What doctors don't know about the drugs they prescribe | Ben Goldacre

708,555 views ・ 2012-09-27

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Translator: Joseph Geni Reviewer: Morton Bast
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Hi. So, this chap here,
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he thinks he can tell you the future.
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His name is Nostradamus, although here the Sun have
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made him look a little bit like Sean Connery. (Laughter)
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And like most of you, I suspect, I don't really believe
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that people can see into the future.
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I don't believe in precognition, and every now and then,
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you hear that somebody has been able to predict something that happened in the future,
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and that's probably because it was a fluke, and we only
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hear about the flukes and about the freaks.
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We don't hear about all the times that people got stuff wrong.
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Now we expect that to happen with silly stories
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about precognition, but the problem is,
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we have exactly the same problem in academia
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and in medicine, and in this environment, it costs lives.
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So firstly, thinking just about precognition, as it turns out,
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just last year a researcher called Daryl Bem conducted
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a piece of research where he found evidence
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of precognitive powers in undergraduate students,
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and this was published in a peer-reviewed academic journal
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and most of the people who read this just said, "Okay, well,
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fair enough, but I think that's a fluke, that's a freak, because I know
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that if I did a study where I found no evidence
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that undergraduate students had precognitive powers,
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it probably wouldn't get published in a journal.
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And in fact, we know that that's true, because
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several different groups of research scientists tried
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to replicate the findings of this precognition study,
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and when they submitted it to the exact same journal,
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the journal said, "No, we're not interested in publishing
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replication. We're not interested in your negative data."
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So this is already evidence of how, in the academic
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literature, we will see a biased sample of the true picture
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of all of the scientific studies that have been conducted.
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But it doesn't just happen in the dry academic field of psychology.
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It also happens in, for example, cancer research.
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So in March, 2012, just one month ago, some researchers
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reported in the journal Nature how they had tried
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to replicate 53 different basic science studies looking at
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potential treatment targets in cancer,
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and out of those 53 studies, they were only able
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to successfully replicate six.
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Forty-seven out of those 53 were unreplicable.
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And they say in their discussion that this is very likely
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because freaks get published.
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People will do lots and lots and lots of different studies,
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and the occasions when it works they will publish,
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and the ones where it doesn't work they won't.
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And their first recommendation of how to fix this problem,
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because it is a problem, because it sends us all down blind alleys,
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their first recommendation of how to fix this problem
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is to make it easier to publish negative results in science,
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and to change the incentives so that scientists are
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encouraged to post more of their negative results in public.
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But it doesn't just happen in the very dry world
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of preclinical basic science cancer research.
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It also happens in the very real, flesh and blood
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of academic medicine. So in 1980,
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some researchers did a study on a drug called lorcainide,
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and this was an anti-arrhythmic drug,
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a drug that suppresses abnormal heart rhythms,
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and the idea was, after people have had a heart attack,
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they're quite likely to have abnormal heart rhythms,
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so if we give them a drug that suppresses abnormal heart
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rhythms, this will increase the chances of them surviving.
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Early on its development, they did a very small trial,
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just under a hundred patients.
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Fifty patients got lorcainide, and of those patients, 10 died.
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Another 50 patients got a dummy placebo sugar pill
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with no active ingredient, and only one of them died.
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So they rightly regarded this drug as a failure,
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and its commercial development was stopped, and because
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its commercial development was stopped, this trial was never published.
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Unfortunately, over the course of the next five, 10 years,
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other companies had the same idea about drugs that would
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prevent arrhythmias in people who have had heart attacks.
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These drugs were brought to market. They were prescribed
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very widely because heart attacks are a very common thing,
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and it took so long for us to find out that these drugs
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also caused an increased rate of death
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that before we detected that safety signal,
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over 100,000 people died unnecessarily in America
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from the prescription of anti-arrhythmic drugs.
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Now actually, in 1993,
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the researchers who did that 1980 study, that early study,
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published a mea culpa, an apology to the scientific community,
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in which they said, "When we carried out our study in 1980,
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we thought that the increased death rate that occurred
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in the lorcainide group was an effect of chance."
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The development of lorcainide was abandoned for commercial reasons,
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and this study was never published;
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it's now a good example of publication bias.
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That's the technical term for the phenomenon where
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unflattering data gets lost, gets unpublished, is left
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missing in action, and they say the results described here
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"might have provided an early warning of trouble ahead."
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Now these are stories from basic science.
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These are stories from 20, 30 years ago.
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The academic publishing environment is very different now.
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There are academic journals like "Trials," the open access journal,
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which will publish any trial conducted in humans
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regardless of whether it has a positive or a negative result.
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But this problem of negative results that go missing in action
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is still very prevalent. In fact it's so prevalent
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that it cuts to the core of evidence-based medicine.
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So this is a drug called reboxetine, and this is a drug
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that I myself have prescribed. It's an antidepressant.
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And I'm a very nerdy doctor, so I read all of the studies
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that I could on this drug. I read the one study that was published
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that showed that reboxetine was better than placebo,
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and I read the other three studies that were published
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that showed that reboxetine was just as good as any other antidepressant,
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and because this patient hadn't done well on those other antidepressants,
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I thought, well, reboxetine is just as good. It's one to try.
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But it turned out that I was misled. In fact,
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seven trials were conducted comparing reboxetine
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against a dummy placebo sugar pill. One of them
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was positive and that was published, but six of them
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were negative and they were left unpublished.
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Three trials were published comparing reboxetine
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against other antidepressants in which reboxetine
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was just as good, and they were published,
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but three times as many patients' worth of data was collected
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which showed that reboxetine was worse than
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those other treatments, and those trials were not published.
