That Secret Vytorin Panel: Truly Independent?
11 CommentsBy Ed Silverman // January 11th, 2008 // 4:27 pm
Earlier today, we noted that Forbes named the presumably independent panel of experts retained by Merck and Schering-Plough to help them assess the results of their long-overdue Enhance study of Vytorin, the cholesterol med that was being compared with Zocor. At first, the drugmakers refused to disclose the panel members, compounding the scandal that ensued after it became known the endpoint for the trial was changed in midstream. And this change was made, by the way, without the knowledge of the lead investigator.
Now, Roy Poses at Health Care Renewal has played our favorite game - connect the dots. Using PubMed, he found a few interesting tidbits about the independent panel members. To wit, three have ties to Merck and Schering-Plough…
J. Robin Crouse - grant or salary support from Merck, Merck-Schering Plough, Pfizer, AstraZeneca, and Kos Pharmaceuticals, and giving lectures for Merck, Merck-Schering Plough, Pfizer, AstraZeneca, Abbott, and Kos;
Greg Evans - grant support and honoraria from AstraZeneca, Organon, and Pfizer, and being a consultant to AstraZeneca and Pfizer;
David Orloff - consultant to Amylin, AstraZeneca, Bristol-Myers Squibb, Glaxo, ISIS, Merck, Novo Nordisk, Pfizer, Roche, Takeda, Vivus, and Wyeth; and owns stock in Abbott Amgen, Genentech, Genzyme, Johnson & Johnson, Eli Lilly, Merck, Pfizer and Wyeth;
Michiel Bots - grants for studies on carotid intima-media thickness and/or honoraria for professional input on carotid intima-media thickness issues from AstraZeneca, Icelandic Heart Foundation, Organon, Pfizer, the Netherlands Heart Foundation, the Netherlands Organisation for Health Research and Development, Servier, and Unilever;
James Stein - research or grant funding from AstraZeneca, Bristol-Myers Squibb, Kos, LipoScience, PreMD, and Sanofi-Aventis, in addition to serving as a consultant to or on the speakers’ bureau for Kos, LipoScience, Merck, Pfizer, Schering-Plough, and Takeda.
We regularly hear how difficult it is for a drugmaker to find an expert without a potential conflict of some sort. Well, if one may exist, the appropriate approach is to identify all relevant affiliations and credentials. By pretending a panel is independent, when potential or perceived conflicts may exist, is misleading. This only casts more doubt on the willingness of these two drugmakers to let the facts speak for themselves - and not spin or cloak info that should be fully vetted.
Hat tip - and hats off - to Health Care Renewal
Dr. Remulac
Experts are the ones doing the research, and most of the clinical research in this country is funded by pharma, like it or not. Someone please explain to me how you find a true expert in any field that does not have some dealings with businesses that develop products in that same field.
Dr. Remulac
The experts named in this piece are dedicated scientists, clinicians, and experts in their fields. They have done nothing wrong other than respond to a request from a pharma company to provide some expert advice. The deceipt, misdirection, and irresponsible behavior has been on the part of the Merck/Schering-Plough joint venture officials. This piece from Health Care Renewal kind of portrays these experts in a negative or at least suspicious light, and that’s just wrong.
Roy M. Poses MD
Um, Dr Remulac, whoever, you may be, read my post in Health Care Renewal a bit more carefully.
http://hcrenewal.blogspot.com/2008/01/who-decided-to-change-outcome-variable.html
I simply identified the experts’ previously disclosed ties to pharmaceutical companies, including Merck and Schering-Plough, and concluded that the panel was not truly independent of the commercial sponsors of the study.
What was suspicious was that these pharmaceutical companies first sought to hide the panel membership, and then, having revealed it, did not disclose the members’ relevant financial relationships.
Dr. Remulac
Dr. Poses, Forgive my misread of your piece. It struck me at first as if you were somehow casting aspersions toward the experts, and if that was not your intent then please accept my apology. We are most definitely in agreement that Merck/Schering-Plough did indeed portray the panel as independent, when in fact they were not. M/S-P are definitely the bad actors here. By the way, I did post a comment on your blog.
Matt
I don’t think any drug company is actually and genuinely looking for experts without conflicts of interests. That would deter their drugs from getting approved and thus affect profits.
