January 18

Big Pharma's sins of omission


The notion that the pharmaceutical industry fiddles with drug studies is one that I harp on constantly. Sometimes they fiddle with the data interpretation process, but more commonly they commit what amounts to lies of omission.
Here’s what most do. If a drug company spends millions of dollars to sponsor a study designed to show that Drug X reduces inflammation and finds when all the data is assessed at the end that Drug X does indeed reduce inflammation to some extent, then you can bet that the company will rush the study in to print. But if this study instead of showing improvement shows that Drug X doesn’t help reduce inflammation or, horror of horrors, actually makes it worse, odds are that the company won’t publish the study.
We end up with a situation in which mainly positive studies get published. These positive studies then lend a aura of efficacy that really doesn’t exist to most of the drugs out there. No one can really point to studies nay saying the drugs in question since those studies were never published.
Yesterdays New England Journal of Medicine (NEJM) outed this execrable practice, at least as it applies to studies of antidepressant drugs. As reported in the New York Times:

In published trials, about 60 percent of people taking the drugs report significant relief from depression, compared with roughly 40 percent of those on placebo pills. But when the less positive, unpublished trials are included, the advantage shrinks: the drugs outperform placebos, but by a modest margin, concludes the new report, …
Previous research had found a similar bias toward reporting positive results for a variety of medications; and many researchers have questioned the reported effectiveness of antidepressants. But the new analysis, reviewing data from 74 trials involving 12 drugs, is the most thorough to date. And it documents a large difference: while 94 percent of the positive studies found their way into print, just 14 percent of those with disappointing or uncertain results did.

The authors of the NEJM study had this to say:

We found a bias toward the publication of positive results. Not only were positive results more likely to be published, but studies that were not positive, in our opinion, were often published in a way that conveyed a positive outcome. We analyzed these data in terms of the proportion of positive studies and in terms of the effect size associated with drug treatment. Using both approaches, we found that the efficacy of this drug class is less than would be gleaned from an examination of the published literature alone. According to the published literature, the results of nearly all of the trials of antidepressants were positive. In contrast, FDA analysis of the trial data showed that roughly half of the trials had positive results. The statistical significance of a study’s results was strongly associated with whether and how they were reported, and the association was independent of sample size. The study outcome also affected the chances that the data from a participant would be published. As a result of selective reporting, the published literature conveyed an effect size nearly one third larger than the effect size derived from the FDA data.

So, we’ve got sins both of omission and commission by Big Pharma. These guys don’t publish the negative studies (the sin of omission) or they publish them in a way that makes them look positive (the sin of commission).
The other way that Big Pharma sins is by sending its henchmen (doctors and researchers on the Big Pharma teat) out to exaggerate the significance of a single study. This sort of chicanery goes on all the time. I’ve said it before and I’ll say it again: there are no definitive medical studies. In other words, there are no single studies that are the last word on anything. All studies are just pieces of the puzzle. Only when enough studies have been reproduced in other labs showing consistent results we can start to feel some confidence in these results.
But what happens is that researchers are so sure of their hypothesis that they tend to disregard all studies showing that their hypothesis doesn’t hold up under investigation. Then when a study comes along that confirms their hypothesis, they declare the study the smoking gun.
This has happened with statins. Study after study has shown no decrease in all-cause mortality, but Big Pharma keeps funding more studies in hopes that one will be positive. Then when one positive one comes along, they shout it to the rooftops.
But what they don’t shout about are the failures that have been published and the many failures that haven’t. When you take it all in the aggregate the picture looks a lot different than the drug companies and the statinators who pimp for them would have you believe.
For these reasons, I’m extremely hesitant about prescribing any medications that I don’t feel have passed the hurdle of fairly long term use without serious problems and that haven’t been shown to be efficacious to my satisfaction.

