RxISK – Making medicines safer for all of us

This is good.

Here’s a new website that Prof David Healy’s involved with. RxISK is a free, independent drug safety website where you can research a prescription drug to see what side effects have been reported and also share your experience and get a free RxISK Report to take to your doctor if need be.

This from RxISK:

A Good Drug is a chemical + Good Information. Most of the information on what drugs actually do is missing. Only you can provide it. Using RxISK will tell you more about the drugs you are prescribed than anything else will. By reporting to RxISK you can help make Good Drugs. Less than 5% of drug side effects are reported. Your voice has been silenced – globally.

Little is known about the effects of drugs on our hair, sex and relationships, violent and other extreme acts or thoughts, and our skin and nails, because these effects are not considered medically significant and are not tracked.

We have created the RxISK Zones with two purposes in mind:

  1. To enable you to easily search for prescription drug side effects on hair, sex, violence, suicide, and other aspects of our every day lives in the more than three million adverse drug event reports filed with the FDA since 2004, as well as our expanding RxISK database.
  2. To make it even easier for you to report these types of prescription drug side effects on RxISK.org and with your country’s drug regulator or the FDA if we don’t yet have your country’s form.

Just imagine — by reporting your experiences, you can help make RxISK the most comprehensive source of independent information on drug side effects in these important personal areas.

How it works

At the bottom of any Zone page, simply enter a prescription drug and click Continue. On the following summary page, check the box next to any side effect you are experiencing, and click the Report a drug side effect button to quickly create your personalized RxISK Report with your RxISK Score to take to your health care professional to help them help you.

The page is here if you want to add to the real world knowledge available about the drugs you take.

Seroxat litigation in the UK – important news

The High Court action against Glaxo isn’t quite over.

There were 500 litigants to start with. This number dropped to about 150.

These 150 people received a letter recently.

And today, I have been sent a copy of this email:

Hi All, If you haven’t already, please can you get in touch with Sarah-Jane Richards at Secure Law to confirm you want to continue in the action and you are happy for her to represent you.  You need to do this and previous correspondence will not count as this involves the instruction of a new law firm…we really need strength in numbers.  Please can you also confirm if you are happy for your email to be added to her list and advise if you are still taking Seroxat and if you are on benefits.

If you’ve got the letter, you’ve got the link.

Use it.

The Antidepressant Era: the movie

No apologies here, this article (and videos) have been lifted straight from David Healy’s excellent website.

It’s important that as many people as possible have the chance to read the piece and take time to watch the film.

As far as the pharmaceutical industry is concerned, I can tell you from first hand experience that the industry still believes in its own hype… do more, feel better and live longer is Glaxo’s strapline and no one in that company thinks there’s even a hint of irony in that.

Now for Dr Healy’s piece:

The Antidepressant Era: the movie

The Antidepressant Era was written in 1995, and first published in 1997. A paperback came out in 1999. It was close to universally welcomed – see reviews 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 . It was favorably received by reviewers from the pharmaceutical industry, perhaps because it made clear that this branch of medical history had not been shaped by great men or great institutions but that other players, company people, had been at least as important.

Nobody objected to it, perhaps because at this point I had not agreed to be an expert witness in a pharmaceutical induced injury case. There were likely no PR companies who had a brief to manage Healy. I knew before The Creation of Psychopharmacology came out in 2002 that the response to it would be very different.

Disease Mongering & the Myth of Lowered Serotonin

Many of the ideas in The Antidepressant Era had appeared earlier. The idea that a lowering of serotonin (chapter 5) was a marketing myth and had nothing to do with science, first appeared in my doctoral thesis in 1985, and later in Psychopharmacological Revolutions in 1987. The idea that companies market diseases as a way of marketing medicines (chapter 6) first appeared in 1990 in Notes toward a History and The Marketing of 5HT.

The Antidepressant Era in turn contained many of the elements of Pharmageddon – the key role of the 1962 amendments to the Food and Drugs Act which, through product patents, prescription-only status for new drugs and the role of clinical trials, have created modern healthcare.

Is Valium a better drug than Prozac?

In 2000 I was approached by Duncan Dallas, an independent television producer from Leeds who wanted to do something critical on the antidepressants. Prozac was still at this point widely seen as a miracle of modern medicine, rather than an inferior drug to older antidepressants. Bioethicists and social scientists were still lining up to herald the creation of the New Man through modern genetics and modern psychotropic drugs.

