The Road To Hell Is Paved With Biological Plausibility
12 CommentsBy Ed Silverman // July 3rd, 2008 // 12:24 pm
An FDA panel met for two days this week and voted 14 to 2 that diabetes drugs should be subject to additional testing to determine cardiovascular risk, a move that will end countless dollars to drug development. And so this testy exchange took place during the meeting between Steve Nissen, a commitee member and FDA critic, who pushed for the recommendation, and Enrico Veltri, a Schering-Plough exec, who gained notoriety with the controversial Enhance trial for Vytorin.
Shortly after Nissen argued why the added testing is needed, Veltri objected, Forbes writes. “Perhaps having renal dialysis or going blind is worse than dying suddenly, which is quick, cheap and painless,” he said.
Veltri objected that Nissen’s proposal would apply to all diabetes drugs, even if there was no scientific reason to believe the treatments would cause any risk, and that this could just slow down drug development. “You’re relegating (drugs to) further testing where you may not have any biologic plausibility.”
Those last two words were loaded. Veltri was a key player in a study of the cholesterol drug Vytorin called Enhance, which was delayed more than a year because Schering-Plough were concerned that some results were “biologically implausible.”
“Our cardiology fellows have a bulletin board,” Nissen replied, “and there’s a quote from me that’s prominently displayed. And the quote says the road to hell is paved with biological plausibility.”
Thanks to Forbes
Paul G
Nissen’s push for extensive CV testing of everything is nothing but a veiled attempt at drumming up research contracts for himself.
What’s next? extensive psychological/suicide testing for all drugs? extensive cancer testing of all drugs? extensive cognitive testing of all drugs?
If all this is done, without a scientific basis of need (i.e. plausibility) then drugs will have to be studied for 20 years in a while bunch of populations before getting approved.
J Dubs
Nissen probably made his fellows tape up his quote.
Dan
Published on http://www.brainblogger.com:
A Failed Attempt to Improve Misperceived Greatness: The ENHANCE Trial
While it seems that pharmaceutical company 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. The trial was named the ENHANCE trial, and possibly this trial was initiated 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 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
Author’s note: What you have read is based upon information and belief. Thank you
Salmon
“What’s next? extensive psychological/suicide testing for all drugs?”
But didn’t the FDA recently recommend determination of suicidality in drug trials?
“If all this is done, without a scientific basis of need (i.e. plausibility) then drugs will have to be studied for 20 years in a while bunch of populations before getting approved.”
Or if there already is a scientific basis and we have knowledge of the populations at most risk. Would it not be unethical not to examine these during the phase III trials or write appropriate labeling to prevent use in high risk populations (or durations or dosages) that are likely to be advocated for off-label use?
Salmon
Doc
Dr. Nissen, Champion of patients, terror to pharma.
CMC guy
Dr Nissen, Champion of Egos maybe. Someone that considers patients would review both risks and benefits and perhaps do better (meta)analysis of data according to some before sounding alarms (see http://drmintz.blogspot.com/2008/06/avandia-vindicated.html)
If true to his proclamation and wants to divert road paving Nissen should open up his own investigation sites to conduct the studies he advocates in order to substantiate his position on how to test all drugs for “biologically implausible” consequences. Accordingly he would be subjected to FDA criteria for running such studies so to achieve statistical significance will have to be huge. Then FDA and others could do their own analyses and could reach different conclusions or find undetected problems. Of course he could not accept any money from drug companies as would bias results.
Justice in MI
Do we know yet what the Advisory Committee actually advised?
Doc
CMC Guy,
If pharma had not ruined its own record of protecting patient well being, the world would not have a place or listen to
Nissen. Pharma perfectly set the stage for him.
Justice in MI
To answer my own question, the best summary I’ve found of the Advisory Committee recs can be accessed at:
http://www.medscape.com/viewarticle/577059
As Dr. Silverman would say, hat tip to medscape…
Ed Silverman
Hi Justice,
There was also this item the other day after the commmittee meeting concluded…
http://www.pharmalot.com/2008/07/fda-panel-tighter-standards-for-diabetes-drugs/
regards
ed
Justice in MI
Thanks, Ed. I found the AP story (I think that’s where it was) pretty vague, even to the point of being misleading in terms of what was being proposed. It went for the melodramatic quotes rather than the policy substance.
BP MD
At least there was no chair-throwing! However, it appears that there’s no love lost between Nissen and Veltri.