Pharma, Evidence, and Trust

A number of the other blogs that have noted the existence of this blog seem to have "Pharma" in their titles in one way or another, and the implication is not that the blogger likes much about Big Pharma.

In the late 1990s, when I was spending much of my clinical time providing HIV care, I was a defender of Pharma on Usenet, at least as it related to HIV. We'd discovered the HIV virus in 1985, and by late 1995 we had a spectacularly successful treatment, due, at least in part, to the efforts of the drug manufacturers. HAART changed the lives of people with AIDS, and the lives of their caregivers, and costs of $10K to $15K per year to keep a young person alive and functional seemed perfectly reasonable to me. I thought the carping about the high prices of these medications was unfair -- it was a remarkable accomplishment to find an effective treatment for a viral infection in so short a time, and the billions spent on it deserved some reward.

By a few years later, though, I was finding myself as distrustful and angry at Pharma as anyone out there. I spend a lot of my time reading research papers and interpreting evidence, and realized one day that Pharma was employing people at least as smart and knowledgeable as I to come up with ways to trick us all about what studies showed. One example of this is running parallel studies of an agent and then only publishing the positive studies while burying the negative studies, as was done with trials of SSRIs in adolescents. The concept of a p value becomes essentially meaningless if researchers perform an unknown N of parallel trials and then publish the ones that show a positive result.

I'll write about other ways of manipulating results in future posts, but for today I want to comment on one pernicious effect of this behavior -- I have come to distrust and then dislike the companies that provide the (often useful) drugs I must use on patients. When the new HDL-raising drug torcetrapib went down in flames a few years ago, I was actually pleased: I was furious with Pfizer for having tried to get torcetrapib approved in a way that would have only marketed it in a combo pill with atorvastatin. Objectively, it makes no sense that I should be happy at the failure of a drug that would have helped my patients had it worked.

Pharma not only tries to manipulate the interpretation of results of trials, in the design, analysis, and publication phases, they apparently also try to sow doubt about existing competitors. Adriane Fugh-Berman wrote in 2005 about how she was recruited to be the author on a ghost-written manuscript intended to highlight the importance of herbal interactions in patients on warfarin (interactions that Dr. Fugh-Berman felt were overstated). The company recruiting her was presumably working for AstraZeneca, the manufacturer of ximelgatran. Ximelgatran, a direct thrombin inhibitor that aimed to replace warfarin, was eventually withdrawn from the market in Europe (never approved in the US) because of hepatotoxicity.

In the face of this comes the RE-LY trial comparing warfarin with dabigatran, another direct thrombin inhibitor. I didn't start blogging until well after the publication of RE-LY, but hopefully others noted that this 18,000 person trial may reflect one of the biggest advances in medical therapy of the decade. Dabigatran appears to be a superior drug to warfarin -- at lower doses it is safer than wafarin and as effective, and at higher doses it is equally safe to warfarin and more effective. Unlike warfarin it does not require a careful diet or routine monitoring of INRs.

By all rights, dabigatran should take over the oral anticoagulation market, at least for atrial fibrillation (we need additional trials in other clinical settings). The natural skeptic in me would always want to wait a bit on using a new drug. Warfarin has been around for decades and has been used in tens of millions of people and we have a good sense of its benefits and (myriad) risks and burdens, while dabigatran has not been used nearly so widely nor for so long. New drugs have a habit of showing up rare side effects once they are out of clinical trials and on the market.

But my greater fear is that somehow Pharma is pulling something over on me, the editors of the NEJM that published RE-LY, and everyone else, and that it will somehow turn out that dabigatran not only isn't as big an advance as it appears, but that its manufacturers already know this and aren't telling.

Ultimately, if I had to bet, I don't think this will be the case with dabigatran. Five to ten years from now, I'm guessing that the residents I teach will have no clue that we used to routinely treat patients with rat poison and monitor bleeding parameters every couple of weeks or so in order to prevent clots and emboli. But I wish I didn't have to fear that the manufacturers of the drugs I use might not actually be working toward the same goals that I am, and instead might be working to fool me yet again.