Saying that what we were witnessing was a triumph of modern marketing rather than modern science caused a frisson in most circles. There were no natural allies – not in psychopharmacology or biological psychiatry but not in social science circles either.

But this is what Duncan wanted. The Antidepressant Era, the movie, opens with some of the hype around SSRIs, has astonishing footage of Roland Kuhn and Alan Broadhurst, two of the key people behind the discovery of imipramine, and outlines the overthrow of the benzodiazepines and their replacement by antidepressants.

It shows how rating scales and screening are used in psychiatry to create problems for which a drug becomes the answer.  It was the first program to wheel on stage the marketing men who created the social anxiety campaigns that sold Paxil, and it outlined the role of DSM III in the creation of depression.

Duncan’s version has a wonderful artistry. The book opens with a quote from George Oppen’s The Skyscraper. The “movie” closes with the same quote.

The Building of the Skyscraper

The steelworker on the girder
Learned not to look down, and does his work
And there are words we have learned
Not to look at,
Not to look for substance
Below them. But we are on the verge
Of Vertigo.

There are words that mean nothing
But there is something to mean.
Not a declaration which is truth
But a thing
Which is ..

Oh, the tree, growing from the sidewalk -
It has a little life, sprouting
Little green buds
Into the culture of the streets.
We look back
Three hundred years and see bare land.
And suffer vertigo.

Downfall – Adolf  Who? 

Its central moment is an astonishing sequence featuring the then President of Hoffman-la-Roche, Adolf Jann, embarking on a rant that looks now like an uncanny forerunner of the famous Adolf Hitler rant in the movie Downfall. The rant that launched a thousand You-Tubes. Adolf Jahn thumps his fist on the table, voice rising, as he angrily tells an interviewer in effect “You – none of you – can do without us – just try”. See section at 20 minutes 50 seconds to 22 minutes.

There is nothing specific to Jann or Roche here. This was and is the common credo of the pharmaceutical industry. This is what the CEOs of GSK, Pfizer, Merck and Lilly are saying to governments today. Healthcare is not sustainable unless we develop drugs that get people well so they aren’t a burden on the State, and if healthcare is not sustainable democracy may not be either. Facilitate us or society as you know it goes down the drain.

It would be a mistake to see this as a horrible modern manifestation of rapacious capitalism. Socialists from George Bernard Shaw in the early twentieth century onwards have turned to biology as an answer to social problems. If we cannot get mankind to agree to change for the better, perhaps we can improve on mankind. This belief powered the efforts of governments to eliminate the unfit from the late nineteenth century through to the eugenics movement and underpins some of our hopes for the New Genetics.

Eugenics looks terrible in retrospect while modern genetics looks like our only hope – but the same impulse underpins both.  There is no better example of what good history is about than this. Anyone writing the history of eugenics should really portray its prime movers in the same light as we now portray the heroes of the the Human Genome Project.

We should always remember that the nominees for the 1937 Nobel Peace Prize included both Gandhi and Hitler. There was a time when one looked at least as likely as the other to contribute to modern civilization.

Revolution’s Little Helper

The same dynamic made Valium look like a very dark drug in 2000 – so that even its name was withdrawn. Prozac in contrast looked like the gateway to the hoped for shiny uplands of the future, when by the mid-1990s Prozac should have been seen as a far darker drug than Valium.

Valium entered a world in which psychiatry in many ways led medicine as it had done for almost a hundred years. Psychiatry was the first branch of medicine to have specialist hospitals and specialist journals. And Valium really did work remarkably well. Far from being simply a superficial treatment it likely led to the disappearance of catatonia and saved a lot of lives.

Valium probably did a lot to stimulate the Revolution of 1968. The conventional wisdom now is that Valium was Mother’s Little Helper and in this role that it played a part in the imprisonment of women in suburbia. In fact, Valium and other benzodiazepines undo conditioned avoidance. They were advertised initially as being among other things useful for salesmen – to overcome their inhibitions. They almost certainly disinhibited many women to speak out against patriarchy. They helped students breach the double-binds that Ronnie Laing and others in the 1960s were preaching were holding back society.

Prozac and the SSRIs in contrast far more often produce an apathy that is destructive to engagement in society as Who Cares in Sweden shows.  Prozac, Paxil, Zoloft, Efexor, Pristiq, and Cymbalta are far more likely to lead to suicide and murderous violence including school shootings than Valium ever did. And the SSRIs lead to just as many cases of dependence as the benzos ever did.

