Regulating Research

August 12th, 2006 by Ben Goldacre in bad science, regulating research | 15 Comments »

Ben Goldacre
Saturday August 12, 2006
The Guardian

Look, I feel sorry for the six men who swelled up “like the Elephant Man” on TGN1412. The interim report is out now, and it has a lot of sensible suggestions about the mechanics of that kind of trial, but it got me thinking: if you wanted to be actuarial about this, and count up the pain and death caused by research shortcomings, where would you find the most tragedy?

How about duff studies? Tardive dyskinesia is a horrible and disabling movement disorder, a side-effect of schizophrenia treatment. A 1996 review looked at 500 studies of 90 treatments for it: not one provided useful data, they all either had too few patients or were too brief. That’s 500 duff studies, while patients continued to suffer, with no outcry, and no regulatory response: I could fill the page with similar examples.

But perhaps that’s too esoteric for our tragedy ledger. How about unnecessary research, through absent mindedness, or the greed of drug companies? By the mid-1970s it was pretty clear, from many well performed trials, that taking antibiotics after bowel surgery reduced your chances of getting an infection afterwards. And yet we continued to perform trials well into the 80s: half the patients were exposed to a placebo, and the risk of painful infection and death.

Meanwhile drug companies squander research money, effort, and patients’ goodwill on “me-too” drugs, minor variations on a theme that are unlikely to bring new benefits, except to shareholders. These “me-too” drugs are often tested in small studies, often comparing them against placebo, to ensure a positive result instead of giving them a fairer fight against their best competitors. Where are the regulators then?

Meanwhile, stand this wastage up against trials that were not done, because they wouldn’t make any money for anyone. Eclampsia is estimated to cause 50,000 maternal deaths worldwide each year, and the best treatment by a huge margin is cheap, unpatented, magnesium sulphate: not the expensive anti-convulsants that were used for many decades.

And yet, although magnesium for eclampsia had been used since 1906, its position as the best treatment was only established in 2002, with the help ofthe World Health Organisation: there was no commercial interest in the research question, because the majority of deaths are in the developing world, and because there’s no money for anyone in magnesium sulphate. Millions of women have died of eclampsia since 1906, many of them avoidable.

Now, I have a comfortable life, I profit from global inequality as much as the next man, I recognise that it’s too much to ask that we dismantle capitalism, increase state funding of trials, and ensure that research effort is deployed according to need and not company profit. But what about the easy stuff? Publication bias, for example, and companies who sit on disappointing findings, still pollutes the research evidence: and a compulsory clinical trials database, suggested decades ago, would solve the problem in one sweep. While no one has swelled up “like the Elephant Man”, they’ve been treated inadequately on the basis of a distorted evidence base: where are the regulators there?

I can identify with six blokes my age in intensive care. But if we spread our remit a bit wider and start looking at the body count, we might find the big stories are elsewhere.

Evidence and tardive dyskinesia. Soares K, McGrath J, Adams C. Lancet. 1996 Jun 15;347(9016):1696-7.

If you enjoy this kind of thing you should buy “Testing Treatments: Better Research For Bettter Healthcare”, written for a popular audience by Evans, Thornton and Chalmers.

www.amazon.co.uk/gp/product/071234909X/202-0727340-5896643?v=glance&n=266239


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15 Responses



  1. mark said,

    August 12, 2006 at 4:01 pm

    it’s too much to ask that we dismantle capitalism, increase state funding of trials, and ensure that research effort is deployed according to need and not company profit.

    Why is that too much to ask? I ask it, indeed I demand it. I’m realistic in having little expectation that this demand will be successful, but I think it has to come down to that.

  2. coracle said,

    August 12, 2006 at 7:45 pm

    I think you may be being a little harsh on the me-toos. I can think of a couple of ways of how me-toos may be beneficial, or at least not evil, although without any examples to back them up.

    1) Competition is good, having a competitive drug market should keep prices down. A company with the rights to the only drug in class can charge what they like for it, if there’s someone else making one then they need to compete.

    2) If you’re going after a me-too target you may end up with a drug that has a better safety profile or a more efficacious one, there’s no way of knowing how that’s going to turn out until you run the trials.

