Reeling from unrelenting press, Congressional investigations and sagging stock prices, the drugmakers this morning issued
a statement saying they "strongly object to mischaracterizations about the Enhance trial" for their Vytorin cholesterol med, and attempt to defend their actions during and after the Jan. 14 release of the controversial study results.
A quick recap: the study was designed to measure plaque in neck arteries, but results weren't released for nearly two years. The drugmakers blame the delay on difficulty reading ultrasound images. But they briefly changed the primary endpoint without consulting their lead investigator; there was no data safety monitoring board, and they appointed an 'independent' panel to review the data, but three members had financial ties to the companies. The results found no statistical significance, prompting some docs to question whether Vytorin should be prescribed, although Vytorin did lower LDL cholesterol more than the much cheaper Zocor (which, along with Zetia, forms Vytorin).
"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," says Tom Koestler, Schering-Plough's chief scientist. "We took numerous actions to assure the quality of the reading of the ultrasound images." And Peter Kim, Merck's chief scientist, adds: "We stand behind Vytorin and Zetia and stand behind our science that has brought these cholesterol-lowering medications to millions of people around the world."
And so they offer a chronology (look here), indicating the trial began in October 2002 and the last patient visit occurred in April 2006. Following the last patient visit, the study required "meticulous examination" of roughly 30,000 ultrasound images of the carotid arteries and 10,000 ultrasound images of the femoral arteries. Examining the images was a "challenging process" and the data analysis took "significantly longer than expected." Numerous steps were taken in 2006 and 2007 to address quality issues and finalize the data analysis, the drugmakers continue.
Then, they attempt to address the allegations of insider stock trading by Carrie Smith Cox, Schering-Plough's president, and some of her colleagues, which has drawn Congressional scrutiny, along with their handling of the trial; Vytorin advertising; financial support of the American Heart Association and the American College of Cardiology (both of which issued statements supporting Vytorin use) and Medicaid payments.
"Until December 31, 2007, the study remained blinded; that is, neither the patients nor the researchers nor the companies knew the group of patients that received each therapy. On that date, statisticians for Schering-Plough Research Institute first became unblinded. Additional personnel at the companies were made aware of the findings during the first two weeks of January, 2008." In other words, they argue the execs wouldn't have known the results at the time they sold their stock.
We've written this before, and we will write this again: changing a primary endpoint - and doing so without consulting the lead investigator - is inappropriate. And failing to provide more meaningful updates to a widely anticipated trial much sooner in the process only caused skepticism and suspicison. And naming a so-called independent panel without releasing names compounds the matter, especially when some panel members aren't independent. If Merck and Schering-Plough execs are upset over "mischaracterization," they have only themselves to blame.
9 Comments
The news release from Schering-Plough and Merck contains some very interesting information about the problems with the ENHANCE trial. As early as late 2005/early 2006, before the study was over, the were quality concerns about the carotid ultrasound data. Work was going on to try to right the ship, but to no avail. By late 2006/early 2007, it had cerainly become evident to all involved inside SP that the trial was not reparable. Is everybody going to believe that Carrie Cox and other executives had no knowledge as to the trouble with the trial until the results were known? No way! This release is further evidence that the top executives certainly knew that the study was very likely to be a failure.
Once again, it's not that the trial was negative that is seriously hurting Schering-Plough right now, but the fact that they continued to tout the study for 9-12 additional months while there were major problems with the data and hence the results. There is no fixing how the study was handled.
The way they managed this entire process, including the spin going on now, is one of the most serious ethical breeches I have ever seen. It is beyond dishonest.
Schering-Plough and Merck have lost all credibility in the past 2 weeks. They deserve whatever they get. Hopefully it will be enough to discourage other Big Pharma companies from the same sort of behavior, but I'm not optimistic.
...."I'm shocked; shocked to find out that there is gambling going on at this establishment"...
"Round up the usual suspects."