Tamiflu – PharMessiah?

Are we incapable of learning? Will we always be seduced by the latest PharMessiah?

The Antidepressant Era, the movie, contains an extraordinary comment on just this that no one could have foreseen when it was finished in 2001. It almost looks like the Scriptwriter in the Sky must have inserted the clip of Adolf Jahn telling us that if we don’t facilitate him and Roche society will collapse. We can only afford to keep our economy and society going if he and his company are let develop new drugs.

Well Roche got to develop Tamiflu. Where Valium was the headline drug in the 1980s for the problems a rampant pharmaceutical industry might pose, Tamiflu is now. Governments throughout the Western world stockpiled billions of dollars worth of Tamiflu on the promise that it would prevent the transmission of influenza and other viruses, and would either keep people in work or get them back to work faster, thus saving our economies huge amounts of money.

Except the drug now appears to be close to worthless and to have always been so. It seems that the impression that Tamiflu might help could only have been created because companies can hide the existence of many and in some cases most of their clinical trials and hide the data from all of them, ghostwriting the ones that are published in a manner that keeps all data out of the public domain.

Facilitate us too much and we will lead to your Downfall.

Connecticut school shooting… an antidepressant connection or not? We need to know the answer

Sadly it’s happened again. This time in an elementary school in Connecticut.

We need to understand the cause and we need to go beyond the usual US gun laws discussion…

I’ve said it before and I’ll say it again – I wonder if antidepressant medication is involved?

I’m not saying antidepressants are the cause, I’m asking for you to consider if an adverse reaction to  medication might be the catalyst for extreme, violent episodes in some patients

Why not check  medical records? Why not collect data? Why not ask the question?

Big pharma has done no research (that we know of, at least), but I know of one study and I’ve made mention of it in a previously, but given recent events in Connecticut, I think it’s worth bringing up once more.

Published on September 12, 2006, this study by David Healy, Andrew Herxheimer and David B. Menkes deals with an issue that cannot be ignored.

“Recent regulatory warnings about adverse behavioural effects of antidepressants in susceptible individuals have raised the profile of these issues with clinicians, patients, and the public. We review available clinical trial data on paroxetine and sertraline and pharmacovigilance studies of paroxetine and fluoxetine, and outline a series of medico-legal cases involving antidepressants and violence.

Both clinical trial and pharmacovigilance data point to possible links between these drugs and violent behaviours. The legal cases outlined returned a variety of verdicts that may in part have stemmed from different judicial processes. Many jurisdictions appear not to have considered the possibility that a prescription drug may induce violence.

The association of antidepressant treatment with aggression and violence reported here calls for more clinical trial and epidemiological data to be made available and for good clinical descriptions of the adverse outcomes of treatment”.

The link to the paper is here and I suggest you scroll down to the end and read the 9 cases listed in the annex.

Also worth a look is SSRI stories.

And there’s a video here, in which film maker Michael Moore discusses possible causes in another school shooting – Columbine.

Stephen Whitehead, ABPI – missing the point completely

I read this article in the New Statesman today and made me really quite annoyed…

It featured a letter written to the New Statesman by the CEO of the Association of the British Pharmaceutical Industry (ABPI), Stephen Whitehead, as a response to issues Ben Goldacre’s new book, Bad Pharma.

It’s amazing just how stupid a response it is – in fact I have to ask if Stephen has actually bothered to read the book at all or if the’s just gone into classic big Pharma knee jerk mode (after all, Stephen did spend 10 years of his career working at Glaxo and Eli Lily).

But no matter, as the New Statesman has printed Ben’s reply to the response.

However the comment I really found strange from Stephen Whitehead was this “…references to companies (GSK, Lilly, Pfizer) being fined are all examples from the US and simply not relevant to the UK market…”

GSK’s fine was, to remind you, the largest healthcare fraud settlement in history at $3bn.

How it isn’t relevant to the UK is beyond me – because what we’re talking about here is not just illegal marketing of drugs – not just bribing doctors to prescribe GSK products – what we’re talking about here are dead people.

Patients died because they were taking drugs that weren’t safe, drugs that weren’t even approved for their treatment.

In the case of Avandia, the drug is so dangerous that it can no longer be prescribed in Europe – it had to be withdrawn from the market because of high levels of heart attack, heart failure and stroke in patients. It had to be withdrawn from the market because it killed too many people.