Comments

[Dan Hackam]

I am not too worried about this issue (safety of new drugs like dabigatran). If you have ever read the data that gets submitted to FDA for new drug approval, the statistics, the reviewer reports, the clinical pharmacology, animal pharmacology, toxicology, minutiae of clinical trial adverse event tables, it is quite incredible how much material they pore over. Of course, industry can distort trial findings and bury them, but they don't tend to do this where the FDA is concerned. Of the hundreds of drugs that have been approved over the past 20-30 years, only about a score of them have been withdrawn from market. And the recent reports over dabigatran combined with antiplatelets in the acute coronary syndrome population seem very reassuring.

Of course, we've been down this road before ... with ximelagatran.

[bev M.D.]

I think the most critical issue in the evaluation of new drugs is post-market monitoring, which inexplicably has only been recognized as an important FDA empowerment recently. Obviously new things show up when the patients number in the millions rather than hundreds.
As for the behavior of the pharm companies, they are not alone. As a pathologist, I had to routinely deal with vendors of laboratory analytic instruments and reagents. They were equally clever at cherry picking research papers positive to their cause, while dropping caustic comments about their competitors.
I found myself developing the same attitude which you describe.

[Carolyn Thomas]

There is too much money at stake in Big Pharma for us to blithely trust that things like drug safety should be in the hands of the industry.

In the words of Dr. Marcia Angell, former editor-in-chief at the New England Journal of Medicine: “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of The New England Journal of Medicine.”

As a heart attack survivor who now takes a fistfull of cardiac drugs every morning, I have no clue which of these meds were prescribed for me based on flawed trials, or tainted journal articles created by Big Pharma-funded medical ghostwriters and their physician/academic pals who fraudulently claim to be the real authors, or the proven influence of industry-paid 'thought leaders' who are schilling drugs to their MD colleagues through pharma-funded speakers bureau and CME training - AND NEITHER DO MY DOCTORS.

The FDA is not in the business of policing "post-market monitoring" so that's not going to happen any time soon - or soon enough to help protect me or millions of other unsuspecting patients, as well as our docs who rely on their drug reps for an astonishingly large percentage of their pharmaceutical education.

As you say, Dr. Rind: drug companies who are "running parallel studies of an agent and then only publishing the positive studies while burying the negative studies" are hardly trustworthy. Why do medical professionals not believe, as patients do, that this is criminal behaviour putting millions of us at risk, and should be aggressively prosecuted? Remember Merck's "Australasian Journal of Bone & Joint Medicine" that looked and felt and smelled like a bona fide medical journal flogging Vioxx - but of course wasn't? Brilliant marketing - prepare to see much more of this fraud.

It's an extremely disturbing reality for all patients. A comment like the previous one: "...Recent reports...seem very reassuring.." is, sadly, a typical reaction from physicians. Drug companies are in the business of making sure that reports are 'reassuring', otherwise no docs would prescribe their drugs.

Stakes are very high in this multi-billion $ industry, and with several blockbuster drugs due to fall off the patent cliff by 2012, we can only expect to see an increasingly desperate explosion of Big Pharma's marketing strategies in ways we haven't even dreamed of yet.

Drug marketers are savvy and smart - we have to learn to outsmart them.

Carolyn Thomas
http://www.ethicalnag.org

[Grace Farris]

Enjoying the blog Dr Rind! The final paragraph of this post nicely sums up the anxieties we all have about novel pharmacotherapies. Well done.

[Graham]

Great post, and can't agree more. I plan on talking about some similar topics in some upcoming posts as well. Great new blog, too!

[riv]

Oooh yes I think you need these. We bin busy. :)

http://www.whp-apsf.ca/pdf/statinsEvidenceCaution.pdf

http://www.whp-apsf.ca/pdf/Evidence%20for%20Caution%20-%20
Facts%20to%20Act%20On.pdf

Both from: Women and Health Protection http://www.whp-apsf.ca/en/index.html

[pcb]

I'm liking this blog already. Good work.

thought you might find another post re: RE-LY by another evidence based blogger interesting, if you haven't read it already:

http://medicalevidence.blogspot.com/2009/09/unreliable-design-of-re-ly-trial-of.html

cheers,

pcb

[David Rind]

pcb, thanks for the interesting link. Although I think Dr. Aberegg is right in general about the ways Pharma plays with noninferiority intervals in drug trials, I'm not so concerned about this particular issue in RE-LY. I'll likely post about noninferiority designs down the road....