Give us the trial data

August 14th, 2010 by Ben Goldacre in bad science, big pharma, libel, publication bias, regulating research | 47 Comments »

Ben Goldacre, The Guardian, Saturday 14 August 2010

This week the drug company AstraZeneca paid out £125m to settle a class action. Over 17,500 patients claim the company withheld information showing that schizophrenia drug quetiapine (tradename Seroquel) might cause diabetes. Why do companies pay out money before cases get to court?

One interesting feature of litigation is that various documents enter the public domain. This is how we know about the tobacco industry’s evil plans to target children, or the fake academic journal that Elsevier created for Merck’s marketing department, and so on.

One of the most revealing single documents ever to come out of a drug company came from an earlier quetiapine case, now part of a large online archive: it is an email from John Tumas, Publications Manager at Astrazeneca. In it, he helpfully admits that they do everything I say drug companies do.

“Please allow me to join the fray”, John begins, in response to a colleague. “There has been a precedent set regarding ‘cherry picking’ of data.” Cherry picking is where you report only flattering data, and ignore or bury data you don’t like. The ears of lawyers will prick up at any use of the word “bury” in relation to drug company data, as it implies something deliberate, but luckily John uses this word himself. The precedents set on cherry picking, he explains, are “the recent Velligan presentations of cognitive function data from Trial 15 (one of the buried trials).”

Trial 15 is a legendary trial commissioned by AstraZeneca. Patients with schizophrenia who were in remission were randomly assigned to receive either AstraZenece’s quetiapine, or a cheap old-fashioned drug called haloperidol. After a year, the patients on Seroquel were doing worse: they had more relapses – a real world outcome that really matters – and worse ratings on various symptom scales. These negative findings were left unpublished: to use John’s word, they were “buried”.

But in among all these important negative findings, on a few measures of “cognitive functioning” – an attention task, a verbal memory test, and so on – Seroquel did better. This finding alone was published – by Velligan et al in 2002 – the fact that patients on Seroquel had worse outcomes for their schizophrenia was not. And Velligan’s paper was not a side show: it went on to become a highly influential piece of work, with over a hundred other academic research papers citing it. Many researchers can only dream of pubishing such a well cited piece of work.

Meanwhile study 15 also found that patients on Seroquel gained, on average, 5kg a year. This plainly put them at increased risk of diabetes, which is what Astrazeneca are now paying to settle on (and in any case, 5kg weight gain is a serious side effect in itself).

Drugs have side effect, and quetiapine is not unique: psychiatric drugs in particular can do more good than harm, overall, but many also have serious, common side effects. When that is the case, it’s especially important that doctors and patients know all the risks, so that sensible and informed trade-offs can be made.

This is just the first paragraph of one email over 100 in the last quetiapine case. It is endless: in exhibit 13 Richard Lawrence sends an internal memo to colleagues: “Lisa has done a great smoke and mirrors job” on trial 15, and so on.

It is also, remarkably, unremarkable. The pharmaceutical industry’s behaviour has collapsed into farce. Doctors and academics – who should feel optimism at working with them to develop new treatments – feel nausea instead, knowing there are only informal and ad hoc systems to deal with buried data, and these systems have clearly failed.

In 2005 the International Committee of Medical Journal Editors put their foot down, and said their journals would only publish trials that were fully registered before they started, which should make trials that went missing much easier to spot. Several years later, as we saw in this column, less than half of all the trials that ICMJE editors published were adequately registered, and more than a quarter weren’t registered at all.

After the New York attorney sued GlaxoSmithKline over their “illegal and deceptive” reporting of the risks of their antidepressant paroxetine (tradename Seroxat), GSK agreed to publish all trial data on a website: but this was only for that one company, and even there it clearly did little to fix the problem. We saw last month that GSK and the FDA sat on data showing that rosiglitazone (tradename Avandia) increased the risk of heart problems, several years after this agreement.

This week in the open access academic journal Trials, two researchers set out some ideas around international law to try and fix this gaping hole, and stop companies hiding data that doctors need to make safe decisions for their patients. They don’t go far enough. Any company withholding trial data harms patients. I can’t understand why any ethics committee would allow any company currently witholding data to confuct further experiments on people. I can’t see why the state doesn’t impose crippling fines. I hope it’s because politicians don’t understand the scale of the harms.


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47 Responses



  1. yer_maw said,

    August 14, 2010 at 2:10 am

    Big pharma: Publish all the data and stop being ridiculous.

    Society: decide whether you would rather have diabetes or schizophrenia.

    If we don’t figure out what we are willing to put up with to help disease, the pharmaceutical industry and the development of new drugs is FINISHED.

    No small molecule will be perfect under the current rules. We either put up with side effects or have no new drugs.

  2. twaza said,

    August 14, 2010 at 6:26 am

    Great journalism again Ben.