How’s that “simply not relevant” to patients in the UK, Stephen?

Should we trust GlaxoSmithKline – and Andrew Witty…?

Trust GlaxoSmithKline?

Trust GSK? – you must be mad.

Sarah Boseley in The Guardian writes:

“The British drugs company GlaxoSmithKline is to open up the detailed data from its clinical trials to the scrutiny of scientists in a bid to help the discovery of new medicines and end the suspicions of critics that it has secrets to hide.

In a speech today [11 Oct] to the Wellcome Trust in London, the chief executive, Andrew Witty, will say openness to the public and active collaboration with scientists and firms outside GSK are essential to finding new drugs to treat the diseases plaguing the world, from novel antibiotics to cures for malaria and tuberculosis.

He told the Guardian GSK had already done much to advance transparency in clinical research, including publishing a summary of every drug trial – whether a success or not – on its website

Said Sir Mark Walport, director of the Wellcome Trust – “In its commitment towards more openness and collaboration, GSK is setting an example of how the pharmaceutical industry must adapt to help drive forward medical advances. Real breakthroughs do not come out of nowhere, but are borne of scientists sharing their knowledge and learning from each other. GSK’s moves are bold and innovative, a very positive sign of its commitment to tackle some of the greatest health challenges facing the world today.”

But hold on a minute – Dr Ben Goldacre’s not sure about GSK :

“But we should judge drug companies by their actions, not by their promises, especially when similar promises have been made in the past, and then broken.

In 1998 GlaxoWellcome promised to set up a clinical trials register, amidst outcry over withheld trial results. But when the company merged with SKB to create GSK, in 2002, this register was unceremonially deleted from the internet. This tragic story is described in an excellent open access article on this history of attempts to get access to hidden data, by Iain Chalmers.

Then, in 2003, GSK were caught withholding clinical trial data showing that their drug seroxat increases the risk of suicide in young people. As part of the settlement on fraud charges, in the US in 2004, GSK were forced to promise to post all trial results on a public website. But in 2012 GSK paid a new $3bn fine for criminal and civil fraud: this included charges over withholding data on the diabetes drug Avandia, as late as 2007, well after this earlier promise of transparency was made”.

That’s a pretty poor record, I’m sure you’ll agree.

As far as GSK is concerned, talk is cheap and promises are routinely broken with no compunction whatsoever.

 

The drugs don’t work: a modern medical scandal – by Dr Ben Goldacre

Here’s an extract from Ben Goldacre’s soon to be published (next week) latest book. To order a copy go to guardian.co.uk/bookshop or Amazon, of course. I’m very pleased that Ben has got to the same page as I’m on… he’s got a few more readers than me.

Ben’s website is here if you’d like to get to know him better.

Now read on…

The doctors prescribing the drugs don’t know they don’t do what they’re meant to. Nor do their patients. The manufacturers know full well, but they’re not telling. Drugs are tested by their manufacturers, in poorly designed trials, on hopelessly small numbers of weird, unrepresentative patients, and analysed using techniques that exaggerate the benefits.

Reboxetine is a drug I have prescribed. Other drugs had done nothing for my patient, so we wanted to try something new. I’d read the trial data before I wrote the prescription, and found only well-designed, fair tests, with overwhelmingly positive results. Reboxetine was better than a placebo, and as good as any other antidepressant in head-to-head comparisons. It’s approved for use by the Medicines and Healthcare products Regulatory Agency (the MHRA), which governs all drugs in the UK. Millions of doses are prescribed every year, around the world. Reboxetine was clearly a safe and effective treatment. The patient and I discussed the evidence briefly, and agreed it was the right treatment to try next. I signed a prescription.

But we had both been misled. In October 2010, a group of researchers was finally able to bring together all the data that had ever been collected on reboxetine, both from trials that were published and from those that had never appeared in academic papers. When all this trial data was put together, it produced a shocking picture. Seven trials had been conducted comparing reboxetine against a placebo. Only one, conducted in 254 patients, had a neat, positive result, and that one was published in an academic journal, for doctors and researchers to read. But six more trials were conducted, in almost 10 times as many patients. All of them showed that reboxetine was no better than a dummy sugar pill. None of these trials was published. I had no idea they existed.

