"Off-Label Promotion By Proxy": How the NEJM and Clinical Trials are Used as an Advertising Apparatus. The Case of Aliskiren

In the print edition of the June 5th NEJM (mine is delivered almost a week early sometimes), readers will see on the front cover the lead article entitled "Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy," and on the back cover a sexy advertisement for Tekturna (aliskiren), an approved antihypertensive agent, which features "mercury-man", presumably a former hypertensive patient metamorphized into elite biker (and perhaps superhero) by the marvels of Tekturna. Readers who lay the journal inside down while open may experience the same irony I did when they see the front cover lead article juxtaposed to the back cover advertisement.

The article describes how aliskiren, in the AVOID trial, reduced the mean urinary albumin-to-creatinine ratio as compared to losartan alone. There are several important issues here. First, if one wants to use a combination of agents, s/he can use losartan with a generic ACE-inhibitor (ACEi). A more equitable comparison would have pitted aliskiren plus losartan against [generic] ACEi plus losartan. The authors would retort of course that losartan alone is a recommended agent for the condition studied, but that is circular logic. If we were not in need of more aggressive therapy for this condition, then why study aliskiren in combination for it at all? If you want to study a new aggressive combination, it seems only fair to compare it to existing aggressive combinations.

Which brings me to another point - should aliskiren be used for ANY condition? No, it should not. It is a novel [branded] agent which is expensive, for which there is little experience, which may have important side effects which are only discovered after it is used in hundreds of thousands of patients, and more importantly, alternative effective agents exist which are far less costly adn for which more experience exist. A common error in decision making occurs when decision makers focus only on the agent or choice at hand and fail to consider the range of alternatives and how the agent under consideration fares when compared to the alternatives. Because aliskiren has only been shown to lower blood pressure, a surrogate endpoint, we would do well to stick with cheaper agents for which there are more data and more experience, and reserve use of aliskiren until a study shows a long-term mortality or meaningful morbidity benefit.

But here's the real rub - after an agent like this gets approved for one [common] indication (hypertension), the company is free to conduct little studies like this one, for off-label uses, to promote its sale [albeit indirectly] in patients who do not need it for its approved indication (BP lowering). And what better advertising to bring the drug into the sight of physicians than a lead article in the NEJM, with a complementary full page advertisement on the back cover? This subversive "off-label promotion by proxy", effected by study of off-label indications for which FDA approval may or may not ultimately be sought, has the immediate benefit of misleading the unwary who may increase prescriptions of this medication based on this study (which they are free to do) withouth considering the full range of alternatives.

My colleague David Majure, MD, MPH has commented to me about an equally insidious but perhaps more nefarious practice that he noticed may be occuring while attending this year's meeting of the American College of Cardiology (ACC). There, "investigtors" and corporate cronies are free to present massive amounts of non-peer reviewed data in the form of abstracts and presentations, much of which data will not and should not withstand peer review or which will be relegated to the obscurity of low-tier journals (where it likely belongs). But eager audience members, lulled by the presumed credibility of data presented at a national meeting of [company paid] experts will likely never see the data in peer-reviewed form, and instead will carry away the messages as delivered. "Drug XYZ was found to do 1-2-3 to [surrogate endpoint/off-label indication] ABC." By sheer force of repetition alone, these abstracts and presentations serve to increase product recognition, and, almost certainly, prescriptions. Whether the impact of the data presented is meaningful or not need not be considered, and probably cannot be considered without seeing the data in printed form - and this is just fine - for sales that is.

(Added 6/11/2008: this pre-publication changing of practice patterns has been described before - see http://jama.ama-assn.org/cgi/content/abstract/284/22/2886 .)

The novel mechanism of action of this agent and the scientific validity of the AVOID trial notwithstanding, the editorialship of the NEJM and the medical community should realize that science and the profit motive are inextricably interwoven when companies study these branded agents. The full page advertisement on the back cover of this week's NEJM was just too much for me.