The only ones with a vested interest in looking for experts without conflicts of interest would be the people using the drugs.
It’s not about the consumer, its about company profits.
Melody
With ongoing examples of ’suspect’ behavior by pharmaceutical companies, it becomes ever more difficult for the layperson to regard these corporations with anything but cynicism and disdain. The doctors/experts who support perceived villainy are thus painted with the same broad brush of cynicism.
Dr. Remulac, you state: “The experts named in this piece are dedicated scientists, clinicians, and experts in their fields.” How do we know that? Because YOU tell us it is so? To the layperson/cynic/potential patient, it APPEARS that their expertise is for sale; their voice for integrity and transparency can be bought.
The legal profession has long used ‘the appearance of impropriety’ as a directive of behavior. Doctors, too, must recognize that ‘the appearance of impropriety’ is as detrimental to them and their profession as impropriety itself.
Hank
Thanks to Roy Poses for doing the work that Forbes did not do, and MSP appears to have tried to prevent anyone from doing.
Those of us who have been involved in such archaeological expeditions know that it’s time-consuming and tedious. As they say in pharma, you have to tap a lot of wells.
Thank you, Roy!
Dr. Remulac
To Melody and others: I know several of these people personally/professionally, and so I am simply offering my firsthand opinion. I understand from your perspective why that may not suffice. However, do let me say that not everything is a deep conspiracy, as is often suggested. True experts are those who are trained in a field/discipline, conduct original research in a field/discipline, have worked for years in a particular filed/discipline, and publish their work in a particular field/discipline. These people are tue experts by this definition. It is a matter of simple statistics: when you are active as an expert in a field one cannot help but have relationships with businesses who are also active in this field. In the case of pharma, like it or not, they provide >70% of drug research dollars in the US. So, if one is an active expert, it is guaranteed that you will cross paths and work with pharma over the years. If you read publications by any of these people, or see their presentations at medical meetings, you’d see that they publicly disclose their potential conflicts of interest (which is how the other forum found that info - it’s in the public domain). The only impropriety perpetrated was by Merck/Schering-Plough in trying to hide the identity of this panel, and in stating that they were independent without disclosing the known relationships.
Hank
Another way to look at it is the wider context of medicine’s relationship with the pharm industry.
It happens I’ve worked for thirty years in an academic area that has nothing to do with the topic of this blog. So when it comes to writing “the textbook,” consulting to journals, speaking at conferences, etc. I’m one of the people who is often asked. And I know the other people who also considered leaders in this field.
There are certainly potential COIs on the ego side. When reviewing a paper, for example, it is critical to keep in mind that this is _someone else’s_ views, and not the paper that one myself might have written. One must do that even if it is in direct contradiction to one’s own findings. Obviously, with as much integrity and clarity as one can, one cites the relevant data and makes the relevant points, allowing for real alternatives to one’s own perspective. That’s academia - whether in science or the arts.
The difference is that my field has virtually nothing to do with the success or failure of a particular product (except maybe this or that article) and certainly not one on which billions of dollars, a comapany’s reputation, and shareholders around the world are riding. That setting puts the usual context of potential COIS, their revelation, and their potential impact in an _entirely_ different context of significance, in my view. It changes things not only quantitatively, but qualitatively.
In the end, it may simply be impossible to live ethically within both worlds, no matter who you are. That’s why Howard Brody, physician and ethicist, has recommended essentially the end - what he calls “divestment” - of the relationship between academic medicine and the industry. There are other ways to compensate experts for their services besided direct cash payments, consulting “fees”, and the like.
This would be the case even with full disclosure on one side, and even when companies - which did _not_ happen in this instance - are straightforward about their reviewing team.
Dr. Remulac
NO DIFFERENCE, as suspected!
Press Release Source: Merck/Schering-Plough Pharmaceuticals
Merck/Schering-Plough Pharmaceuticals Provides Results of the ENHANCE Trial
Monday January 14, 8:05 am ET
WHITEHOUSE STATION, N.J. & KENILWORTH, N.J.–(BUSINESS WIRE)–Merck/Schering-Plough Pharmaceuticals announced today the primary endpoint and other results of the ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia) trial. Merck/Schering-Plough has submitted an abstract on the ENHANCE trial for presentation at the American College of Cardiology meeting, which will be held in March 2008, and is awaiting notification of acceptance from the College.
