Monday, June 2, 2008

"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 .)

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.


  1. Dr. Aberegg,

    As a point of clarification, is there a generic formulation of losartan currently available in the United States? Perhaps I am just behind on medications predominantly utilized in the community.

  2. Sir - you are correct, Losartan does not lose patent protection until 2010, thank you for pointing this out.

  3. Perhaps more importantly, any insight as to why Novartis chose a competitor's angiotensin receptor blocker as opposed to their own valsartan? This simply does not make sense to me, if you are going to answer these extremely important "scientific" questions, why not go for the knock out punch (ie, "two of our drugs are better than one", or better yet, compare aliskiren plus valsartan versus losartan alone and make the "two of our drugs are better than one of theirs"). I haven't seen the actual article yet, so I could be missing something here, just not sure why a Merck drug would even be invited to a blatant Novartis party.

  4. Nice post. I think I will stick with the valsartan/lisinopril combo at the South High Center for Primary Care (urban poor). I hope I don't forget how to use inexpensive but effective and time-proven medications when I leave residency.

  5. I must ask, are you against the pharmaceutical industry? I only ask because of the scathing comments in many of your blogs. I must point out that the industry sponsors much of the research that your institution performs that indeed helps to better the care of your patients.

  6. The stated goal of this blog is to discuss (and promote) the search for the truth, insomuch as we can know it. To the extent that the pharmaceutical industry conceals or obfuscates the truth, they will be met with criticism here. I think you will also find examples where well-done studies are commended deservedly. I have stated before, but perhaps not on this blog, that institutions should rethink the ethics of receiving monies such as clinical trials "residuals" that could cause them to be beholden to industry interests, or to conduct trials that may not be in the best interest of patients and society, but rather corporate coffers. However, these issues are beyond the scope of this blog, and its stated purpose as related above.

  7. Have any of their representatives shared this information with you?
    One would think they already have the indication.

  8. Representatives HAVE promoted this to physicians.
    There is only one indication for Tekturna. Wait until you hear what they say about "Valturna."

  9. If you can prove those guys promoting off label use are getting money from the company you can fund your retirement with the proceeds of a False Claims Act lawsuit.


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