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 drugs studied were Vytorin, which was compared 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, possibly because Zocor is generic now, and not a priority from a profit paradigm of its creator.

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 upon information and belief.
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, meaning a fear of shareholder reaction. Perhaps for Schering in particular, it was more of a calamity, since over half of their profits and earnings were from these two drugs with Schering, I understand.
Being the responsible corporations both companies are, of course, alterations occurred after such events were discovered that fractured numerous rules and regulations with clinical trials, possibly in illegal and unethical tactics.

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 following the original results of this ENHANCE study. 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. Sort of like sorting cards to make a good hand not dealt to you. Anyway, since their deliberate concealment of these trial results was clearly wrong, to respond to those who asked where the results were actually as they had been anticipated for quite some time, and 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 as implied by the trial sponsors, one could conclude. 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 due to such suspicions on the facts known and presented, 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, as expected. In the spring of 2008, a very large cardiology meeting was held, where the audience was told, I understand, to stick with statins due to this trial’s lack of outcomes for Vytorin, when the ENHANCE trial was discussed at this meeting. Furthermore, it has been said that a cardiologist at this meeting also suggested that a moratorium should occur with the utilization of Vytorin by prescribers, since statins are much less expensive, and are highly regarded, as they have been available for a couple of decades, starting with Mevacor in the 1980s. 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. Also during much of this year, Schering in particular blamed the media for amplifying the situation regarding the ENHANCE trial.

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 claims were is entirely void of proof, which is not unique to any pharma rep, in my opinion. No remorse or regret from the makers of these drug makers, either, which did not shock many. Yet what is known now is that these companies, as stated by other researchers, performed junk science with their deliberate manipulation of this ENHANCE trial using such tactics. Also, 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. Possibly if they presented the truth, the future of these meds might be better than what is anticipated presently.
Worst of all regarding this ENHANCE trial scandal 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- the health care providers in particular.
This whole situation is another example of the progressively frequent discovery of corruption of the scientific method by placing profits over the well-being of patients, which harms the well being of patients. In addition, 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 ethical atrophy that desperately needs to be stopped and corrected for the sake of others. For the sake of everyone.

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

We have seen the cases of the COX-2 inhibitors, where manufacturers concealed the risks to cardiovascular health and with Ezetimibe this seems but another chapter.

As a junior doctor I have often witnessed the marketing spin of the pharmaceutical industry first hand (though I now take pains to avoid it). The only defence we have is knowledge- that is why Ben again deserves praise for bringing this to a mainstream audience.

Many of my peers lamentably fail to utilise their ‘critical appraisal’ skills when faced with a drug-rep sponsored meal or presentation. Every time this happens we are in a small way failing our patients. As this article demonstrates, the desire to market a product that ‘works’ goes all the way to the core.

The damage we have already done to our profession is for all to see; gone are the days of ‘doctor knows best’- and rightly so. If the medical profession are to maintain the trust of the public (still the most trusted profession in contemporary polls), the new breed of doctor must be alert to attempts to deceive and conceal in research. This requires more space in medical student training and a more general acknowledgement of the dangers on the part of medical establishments. Doctors too must shoulder the responsibility and utilise systematic review resources such as Cochrane, Bandolier and BMJ Clinical Evidence.

The sad reality remains that the most a junior doctor may hear about the ENHANCE trial will be the small-print references on the back of the Ezetimibe adverts.

[Competing Interests: For my part I have helped with the inception of Pharmaware, a UK based group that aims to create new health-care professionals that interact responsibly and ethically with the pharmaceutical industry.]

www.bmj.com/cgi/content/full/327/7429/1442?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&author1=sackett&title=oldest+professions+harlot&andorexacttitle=and&andorexacttitleabs=and&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT

J

An incorrect drug prescription is not bad science.

It is a human error caused either by the person prescribing being mistaken in diagnosis or possibly being wrong re. the name of the drug.

These things are not down to badscience but possibly bad doctors.

If, how ever, a company produces a study on the effects of it’s new wonder drug and misrepresents it’s effects to the doctors who do the prescribing then it is bad science.

The doctor who then prescribs it does so in good faith that the company making the stuff hadn’t told him a bunch of lies hidden by cherry picked data and poor study design.

Is the point that errors are common and serious (certainly true),or that the data relating to errors is unreliable in a way that is suggestive of bias?

I wish in no way to dismiss the importance of prescribing error, but I was under the impression that this post was on the subject of how scientific data about a drug effect is presented (or not)…

start a blog, especially as you seem so passionate about the topic.

post the link here, or on the badscience forums and you’ll get plenty of hits and comments.

But if you don’t believe that Merck just forgot such an important detail, then the only other way of looking at it would be that Merck were trying to pull very nasty deception. Just out of interest what would be the potential penalty for such a deception?

There is a fascinating discussion to be had about the many reasons that a doctor might prescribe the wrong drug. I wonder if that’s the conversation that neilcam2001 wants to have. Probably not, judging by his other comment at www.badscience.net/?p=602#comment-19265

One also comes back to the fact that the professionals handing out the drugs are actively trying to do it the best they can and to improve where necessary – e.g. the recent drive to beef up training of junior doctors in how to prescribe drugs has come largely from the junior doctors themselves. I am, erm, not entirely sure the same ethos – “trying hard to be scrupulously honest” can be assumed of those writing the glossy PharmaCo brochures trying to persuade the docs to hand out MyDrug rather than TheirDrug. Call me cynical…

I’m certain that there are many instances of a doctor giving a patient the wrong drug (they are human and therefore fallible), but did you have any particular example in mind?

There’s much more fishiness in the opaque supplement pushers market than Big Pharma.

J

At last, a life-roadmap in handy flow-chart form.

I thought that doctors were quite open about their responsibility regarding patient safety.

Certainly I’m obliged (sure out of medico legal defence, but more importantly in order to provide best care) to record decisions, results etc, and my patients have a right to see that data.

In addition I’m obliged to be open and honest with my patients about what is happening to them and what we are thinking. That includes being open and honest about mistakes.

In addition I’m obliged to subscribe to the general medical council, who regulate my practice.

J

By the way I’m glad to see you like Peep Show.

I can also recommend the Feynman flow chart:

www.wellingtongrey.net/miscellanea/archive/2006-12-25-what-would-richard-feynman-do.html

J

“The gravitational force is weak,” he said at one conference, introducing his work on quantizing gravity. “In fact, it’s *damned* weak.” At that instant a loudspeaker demonically broke loose from the ceiling and crashed to the floor. Feynman barely hesitated: “Weak — but not negligible.”

just been reminded by john connell of this truly excellent feynman quote on the same subject:

“You know, the most amazing thing happened to me tonight. I was coming here, on the way to the lecture, and I came in through the parking lot. And you won’t believe what happened. I saw a car with the license plate ARW 357. Can you imagine? Of all the millions of license plates in the state, what was the chance that I would see that particular one tonight? Amazing…”