The drug industry
"Pick your
pill out of a hat!"
Sep
29th 2012 The Economist
They might do you some good, with
luck
"Bad
Pharma." By Ben Goldacre. Fourth Estate; 430 pages;
£13.99. Also available as a Kindle book £8.99
DOCTORS like to project an air of authority when making their clinical decisions. Patients like it too, for it is reassuring to think that one’s health is in the hands of an expert. It would be unsettling if, upon prescribing you a drug, your doctor admitted that the scientific research about what exactly the drug did, and how effective it was at doing it, was patchy and distorted, sometimes to the point where nobody has any real idea of what effects the drugs they are prescribing are likely to have on their patients.
But
that is the reality described in “Bad Pharma”, Ben Goldacre’s new book. A
British doctor and science writer, he made his name in 2008 with “Bad Science”,
in which he filleted the credulous coverage given in the popular press to the
claims of homeopaths, reiki therapists, Hopi ear-candlers and other purveyors
of ceremonious placebos. Now he has taken aim at a much bigger and more
important target: the $600-billion pharmaceutical industry that develops and
produces the drugs prescribed by real doctors the world over.
The book is slightly technical, eminently readable, consistently shocking, occasionally hectoring and unapologetically polemical. “Medicine is broken,” it declares on its first page, and “the people you should have been able to trust to fix [its] problems have failed you.” Dr Goldacre describes the routine corruption of what is supposed to be an objective scientific process designed to assess whether new drugs work, whether they are better than drugs already on the market and whether their side effects are a price worth paying for any benefits they might convey. The result is that doctors, and the patients they treat, are hobbled by needless ignorance.
So, for instance, pharmaceutical companies bury clinical trials which show bad results for a drug and publish only those that show a benefit. The trials are often run on small numbers of unrepresentative patients, and the statistical analyses are massaged to give as rosy a picture as possible. Entire clinical trials are run not as trials at all, but as under-the-counter advertising campaigns designed to persuade doctors to prescribe a company’s drug.
The bad behaviour extends far beyond the industry itself. Drug regulators, who do get access to some of the hidden results, often guard them jealously, even from academic researchers, seeming to serve the interests of the firms whose products they are supposed to police. Medical journals frequently fail to perform basic checks on the papers they print, so all sorts of sharp practice goes uncorrected. Many published studies are not written by the academics whose names they bear, but by commercial ghostwriters paid by drug firms. Doctors are bombarded with advertising encouraging them to prescribe certain drugs.
The danger with a book like this is that it ends up lost in abstract discussion of difficult subjects. But Dr Goldacre illustrates his points with a plethora of real-world stories and examples. Some seem almost too breathtaking to be true—but every claim is referenced and backed up by links to research and primary documents. In scenes that could have come straight from a spy farce, the French journal Prescrire applied to Europe’s drug regulator for information on the diet drug rimonabant. The regulator sent back 68 pages in which virtually every sentence was blacked out.
And of course, the upshot of all this is anything but abstract: doctors are left ignorant about the drugs they are prescribing, and which will make their patients sick or get well, or even live or die. Statins, for instance, lower the risk of heart attacks, and are prescribed to millions of adults all over the world. But there are several different sorts of statin. Because there is little commercial advantage to be gained by comparing the efficacy of the different varieties, no studies have done so in a useful way.
Bereft of guidance, doctors must therefore prescribe specific statins on the basis of little more than hunches or personal prejudice. As Dr Goldacre points out, if one drug is even a shade more effective than its competitors, then thousands of people prescribed the inferior ones are dying needlessly every year for want of a bit of simple research. That is a scandal. Worse, the bias and distortions that brought it about are repeated across the entire medical industry. This is a book that deserves to be widely read, because anyone who does read it cannot help feeling both uncomfortable and angry.
+ OBSERVER INTERVIEW - 7-10-12.
