Ben Goldacre
The Guardian,
Saturday January 5 2008
It is rare that a bad pharma story is left untouched by the British media, but this one unfolded while everyone was drunk in December, and perhaps it was just too geeky. Luckily, you share my taste for details. Ezetimibe is a best-selling cholesterol drug with sales of more than £2bn last year. It can modify cholesterol levels but no one knows whether it cuts the incidence of real outcomes such as heart attacks, or, you know, death. Is that the bad thing?
No. There was a trial, called ENHANCE, which looked at this more closely, running for years and ending two years ago. Doctors still give out the drug and they could do with this medical evidence to help with prescribing: but it’s nowhere to be found.
Is that the bad thing? Kind of. Let’s imagine we’re playing snakes and ladders. I roll the die three times in a row then pick the best score as my actual roll, as if the other two were just practice. I invite you, winningly, to ignore those other rolls. You would rightly kick the board over, declaring I was a cheat. I waited until after I knew the results and then I chose the score that suited me best.
Similarly, in a trial, you might measure many things but you have to say which is the “primary outcome” before you start: you can’t change your mind about what you’re counting as your main outcome after you’ve finished and the results are in. It’s not just dodgy, it also messes with the statistics.
You cannot find your starting hypothesis in your final results, unless you are a time lord. What if the results were completely random, like our die, and you just selected the one six, making it look as if you were a winner?
But the people running the ENHANCE trial altered their chosen endpoint when the trial was over. They say they did so before they knew the results. That may be so, but it doesn’t look good, and they’ve now had a very serious letter from a US congressional committee demanding to know why it was done. (I seriously recommend you read it, the letter is a hoot, and it pulls no punches). Then they announced they were changing the endpoints back, in a press release FAQ dated the same day this committee’s letter was sent.
You cannot change the rules after the game has started. You cannot even be seen to do that.
To stop firms doing this kind of thing we have registers of clinical trials. Before your trial starts you put it on the register and publish detailed information about what you’re going to do – so you can’t change your mind once the game has begun or bury unfavourable data. That’s the point of a clinical trials register.
Was the Enhance trial registered? Yes. Oh no, hang on, yes, but registered on October 31 2007, more than 18 months after it finished. And looking at some original papers, this register entry in fact had the cheeky altered outcomes. So is that the really bad thing?
No. Here is the very bad thing. It also transpires there are more unpublished studies on Ezetimibe, from five years ago, and some regard safety. A Schering executive, Robert J Spiegel, says the firms had not considered those studies scientifically important enough to publish. Some, he suggests, could be eventually placed in the public domain.
And that is the final straw: because all of this breaks the most fundamental and sacred contract in clinical research, the moral contract between patient and researcher. Patients are in the hands of researchers on the understanding they are taking modest risks to benefit mankind as a whole, to improve prescribing. Ezetimibe may well be safe. But nonetheless the data belongs to patients – and to the people whose bodies are used.
le canard noir said,
January 5, 2008 at 1:01 am
It is interesting that alternative medicine critics of conventional medicine like to point to the faults of pharmaceutical companies and then claim evidence-based medicine is rotten. The reality is that the intellectual journey of creating healthcare systems based on science is driving the cultural and legislative environment that forces ‘Big Pharma’ to behave in appropriate ways.
That journey is not complete and has different problems in different countries; the US being quite different from the UK in many ways.
What is without doubt is that the homeopaths, nutritionists and other dubious health professions could be criticised of having similar faults. However, they do not benefit from their own internal criticism forcing their own standards higher.
Ben Goldacre said,
January 5, 2008 at 1:24 am
re: “You cannot find your starting hypothesis in your final results”
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…”
Munin said,
January 5, 2008 at 11:24 am
Any excuse for a Feynman story:
“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.”
neilcam2001 said,
January 5, 2008 at 12:29 pm
Patients are also in the hands of doctors. Does Ben also blame Big Pharma for doctors who misprescribe medication? Why are members of the medical profession always so mysteriously blame-free in the world that Ben inhabits?
jodyaberdein said,
January 5, 2008 at 12:31 pm
Very interesting. I can’t wait for the response!
