decisions about whether Vytorin has superior abilities to cut heart attack and other cardiology risks should be delayed until more information is available. The FDA echoed these groups, stating, 'There are no clinical studies available that demonstrate a reduction in risk of heart attack or stroke when ezetimibe is used alone or in combination with a statin, including the fixed-dosed combination drug of ezetimibe and simvastatin, Vytorin. While the overall incidence of cardiovascular events in ENHANCE was similar in both the ezetimibe/simvastatin and simvastatin-alone groups, there were not enough patients in this study to reliably test whether treatment with ezetimibe/simvastatin compared with simvastatin alone reduces the risk of cardiovascular events. An ongoing trial known as IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) is examining this question in 12,500 patients and will likely be completed in 2011. Physicians and patients should carefully consider the available data and current labeling for Zetia and Vytorin as they make individual treatment decisions.' FDA Early Communication about an Ongoing Data Review for Ezetimibe/Simvastatin (marketed as Vytorin), Ezetimibe (marketed as Zetia), and Simvastatin (marketed as Zocor), 1/25/08 http://www.fda.gov/cder/drug/early_comm/ezetimibe_simvastatin.htm (last accessed 1/27/08).

Conclusion

The ENHANCE study showed that Vytorin decreased bad cholesterol, but it did not show a statistically significant difference in the buildup of arterial plaque in those taking Vytorin vs. generics. However, the thickness of arterial plaque is just one measure of risk. The real question, ultimately, has to be: 'Does Vytorin decrease the incidence of heart attacks and other cardiac problems?' More clinical trials that aim to answer this and other questions are ongoing, and they involve a larger patient sample than the mere 700+ participants who took part in the ENHANCE trial. Consequently, a final verdict on the value of Vytorin over generics will have to wait.

Still, the main cause for outrage in the present situation is not whether one drug works better than another. What lawmakers, shareholders, physicians and patients want to know now is pretty much the same thing the public wanted to know at the height of the Watergate Scandal: Who knew what, and when did they know it?

Janice G. Inman is Editor-in-Chief of this newsletter.

The news that the drug Vytorin' may not be very effective for its advertised purpose has created a crisis for its manufacturers. Critics claim the results of a clinical trial of the medication's efficacy were released months, if not years, after the drug companies knew their product was not what they had originally claimed. Now, government oversight agencies are investigating the possibility that the drug's manufacturers are guilty of insider trading, medical test manipulation and/or false advertising. In addition, shareholders are upset and consumers are suing.

Vytorin contains two medications: Zocor' (simvastatin), manufactured by Merck & Co.; and Zetia' (ezetimibe), manufactured by Merck and Schering-Plough Corp. It is indicated for some patients who need to reduce total cholesterol and LDL (bad) cholesterol, and raise HDL (good) cholesterol.

Because Vytorin is more expensive than its component parts, Zocor and Zetia, health-care providers, government entities, insurers and patients have an interest in knowing if they are spending money wisely to obtain the combination drug. However, by late last year it was widely known that the test had long-since been completed, but Vytorin's makers continued to keep the results from the medical community and the general public.

The Clinical Trial

The clinical trial of Vytorin that is causing the controversy is known as ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the atherosclerotic Process in Subjects With Heterozygous Familial Hyperchol-esterolemia). According to Merck, the study was designed as a 'multinational, randomized, double-blind, trial that examines the effects of the highest approved dose of VYTORIN/ INEGY (10 mg ezetimibe + 80 mg simvastatin) versus the highest approved dose of simvastatin 80 mg alone in patients with Heterozygous Familial Hypercholesterolemia (HeFH). Patients with this uncommon genetic condition usually have very high cholesterol levels.' Merck Product News, 11/19/07, http://www.merck.com/newsroom/press_releases/product/2007_1119.html (last accessed 1/25/08). The study, which involved the testing of more than 700 patients with hereditarily high cholesterol levels, began in 2002 and ended in April 2006.

Many were anxious to see the results, but they were not immediately forthcoming. Late in 2007, some doctors and news media outlets began asking publicly why a test that had been completed in the spring of 2006 was still under wraps. What were the makers of Vytorin trying to hide, they asked? Causing further suspicion was the fact that the manufacturers did not register the trial with the National Institutes of Health until 18 months after the study was completed.

In a November 2007 release, Merck attempted to answer its critics, stating that although the trial had been completed, the company was unready to release the results because of ongoing analysis of the data. Id. That analysis, Merck said, was going to take longer than originally anticipated, due to the need to examine more than 40,000 scans of arteries collected in 18 multi-national study locations. In addition, the manufacturers said they were going to need more time because they had ' just one day before issuing the release ' convened what Merck termed an 'independent panel of clinical and biostatistics experts.' That panel recommended altering the test's stated endpoint ' thus, according to skeptics, allowing for a more flattering assessment of the health attributes of Vytorin use. It was these trail results, altered in accordance with the 'independent panel's' recommendation, that Merck proposed it would report at a meeting of the American College of Cardiology, in March 2008.