    I think that the problem is quite general, and not peculiar to Big Pharma. In any enterprise (big or small; pharmaceuticals, CAM, or banking) the marketing mindset rules. And as as it only values short term returns, it ignores any evidence about long term outcomes. It displays what Roger Scrutom happily calls “unscrupulous optimism” about the future.

  3. Goblok said,

    August 14, 2010 at 8:08 am

    Why isn’t the answer simple? Every country has drug regulators – in the UK it is NICE.

    Surely, it is not beyond the wit of regulators to stipulate (legislate) that ONLY drugs derived from FULLY disclosed trials will even be considered for authorisation. Make it a criminal offence to withold ANY trials result – good or bad – (leading to imprisonment of Directors).

    If (eg) Zimbabwe or Mongolia don’t want to implement such legislation, so be it – their problem. But no drug which does not comply will ever be used in this country, whatever the alleged benefits achieved elsewhere.

    I suspect that nothing less than that will stop big money killing people. And it is not really difficult – just beyond the lilylivered legislators to really protect us from the powerful.

  4. crichmond said,

    August 14, 2010 at 8:56 am

    Funny, that. I used to write obituaries for the Lancet, an Elsevier journal. Two other Elsevier journals were edited by David Horrobin, the evening primrose oil supremo. The journals were Medical Hypotheses and Prostaglandins, Leukotrienes and Essential Fatty Acids. The latter published countless papers by Horrobin that flattered EPO.
    In May 2003 I published critical obituaries of Horrobin in the BMJ and Independent. For the next seven years the Lancet declined to take obituaries from me (their loss, in my view). I only resumed working for them this year. It will be interesting to see if writing this comment will dry up my work for the Lancet. Incidentally, there is now a Wikipedia entry for Horrobin and it reveals him as a far worse crook than I ever knew.

  5. DavidWaldock said,

    August 14, 2010 at 9:03 am

    NICE is not a drug regulator.

    The MHRA is the UK drugs regulator.

  6. Goblok said,

    August 14, 2010 at 10:10 am

    I stand corrected – but not answered.

    Why does this have to be a problem? Like so many others!

  7. muscleman said,

    August 14, 2010 at 10:11 am

    But, but Ben the Altmed crowd say you are a shill to BigPharma.

    Excellent article though, please continue to tell it like it is. For one thing your academically restrained anger is coming through nicely.

    More power to your elbow.

  8. muscleman said,

    August 14, 2010 at 10:17 am

    @Goblok
    “Why does this have to be a problem? Like so many others!”

    Because our biology is complex, genes and proteins are used in many different places, times and situations, they have closely related molecules that cross react, etc. etc.

    The wonder is not that drugs have side effects but that we have some drugs that very few or only minor side effects. Sadly those seem to be at the lower end of the efficacy scale.

    Even treatments that have only one target can cause problems in sick people because our physiology is interlinked. So you take Drug A but it leads inevitably to kidney stones or you must take Drug B to deal with not a side effect per se but the reaction of the diseased organism. Balance is a difficult thing sometimes and clinicians have my sympathy trying to do it. They give you Drug B instead of a different Drug B because Drug A is their most effective weapon and it is a risk/benefit analysis.

  9. jodyaberdein said,

    August 14, 2010 at 10:55 am

    Yes that would be the entirely credible MHRA then

    tinyurl.com/2v4r8ms

  10. CoralBloom said,

    August 14, 2010 at 11:39 am

    ‘I hope it’s because politicians don’t understand the scale of the harms.’

    There was a time in my life I’d have thought that too. Now I’m a lot older and I don’t.

    Good work Ben, keep banging the drum.

  11. Nile said,

    August 14, 2010 at 11:42 am

    David Waldock has pointed out – correctly – that NICE are not a regulatory agency; that task falls to the MHRA in the United Kingdom.

    However, NICE is the body that recommends whether or not the NHS (and individual practitioners within the NHS) purchase drugs; if they state that they will not recommend or fund any treatment without full access to the data then that’s a far more serious sanction than vague threats from an inactive regulator.

    The regulatory committee of the MRHA could easily impose full disclosure on pharmaceutical companies; they could also impose a targeted requirement for additional (or even retrospective) clinical trials on companies with a proven history of ‘cherry-picking’ or ‘burying’ data. These actions are available with the exising powers of the agency: however, the fact that they have not seen fit do do so in the past gives me little reason to suppose that they will do so in future.

    I suppose that we must take the view that the MRHA are far better-informed than Dr. Goldacre, as a regulatory agency must surely have the data to make a systematic study rather than pick up on anecdotal evidence and unpleasant surprises from legal disclosures in the USA. But it is difficult to exclude the suspicion that there has been some degree of ‘regulatory capture’ and, at the very least, that the MRHA is pursuing a ‘light touch’ regulatory approach in a political climate that favours a ‘laissez-faire’ style of regulation that will, we hope, encourage commerce and the economic benefits of the Free Market.