It got worse. The trials comparing reboxetine against other drugs showed exactly the same picture: three small studies, 507 patients in total, showed that reboxetine was just as good as any other drug. They were all published. But 1,657 patients’ worth of data was left unpublished, and this unpublished data showed that patients on reboxetine did worse than those on other drugs. If all this wasn’t bad enough, there was also the side-effects data. The drug looked fine in the trials that appeared in the academic literature; but when we saw the unpublished studies, it turned out that patients were more likely to have side-effects, more likely to drop out of taking the drug and more likely to withdraw from the trial because of side-effects, if they were taking reboxetine rather than one of its competitors.

I did everything a doctor is supposed to do. I read all the papers, I critically appraised them, I understood them, I discussed them with the patient and we made a decision together, based on the evidence. In the published data, reboxetine was a safe and effective drug. In reality, it was no better than a sugar pill and, worse, it does more harm than good. As a doctor, I did something that, on the balance of all the evidence, harmed my patient, simply because unflattering data was left unpublished.

Nobody broke any law in that situation, reboxetine is still on the market and the system that allowed all this to happen is still in play, for all drugs, in all countries in the world. Negative data goes missing, for all treatments, in all areas of science. The regulators and professional bodies we would reasonably expect to stamp out such practices have failed us. These problems have been protected from public scrutiny because they’re too complex to capture in a soundbite. This is why they’ve gone unfixed by politicians, at least to some extent; but it’s also why it takes detail to explain. The people you should have been able to trust to fix these problems have failed you, and because you have to understand a problem properly in order to fix it, there are some things you need to know.

Drugs are tested by the people who manufacture them, in poorly designed trials, on hopelessly small numbers of weird, unrepresentative patients, and analysed using techniques that are flawed by design, in such a way that they exaggerate the benefits of treatments. Unsurprisingly, these trials tend to produce results that favour the manufacturer. When trials throw up results that companies don’t like, they are perfectly entitled to hide them from doctors and patients, so we only ever see a distorted picture of any drug’s true effects. Regulators see most of the trial data, but only from early on in a drug’s life, and even then they don’t give this data to doctors or patients, or even to other parts of government. This distorted evidence is then communicated and applied in a distorted fashion.

In their 40 years of practice after leaving medical school, doctors hear about what works ad hoc, from sales reps, colleagues and journals. But those colleagues can be in the pay of drug companies – often undisclosed – and the journals are, too. And so are the patient groups. And finally, academic papers, which everyone thinks of as objective, are often covertly planned and written by people who work directly for the companies, without disclosure. Sometimes whole academic journals are owned outright by one drug company. Aside from all this, for several of the most important and enduring problems in medicine, we have no idea what the best treatment is, because it’s not in anyone’s financial interest to conduct any trials at all.

Now, on to the details.

In 2010, researchers from Harvard and Toronto found all the trials looking at five major classes of drug – antidepressants, ulcer drugs and so on – then measured two key features: were they positive, and were they funded by industry? They found more than 500 trials in total: 85% of the industry-funded studies were positive, but only 50% of the government-funded trials were. In 2007, researchers looked at every published trial that set out to explore the benefits of a statin. These cholesterol-lowering drugs reduce your risk of having a heart attack and are prescribed in very large quantities. This study found 192 trials in total, either comparing one statin against another, or comparing a statin against a different kind of treatment. They found that industry-funded trials were 20 times more likely to give results favouring the test drug.

These are frightening results, but they come from individual studies. So let’s consider systematic reviews into this area. In 2003, two were published. They took all the studies ever published that looked at whether industry funding is associated with pro-industry results, and both found that industry-funded trials were, overall, about four times more likely to report positive results. A further review in 2007 looked at the new studies in the intervening four years: it found 20 more pieces of work, and all but two showed that industry-sponsored trials were more likely to report flattering results.

It turns out that this pattern persists even when you move away from published academic papers and look instead at trial reports from academic conferences. James Fries and Eswar Krishnan, at the Stanford University School of Medicine in California, studied all the research abstracts presented at the 2001 American College of Rheumatology meetings which reported any kind of trial and acknowledged industry sponsorship, in order to find out what proportion had results that favoured the sponsor’s drug.

In general, the results section of an academic paper is extensive: the raw numbers are given for each outcome, and for each possible causal factor, but not just as raw figures. The “ranges” are given, subgroups are explored, statistical tests conducted, and each detail is described in table form, and in shorter narrative form in the text. This lengthy process is usually spread over several pages. In Fries and Krishnan (2004), this level of detail was unnecessary. The results section is a single, simple and – I like to imagine – fairly passive-aggressive sentence:

“The results from every randomised controlled trial (45 out of 45) favoured the drug of the sponsor.”