Consumer Suits Follow News

In the period after the ENHANCE trial was completed, advertisements touting the superior benefits of Vytorin over less expensive generic cholesterol-lowering drugs continued ' and as of the end of January, still continue. You've undoubtedly seen some of them. A voice-over tells you that cholesterol comes from two sources: food and family. On one side of a split screen is a food item, such as a fancily decorated cake; on the other side, a 'family member' who dresses remarkably like that food ' in the case of the cake, it's a middle-aged woman in a cake-like hat. The voice-over tells you that Vytorin works both to reduce absorption of dietary cholesterol and to reduce genetically high cholesterol.

The problem with these advertisements, critics say, is that they don't tell the whole story. The ENHANCE trial results showed that Vytorin did indeed decrease cholesterol, but that the combination of the two drugs in Vytorin is no better at decreasing arterial plaque than Zocor alone. It is the buildup of arterial plaque that is believed to lead to coronary events, due to the plaque's blockage of the free-flow of blood. Keeping cholesterol levels low is considered important because lower cholesterol levels are associated with lower levels of arterial plaque. If the combination drug Vytorin has no added benefit over less expensive single drugs in decreasing arterial plaques, where is the added benefit?

On the heels of this news, consumers reacted swiftly.

Steve Berman at Hagens Berman Sobol Shapiro in Seattle was reading about the clinical trial results one day. Said Berman, 'I hadn't even finished reading the article when people were calling me, irate. They were paying out of pocket because they were told [Vytorin] would lower their plaque. They wouldn't have paid for it if the drug was truthfully marketed.” Berman's suit, filed on Jan. 17 in the U.S. District Court for the District of New Jersey, seeks the return of money to purchasers of Vytorin. Lionel Galperin v. Merck & Co. Inc. , No. 08-cv-349.

Another suit, Rheingold v. Merck, No. 08-CV-00438, was filed on Jan. 17 in the U.S. District Court for the Southern District of New York. The plaintiff is a Vytorin user and the wife of David B. Rheingold of Rheingold, Valet, Rheingold, Shkolnik & McCartney. He said the filing of the suit was 'almost reflexive,” following his reading of newspaper articles about the study.

David Krangle of Parker Waichman Alonso in Great Neck, NY, quickly assembled a team of firms to bring suit in the U.S. District Court for the Eastern District of New York after receiving calls from potential plaintiffs who purchased the drug in New York. The suit is Tomaszewski v Merck, No. CV 08-258. Krangle's firm is partnering with New York's Douglas & London; Becnel Law Firm of Reserve, La.; Levin Simes Kaiser & Gornick of San Francisco; Houston's Bailey Perrin Bailey; and Weitz & Luxenberg of New York. 'We like to team up to get everyone's resources to handle the case more effectively,” Krangle said. 'We moved quickly because there are certain advantages to getting started early. When the class counsel is appointed, one of the things a judge will look at it is who filed the case first, so that's why cases are filed quickly.”

Government Steps In

On Dec. 11, 2007, the co-chairmen of the Congressional Committee on Energy and Commerce, John D. Dingel (D-MI) and Bart Stupak (D-MI), sent letters to the Chairmen of the Boards of Schering-Plough and Merck, informing them that the Congressional Committee on Energy and Commerce and the Subcommittee on Oversight and Investigations were opening an investigation into the companies' alleged wrongful withholding of clinical trail data. In their letters to Merck and Schering-Plough, the Congressmen asked the manufacturers to make company representatives and some who conducted the study available for questioning, and to provide explanations for the failure to timely register the study, among other things.

Said Dingell in a release at the time of the opening of the congressional investigation: 'Today's announcement that the ENHANCE study failed to find any positive benefit from the addition of Zetia to a common, inexpensive, generic therapy raises concerns that attempts were made to mask the minimal value of this new drug. Additionally, Merck and Schering-Plough's delay in releasing study results, as well as their attempt to manipulate the data is, quite frankly, suspicious. Heart disease is a serious and growing national problem. American consumers and their doctors should not have had to wait nearly two years for this information. Why did Merck and Schering-Plough go to great lengths to delay the study results? Why did they attempt to manipulate the data? We will continue our investigation until these questions are answered.' News release 1/14/08, at: http://energycommerce.house.gov/Press_110/110nr171.shtml (last accessed 2/1/08).