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  1. “Here’s what most do. If a drug company spends millions of dollars to sponsor a study designed to show that Drug X reduces inflammation”
    There’s the problem right there. By rights, the study should be designed to show IF. . . IF drug X reduces inflammation. That’s the problem with nutrition ‘research’ too. It’s not set up to determine IF something occurs, or to find out WHAT happens. Much feels like it was stacked to arrive at the pre-conceived result.
    I would say that ‘most’ does.

  2. Now that you are on the subject of mis-information here’s the latest salvo from the carb industry – http://www.potato2008.org/en/index.html
    The UN (surprise, surprise) has declared 2008 as ‘The Year of the Potato’ portraying the potato, a carbohydrate rich food and source of energy, as the salvation of third world nations. The news is trumpeted on http://www.potato.org.
    Could this be the long awaited response to Taubes ‘Good Calories, bad Calories’?
    They’ve got to save Big Agra just like they do Big Pharma.

  3. In response to Dr Eades comment: “They’ve got to save Big Agra just like they do Big Pharma.”
    I think we are in a quandary here. In order to feed the growing population (very soon will be 7 billions) there is no other choice but to push wheat, soy and corn to the mass. Even with that non-optimal choice a tremendous amount of fossil fuel is still required as fertilizer; and to add insult to injury, rising oil price is now diverting corn to ethanol production further raising food price.
    Those who can afford, eat the animals fed by the corn and supplemented with omega-3 that comes from the (soon to be exhausted) ocean. The elite has a slight different plan (organic, free-range, grass-fed, farmer-market, etc.)
    The choice of healthful and edible foods is not available to everyone of us.
    I don’t think I ever said that it was. But, if one has the option, the best diet is organic, free-range, grass-fed, etc.

  4. Discouraging. Is their nothing we can believe in today (besides you, of course)?
    Heck, don’t even believe me. I’m certainly not infallible.

  5. You are such a breath of fresh air for the masses, doc. If only all docs were so honest. Seems that 99% (yes, that high) of all docs got it wrong. Drugs and surgery is all they know. How many times does a person go to a doc and NOT get a prescription? How many times do they ask them about their diet and lifestyle habits? I suppose they think the latter doesn’t have anything to do with health? It really is a sick care industry. We got it somewhat backwards.
    I suppose there’s hope that more docs will grow up like you. We’d all be a heckuva lot better off.
    One thing that is a bit of a surprise is that this article was published in NEJM in the first place. It’s almost like I expect Big Pharma to say “No, DON’T publish that!” After all, don’t you think it’s quite an indictment? I do and it’s quite a revelation. I keep having these revelations about just how bad things are in the truth department.
    Hi Bill–
    I’m sure Big Pharma wasn’t thrilled to have it printed, but Big Pharma also knows that people have short memories. After a few months few will remember this paper, and it will be back to business as normal. And the NEJM will have enhanced its reputation as not bowing to the pressure of Big Pharma. It will be interesting to see how often this paper is cited in other papers in the months and years to come. I doubt it will be cited often.