ENHANCE was a surrogate endpoint trial conducted in 720 patients with Heterozygous Familial Hypercholesterolemia (HeFH), a rare condition that affects approximately 0.2 percent of the population. All analyses were conducted in accordance with the original statistical analysis plan. The primary endpoint was the mean change in the intima-media thickness (IMT) measured at three sites in the carotid arteries (the right and left common carotid, internal carotid and carotid bulb) between patients treated with ezetimibe/simvastatin 10/80 mg versus patients treated with simvastatin 80 mg alone over a two year period.
There was no statistically significant difference between treatment groups on the primary endpoint. The change from baseline in the mean carotid IMT was 0.0111 mm for the ezetimibe/simvastatin 10/80 mg group versus 0.0058 mm for the simvastatin 80 mg group (p =0.29). At baseline, the mean carotid IMT measurement for ezetimibe/simvastatin was 0.68 mm and for simvastatin 80 mg was 0.69 mm. There was also no statistically significant difference between the treatment groups for each of the components of the primary endpoint, including the common carotid artery. Key secondary imaging endpoints showed no statistical difference between treatment groups.
The overall incidence rates of treatment-related adverse events, serious adverse events or adverse events leading to discontinuation were generally similar between treatment groups. The incidence of consecutive elevations of serum transaminases (≥ 3x ULN) was 10 out of 356 for ezetimibe/simvastatin (2.8 percent) as compared to 8 out of 360 for simvastatin (2.2 percent). Incidence of elevated creatine phosphokinase (≥10xULN) was 4 out of 356 (1.1 percent) in the ezetimibe/simvastatin group and 8 out of 360 (2.2 percent) in the simvastatin group and two cases (0.6 percent) of CPK≥10xULN associated with muscle symptoms in the ezetimibe/simvastatin group and one case (0.3 percent) in the simvastatin group. There were no cases of rhabdomyolysis. Both medicines were generally well tolerated.
Overall, the safety profiles of ezetimibe/simvastatin and simvastatin alone were similar and generally consistent with their product labels.
After washout, patients enrolled in the study had baseline LDL cholesterol levels of 319 mg/dL in the group randomized to ezetimibe/simvastatin and 318 mg/dL in the simvastatin group. Approximately eighty percent of the patients enrolled in the ENHANCE trial had previously been treated with statins.
In the trial, there was a significant difference in low-density lipoprotein (LDL) cholesterol lowering seen between the treatment groups — 58 percent LDL cholesterol lowering at 24 months on ezetimibe/simvastatin 10/80 mg as compared to 41 percent at 24 months on simvastatin 80mg alone, (p
C.R.E.
All Right!!! Another scientific paper reviewed by newspaper “experts.” So we’ll have the usual plots and perjorative language (”presumably,” “scandal,” “refused,” and “game” etc.) which hardly allows a reasoned, interchange of ideas AND OPINIONS.
A careful reader will note the report issued was LIMITED to 720 patients (360 in each group) of a condition which is estimated in 2/1000 U.S. population. WIthin the two-year trial, no SIGNIFICANT difference was found in either arm.
After practicing medicaine for four (4) decades, I’d challenge the nay-sayers to show me a difference in intimal thickness for those who stop smoking, or who are on anti-hypertensives (controlled or not) or a whole constellation of conditions and medications. Yet the benefits are expected and we keep “pushing” these treatments as beneficial IN THE OVERALL HEALTH of our patients.
Those who actually care for patients are aware this is one of the factors affecting their existence. It is NOT the sum total. All medications need to be evaluated whether they are “effective” and perhaps, we could occasionally agree on the definitions of “effective.”
But let’s also try to show some consistency in our existence. Let’s stop purchasing the products (all consumer products) of those advertising on programs which promote violence, dissolution of the society, modern-day gladiators (sports) and the like. These not only are ineffective in a positive way, they are promoters of undesirable societal behaviors.
To the conspiracy-lovers: go ahead and continue in your pretend world. But allow those of us in the trenches (the REAL world) the privilege of thinking and evaluating. We’re not quite the idiots we’re presumed to be…