    3) Simultaneous research. Say a target is identified by an academic lab, who publish it, a whole bunch of companies are going to prick up their ears, start twitching their noses and think to themselves ‘hold on lads, I’ve got an idea..’ As a result, 5 (or any other number) companies are going to launch into there drug discovery, lead opt process and about 10 years down the line they’ve each got a candidate drug to dope into some willing victim volunteer. One of them manages to rush through trials and gets approval for their drug. Now what are the other n-1 companies going to do? Say, ‘well it was a good race, decent sports that lot, fair play to them, we’ll just put these proto-drugs back where we found them’? No, and I think it would be detrimental to expect them to.

    Or, for another take, have a look at this blokes blog:More From the Me-Too Front

  3. coracle said,

    August 12, 2006 at 7:46 pm

    Damn, what happened there?

  4. coracle said,

    August 12, 2006 at 7:48 pm

    Ok, hopefully that’s sorted out, here’s point three again in case anyone wants to read it.

    3) Simultaneous research. Say a target is identified by an academic lab, who publish it, a whole bunch of companies are going to prick up their ears, start twitching their noses and think to themselves ‘hold on lads, I’ve got an idea..’ As a result, 5 (or any other number) companies are going to launch into there drug discovery, lead opt process and about 10 years down the line they’ve each got a candidate drug to dope into some willing volunteer. One of them manages to rush through trials and gets approval for their drug. Now what are the other n-1 companies going to do? Say, ‘well it was a good race, decent sports that lot, fair play to them, we’ll just put these proto-drugs back where we found them’? No, and I think it would be detrimental to expect them to.

    Or, for another take, have a look at this blokes blog:More From the Me-Too Front

  5. JohnD said,

    August 12, 2006 at 8:39 pm

    You’re right about Magnesium for eclampsia, but its efficacy was demonstrated and widely used first in the USA, that bastion of capitalism. It’s only now that the WHO study has shown how well, and cheaply that it works that the NHS, that bastion of social medicine, has now taken it up. What’s that say about the two schools?

    This is less about me-too pharmacy, more about ‘orphan drugs'; drugs that either are for such a small patient base or are so cheap to make like MgSO4, that a drug company cannot afford to do the work that makes it marketable.

    However, I remember that tamoxifen was once such an orphan. ICI first synthesized it in the Fifties; its patent was nearly run out by the time it was marketed in the Seventies for use in ovulation induction. When it was used against breast cancer, there was fear that it would remain an orphan, but due praise to ICI/Astra-Zeneca for taking on developement for a different use.

    John

  6. ACH said,

    August 13, 2006 at 8:51 am

    Orphan drug designation is specific to the prevalence of the disease for which the drug is being developed. In the USA, which enacted the Orphan drugs act in 1984, orphan status is a disease affecting less than 200,000 of the population (which equtes to a prevalence of approx 7.5/10,000) In the EU (the legislation coming much later in 1999) the designation is

  7. ACH said,

    August 13, 2006 at 8:53 am

    Oops, lost the end of that – it didn’t seem to like the “less than” sign. European orphan designation is for diseases with a prevalence of less than 5/10,000.

  8. Teek said,

    August 13, 2006 at 12:05 pm

    “it’s too much to ask that we dismantle capitalism, increase state funding of trials, and ensure that research effort is deployed according to need and not company profit.”
    shame, cos if the above aims were achieved we’d all be a lot better off…!!

    IMHO, if there are diseases that private big pharma corporations are not interested in (for reasons of shareholder value, which legally is there only concern), government agencies such as MRC and BBSRC (in UK, NIH in US, etc) ought to be able to step in and fund extensive research into drugs/therapies etc. it would cost the government a proverbial limb to do so, but to paraphrase Chomsky (God i need to get out more…), “whilst a private corporation would never run an enterprise or project at a loss, for a state entity it may be worth it, because to develop a drug (or make steel in his original example, or indeed run a railway) at a cost of X, then ‘sell the service’ at half X, may represent a loss in itself, but could save billions elsewhere in avoidable healthcare and environmental costs…”

    does that rambling post make any bleeding sense by the way…? i’m writing a phd thesis so my mind’s an effing muddle to say the least…!!

  9. Robert Carnegie said,

    August 13, 2006 at 11:09 pm

    It’s one thing to develop me-too drugs scientifically, and another to develop them and perform research with them in a particular way. Dr. Ben’s comment specifically on testing new drugs against placebo instead of against known good drugs hits home, I think.