By the way I’m glad to see you like Peep Show.
I can also recommend the Feynman flow chart:
http://www.wellingtongrey.net/miscellanea/archive/2006-12-25-what-would-richard-feynman-do.html
J
jodyaberdein said,
January 5, 2008 at 12:37 pm
re 4:
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
bootboy said,
January 5, 2008 at 12:41 pm
“I can also recommend the Feynman flow chart:
http://www.wellingtongrey.net/miscellanea/archive/2006-12-25-what-would-richard-feynman-do.html
J
At last, a life-roadmap in handy flow-chart form.
evidencebasedeating said,
January 5, 2008 at 5:54 pm
heh
this seems to be the ‘Equazen’ (TM) approach to research. Guess we can expect a publication from Madeleine Portwood and Durham LEA ooh, say, Jan 2009?
There’s much more fishiness in the opaque supplement pushers market than Big Pharma.
manigen said,
January 5, 2008 at 9:40 pm
neilcam2001:
Which misprescription where you thinking of? Doctors can hardly be blamed for prescribing Ezetimibe incorrectly if the reason for that mistake is that information was hidden from them.
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?
Dr Aust said,
January 6, 2008 at 1:47 am
There are many reasons for prescribing errors. Being fed inaccurate information about the pills is certainly one, but of course poor doctoring is another. In this context it is worth pointing out that doctors and pharmacists can get into plenty of trouble for such errors, certainly including being suspended and being sued for incompetence / negligence if it is clearly their mistake, or based on substandard skills and knowledge.
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…
manigen said,
January 6, 2008 at 11:21 am
Shockingly cynical, Dr Aust.
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 http://www.badscience.net/?p=602#comment-19265
ayupmeduck said,
January 6, 2008 at 7:32 pm
If I understand this correctly I guess that there are two ways of looking at this right? The one that Merck are now effectively presenting is that it’s just an innocent mistake – after all they are still blind to the results. To believe this, you have to accept that Merck somehow forgot about the importance of the endpoint even though this is core to their research procedures. It’s sort of difficult to believe this isn’t it?
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?
neilcam2001 said,
January 7, 2008 at 10:59 am
As a survivor of misprescribing by a psychiatrist 8 years ago I just keep wondering why Ben never seems to tackle the issue this issue, especially with regard to anti-psychotic drugs as I understand he is an expert in neuroscience. I recently asked why he ignored a Panorama documentary which touched on the issue with regard to an elderly person with dementia and merely received from one of his adulators some arrogant statement previously made by Ben regarding a similar request. Basically I am coming to the conclusion that this website should be renamed either ‘bad journalism’ or ‘ben goldacre (self)adulation’ rather than ‘bad science’, which is a pity because I think bad science is a better subject for debate.
superburger said,
January 7, 2008 at 1:59 pm
hey neilcam2001,
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.
jodyaberdein said,
January 7, 2008 at 2:42 pm
Re: prescribing errors,
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)…
emilypk said,
January 7, 2008 at 3:02 pm
Indeed. There is a horrendous lack of apples in this thread about orange.
manigen said,
January 7, 2008 at 6:28 pm
Yes, you’re right, we’ve wandered off topic. So I’ll just second superburger’s great suggestion that neilcam2001 start a blog.
Delster said,
January 8, 2008 at 12:35 pm
Neilcam2001
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.
jodyaberdein said,
January 9, 2008 at 6:16 am
This has reminded me of a relatively new company to enter the
scene:
http://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
danbeck said,
January 9, 2008 at 10:33 pm
It is an unfortunate reality that when multiple-billion dollars are at stake, there follow attempts to conceal and mislead.
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.]
diohdan said,
May 27, 2008 at 2:50 am
Published on http://www.brainblogger.com:
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