SITE MENU
Welcome to DSI
For Patients
Concierge Care Club
Patient Resources
Enroll in a Study
Basic Research
Preventive Medicine
For Industry
For Doctors
About Us
Employment
Other Sites
Site Map
DSI Newsletters, Issue 70:
Vytorin
Vytorin = Zocor (Simvastatin) + Zetia (Ezetimibe)
Merck & Schering-Plough did a trial known as ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) to evaluate ZETIA 10 mg and simvastatin 80 mg versus simvastatin 80 mg alone in reversing the atherosclerotic thickening of the carotid artery in patients with high cholesterol.
The 700 patients in the ENHANCE trial, who all had a genetic disease (FH) causing their levels of bad cholesterol (LDL) to spike without treatment, were all on the top dose of the cholesterol-lowering drug Zocor; 80 mgm. Half of them also got Zetia, a second cholesterol drug, but there was no additional benefit on artery plaque. Vytorin is a combo pill of Zetia and Zocor. There was no sign Zetia was unsafe.
The allegation is that ENHANCE lacked expert committees that might have helped the companies avoid delays in releasing the data. Those committees may also have given them a legitimate way to handle any problems that came up, averting the public relations disaster that has caused share price declines of 15% for Merck and 25% for Schering as investors worry about the future of the companies' $5 billion cholesterol franchise.
Schering chief medical officer Robert Spiegel provided the answer in an interview with Forbes.com more than a week ago. This study had neither a steering committee, as a group of experts who regularly convened to discuss the trial and its data, nor a data safety monitoring board (DSMB), which carefully watches study information to make sure patients are not harmed.
The lack of a data safety monitoring board is "sub-optimal," says Steven Joffe, a bioethicist and researcher at the Dana Farber Cancer Center. A DSMB might not take direct accountability, he notes, but it provides a mechanism that can reassure the public when problems happen.
Not everyone agrees. "I do not think a DSMB for ENHANCE was necessary," says Steven Nissen, head of cardiology at the Cleveland Clinic. He does, however, think the lack of a steering committee was "irregular."
Here's the rub: Schering-Plough wound up calling an ad hoc group on Nov. 16, 2007, to try to decide how to deal with what the company says were data problems. Schering and Merck have blamed the long delay in releasing details of the ENHANCE study on problems the companies saw with the imaging data in the study.
"We did think it was appropriate, as the study was still blinded, to try and get some outside opinions to just validate that the assumptions we made when the study started," said Spiegel.
If that decision had been made by a standing group of experts instead of an ad hoc group, it would have drawn less scrutiny. The same goes for the long delay in the study--if outside experts had been named ahead of time to make decisions about the data; there would be no debate over whether Merck and Schering did the right thing with regard to this trial.
Instead, they must now face a debate in which many top cardiologists argue that their drugs should only be used as second-choice options--and a congressional committee that is questioning every step they took--with the benefit of 20/20 hindsight.
What I, Dr. Saponaro take from this Vytorin controversy is the following:
Sincerely:
Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP
PI (Principal Investigator), DSI (Drug Study Institute)
Board Certified Internist, JPMC (Jupiter Preventive Medicine Center)
DABIM (Diplomat American Board of Internal Medicine)
FACP (Fellow American College of Physicians)
CPI (Certified Physician Investigator) by the AAPP (American Academy of Pharmaceutical Physicians)
CCTI (Certified Clinical Trial Investigator) by the ACRP (Association of Clinical Research Professionals)
CCI (Certified Clinical Investigator) by the DIA (Drug Information Association)
CCRC (Certified Clinical Research Coordinator) by the ACRP (Association of Clinical Research Professionals)
CCRP (Certified Clinical Research Professional) by SoCRA (Society of Clinical Research Associates)
Member, SIMPD (Society for Innovative Medical Practice Design)
Member, ACPM (American College Preventive Medicine)
Ethics Committee Member, Jupiter Medical Center
IRB Member, Jupiter Medical Center
Founder, CertifiedResearchers.com
Merck & Schering-Plough did a trial known as ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) to evaluate ZETIA 10 mg and simvastatin 80 mg versus simvastatin 80 mg alone in reversing the atherosclerotic thickening of the carotid artery in patients with high cholesterol.