On Jan. 14, the Merck and Schering-Plough issued a press release outlining the results of the ENHANCE trail, ahead of the scheduled March 2008 date. As we've noted, rather than quelling concerns, the trail's results caused an even bigger uproar because it appeared that Vytorin, while better at lowering bad cholesterol, was no more effective at reducing arterial plaque than generic versions of Zocor. Statistically, the drugs yielded like results, but the higher cost of Vytorin should have made it a less attractive alternative to generic Zocor.

Soon, the urgency of the government's investigations appeared to be stepped up. Congressmen Dingel and Stupak asked the Centers for Medicare and Medicaid Services (CMS) to provide the Energy and Commerce Committee with the dollar amount it had expended on Vytorin prescriptions since April 2006, presumably to discover how much money the government may have overpaid for a drug whose benefits over cheaper medications is questionable.

Insider trading questions also arose. Charles Grassley of the Senate Committee on Finance wrote to the Chairman of the Securities and Exchange Commission asking that that organization investigate the companies for this possibility. 'What disturbs me,' wrote Grassley, 'is that, according to news reports, while the Companies failed to release the ENHANCE trial results, several executives at Schering-Plough sold stock. This sequence of events raises serious questions about whether executives at the Companies sold stock because they knew that the results of ENHANCE were negative which in turn would negatively affect stock value.' Letter to SEC Chairman Cox, http://www.senate.gov/~finance/press/Gpress/2008/prg012408e.pdf (last accessed 1/27/08).

Merck and Schering-Plough Respond

In a joint release from the two drug manufacturers defending their companies' actions, Thomas Koestler, Ph.D., president of the Schering-Plough Research Institute, stated, 'While the ENHANCE trial was time consuming and took longer than originally anticipated to complete, our companies acted with integrity and good faith in connection with the trial. We took numerous actions to assure the quality of the reading of the ultrasound images.' Merck Product News, 1/25/08, www.merck.com/newsroom/press_releases/product/2008_0125.html (last accessed 1/27/08). The release went on to describe some of the causes for the delays in reporting the ENHANCE trial's results. Significantly, it also asserted that the study remained blinded ' with no one in the company, on the research team or among the study's participants knowing which study subjects received which drug treatment ' until at least Dec. 31, 2007. (The companies have provided the public with a timeline of events surrounding the Vytorin ENHANCE study. It can be accessed at: http://www.merck.com/newsroom/pdf/ENHANCE_Chronology_1-25-08.pdf.)

If these claims are true, the Merck and Schering-Plough employees suspected of insider trading may have had no reason to doubt Vytorin's value or to anticipate any drop in share prices upon publication of the study's results. Likewise, the manufacturers' advertised claims that Vytorin is superior to other drugs at reducing cholesterol could have been based on genuinely held beliefs.

In fact, many in the world of medical care are urging caution in the apparent rush to tar and feather Merck and Schering-Plough. Both the American Heart Association and the American College of Cardiology said decisions about whether Vytorin has superior abilities to cut heart attack and other cardiology risks should be delayed until more information is available. The FDA echoed these groups, stating, 'There are no clinical studies available that demonstrate a reduction in risk of heart attack or stroke when ezetimibe is used alone or in combination with a statin, including the fixed-dosed combination drug of ezetimibe and simvastatin, Vytorin. While the overall incidence of cardiovascular events in ENHANCE was similar in both the ezetimibe/simvastatin and simvastatin-alone groups, there were not enough patients in this study to reliably test whether treatment with ezetimibe/simvastatin compared with simvastatin alone reduces the risk of cardiovascular events. An ongoing trial known as IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) is examining this question in 12,500 patients and will likely be completed in 2011. Physicians and patients should carefully consider the available data and current labeling for Zetia and Vytorin as they make individual treatment decisions.' FDA Early Communication about an Ongoing Data Review for Ezetimibe/Simvastatin (marketed as Vytorin), Ezetimibe (marketed as Zetia), and Simvastatin (marketed as Zocor), 1/25/08 http://www.fda.gov/cder/drug/early_comm/ezetimibe_simvastatin.htm (last accessed 1/27/08).

Conclusion

The ENHANCE study showed that Vytorin decreased bad cholesterol, but it did not show a statistically significant difference in the buildup of arterial plaque in those taking Vytorin vs. generics. However, the thickness of arterial plaque is just one measure of risk. The real question, ultimately, has to be: 'Does Vytorin decrease the incidence of heart attacks and other cardiac problems?' More clinical trials that aim to answer this and other questions are ongoing, and they involve a larger patient sample than the mere 700+ participants who took part in the ENHANCE trial. Consequently, a final verdict on the value of Vytorin over generics will have to wait.

Still, the main cause for outrage in the present situation is not whether one drug works better than another. What lawmakers, shareholders, physicians and patients want to know now is pretty much the same thing the public wanted to know at the height of the Watergate Scandal: Who knew what, and when did they know it?

Janice G. Inman is Editor-in-Chief of this newsletter.