    It hasn’t occurred to ayone in Whitehall or in Parliament that free markets require good information; that bad purchasing decisions in any market have substantial costs and that this is especialy true of medicine; and that we might reap economic benefits from private-sector ‘medical tourism’ if affluent foreigners lose trust in the integrity and safety of their domestic healthcare systems – a plausible outcome if their only ‘regulatory’ process is civil litigation costing millions of dollars, a process that is of little benefit unless thousands, or tens of thousands of patients, have suffered a legallly-profitable and clearly-defined injury from years of mistaken or wilfully-misled prescribing. Little benefit, and late; and entirely lacking in preventative or precautionary safety.

  12. hapsci said,

    August 14, 2010 at 1:03 pm

    I believe scientific information should be freely available to everyone. All experimental results should be available, not just published papers. I think science should move towards electronic data recording (e lab books) that are available to search and look at results. I have been blogging about the pros and cons of this here – sciencehastheanswer.blogspot.com

  13. elecuanime said,

    August 14, 2010 at 3:02 pm

    The most e-mailed story in today´s nytimes is directly related to hapsci´s comment. It seems that a breakthrough has been made in Alzheimer´s research. I find it particularly striking that one of the interviewed scientists was able to say (not jokingly):

    “It’s not science the way most of us have practiced it in our careers. But we all realized that we would never get biomarkers unless all of us parked our egos and intellectual-property noses outside the door and agreed that all of our data would be public immediately.” (attributed to Dr. John Q. Trojanowski)

    The conflict of interest that plagues medical doctors (namely, they make money off sickness) is very clearly brought out by this quote, as well as their apparent ignorance of basic morality.

  14. Goblok said,

    August 14, 2010 at 4:10 pm

    Muscleman:
    I never question the unfortunate necessity to accept side effects. We, and the experts who advise us, have to make choices – that is life.

    Informed choices demand full knowledge of all the available evidence – not just the bits those who profit want us to know.

    Elecuanime:
    I like the last word of your quote – immediately. That is what we need – not the publication a year later when dozens have suffered needlessly.

    Thanks to Nile, hapsci and elecuanime for detailing why my own thinking is not far off the mark. If NICE refused to fund any drug for which FULL data was not posted on a freely accessible site, there would be an overpowering commercial reason to publish the truth, the full truth and nothing but the truth (remember that phrase?).

    Then we could all make informed choices to suffer the side effects in the hope of postponing the funeral. Suffering the side effects AND the funeral to line the pockets of the pillpushers is not acceptable.

  15. jwm said,

    August 14, 2010 at 9:54 pm

    Elecuanime:

    “The conflict of interest that plagues medical doctors (namely, they make money off sickness) is very clearly brought out by this quote, as well as their apparent ignorance of basic morality.”

    Actually, doctors make money from curing, or at least, trying to improve, sickness. Ergo, it’s in our interest to do this, otherwise who would pay for our services? (ignoring that homeopathists somehow manage this daily).

    You seem to be confusing medics with researchers (some of whom are indeed doctors), who in the majority are funded by the drug companies. As we have seen described in Bens article the pharmaceutical companies (not doctors) will do anything to ensure a lucrative margin with “apparent ignorance of basic morality”. Indeed the sponsorship for the trial you refer came from the FDA, NIH, and non-profit organisations, hence it’s science but not as we know it approach. Although even this is a bit of PR hyperbole by Dr Trojanowski as it’s done quite regularly and has been for years.

  16. T.J. Crowder said,

    August 15, 2010 at 10:35 am

    @yer_maw

    Society: decide whether you would rather have diabetes or schizophrenia.

    But the point is that in addition to (apparently) increasing risk of diabetes, the Velligan trial demonstrated that Seroquel does a worse job of mitigating schizophrenia than other drugs like haloperidol. So you don’t have to make that specific choice (instead, you have to choose between haloperidol’s [significant] adverse effects and schizophrenia).

  17. steveg said,

    August 16, 2010 at 12:02 am

    Paper from Annals of Internal Medicine this week shows that among trials registered on ClinicalTrials.gov those funded by industry were less likely to be published within 2 years of study completion and were more likely to report positive outcomes than those funded by governments.
    www.annals.org/content/153/3/158.abstract

    Most government funded trials in the UK are now through the Health Technology Assessment (HTA) programme. The findings of all HTA trials are published in an open access online journal on the HTA website, along with the original trial protocol.

    Making your data publicly available already is science as we know it.

  18. msjhaffey said,

    August 16, 2010 at 11:03 am

    As I blogged here, the scientific community needs to come up with procedures that are less open to abuse.

    While it’s common to beat up big pharma for abusing the current process, and much of this criticism is justified, they are by no means the only people who get things wrong. Improving the process is in everyone’s interests, whether it’s the consumers, big pharma or the people who “discovered” cold fusion.