How does this happen? How do industry-sponsored trials almost always manage to get a positive result? Sometimes trials are flawed by design. You can compare your new drug with something you know to be rubbish – an existing drug at an inadequate dose, perhaps, or a placebo sugar pill that does almost nothing. You can choose your patients very carefully, so they are more likely to get better on your treatment. You can peek at the results halfway through, and stop your trial early if they look good. But after all these methodological quirks comes one very simple insult to the integrity of the data. Sometimes, drug companies conduct lots of trials, and when they see that the results are unflattering, they simply fail to publish them.

Because researchers are free to bury any result they please, patients are exposed to harm on a staggering scale throughout the whole of medicine. Doctors can have no idea about the true effects of the treatments they give. Does this drug really work best, or have I simply been deprived of half the data? No one can tell. Is this expensive drug worth the money, or has the data simply been massaged? No one can tell. Will this drug kill patients? Is there any evidence that it’s dangerous? No one can tell. This is a bizarre situation to arise in medicine, a discipline in which everything is supposed to be based on evidence.

And this data is withheld from everyone in medicine, from top to bottom. Nice, for example, is the National Institute for Health and Clinical Excellence, created by the British government to conduct careful, unbiased summaries of all the evidence on new treatments. It is unable either to identify or to access data on a drug’s effectiveness that’s been withheld by researchers or companies: Nice has no more legal right to that data than you or I do, even though it is making decisions about effectiveness, and cost-effectiveness, on behalf of the NHS, for millions of people.

In any sensible world, when researchers are conducting trials on a new tablet for a drug company, for example, we’d expect universal contracts, making it clear that all researchers are obliged to publish their results, and that industry sponsors – which have a huge interest in positive results – must have no control over the data. But, despite everything we know about industry-funded research being systematically biased, this does not happen. In fact, the opposite is true: it is entirely normal for researchers and academics conducting industry-funded trials to sign contracts subjecting them to gagging clauses that forbid them to publish, discuss or analyse data from their trials without the permission of the funder.

This is such a secretive and shameful situation that even trying to document it in public can be a fraught business. In 2006, a paper was published in the Journal of the American Medical Association (Jama), one of the biggest medical journals in the world, describing how common it was for researchers doing industry-funded trials to have these kinds of constraints placed on their right to publish the results. The study was conducted by the Nordic Cochrane Centre and it looked at all the trials given approval to go ahead in Copenhagen and Frederiksberg. (If you’re wondering why these two cities were chosen, it was simply a matter of practicality: the researchers applied elsewhere without success, and were specifically refused access to data in the UK.) These trials were overwhelmingly sponsored by the pharmaceutical industry (98%) and the rules governing the management of the results tell a story that walks the now familiar line between frightening and absurd.

For 16 of the 44 trials, the sponsoring company got to see the data as it accumulated, and in a further 16 it had the right to stop the trial at any time, for any reason. This means that a company can see if a trial is going against it, and can interfere as it progresses, distorting the results. Even if the study was allowed to finish, the data could still be suppressed: there were constraints on publication rights in 40 of the 44 trials, and in half of them the contracts specifically stated that the sponsor either owned the data outright (what about the patients, you might say?), or needed to approve the final publication, or both. None of these restrictions was mentioned in any of the published papers.

When the paper describing this situation was published in Jama, Lif, the Danish pharmaceutical industry association, responded by announcing, in the Journal of the Danish Medical Association, that it was “both shaken and enraged about the criticism, that could not be recognised”. It demanded an investigation of the scientists, though it failed to say by whom or of what. Lif then wrote to the Danish Committee on Scientific Dishonesty, accusing the Cochrane researchers of scientific misconduct. We can’t see the letter, but the researchers say the allegations were extremely serious – they were accused of deliberately distorting the data – but vague, and without documents or evidence to back them up.

Nonetheless, the investigation went on for a year. Peter Gøtzsche, director of the Cochrane Centre, told the British Medical Journal that only Lif’s third letter, 10 months into this process, made specific allegations that could be investigated by the committee. Two months after that, the charges were dismissed. The Cochrane researchers had done nothing wrong. But before they were cleared, Lif copied the letters alleging scientific dishonesty to the hospital where four of them worked, and to the management organisation running that hospital, and sent similar letters to the Danish medical association, the ministry of health, the ministry of science and so on. Gøtzsche and his colleagues felt “intimidated and harassed” by Lif’s behaviour. Lif continued to insist that the researchers were guilty of misconduct even after the investigation was completed.