  10. Ben Goldacre said,

    August 13, 2006 at 11:41 pm

    It’s one thing to develop me-too drugs scientifically, and another to develop them and perform research with them in a particular way. Dr. Ben’s comment specifically on testing new drugs against placebo instead of against known good drugs hits home, I think.

    if you were sat down rationing out research effort instead of leaving it to market forces, me-toos might not get as much attention as they do, and when you came to test them, you would definitely do a better job of it than the biased studies on them currently, because you would want a fair test, giving the most useful answer for doctors and patients. now, the shortcomings of these tests are there in the write-ups for all to see, nothing’s hidden, this is no excuse for “you cant trust a study on account of who funded it” weakmindedness, because you can critique the studies quite adequately on the basis of the write up, the paper itself. but it is an argument for saying they are a waste of resources, of which patient time and flesh seems the most heinous to me.

    this was going to be a two-parter on how research regulation has missed the point, focussing next week on how ethics committees have restricted research locally without recognising the global impact that has on restricting the development of new knowledge that saves lives.

    i could randomly decide to give half my patients one drug, for fun – of course i wouldn’t – and half of them another, and the regulations on informed consent would be the usual gmc (almost but not quite “whatever you reasonably think is best under the circumstances”) line; if they were in a trial, i’d have to fill out six forms and inform them to hell and back whilst being watched by crowds of onlookers. i’m not saying one is right and one is wrong, i’m just not sure the disparity is justified, and i think a lot of good work is held back by restrictions that are well intentioned but disproportionate.

    now of course i just want to attack the postmodernists and leave this second and more interesting half of the argument for another year…

  11. superburger said,

    August 14, 2006 at 2:09 am

    whilst “me too” drugs may be un-needed (we have a treatment for disease X, why do we need another) it is always possible that by testing a similar compound we might get an unusual result.

    Unusual could be instant gruesome death of the volutneer, or it may be more worthwhile.

    I think minoxidil (for the folllically challanged) was discovered as a side effect of the drugs orginal use – for heart conditions.

    I’m not saying a cure for male pattern baldness is the greatest discovery for all mankind (though it would probably makes as much money as a cure for cancer…) but it does provide an example of the reasons why it is important to test, as safely as possible, potential drugs.

  12. wotsisnameinlondon said,

    August 14, 2006 at 7:24 pm

    The drug industry is like any other industry.It is driven by the profit motive and investors will only put up money for research if they think they will make a better return than putting the same money in , say, Premium Bonds. To expect any different is naive. State funded r&d is fine in theory but tends to produce bureacracy and bloated management in practice.

    There are other ways to ensure that drugs are tested in a safe manner. Here’s two suggestions

    1. Require that the financial beneficiaries of a successful drug e.g. the major shareholders in the companies concerned (5% of shares perhaps) and financial backers who would share in profits be available for selection as testees.

    2. Make unlimited insurance cover on the London insurance market a requirement of allowing the tests to proceed.

    These two measures would go a long way to ensuring that the drugs are made as safe as can be before tests proceed, and that compensation for any subsequent damage is not a problem. If one capitalist organisation (big Pharma) cannot persuade another (Insurance) that the trials are safe, then perhaps they shouldn’t proceed in the first place.

  13. coracle said,

    August 15, 2006 at 10:55 am

    Wotsisname

    I think #1 would severely restrict any trial because of the shareholder demographic. As much as anything, I’d love to see how the pharmacokinetics of a drug would be determined in a pension scheme!

    AUC = hr*ng/share?

  14. icarus said,

    August 17, 2006 at 10:30 am

    I have seen that so much of wasted research within the Pharma ind. into pre-clinical or FTIM studies is actually due to a relatively inexperience pharmacologist, an over worked Director of Discovery Medicine and a couldn’t-care-less VP of the Theraputic Area.

    The idea of malicious drug development is a little media driven in itself. I would hesitate to say that drug’s for profit is a major problem, but given the governments (at least in the UK) tendancy to rely on charity funding for academic research, and not state funding – we as a people are actively promotiing drug company health ethics, becuase we do not demand social health ethics as a mandate of our state.

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