  19. AdamJacobs said,

    August 16, 2010 at 12:45 pm

    Woah, hold on a minute there Dr Goldacre, you seem to be extrapolating beyond the limits of your data. Now, that’s not like you, so maybe I’ve misunderstood you, or maybe you have some more data somewhere that you haven’t mentioned in this blog, but if neither of those things is true, then you have fallen short of your normally excellent standards of evidence-based blogging.

    You describe some behaviour by the Seroquel team that is outrageous and totally indefensible. If everything really happened as you describe, then those responsible deserve nothing less than to be strung up by the goolies. No question.

    However, you then go on to say “The pharmaceutical industry’s behaviour has collapsed into farce”. And your evidence for that would be…?

    If I wrote a blog post describing the crimes of Harold Shipman, and then concluded “Doctors have collapsed into a bunch of murderous psychopaths”, you would be pretty quick to point out the flaw in that argument, but that’s not a whole lot different from what you have done here. You have extrapolated one case of bad behaviour to the entire pharmaceutical industry.

    Now, I know that this story isn’t a one-off, and that you could come up with other anecdotes about unethical behaviour by pharma employees (the Neurontin story springs immediately to mind). But as I’m sure you must have said yourself many times, the plural of anecdote is not data. The global pharmaceutical industry is enormous. They do thousands of clinical trials every year. It’s hardly surprising if there are serious shortcomings in the way a few of them are published. That’s not to defend such behaviours, of course, merely to put them in perspective.

    OK, declaration of interest time: although I don’t work for a pharma company, I run a clinical research consultancy company, and most of my clients are pharma companies. Maybe that makes me biased, but it also gives me an insider’s perspective, and I just don’t recognise the kind of behaviour you describe here for Seroquel. We get to hear about such cases because they are newsworthy and make a great story to sell papers or get blog traffic, but it doesn’t mean they are at all representative. In the more than 11 years I’ve been running my company, I have never come across behaviour like that. A far more typical experience is to find pharma employees who are ethically minded people who want to publish their research in a responsible and ethical manner.

    Where I’m sure we can easily agree, Ben, is that the standard of publication of clinical trials in general is abysmal, and of course the pharma industry are part of that. However, I am not aware of any evidence suggesting that the industry are worse than anyone else: it’s a general problem in clinical research, and not one specific to the pharma industry.

    In fact some of the research I’ve seen suggest that the industry might be a bit better than other people who publish clinical research. An abstract published at last year’s peer review congress showed that when papers were retracted, the retraction was less likely to be due to misconduct if the paper was industry-sponsored. And a paper published in Annals of Internal Medicine very recently (which I know you’ve read, because you tweeted about it) showed that a discordance between registered (ie pre-specified) primary outcomes and published primary outcomes was less likely in industry-sponsored papers. It also found that papers were more likely to be published or otherwise made publicly available if they were industry sponsored (industry studies were slower to be published, possibly because of their greater complexity, but more likely to be published in the end).

    So, do you have some evidence that “the pharmaceutical industry’s behaviour has collapsed into farce”, or do you want to reconsider that statement?

  20. Ben Goldacre said,

    August 16, 2010 at 12:53 pm

    hi adamjacobs

    i’ve written extensively on the pharmaceutical industry hiding negative findings, i’m not extrapolating from this one case, it’s a deeprooted systematic flaw from the people who do 90% of all published clinical trials.

  21. AdamJacobs said,

    August 16, 2010 at 2:26 pm

    I know you’ve written about it extensively, but what I’m asking is what is your evidence that it’s a “deeprooted systematic flaw” in the pharmaceutical industry?

    I don’t doubt for a minute that negative trials are less likely to be published than positive trials: that’s well documented. I’m just not aware of any evidence suggesting that the pharma industry is any worse in that regard than anyone else. Is there any?

    BTW, where does that 90% figure come from?

  22. raven said,

    August 16, 2010 at 2:53 pm

    There’s an inevitable conflict if companies that will profit from a new drug are also funding the research to show it works.
    But we’re told the cost of researching and developing new drugs is high, and the way to get new drugs is to let pharmaceutical companies bear that cost. So we’re stuck with them funding the initial research at least.

    Once a drug is licensed and out on the market, I assume it’s possible for independent research to be done.( I’m imagining doctors distrustful of industry research getting together to do their own.)
    Does that happen?

  23. Trodamus said,

    August 16, 2010 at 9:00 pm

    AdamJacobs,

    Ben has, on this blog, discussed meta analyses that compare published results with actual data in the trials, along with the tone of the concluding statements and found that most published studies are indeed cherry picking, when they aren’t blatantly claiming something that is not supported in the trial.

    If you give me an hour I’ll try to find the link, but any meta analysis of trial data versus published findings is going to look like someone had an agenda, at least going in direct proportion to the amount of money that could be made off of a favorable trial.

  24. Jered said,

    August 17, 2010 at 6:09 am

    Does health care in a capitalist society have it’s drawbacks?