  6. Dr. Mike, it occurs to me that a recent article in the WSJ about testosterone deficiency in men is on topic. Here’s the lead in to that article by Dr. Benjamin Brewer:
    * * * *
    A decline in Testosterone
    May Give Rise to Many Ills
    January 17, 2008
    My boyhood baseball hero Rich “Goose” Gossage made it into the baseball Hall of Fame last week. His 98-mph fastball and 22-year career as a fearsome relief pitcher were achieved without the use of steroids. His best years were back in the ’70s and early ’80s when men were men and made their own testosterone naturally. But even the most macho among us face a decline in the quintessential male hormone as we age. Recent evidence points to a decline in testosterone levels in the general population of men, regardless of age.
    A 20-year study of testosterone levels in men found that testosterone concentrations dropped about 1.2% per year, or about 17% overall, from 1987 to 2004. The downward trend was seen in both the population and in individuals over time……..
    * * * * *
    If I understand this correctly, the study Dr. Brewer refers to suggests that maybe the apparently normal decline of testosterone in aging men may have started to trend upward or accelerate commencing in the mid 1980s (when statin drugs started to be commonly prescribed?). I know this may be a leap on my part, but it makes me wonder if there could be a connection there. Do you know if there has been any credible research or investigation into this? Is declining testosterone in men as they age really a normal, inevitable phenomenon?
    Separately, you wrote in PPLP in 2000 that insulin resistance and hyperinsulinemia has an adverse affect on production of the sex hormones. I would be very interested in knowing your take on the trend (if it is a trend) suggested by reading between the lines of the article, as well as any incidental thoughts you may have about the possible relationship between the (unwary or unthinking) acceptance by so many people of the low fat/high carb diet hypothesis and the broader topic addressed in the article.
    Hey Wil–
    I can understand the confusion based on the quote you provided. I would have to see the actual study to see what’s going on. There is a definite decrease in testosterone with aging. I don’t know whether or not there is an overall decline in testosterone that is not correlated with aging, however.
    Hyperinsulinemia drives the liver to make more sex-hormone binding globulin, meaning that there is less free testosterone, so in that sense elevated insulin levels do in essence decrease sex hormones.

  7. Hello Dr. Eades,
    Sorry, I couldn’t see where I could just send you an email directly without commenting on a post. I just wanted to send this link for an article about a recent study showing protein had the best appetite suppression abilities and carbs were second best but only in the short term. They soon made people hungrier. Nothing new to you of course but good to see it in the mass media.
    Yes, Zack, this is a pretty good paper. I’ve pulled it and skimmed it. I need to read it more thoroughly then post on it.

  8. Interesting fact from: http://www.potato2008.org/en/index.html site: Annual potato consumption / capita in Belarus (highest in the world) is 337.99 kilograms = 745.1404 pounds.
    Now, I don’t know how much of that is consumed in form of vodka, but one way or another, it is scary…
    Real scary. I wonder what the obesity statistics are for Belarus?

  9. I’ve become increasingly disenchanted with the way Western medicine is researched. (This isn’t to say I’m all that fond of New Age interpretations of Eastern stuff either…I can’t speak to real Eastern medicine.) They tend to do big studies on large populations of [white college-age male] Americans, and the drug has to be better than a placebo. But what if a drug works great for older African-American women? For vegetarians? For people who have insulin resistance, or don’t? For people with particular genes or phenotypes? Overall, it’s not going to beat the placebo, because it isn’t better for most people. But sometimes it could be the right thing.
    I got to thinking about this when I found I couldn’t tolerate the generic for a patent drug that worked. Since the party line is that the generic is the same and only the ingredient they say is active matters, there’s no way to get the patent version on my health insurance. I finally switched to another patented variation of the drug, which fortunately lets me sleep.
    You are correct on all counts. Thanks for the insightful comment.

  10. Now Merck wants the FDA to approve OTC low-dose cholesterol-lowering drugs, that you can buy right alongside your aspirin and Pepto. Of course, all the “studies” show that we must lower our cholesterol or we’re going to die, so John Q. Public can go to his local discount store and buy this OTC drug so he can have low cholesterol, even though he has no idea what is a good number, has no way to check his levels, probably doesn’t know anything about LDL vs HDL, just knows that he “must” have lower cholesterol or he’s sure to keel over any day now with a major heart attack. And as gullible as many people are, especially older people who believe everything the doctor tells them, and take whatever the doctor prescribes without question, Merck is bound to make a fortune if the FDA approves this. After all, if lower cholesterol levels are healthier, then this stuff is sure to be good. Right?
    At least the FDA has turned them down twice. I hope they turn them down for the 3rd time, too.
    I hope they turn them down, too. Maybe all this negative press that’s come out will at least inject a modicum of sanity to the debate.