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I felt misled.
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Now you might say, well, that's an extremely unusual example,
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and I wouldn't want to be guilty of the same kind of
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cherry-picking and selective referencing
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that I'm accusing other people of.
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But it turns out that this phenomenon of publication bias
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has actually been very, very well studied.
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So here is one example of how you approach it.
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The classic model is, you get a bunch of studies where
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you know that they've been conducted and completed,
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and then you go and see if they've been published anywhere
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in the academic literature. So this took all of the trials
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that had ever been conducted on antidepressants
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that were approved over a 15-year period by the FDA.
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They took all of the trials which were submitted to the FDA as part of the approval package.
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So that's not all of the trials that were ever conducted on these drugs,
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because we can never know if we have those,
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but it is the ones that were conducted in order to get the marketing authorization.
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And then they went to see if these trials had been published
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in the peer-reviewed academic literature. And this is what they found.
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It was pretty much a 50-50 split. Half of these trials
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were positive, half of them were negative, in reality.
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But when they went to look for these trials in the peer-reviewed academic literature,
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what they found was a very different picture.
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Only three of the negative trials were published,
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but all but one of the positive trials were published.
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Now if we just flick back and forth between those two,
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you can see what a staggering difference there was
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between reality and what doctors, patients,
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commissioners of health services, and academics
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were able to see in the peer-reviewed academic literature.
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We were misled, and this is a systematic flaw
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in the core of medicine.
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In fact, there have been so many studies conducted on
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publication bias now, over a hundred, that they've been
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collected in a systematic review, published in 2010,
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that took every single study on publication bias
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that they could find.
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Publication bias affects every field of medicine.
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About half of all trials, on average, go missing in action,
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and we know that positive findings are around twice as likely
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to be published as negative findings.
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This is a cancer at the core of evidence-based medicine.
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If I flipped a coin 100 times but then
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withheld the results from you from half of those tosses,
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I could make it look as if I had a coin that always came up heads.
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But that wouldn't mean that I had a two-headed coin.
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That would mean that I was a chancer
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and you were an idiot for letting me get away with it. (Laughter)
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But this is exactly what we blindly tolerate
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in the whole of evidence-based medicine.
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And to me, this is research misconduct.
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If I conducted one study and I withheld
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half of the data points from that one study,
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you would rightly accuse me, essentially, of research fraud.
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And yet, for some reason, if somebody conducts
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10 studies but only publishes the five that give the result that they want,
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we don't consider that to be research misconduct.
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And when that responsibility is diffused between
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a whole network of researchers, academics,
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industry sponsors, journal editors, for some reason
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we find it more acceptable,
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but the effect on patients is damning.
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And this is happening right now, today.
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This is a drug called Tamiflu. Tamiflu is a drug
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which governments around the world have spent billions
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and billions of dollars on stockpiling,
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and we've stockpiled Tamiflu in panic,
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in the belief that it will reduce the rate of complications of influenza.
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Complications is a medical euphemism for pneumonia
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and death. (Laughter)
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Now when the Cochrane systematic reviewers
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were trying to collect together all of the data from all
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of the trials that had ever been conducted on whether Tamiflu actually did this or not,
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they found that several of those trials were unpublished.
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The results were unavailable to them.
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And when they started obtaining the writeups of those trials through various different means,
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through Freedom of Information Act requests, through
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harassing various different organizations, what they found was inconsistent.
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And when they tried to get a hold of the clinical study reports,
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the 10,000-page long documents that have
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the best possible rendition of the information,
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they were told they weren't allowed to have them.
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And if you want to read the full correspondence
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and the excuses and the explanations given by the drug company,
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you can see that written up in this week's edition
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of PLOS Medicine.
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And the most staggering thing of all of this, to me,
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is that not only is this a problem, not only do we recognize
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that this is a problem, but we've had to suffer fake fixes.
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We've had people pretend that this is a problem that's been fixed.
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First of all, we had trials registers, and everybody said,
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oh, it's okay. We'll get everyone to register their trials, they'll post the protocol,
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they'll say what they're going to do before they do it,
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and then afterwards we'll be able to check and see if all the trials which
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have been conducted and completed have been published.
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But people didn't bother to use those registers.
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And so then the International Committee of Medical Journal Editors came along,
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and they said, oh, well, we will hold the line.
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We won't publish any journals, we won't publish any trials,
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unless they've been registered before they began.
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But they didn't hold the line. In 2008, a study was conducted
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which showed that half of all of trials published by journals
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edited by members of the ICMJE
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weren't properly registered, and a quarter of them weren't registered at all.
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And then finally, the FDA Amendment Act was passed
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a couple of years ago saying that everybody who conducts
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a trial must post the results of that trial within one year.
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And in the BMJ, in the first edition of January, 2012,
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you can see a study which looks to see if people kept
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to that ruling, and it turns out that only one in five
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have done so.
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This is a disaster.
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We cannot know the true effects of the medicines
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that we prescribe if we do not have access
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to all of the information.
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And this is not a difficult problem to fix.
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We need to force people to publish all trials
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conducted in humans, including the older trials,
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because the FDA Amendment Act only asks that you publish the trials conducted after 2008,
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and I don't know what world it is in which we're only
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practicing medicine on the basis of trials that completed in the past two years.
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We need to publish all trials in humans,
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including the older trials, for all drugs in current use,
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and you need to tell everyone you know
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that this is a problem and that it has not been fixed.
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Thank you very much. (Applause)
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(Applause)
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