Am I correct in reading that they didn't start looking at the ultrasound until after the last patient visit - and then found the images hard to analyze? Stunning! As someone with experience in the ultrasound field, I was amazed to find that they thought they could measure change in plaque in the carotid and femoral arteries in the first place, and then to try and tell us that they didn't look at any of these images until after the last patient visit is simply incredible. Did they have no data quality control process at all?
I hope that this is a case of incompetence in trial design and management - but I the other evidence suggests something much more seriously unethical.
My reading is that the press release indicates that SP indeed knew of data quality problems as early as late 2005/early 2006. They tried and tried to deal with it, but were not successful. Anybody with knowledge of these types of studies, like the poster above, knows that one minor problem with the data spells absolute disaster and complete failure. The IMT thickness is so small and the progression numbers are even smaller. There is no way to fix it. Read the chronology they provide for ENHANCE. It contains the most damaging evidence thus far regarding when people at the company knew the study had major issues!
For SP to ask the public to believe that the people inside the company didn't know the study was negative until the unblinded analyses were run is absolutely ludicrus. The top executives certainly had to know that the study was in deep trouble by the Summer of 2006 at the latest. Anyone that accepts their assertions is very foolish. Once again, they are not coming clean. They haven't yet learned their lesson and no doubt are acting at this time to protect their top executives, particularly Ms. Carrie Smith Cox. Fred Hassan will never fire her. She knows too much about his actions with previous companies (Wyeth, Pharmacia) to ever be let go. if she eventually is let go, then she'll no doubt walk away with millions from SP, on top of the outrageous amount of money she already received in the Spring of 2007. My, what a tangled web they are weaving - more tangled all the time.
PRSP and others, I'm glad you know the inner workings of big pharma well enough that you can say without doubt that management knew the results of the clinical trial well in advance of December 2007. Let's just send them all the jail now -- why bother with an investigation?
Unblinding a clinical trial is a serious matter -- if SP says that they didn't unblind the trial until Dec of 2007, then I believe them. It should be easy enough to prove if they are lying.
They should have conducted things more "in the open", but after reading the chronology, it appears to me that this was simply a case of designing a clinical trial that was too complicated. They didn't know how to interpret the results. Sure, they should have issued an earlier press release to say something to that effect. But the lack of a press release doesn't necessarily mean that something sinister was going on.
As for changing the primary endpoint: I don't see how that is a big deal (as long as you are honest about reasons for doing so). If a drug fails to do what you expect it to, but you find that it has some other beneficial effect, then why not?
A big deal has also been made of the fact that the lead investigator for this study resigned during the study. If you read the chronology, you'll find that there is a perfectly plausible explanation. I'll quote: the "principle investigator recluses himself from the meeting in order to help ensure that the panel members feel open to provide critical observations concerning the study, the principle investigator, and the core reading laboratory affiliated with the principle investigator."
They may have done something seriously wrong and illegal. However, their timeline makes sense of most of the odd behavior over the last year. It should be easy enough to determine whether or not the timeline they provided is accurate. Most of the things in the timeline should be well-documented by internal records.
Hi Nathan,
You may want to look at this link to see what the lead investigator on the Vytorin trial, John Kastelein, had to say himself about the way the drugmakers handled the issue of the primary endpoint and the data.
http://www.pharmalot.com/2007/12/vytorin-researcher-regrets-not-fighting-back/
Cheers ed
Nathan
I agree with your assessment that the records should show whether any illegal activity has occurred, and I certainly hope that all parties will cooperate as openly as humanly possible with the investigations - and that the investigators will do a thorough and transparent job - so that we can all know and understand what happened. I was simply pointing out what appears to me to be a pretty poor piece of trial design.
I must disagree with you over the primary endpoint. If we follow your argument then we would not need to have primary end points at all, and all trials could simply be a fishing expedition to see what the drug does. Not only is this poor science, it is a very good way to find ourselves in a position of not really knowing how any drug should be labeled.