The Guardian, Ben Goldacre, Friday 21 September 2012
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| 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. Photograph: Photograph: Getty Images. Digital manipulation: Phil Partridge for GNL Imaging |
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.
 |
Bad Pharma: How drug companies
mislead doctors and harm patients
by Ben Goldacre
|
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1,657 patients' worth of data was left unpublished, and this unpublished data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.
This is
an edited extract from Bad Pharma, by Ben Goldacre, published next week by
Fourth Estate at £13.99. To order a copy for £11.19, including UK mainland
p&p, call 0330 333 6846, or go to guardian.co.uk/bookshop.
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