The 700 patients in the ENHANCE trial, who all had a genetic disease (FH) causing their levels of bad cholesterol (LDL) to spike without treatment, were all on the top dose of the cholesterol-lowering drug Zocor; 80 mgm. Half of them also got Zetia, a second cholesterol drug, but there was no additional benefit on artery plaque. Vytorin is a combo pill of Zetia and Zocor. There was no sign Zetia was unsafe.
The allegation is that ENHANCE lacked expert committees that might have helped the companies avoid delays in releasing the data. Those committees may also have given them a legitimate way to handle any problems that came up, averting the public relations disaster that has caused share price declines of 15% for Merck and 25% for Schering as investors worry about the future of the companies' $5 billion cholesterol franchise.
Schering chief medical officer Robert Spiegel provided the answer in an interview with Forbes.com more than a week ago. This study had neither a steering committee, as a group of experts who regularly convened to discuss the trial and its data, nor a data safety monitoring board (DSMB), which carefully watches study information to make sure patients are not harmed.
The lack of a data safety monitoring board is "sub-optimal," says Steven Joffe, a bioethicist and researcher at the Dana Farber Cancer Center. A DSMB might not take direct accountability, he notes, but it provides a mechanism that can reassure the public when problems happen.
Not everyone agrees. "I do not think a DSMB for ENHANCE was necessary," says Steven Nissen, head of cardiology at the Cleveland Clinic. He does, however, think the lack of a steering committee was "irregular."
Here's the rub: Schering-Plough wound up calling an ad hoc group on Nov. 16, 2007, to try to decide how to deal with what the company says were data problems. Schering and Merck have blamed the long delay in releasing details of the ENHANCE study on problems the companies saw with the imaging data in the study.
"We did think it was appropriate, as the study was still blinded, to try and get some outside opinions to just validate that the assumptions we made when the study started," said Spiegel.
If that decision had been made by a standing group of experts instead of an ad hoc group, it would have drawn less scrutiny. The same goes for the long delay in the study--if outside experts had been named ahead of time to make decisions about the data; there would be no debate over whether Merck and Schering did the right thing with regard to this trial.
Instead, they must now face a debate in which many top cardiologists argue that their drugs should only be used as second-choice options--and a congressional committee that is questioning every step they took--with the benefit of 20/20 hindsight.
What I, Dr. Saponaro take from this Vytorin controversy is the following:
- Vytorin and its components, Zocor (Simvastatin) + Zetia (Ezetimibe) are safe. The study was not questioning its safety. Public reaction to this has been to question the safety of the drugs and to have concern whether they should continue taking them. But the truth is the original study critics did not have drug safety concerns. That is Vytorin and its components are safe.
- The study questions the effectiveness and in particular the cost effectiveness of the more expensive Vytorin compared to generically available Zocor. When imaging studies of atherosclerosis (cholesterol in the coronary arteries) were taken, there was no difference in the Vytorin vs. Zocor group. It is very possible the studies were not conducted properly to come to this conclusion. More study is needed prior to making any judgment calls.
- Zetia is one of the safest medications. It is not systemically absorbed so it does not enter the bloodstream. It does not have the liver and muscle side effects of statins. Its weak point is efficacy; that is, it is not as strong a cholesterol lowering drug as a statin.
- Vytorin does lower the cholesterol more than Zocor alone. It may be important how the cholesterol is lowered, but this is still to be determined with future studies.
Sincerely:
Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP
PI (Principal Investigator), DSI (Drug Study Institute)
Board Certified Internist, JPMC (Jupiter Preventive Medicine Center)
DABIM (Diplomat American Board of Internal Medicine)
FACP (Fellow American College of Physicians)
CPI (Certified Physician Investigator) by the AAPP (American Academy of Pharmaceutical Physicians)
CCTI (Certified Clinical Trial Investigator) by the ACRP (Association of Clinical Research Professionals)
CCI (Certified Clinical Investigator) by the DIA (Drug Information Association)
CCRC (Certified Clinical Research Coordinator) by the ACRP (Association of Clinical Research Professionals)
CCRP (Certified Clinical Research Professional) by SoCRA (Society of Clinical Research Associates)
Member, SIMPD (Society for Innovative Medical Practice Design)
Member, ACPM (American College Preventive Medicine)
Ethics Committee Member, Jupiter Medical Center
IRB Member, Jupiter Medical Center
Founder, CertifiedResearchers.com