September 23rd, 2011

Former NEJM Editor Questions Decision to Publish ARISTOTLE

The following guest post is reprinted with permission from the blog of Alison Bass

At a Harvard event last night honoring Paul Thacker, a former investigator for Senator Chuck Grassley, someone in the audience wanted to know how the topic of Thacker’s talk — Dollars for Doctors: Who owns your physician? — was related to the soaring cost of medical care in this country. A video of the talk is available here.

As Thacker noted at the outset of his talk, Medicare and Medicaid now consume a larger portion of the federal budget than the Pentagon, and health care now equals 23 percent of all federal expenditures. Part of the problem, he noted, is the fact that our medical system is stacked toward the widespread adoption of expensive new drugs over older generics, even when the new agents are not necessarily safer or more effective than cheaper drugs.

It was left to Dr. Arnold Relman, Professor Emeritus at Harvard Medical School, to showcase a fresh-off-the-page example of how studies that are funded by drug makers and conducted by researchers who have financial ties to the industry present skewed research results that favor expensive new drugs over generics.

His case in point: The New England Journal of Medicine published a study last week concluding that a new anticoagulant known as apixiban (brand name: Eliquis) was superior to the generic drug warfarin in preventing stroke and deaths in patients with atrial fibrillation (abnormal heart rhythm). The study was funded by Bristol Myers Squibb and Pfizer, which jointly manufacture Eliquis, and featured a lengthy roster of authors, many of whom have extensive financial ties to the drug industry (in the form of speaking and consulting fees). At least three of the authors were Bristol Myers Squibb employees, as the fine print at the end of the study disclosed.

The issue Relman, a former editor of the New England Journal of Medicine, raised was how these financial conflicts may have influenced the way the paper itself was skewed in favor of the new drug. He noted two major omissions in the discussion section of the study. One: the anticoagulant showed no efficacy over the much cheaper warfarin generic in the 7,000 patients recruited in Europe (this was a multi-center trial involving 18,000 patients from the U.S., Latin America, Asia and Europe). Two: 35 percent of the patients on warfarin were not taking a therapeutic dose of the drug, which, he said, could explain why they had a higher rate of blood clotting and stroke than patients taking the new anticoagulant.

Yet neither of these key limitations was mentioned in the study’s discussion, a glaring omission, according to Relman. He said that the journal itself was remiss in publishing the study without mentioning these limitations.

“This study was not well peer reviewed,” Relman said. “Neither [Dr. Marcia Angell, also a former editor of NEJM] nor I would have accepted this paper for publication.”

Yet as a result of its publication, many heart doctors will now be steered toward prescribing a much more expensive drug when the cheaper generic would do just as well in many cases.

The study, Relman said, is a prime example of why the disclosure of conflicts of interest (which most leading journals now require) is not enough to curb bad or biased science. He suggested that medical institutions simply prohibit their faculty from doing research on drugs when they are receiving lucrative speaking and consulting payments from the industry. (Research shows a clear link between company funding of a trial and favorable results for that company’s drug — see here and here.)

“The real solution is for medical institutions to get rid of these unethical practices,” Relman said. “Disclosure is not a solution.”

Thacker agreed. The Physician Payment Sunshine Act, which he helped shepherd into law and requires drug companies to disclose all payments to doctors, should be considered a first step, he said.

“It’s a way to get a handle on just how widespread the problem of financial conflicts of interest are, so we can start to make real changes,” he said.

If the documented harm to patients from such conflicts of interest is not enough of a reason, perhaps the unsustainable costs to our overburdened health care system will eventually tip the balance toward change.

17 Responses to “Former NEJM Editor Questions Decision to Publish ARISTOTLE”

  1. Steven Greer, MD says:

    Sir Thacker got that idea of stating that CMS is bigger than the military from yours truly.

    Thacker was being roasted at Harvard or honored? I tease, know him well

    Good work on Physician Sunshine Act

    Competing interests pertaining specifically to this post, comment, or both:

  2. Steven Greer, MD says:

    Dr. Relman makes some great points that we wrote about in The Healthcare Channel. Harvard’s pediatric psychiatrist Biederman is a big violator of may of these academic ethical rules.

    Competing interests pertaining specifically to this post, comment, or both:

  3. Don’t agree with the assessment. Granger’s study was unique in showing superiority and safety benefits over a standard of care drug that is old, dangerous, and difficult to use…. and, which millions and millions of patients take worldwide. This is not a sunshine act issue at all- that is a separate legislative piece. And, regarding publishing decisions, it is sometimes about the conversation that ensues, as much as it is about the research itself. The ensuing conversation is one of an evolving pharmacopeia of alternative anticoagulants which can be considerably easier for patients to take. The consideration of cost effectiveness is useful here, but criticism of the paper on a CE basis is not fair given the separateness of that discussion from the research findings themselves.