  11. Dr Eades,
    I really hope this comment reaches you.
    Please dont flame me for my ineptitude, but I searched and also I didnt know where to contact you. (I probably didnt spend enough time looking, I’m so very sorry.)
    BTW, on a related note to the pharma saga, we get goodies and catered lunches all the time from the drug companies, not just when they give presentations for the doctors, but ‘just because’. Their logos are all over the clinic (cardiology.) I have to admit I cant turn down a free sandwich.
    Anyway, I just came across this 3 year old study regarding ketosis and methylglyoxal while researching CRON. I have not heard about this compound before and only did a quick internet search on it. I have read about glycation and AGE’s though.
    “Ketosis Leads to Increased Methylglyoxal Production on the Atkins Diet
    Sections of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire 03756, USA
    Address for correspondence: Paul J. Beisswenger, M.D., Professor of Medicine, Dartmouth Medical School, Dartmouth Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH 03756.Voice: 603-650-8630/1808; fax: 603-650-2240/1808. paul.j.beisswenger@dartmouth.edu
    In the popular and widely used Atkins diet, the body burns fat as its main fuel. This process produces ketosis and hence increased levels of ß-hydroxybutyrate (BOB) acetoacetate (AcAc) and its by-products acetone and acetol. These products are potential precursors of the glycotoxin methylglyoxal. Since methylglyoxal and its byproducts are recognized as a significant cause of blood vessel and tissue damage, we measured methylglyoxal, acetone, and acetol in subjects on the Atkins diet. We found that by 14-28 days, methylghyoxal levels rose 1.67-fold (P = 0.039) and acetol and acetone levels increased 2.7- and 6.12-fold, respectively (P = 0.012 and 0.028). Samples from subjects with ketosis showed even greater increases in methylglyoxal (2.12-fold), as well as acetol and acetone, which increased 4.19- and 7.9-fold, respectively; while no changes were seen in samples from noncompliant, nonketotic subjects. The increase in methylglyoxal implies that potential tissue and vascular damage can occur on the Atkins diet and should be considered when choosing a weight-loss program.
    Key Words: Atkins diet • ketosis • methylglyoxal • acetone • acetol”
    I dont really have any particular thoughts on it because as I get older I am finding out that there always seems to be a good and a bad side to just about everything.
    The only thing I’m concerned of is that this methylglyoxal thing appears to be particularly and extremely toxic.
    Thank you so so much for your time!
    – Hines
    Hi Hines–
    I’ve answered this question in the comments at least four or five times so far, which is one of the reasons that I want to quit spending so much time on comments. A lot of people don’t read them and the search option doesn’t really search them. Unless you are a comment reader you wouldn’t know, so don’t think I’m taking you to task for asking the question. I almost never read the comments on the blogs I read, so I figure a large number of people don’t read the comments on mine. It’s much better to put this kind of info in a post so that all can read it and newcomers can find it by using the search option.
    If you go to this post and scroll down through the comments to the four or five comment exchange I had with Tim Lundeen (it’s near the bottom of the comment list), you can find my thoughts on this issue.

  12. “The UN (surprise, surprise) has declared 2008 as ‘The Year of the Potato’ portraying the potato, a carbohydrate rich food and source of energy, as the salvation of third world nations.”
    Because it did such a fantastic job in the 19th century in Ireland!
    Indeed! Those who forget the lessons of history are doomed to repeat them.

  13. This is one of the many reasons why studies should never be done by the interested parties themselves. Universities should be doing this free of any connection with Big Pharma. As Taubes has pointed out, too many of the scientists seeking grants from both government and private sources have to present proposals that compromise the science before it even gets started.

  14. Re: the search option
    A search method that does search the comments is Google. Enter the search terms along with:
    That will confine the search to this site. Google’s cache might not have the most recent blog comments, but it will have the older comments from the archives.

  15. Google’s cache might not have the most recent blog comments, but it will have the older comments from the archives.
    In fact, Google has added so many more computers lately that it should have added new comments to its index within a few hours.

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