    I think one could easily conclude that the pharmaceutical companies are primarily driven to make more money, and less driven to make sure that everything they put on the market is 100% safe and accurate.

  25. msjhaffey said,

    August 17, 2010 at 8:04 am

    If a large pharma company consistently tried to push medicine that was harmful, it would be self-defeating in the long run, as they’d get a reputation for it and doctors would decline to prescribe it or patients to take it. I’m not saying there haven’t been cases but rather that I believe these are the exception.

    There are a number of statements on this web page that imply or openly state that big pharma is, more often than not, deceitful in the studies that it publishes.

    It would be interesting to do a comprehensive study of this and not one with cherry-picked results.

  26. Guy said,

    August 17, 2010 at 8:55 am

    KSJhaffey,
    This has been done many times. I think Ben in his book mentioned that the comparative trials of anti-inflammatory drugs always compare their drug with a competitor. In all cases their drug is better, which is clearly ridiculous. So all the negative trials are buried.
    I myself have done a lot of literature reviews of drugs for overactive bladder. Tiny non clinically signficant differences are exaggerated and their drug is always superior.
    I personally wouldn’t use a drug that only had drug company published data. If it hasn’t been replicated by a non sponsored trial then it shouldn’t be trusted.

  27. AdamJacobs said,

    August 17, 2010 at 9:33 am

    @raven:

    Yes, that kind of thing does happen. I know that for a fact as I personally worked on an independent study of a drug a few years back.

    I expect the next thing you’re going to ask is how common it is, and unfortunately I’m not aware of any data on that. If anyone knows of any I’d be interested to see it.

    You’re right, of course, that there is a conflict of interest when pharma companies investigate the drugs that they sell. The way that most western countries manage that conflict is to have very strict regulation of industry-run clinical trials. Even if someone in a pharma company wanted to fiddle the way the trial is run (and of all the many people I’ve worked with in pharma companies, I’ve yet to meet one who I suspect would want to), it would be extremely difficult if not impossible to do.

  28. AdamJacobs said,

    August 17, 2010 at 9:39 am

    @Trodamus

    Yes, I’ve also read much research looking at the quality of research reporting, and it’s true that it’s mostly pretty bad. However, in the studies I’ve seen, that finding applies across the board, and not specifically to the pharmaceutical industry.

    I’m not claiming that the industry are brilliant at reporting their results. Clearly they’re not. All I’m saying is that poor reporting is a universal problem in clinical research, and I am not aware of any evidence that research done by the pharma industry is any worse than research done by others.

    If anyone can show me good quality evidence that says that it is, I’ll be happy to change my mind.

  29. raven said,

    August 17, 2010 at 3:56 pm

    Thanks Adam, I thought doctors were pretty free to do independent trials. Obviously side effects will come to light anyway once the drug is on the market & being used.
    As the initial trials are likely to be smaller, I presume that they don’t always pick up all side effects so it wouldn’t necessarily mean the drug company had hidden data if things came to light once more patients are on the drug.

    From Ben’s article this company did know about the weight gain, but I can’t see why they thought they would get away with not acknowledging they’d found that in their trails. It might delay doctors and patients knowing about it for a while,gain them a few years of extra sales, but then once the side effect was known & someone went back to the original trial it makes the company liable. And loses them reputation. Doesn’t make commercial sense to me, but that’s what seems to have happened. Current regulation doesn’t seem to be tight enough.

  30. CampFreddie said,

    August 17, 2010 at 5:10 pm

    One problem is the congitive dissonance of industry scientists. If you’ve got a trials that shows unexpected weight gain, then either your drug has problems OR the trial is dodgy.
    Biological trials of any type will generally have wide error bars, so it’s very easy to subconciously accept the ‘good’ trials that support your beliefs and dismiss the ‘bad’ trials.

    The other problem is that drug company scientists don’t think that it’s their job to be critical of their own product. Certainly, their paymasters don’t. It’s the regulators job to ensure public safety. And everyone knows that regulators put a negative spin on everything, so it’s the industry scientist’s job to put a positive spin on things to balance it out.

    I know from doing some consultancy that clients don’t like it if you say, “I think your product will cause problems because the data is rubbish”. They truly believe their product is great and they don’t like some arrogant consultant telling them it isn’t.
    On the other hand, they are happy if you say, “The regulators are unlikely to accept the data because factor A/B/C suggests a potential risk. I think you’ll need X/Y/Z extra studies to prove that your product is safe”.

    An enforced registered trial database is probably the only way to fix things for medical trials. Outside of medicine the problems are much more difficult to solve, though at least the risks to public health are generally lower (i.e. people won’t die if some chemical doesn’t do exactly what it says on the tin).

  31. AdamJacobs said,

    August 17, 2010 at 5:20 pm

    @raven

    “Current regulation doesn’t seem to be tight enough”

    Depends on which bit of the process you’re looking at. Conduct of clinical trials by pharma companies and the way they are reported to regulators is very tightly regulated indeed.