  4. It impossible for a researcher to not have ties to the company funding the research! I see no alternative.

    Perhaps the NIH should fund all definitive studies on new pharmaceuticals. This would eliminate this otherwise inevitable guilt by association.

    Don’t single out this study as an unusual example of conflict of interest. I am not aware of many studies where a conflict does not exist. That is the very reason that we rely on editorial boards, who incidentally usually also have conflicts of interest.

    Competing interests pertaining specifically to this post, comment, or both:

    • NIH is not the answer. They can innovate, but testing efficacy and effectiveness has simply not been their strength over the past 5-8 years within CV trials. They don’t have the budget or singular focus needed to develop or test agents with a strict eye on efficacy, which is the focus of ARISTOTLE. The full story will rely upon comparative effectiveness among new agents, and this will require pragmatic approaches to the assessments conducted within real world environments. (a.k.a., not NIH; and often NOT the interest of industry). This is where PCORI comes to play as funded with the Affordable Care Act. This is the one element of ACA that we can all be enthused about. So, I say good on the NEJM for publishing ARISTOTLE, and congrats to Dr. Granger and his group for the step forward.

      3+ Impugning the rigor of this trial

  5. Venkatesan Sangareddi, MD.DM says:

    I entirely agree with Paul Thackers views.
    I wonder the purpose of declaring the conflict of interest in the
    foot end of drug trials . I would argue , It should be near the title or the title itself !
    It brings to the analogy in anti-tobacco advertisement.
    “smoking is bad for you , we hereby warn you”

    Here is a model template for the caution message , that should appear with every drug and device trials that are regularly churned out today.

    We the authors are declaring the following conflicts. To be precise, we are not declaring by our conscience, we are actually forced to do so. In fact, in our estimate in best of days, we would not be more than 10% transparent about the trial! Please, make your own conclusions about the seriousness of the conflicts. Reading, following and applying the results of this study in your patients may be fraught with the risk of financial and academic futility and even serious danger to your patient’s life.

    Please allow me to link a related article in my blog

    Double blinded , prospective , multicentre , randomised nonsense !

    Competing interests pertaining specifically to this post, comment, or both:
    The only conflict of interest in my mind is with the “definition of conflict”

  6. Earth to everyone – ALL trials of new drugs are funded by the company that makes the drug. Thus EVERY bit of our current medical therapy/evidence based medicine is based on trials funded by the manufacturer of the drug (which usually also includes scientists who discovered and developed it). Thus all the chest beating of how these trials are bad is ridiculous and naive. This and all major trials are conducted to high standards, and if successful, they are then reviewed by FDA, and often approved – thus they meet VERY high levels of scrutiny.
    People need to get off their high horses and stop trying to make headlines. And former editors might look back at the papers they did publish and see that they too had many drug trial sponsored by drug companies (that had the same high level of excellent conduct).

    Competing interests pertaining specifically to this post, comment, or both:
    Research grants/support from the following companies:
    Accumetrics, AstraZeneca, GlaxoSmithKline, Merck, Takeda
    Advisory Board (but funds donated to charity): Bristol-Myers Squibb/Sanofi, Novartis, Alnylam
    Honorarium for development of independent educational symposia: Pfizer, AstraZeneca
    Clinical Advisor, equity in Automedics Medical Systems.

  7. Louis Krut, MB.ChB. MD says:

    I have never understood the point of declared potential conflicts of interest. What is the reader supposed to do with it. Does one believe X% of it, and if so which part.
    Cannon illustrates well that we are not special. We are corruptible and that our profession has been corrupted. Physicians could make a living more honestly by selling apples from a street barrow.
    There is obviously much that needs to be said to support my opinion. But equally there is much more to be said by Cannon and those who would share his naivety.

    Competing interests pertaining specifically to this post, comment, or both:

    • Please see below.
      But you make claims of “corrupted”. What do you find as bad? In this trial, investigators (friends and colleagues at DCRI and Upsulla) have found a new therapy that reduces bleeding and mortality compared with the therapy that we all use now. It was a well done study. I dont’ see why people don’t like it – a new beneficial therapy we can offer our patients.

      Competing interests pertaining specifically to this post, comment, or both:
      posted above

  8. Edgar Abovich, MD says:

    I guess, Dr. Cannon, you are trying to get people face the reality, which is very noble of you. Unfortunately, most people are well aware of it and apparently don’t like it. Maybe you are the one who is riding the high horse. Even though lots of trials are sponsored/funded by pharmaceutical companies, the investigators of these trials should be clear of any connections with them and definitely not on their payroll. Under these circumstances, the bias will be substantially reduced and hopefully, as you say, “high standards” will prevail. As far as oversight is concerned, does anybody think that peer review or even FDA are sufficiently qualified and have no special agendas?
    Dr. Cannon, maybe you are the one who needs to get off the high horse and face the reality!