Paroxetine is a commonly used antidepressant, from the class of drugs known as selective serotonin reuptake inhibitors or SSRIs. It’s also a good example of how companies have exploited our long-standing permissiveness about missing trials, and found loopholes in our inadequate regulations on trial disclosure.

To understand why, we first need to go through a quirk of the licensing process. Drugs do not simply come on to the market for use in all medical conditions: for any specific use of any drug, in any specific disease, you need a separate marketing authorisation. So a drug might be licensed to treat ovarian cancer, for example, but not breast cancer. That doesn’t mean the drug doesn’t work in breast cancer. There might well be some evidence that it’s great for treating that disease, too, but maybe the company hasn’t gone to the trouble and expense of getting a formal marketing authorisation for that specific use. Doctors can still go ahead and prescribe it for breast cancer, if they want, because the drug is available for prescription, it probably works, and there are boxes of it sitting in pharmacies waiting to go out. In this situation, the doctor will be prescribing the drug legally, but “off-label”.

Now, it turns out that the use of a drug in children is treated as a separate marketing authorisation from its use in adults. This makes sense in many cases, because children can respond to drugs in very different ways and so research needs to be done in children separately. But getting a licence for a specific use is an arduous business, requiring lots of paperwork and some specific studies. Often, this will be so expensive that companies will not bother to get a licence specifically to market a drug for use in children, because that market is usually much smaller.

So it is not unusual for a drug to be licensed for use in adults but then prescribed for children. Regulators have recognised that this is a problem, so recently they have started to offer incentives for companies to conduct more research and formally seek these licences.

When GlaxoSmithKline applied for a marketing authorisation in children for paroxetine, an extraordinary situation came to light, triggering the longest investigation in the history of UK drugs regulation. Between 1994 and 2002, GSK conducted nine trials of paroxetine in children. The first two failed to show any benefit, but the company made no attempt to inform anyone of this by changing the “drug label” that is sent to all doctors and patients. In fact, after these trials were completed, an internal company management document stated: “It would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine.” In the year after this secret internal memo, 32,000 prescriptions were issued to children for paroxetine in the UK alone: so, while the company knew the drug didn’t work in children, it was in no hurry to tell doctors that, despite knowing that large numbers of children were taking it. More trials were conducted over the coming years – nine in total – and none showed that the drug was effective at treating depression in children.

It gets much worse than that. These children weren’t simply receiving a drug that the company knew to be ineffective for them; they were also being exposed to side-effects. This should be self-evident, since any effective treatment will have some side-effects, and doctors factor this in, alongside the benefits (which in this case were nonexistent). But nobody knew how bad these side-effects were, because the company didn’t tell doctors, or patients, or even the regulator about the worrying safety data from its trials. This was because of a loophole: you have to tell the regulator only about side-effects reported in studies looking at the specific uses for which the drug has a marketing authorisation. Because the use of paroxetine in children was “off-label”, GSK had no legal obligation to tell anyone about what it had found.

People had worried for a long time that paroxetine might increase the risk of suicide, though that is quite a difficult side-effect to detect in an antidepressant. In February 2003, GSK spontaneously sent the MHRA a package of information on the risk of suicide on paroxetine, containing some analyses done in 2002 from adverse-event data in trials the company had held, going back a decade. This analysis showed that there was no increased risk of suicide. But it was misleading: although it was unclear at the time, data from trials in children had been mixed in with data from trials in adults, which had vastly greater numbers of participants. As a result, any sign of increased suicide risk among children on paroxetine had been completely diluted away.

Later in 2003, GSK had a meeting with the MHRA to discuss another issue involving paroxetine. At the end of this meeting, the GSK representatives gave out a briefing document, explaining that the company was planning to apply later that year for a specific marketing authorisation to use paroxetine in children. They mentioned, while handing out the document, that the MHRA might wish to bear in mind a safety concern the company had noted: an increased risk of suicide among children with depression who received paroxetine, compared with those on dummy placebo pills.

This was vitally important side-effect data, being presented, after an astonishing delay, casually, through an entirely inappropriate and unofficial channel. Although the data was given to completely the wrong team, the MHRA staff present at this meeting had the wit to spot that this was an important new problem. A flurry of activity followed: analyses were done, and within one month a letter was sent to all doctors advising them not to prescribe paroxetine to patients under the age of 18.