    However, the way results are published in peer-reviewed journals is barely regulated at all. The idea seems to be that peer review is an adequate guarantee of quality, which is an utterly ludicrous idea to anyone who knows anything about peer review and all its many flaws. So we find a great many publications which are rubbish.

    But that, as I’ve said before and will keep saying unless anyone provides any evidence to prove me wrong, is a problem with biomedical publishing in general, and not one specific to the pharmaceutical industry.

  32. msjhaffey said,

    August 18, 2010 at 8:02 am

    >AdamJacobs

    You wrote “However, the way results are published in peer-reviewed journals is barely regulated at all.”

    I am not sure that regulation is necessarily the best way out. Politicians have shown themselves poor judges of scientific fact and asking them therefore to regulate science (or in this case medicine) would, I suspect, lead to process without effect. Furthermore, if big pharma or anyone else is as corrupt as some have written on this page, then written law will simply have them looking for loopholes.

    Surely it is far better for the experts in the field, such as the journals and the BMA, to draw up a protocol for trials? This would need to include stating at the outset the objective of the trial, methodology, sound statistical measurement and publication of all relevant results.

    Big disclaimer: I don’t work in the industry and I don’t claim to be a scientist.

  33. AdamJacobs said,

    August 18, 2010 at 8:47 am

    Ben, I’m a little disappointed that you’ve not provided data to back up your claim that the problems you describe in the pharma industry are “deep rooted and systematic”.

    To be clear, I am perfectly satisfied that you have already provided, either in this blog post or in your previous writing, good evidence to support the following 2 statements:

    1. Some people in the pharma industry have behaved unethically, sometimes to the point of being criminally fraudulent.

    2. Negative trials by the pharma industry are less likely to be published than positive ones.

    However, both those things are also true of clinical researchers who are independent of the pharma industry. If you are going to claim deep rooted and systematic flaws in the pharma industry, then you need to provide data showing that those problems are significantly worse in the pharma industry than they are elsewhere, or maybe explain some other reason why you think your claims are supported by evidence.

    I’m not saying I believe systematic flaws in the industry to be an impossibility: just that I haven’t seen the evidence that they exist. If you can show me the evidence, then I’ll believe you, and maybe even try to do something about it, if I can (I do have a bit of history in trying to get the pharma industry to clean up its act, as you’ll no doubt be aware if you’ve followed the literature on ghostwriting).

    I realise you must be very busy and probably don’t want to spend time getting into discussions on your blogs, but you of all people should understand the importance of being able to provide good-quality data to back up anything you claim to be a fact.

  34. eponymous85 said,

    August 18, 2010 at 1:52 pm

    A couple of points I feel need raising in response to some of the comments on here.

    1.Schizophrenia is not a disease in the same way diabetes is. You can’t die from it and it is largely down to subjective judgement whether it is diagnosed or not (albeit trained subjective judgement).
    Deciding whether to take antipsychotic medication is therefore much more about quality of life than ‘postponing the funeral’.

    2. Antipsychotic medication like quetiapine does not ‘cure’ schizophrenia; it can only alleviate some of its symptoms. The choice ‘do you
    want schizophrenia or diabetes’ is therefore far more complex.

  35. raven said,

    August 18, 2010 at 3:17 pm

    @Adam

    Re my comment “Current regulation doesn’t seem to be tight enough”.

    I’ve only read the article, I don’t know anything else about this case. The article says trial 15 found weight gain, and that the company has settled with patients who claimed they weren’t told the drug would increase risk of diabetes.

    So my comment meant that there seems to be a loophole in the regulations as the company had results showing a side effect and that information didn’t get passed on to doctors & patients.

    I don’t know when trial 15 was done, so perhaps regulation has changed since, as you say reporting trials to regulators is now tightly controlled. (and I’m assuming if all the results from trial 15 had been available to regulators at the time, weight gain would have been listed as a side effect on patient information for this drug)

    Why is it a problem that peer review is less controlled? I am assuming regulatory bodies know this and will use actual trial data to make decisions, not just peer review articles.

  36. AdamJacobs said,

    August 18, 2010 at 5:03 pm

    @msjhaffey & raven:

    I’m not necessarily saying that regulation of publications is the way to go. That probably would be overly bureaucratic and not very effective. Just pointing out that it isn’t regulated, and that peer review is not nearly as effective a form of quality control as some people think it is. So a lot of papers in the medical literature are total crap.

    One of the best ways to make sure people don’t cheat is to require prospective registration of clinical trial designs, and this is now happening. I’m not sure it’s mandatory in all jurisdictions, but it is becoming the norm in the industry, and that’s great. It is a useful safeguard against selectively reporting favourable outcomes and ignoring the negative prespecified outcomes (people still do that, of course, but now it’s a lot easier for them to be caught out). Perhaps that’s the bit that needs to be regulated.

    raven, you’re right that the regulators would know about the side effects, even if they’re not published. The Seroquel prescribing information does indeed list weight gain as a side effect, although I don’t know whether that was listed when Seroquel was first licensed.