    Competing interests pertaining specifically to this post, comment, or both:

    • Thanks – I should calm down.
      BUT – try to think of any therapy you use – and then look to the evidence supporting it. It will have been a trial, where the funding came from the maker of the drug. it would be published in a major journal, usually with an academic group leading a large trial (in cardiology anyway), and the FDA would have had to review it. Thus EVERYTHING we do in medical therapeutics for our entire generation has been developed in this way.
      So – do you “not believe” the data because of this? IF not – what would you believe in terms of support.

      The key is to follow good clinical trial procedures, which is scrutinized in peer review and highlighted in reviews and editorials. then at FDA, if the trial is poorly conducted, it won’t lead to approval. And if it were a non-convincing trial (too small, lots of cross overs, bad background therapy) – then physicians won’t use the drug.
      These are the multiple layers of safeguards in the current trial system – that has led to dramatic reductions in mortality and morbidity in CV disease – thus a big success story.

  9. Dan Hackam, MD PhD says:

    This is slightly ridiculous. Without pharmaceutical companies funding major clinical trials of NMEs — which automatically introduces a so-called conflict of interest for the investigators who steer those trials — we would not even have a modern therapeutic evidence base to treat patients. Do you expect NIH or some other entity to spend the billions of dollars to run the trials? Nice pipe dream when most economies are facing precipitate bankruptcy.

  10. Most of the major advances in cardio-vascular medicine have been due to industry efforts ( statins, beta-blockers, thienopyridines, ACe inhibitors) and most lab discoveries need industry to bring them to the market. The industry funding of trials with oversight by academic investigators is a system that works. It may be awful ( according to some) but it the best solution we have. It is fashionable to blame industry for all ills but lets not forget that modern medicine is where it is today in some parts due to partnership with industry.

    Competing interests pertaining specifically to this post, comment, or both:
    Almost all of the drugs I prescribe (mostly generic) and stents I deploy generate some profit for some company.

    Research funding; NIH and Blue Cross Blue Shield Foundation of MIchigan

  11. Stewart Mann, DM (Oxon), FRCP(UK), FRACP says:

    1) The bias felt by authors to publish positively data they have spent many working hours generating is possibly greater than any direct commercial influences – a good reason to take an initial sceptical approach to all positive results.
    2) I don’t suppose the European cohort in ARISTOTLE was a prespecified subgroup for analysis – do we have to refer to the ISIS-2 analysis by star signs again”? Admittedly, regional differences can spark useful hypothesis generation and can have feasible reasons (eg GUSTO-1 which was an open trial and PLATO with differential aspirin dosage).
    3) To have 65% of INR results in the target range throughout a study is probably better than usual non-trial practice (a valid comparator) achieves.

    Competing interests pertaining specifically to this post, comment, or both:

  12. Joel Wolkowicz, MDCM says:

    I respect Dr. Relman. But is he a practicing physician? Is he aware that TTR of 65% for warfarin is probably no worse than the average in the US, and better than many? I suspect he does. But the lay person or governmental bureaucrat or politician does not. He also mentions the cost of the new medication, but neglects to mention the cost of frequent INR monitoring or the (non-compensated) physican time in dealing with this. I manage an anti-coagulation clinic with 200 patients, and a fixed dose anti-coagulant would be a huge improvement.

    Competing interests pertaining specifically to this post, comment, or both:

  13. David Powell , MD, FACC says:

    The attack on ARISTOTLE was inappropriate. I mostly agree with Dr. Cannon re the proper conduction of a large trial and multiple safeguards. Indeed, negative results for fairly large trials are plentiful (such as PROVE-IT and more recently SATURN or AIM-HIGH). The problems happen with the spin on the results. Spin often start with the published article…the interpretation of the results, seemingly subtle but important leaps in logic, sometimes evident in the abstracted conclusion itself. Safeguards here may be insufficient. An accompanying editorial is helpful. But then comes the marketing and the ” expert speakers”. Anyone involved with the trial and/or paid by the drug maker is inherently biased. Denial of such bias flies in the face of neurocognitive research. Finding and funding unbiased speakers and forums for discussion like this cyberplace: that is our challenge.

  14. I fully agree with Dr.Powell.
    Each trial should be conducted by two groups – investigators with ensuing conflicts of interests (doing their job for the company, paid by the company and therefore in position of industry employees) and independent surveyors without conflicts of interest (paid by independent organisation e.g. ACC or national institute of health, that would get the money from the company). Though this would entail bigger costs for the company, yet the results of the trial would be made unbiased in this way. This is what I have written last year and now I can just add that big company profits would easily cover the increased costs for conducting the trials in this way. The company and its investigators might become credible, then.
    One more remark: I think I am not the only one who just after seeing the trial design has guessed the trial result. It is no science to prove something that is likely to be proved on the basis of biased design or the wrong comparator.