How is it possible that our systems for getting data from companies are so poor, they can simply withhold vitally important information showing that a drug is not only ineffective, but actively dangerous? Because the regulations contain ridiculous loopholes, and it’s dismal to see how GSK cheerfully exploited them: when the investigation was published in 2008, it concluded that what the company had done – withholding important data about safety and effectiveness that doctors and patients clearly needed to see – was plainly unethical, and put children around the world at risk; but our laws are so weak that GSK could not be charged with any crime.

After this episode, the MHRA and EU changed some of their regulations, though not adequately. They created an obligation for companies to hand over safety data for uses of a drug outside its marketing authorisation; but ridiculously, for example, trials conducted outside the EU were still exempt. Some of the trials GSK conducted were published in part, but that is obviously not enough: we already know that if we see only a biased sample of the data, we are misled. But we also need all the data for the more simple reason that we need lots of data: safety signals are often weak, subtle and difficult to detect. In the case of paroxetine, the dangers became apparent only when the adverse events from all of the trials were pooled and analysed together.

That leads us to the second obvious flaw in the current system: the results of these trials are given in secret to the regulator, which then sits and quietly makes a decision. This is the opposite of science, which is reliable only because everyone shows their working, explains how they know that something is effective or safe, shares their methods and results, and allows others to decide if they agree with the way in which the data was processed and analysed. Yet for the safety and efficacy of drugs, we allow it to happen behind closed doors, because drug companies have decided that they want to share their trial results discretely with the regulators. So the most important job in evidence-based medicine is carried out alone and in secret. And regulators are not infallible, as we shall see.

Rosiglitazone was first marketed in 1999. In that first year, Dr John Buse from the University of North Carolina discussed an increased risk of heart problems at a pair of academic meetings. The drug’s manufacturer, GSK, made direct contact in an attempt to silence him, then moved on to his head of department. Buse felt pressured to sign various legal documents. To cut a long story short, after wading through documents for several months, in 2007 the US Senate committee on finance released a report describing the treatment of Buse as “intimidation”.

But we are more concerned with the safety and efficacy data. In 2003 the Uppsala drug monitoring group of the World Health Organisation contacted GSK about an unusually large number of spontaneous reports associating rosiglitazone with heart problems. GSK conducted two internal meta-analyses of its own data on this, in 2005 and 2006. These showed that the risk was real, but although both GSK and the FDA had these results, neither made any public statement about them, and they were not published until 2008.

During this delay, vast numbers of patients were exposed to the drug, but doctors and patients learned about this serious problem only in 2007, when cardiologist Professor Steve Nissen and colleagues published a landmark meta-analysis. This showed a 43% increase in the risk of heart problems in patients on rosiglitazone. Since people with diabetes are already at increased risk of heart problems, and the whole point of treating diabetes is to reduce this risk, that finding was big potatoes. Nissen’s findings were confirmed in later work, and in 2010 the drug was either taken off the market or restricted, all around the world.

Now, my argument is not that this drug should have been banned sooner because, as perverse as it sounds, doctors do often need inferior drugs for use as a last resort. For example, a patient may develop idiosyncratic side-effects on the most effective pills and be unable to take them any longer. Once this has happened, it may be worth trying a less effective drug if it is at least better than nothing.

The concern is that these discussions happened with the data locked behind closed doors, visible only to regulators. In fact, Nissen’s analysis could only be done at all because of a very unusual court judgment. In 2004, when GSK was caught out withholding data showing evidence of serious side-effects from paroxetine in children, their bad behaviour resulted in a US court case over allegations of fraud, the settlement of which, alongside a significant payout, required GSK to commit to posting clinical trial results on a public website.

Nissen used the rosiglitazone data, when it became available, and found worrying signs of harm, which they then published to doctors – something the regulators had never done, despite having the information years earlier. If this information had all been freely available from the start, regulators might have felt a little more anxious about their decisions but, crucially, doctors and patients could have disagreed with them and made informed choices. This is why we need wider access to all trial reports, for all medicines.

Missing data poisons the well for everybody. If proper trials are never done, if trials with negative results are withheld, then we simply cannot know the true effects of the treatments we use. Evidence in medicine is not an abstract academic preoccupation. When we are fed bad data, we make the wrong decisions, inflicting unnecessary pain and suffering, and death, on people just like us.

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