  37. SteveGJ said,

    August 18, 2010 at 5:58 pm

    There is a fundamental problem in publishing all clinical trials, including negative outcomes, is that there is a commercial value to these results. If competitors can gain value from such published results without going through the enormous costs of running their own, then that’s a potentially massive cost advantage. Now I realise this particular trial is about a commercialy available drug, and the circumstances in this case may not have given value to competitors (although one suspects that almost any such information has value), but there are plenty where this would be the case, especially in early stage trials.

    Now I realise that there are many here that say this doesn’t matter a jot (the big pharma is evil brigade for one), it’s the interests of the patients that matter, but it certainly is an issue if it is a disincentive to encourage research and innovation.

    There is surely a role for an interim measure whereby a disinterested party can review any such trials for information where it is in the public interest to publish full trial outcomes. However, we should be aware of creating perverse incentives. Quite a lot of Ben’s articles tend not to handle that particular issue.

    I think there is actually a better way as there are plenty of pre-clinical trials with negative outcomes which are of enormous commercial value. Forcing all drug trial test results, whether clinical, animal, test tube and so on would avoid a huge amount of expensive duplication. Now I realise Ben is not proposing to go that far, but I think a better approach would be to recognise the commercial value of such trial data and come up with a system which would allow access to such data but at some commercial rate. It’s difficult to come up with such a system of course, but if it could be made to work it would be potentially of considerable value. It’s not open publication of course, but that’s not the way that pharmaceutical research works in the real world.

  38. Sqk said,

    August 18, 2010 at 9:12 pm

    After a quick internet rootle I’ve found various news articles but been unable to find:

    1) the claim presented

    2) ‘study 15′

    Is it possible that someone could post the links as I’d like to read them through before I ask what could be today’s most controversial and ill-understood question?

    If they’re already on here somewhere could someone be sporting and point them out please?

  39. tomrees said,

    August 19, 2010 at 9:13 am

    Isn’t this a problem that’s already been solved? All pharma trials are now registered and the primary outcomes released (via publication or registry) in a timely way. Marketing is firewalled from medical publications. People who are interested in this topic should read up on the latest Good Publication Practice Guidelines, which is what the industry adheres to (www.gpp-guidelines.org/). Disclaimer, I’m also an industry insider.

  40. psybertron said,

    August 19, 2010 at 3:59 pm

    @AdamJacobs and @CarolineRichmond

    Just want to join up some dots. Glad to see you defending professionals against the baying crowd Adam. The danger of generalizing from reported failings. You also said
    ” The idea seems to be that peer review is an adequate guarantee of quality, which is an utterly ludicrous idea to anyone who knows anything about peer review and all its many flaws.”

    Caroline mentioned that she previously worked for the non-peer-reviewed journal “Medical Hypotheses” and we are in danger of tarring the non-peer-reviewed idea by naming one infamous past editor as a crook.

    I happen to believe we’d be much healthier if we simply recognized that all publication has “interests” and acted accordingly based on who we trust, rather than wishing for some kind of regulated perfection.

  41. Mike Kelly said,

    August 19, 2010 at 5:36 pm

    eponymous85 said,
    August 18, 2010 at 1:52 pm
    A couple of points I feel need raising in response to some of the comments on here.
    1.Schizophrenia is not a disease in the same way diabetes is. You can’t die from it and it is largely down to subjective judgement whether it is diagnosed or not (albeit trained subjective judgement).
    Deciding whether to take antipsychotic medication is therefore much more about quality of life than ‘postponing the funeral’.
    2. Antipsychotic medication like quetiapine does not ‘cure’ schizophrenia; it can only alleviate some of its symptoms. The choice ‘do you
    want schizophrenia or diabetes’ is therefore far more complex

    Bollocks

    Look at the death rate in untreated schizophrenia. Many are diagnosed following suicide attempts.

    You don’t have to spend very much time around schizophrenia patients to realise that for many the drugs are the only thing that’s giving them a life at all.

    That said there’s a difference in choosing the risk of diabetes in an informed way and taking the risk unknowing

  42. Sqk said,

    August 20, 2010 at 12:51 am

    @eponymous85 and @Mike Kelly

    It is a shame that typing removes nuance and tone. I actually read your points as saying the same thing. I suspect it comes down to the background from which I come when I approach your comments.

    As you will both be aware both ‘diseases’ (although they’re not technically diseases but ‘conditions’ when I last looked, as they do not directly communicate) require careful management as they both have the potential to be nasty. However, both, if you don’t have the means, the understanding, the support around you, or even if you do have all that and are just unfortunate, do have the ability to seriously reduce quality of life and directly, or indirectly, reduce your lifespan. I am not in a position to look up who made the original quote, “some life-long illnesses kill you, some just make you wish you were dead” but it does apply here. There’s a tendency to forget that to lose your life you don’t actually have to die. Now, that’s not to say for a moment that that occurs to everyone, hence I used the word ‘ability’ to state a possibility and not a certainty, but I feel you’d agree that one person is one too many.