MRK and SGP: Ye shall know the truth, and the truth shall send thy stock spiralling

Apparently, the editors of the NEJM read my blog (even though they stop short of calling for a BOYCOTT):

"...it seems prudent to encourage patients whose LDL cholesterol levels remain elevated despite treatment with an optimal dose of a statin to redouble their efforts at dietary control and regular exercise. Niacin, fibrates, and resins should be considered when diet, exercise, and a statin have failed to achieve the target, with ezetimibe reserved for patients who cannot tolerate these agents."

Sound familiar?

The full editorial can be seen here: http://content.nejm.org/cgi/content/full/NEJMe0801842
along with a number of other early-release articles on the subject.

The ENHANCE data are also published online (http://content.nejm.org/cgi/content/full/NEJMoa0800742
and there's really nothing new to report. We have known the results for several months now. What is new is doctors' nascent realization that they have been misled and bamboozled by the drug reps, Big Pharma, and their own long-standing, almost religious faith in surrogate endpoints (see post below). It's like you have to go through the stages of grief (Kubler-Ross) before you give up on your long-cherished notions of reality (denial, anger, bargaining, then, finally, acceptance). Amazingly, the ACC, whose statement just months ago appeared to be intended to allay patients' and doctors' concerns about Zetia, has done a apparent 180 on the drug: "Go back to Statins" is now their sanctimonious advice: http://acc08.acc.org/SSN/Documents/ACC%20D3LR.pdf

I was briefly at the ACC meeting yesterday (although I did not pay the $900 fee to attend the sessions). The Big Pharma marketing presence was nauseating. A Lipitor-emblazoned bag was given to each attendee. A Lipitor laynard was used to hold your $900 ID badge. Busses throughout the city were emblazoned with Vytorin and Lipitor advertisements among others. Banners covered numerous floors of the facades of city buildings. The "exhibition hall," a veritable orgy of marketing madness, was jam-packed with the most aesthetically pleasing and best-dressed salespersons with their catchy displays and gimmicks. (Did you know that abnormal "vascular reactivity" is a heretofore unknown "risk factor"? And that with a little $20,000 device that they can sell you (which you can probably bill for), you can detect said abnormal vascular reactivity.) The distinction between science, reality, and marketing is blurred imperceptibly if it exists at all. Physicians from all over the world greedily scramble for free pens, bags, and umbrellas (as if they cannot afford such trinkets on their own - or was it the $900 entrance fee that squeezed their pocketbooks?) They can be seen throughout the convention center with armloads of Big Pharma propaganda packages: flashlights, laser pointers, free orange juice and the like.

I just wonder: How much money does the ACC receive from these companies (for this Big Pharma Bonanza and for other "activities")? If my guess is in the right ballpark, I don't have to wonder why the ACC hedged in its statement when the ENHANCE data were released in January. I think I might have an idea.

Have the Peddlers of Antidepressants (Big Pharma) been Successful in Suppressing Negative Trial Results?

Yes, according to this article in yesterday's NEJM:
http://content.nejm.org/cgi/content/short/358/3/252

Talk about publication bias. According to Erick H. Turner, M.D. and coauthors, the selective publication of only "positive" trials, in addition to publishing in a positive light studies that the FDA considered "negative" leads to a 32% increase in the apparent efficacy of antidepressant drugs, on average (range 11-69%). Once again, profit trumps science, safety, and patient and public health.

What can we do about it? First, reduce by one third the effect size of any antidepressant results you see in an industry-sponsored clinical trial. Next, carefully consider whether whatever [probably modest] effect remains is worth the side effects (e.g., increase in suicide), cost, and nuisance of the drug. Third, prescribe generic agents. Fourth, don't allow pharmaceutical reps to speak with you about new products. Fifth, consider alternative treatments.

I am reminded of a curious occurrence relating to a drug that I think is definately worth the cost, side effects, and nuisance associated with it: Chantix (varenicline) - Pfizer's smoking cessation drug. In JAMA in July 2006,
(http://jama.ama-assn.org/content/vol296/issue1/index.dtl)
two nearly identical articles described two nearly identical studies, which shared many of the same authors. What was the intent of this? Why not conduct one larger study? Was the intent to diversify the risk of failure and allow for selective publication of positive results? I'm very interested in any information anyone can provide about this curious arrangement, which appears to be without precedent. Please leave your comments below.