    I did attempt to post the links to the side-effects of the medication and when and how they have been updated over the last few years, but it appears to have become lost in a spam-filter. My earlier question related to wondering whether weight-gain was listed separately to diabetes incidence and whether one was being automatically assumed to lead to the other. In the side effects that I linked to increased blood-sugar levels and weight-gain are listed separately.

    (P.S. I am aware of the link between obesity/diabetes and why. I was curious on another point).

  43. skyesteve said,

    August 20, 2010 at 5:22 pm

    Sorry eponymous85 but have to agree with Mike – when you say things like “schizophrenia is not a disease like diabetes” and “you can’t die from it” your aren’t just talking nonsense but your actually contributing to the ongoing prejudice that surrounds mental illness.
    With the exception of antimicrobials there are very few medicines that “cure” anything – most just alleviate.
    Antidiabetics don’t cure daibetes, antiepileptics don’t cure epilepsy, antihypertensives don’t cure hypertension, and so on. But by alleviating they can improve longevity and life quality and that is true of antipsychotics too. If you want a “cure” surgery might be the better place to look.
    No drug is without potential side effects and, as others have said, all we really want is the ability to make an informed choice. Then we can decide whether we want to take something or not and we must be prepared to live with the consequences either way.
    So, for example, would I have chemotherapy if I had lung cancer? Probably not but I would certainly consider it if I had testicular cancer or certain haematological cancers. Would I have warfarin if I had atrial fibrillation? On personal balance probably not but in doing so I would have to accept the possible increased risk of having a stroke.
    Don’t get me wrong, I think there are very real issues around (and questions to be asked about) the way we use antipsychotics and antidepressants but that should not result in a denial that some people have had their lives transformed and, possibly, saved by these medications. And don’t forget also the devastating impact something like schizophrenia can have on family, friends and loved ones.

  44. Guy said,

    August 20, 2010 at 6:06 pm

    Well said Steve. It was a particularly unfortunate example for two reasons. Firstly that schizophrenia is an absolutely devastating condition which wrecks lives and families. Secondly that ambivalent as I am about many pscyhotropic drugs, the modern drugs for schizophrenia are frankly brilliant and have revolutionised many sufferer’s lives. Bad example. Its a devastating illness, not a life choice!

  45. mikewhit said,

    August 25, 2010 at 5:45 pm

    “pubishing”, Ben ? Is that what people do with articles to cover their embarrassment …

  46. ferguskane said,

    September 5, 2010 at 2:08 am

    Guy. Agree with the general sentiment. However, the ‘modern drugs’ for schizophrenia are certainly not brilliant. They are sometimes very effective, sometimes useless and often truly awful at the same time. Many people with a diagnosis of schizophrenia have to walk the tightrope of balancing the life destroying side effects of their medications against the life destroying effects of their symptoms. Furthermore, apart from being much more expensive, the newer generation of antipsychotics are slowly being shown to be little better than the older generation.

    The very slow recognition of the serious weight gain side effects of the newer medication has led to patients’ physical health being seriously compromised. To me, the rate at which medicated patients put on weight is truly shocking and I’m bemused by long the problem has taken to be addressed. I view pharma as being heavily complicit in this slow recognition – I don’t have hard evidence or memos to hand (and how could I, pharma is never knowingly transparent) – but a combination of knowing what companies are capable of, questioning of drug reps and working in psychiatric research makes it hard to see otherwise.

    This of course, is where effective trial regulation becomes critical. Without effective trial regulation, we’ll not be able to say which drugs are truly the most effective and we will find out about the side effects far to late in the day.

  47. Oletaolyta said,

    February 27, 2011 at 12:10 am

    I searched this topic deliberately, because I have Schizoaffective disorder and have been taking seroquel in increasing amounts since 2003. When I began taking it, I was already slightly overweight, and was prescribed seroquel over olanzepine on the basis that it would be better for avoiding weight-gain. I would laugh, but it’s not really that funny. I am now due to have weight-loss surgery, an expense for the NHS and an anxious time for me while I (laugh at this) have to try to stay stable enough for surgery partly by continuing to take the very drug that has made me need surgery in the first place.

    Perhaps I will continue to take Seroquel even knowing what I now know, because it has been a life-changer for me, with longer gaps between episodes and less residual psychotic symptoms than other drugs I tried, although I am concerned by how much the doses have increased over the years. The difference is this: I would have had the choice, I would have been fore-warned of what to expect and my weight could have been monitored and measures taken before it got this far. ‘Bad Science’ isn’t about an ‘oh those rogues’ academic smugness on the part of those who ‘know’, it can seriously mess up your life.

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