Ben Goldacre: 'The world would be a better place if
doctors were less enthusiastic about adopting very new drugs.' Photograph:
Linda Nylind for the Guardian
The
blindingly obvious inference of the extract from your book
published in the Guardian– as of so many others you once commendably
wrote in your Bad Science column – is
that this is an industry totally unsuited to being run on profit-maximising
lines by conventional shareholder companies. Given that, and the tremendous
level of subsidy the industry already receives from governments around the
world, why not spell out the vital necessity of locating it within publicly
owned/non-profit organisations where there need be no obstacle to full
transparency?
Harry
Shutt, via email
I
am a realist about this. I don't want a central-command state economy. In
general, drug companies are reasonably good at developing new treatments and
there's also a lot of good in the industry. The point of my book is that it's
possible for good people in badly designed systems to perpetrate acts of great
evil completely unthinkingly. I don't think any of the people I write about
would punch an old lady in the face, but they would inflict the same level of
harm when they are abstracted away from the outcomes of their actions.
This
is made easier, I think, because in general, most drugs
do work better than nothing: it's just that we may be misled into using, for
example, an expensive new drug where an older, cheaper one is more effective.
Overall,
the problem is we don't have a competent regulatory framework that prevents
things from going horribly wrong. If companies are allowed to hide the results
of clinical trials then they will, and that will distort clinical practice. Doctors
and patients will be misled and make sub-optimal decisions about what treatment
is best for them.
Similarly,
if you can get on to the market by making a me-too copycat drug that represents
little or no therapeutic advance and is even less effective than the drugs that
it copies, then you will. And you can get such a drug to the market because
regulators approve new treatments even when they've only been shown only to be
better than placebo…
The
Observer: Rather than the best current treatment available?
Exactly.
When that happens, then there's less drive to innovate new medicines. So a lot
of people think they know how you test a new drug, they think it's a
placebo-controlled randomised trial, and that's kind of true. However, for most
situations we already have some kind of treatment, so we're not interested in
whether your treatment is better than nothing; we're interested in whether it's
better than what we're already using. But you can get on to the market without
ever comparing your drug against the best currently available treatment, and
then you can bamboozle doctors and patients into using it by distorting the
clinical evidence with all the tricks I describe, and then by giving a biased
picture of that distorted evidence to doctors and patients through your
marketing activity. All of that means, crucially, you can turn a profit by
producing drugs that aren't very innovative.
So
at the moment our regulatory frameworks do not represent a good set of
incentives for innovation. When people say, "Oh my God, it's dreadful all
these companies have had to pull out of developing new drugs for
Alzheimer's", on the one hand Alzheimer's is a very difficult problem, on
the other hand we haven't created a regulatory framework that sufficiently
incentivises people to take serious risks, and research entirely new
treatments.
I
have been in healthcare marketing communications for more than 30 years
(flogging drugs to doctors) and can confirm that much of the sharp practice you
describe is caused by the pressure exerted on researchers by marketing
departments. When a new drug entity makes it through Phase I, the pharmaceutical
company's marketers carry out market research studies to find out what doctors
expect and desire from such a product. The results of these studies are used to
develop "guidance" for researchers designing Phase II and III trials.
One issue is the speed with which some doctors ("innovators" in
marketing speak) adopt new medicines. There is a drug surveillance system in
this country that requires doctors to report all adverse events occurring in
patients taking new drugs. So if doctors were a little less enthusiastic and
prescribed new products to no more than a couple of patients at first, most
problems would come to light before large numbers were affected.
arghbee,
via web
I
agree, the world would be a better place if doctors were less enthusiastic about
adopting very new drugs. When I was taught how to prescribe by my clinical
pharmacology professors, as an undergraduate in medicine, we were told: don't
prescribe new drugs unless they are spectacularly superior to what you already
have; let other doctors take the chance. And that's what I teach students
myself. Regard the whole of the rest of humanity as unpaid stunt doubles.
Because, when you prescribe a new drug, often you are prescribing something
that has only been tested in a few thousand people for a very short period of
time, perhaps only six months, and that's not long enough to know whether there
are any medium- or long-term side-effects. It's also too few recipients of the
drug to find out about rarer side-effects. On top of that, when drugs come to
market they've only often been shown to be effective on short-term outcomes,
and on surrogate outcomes, weak outcomes, theoretical outcomes. So a new drug
might have shown to affect a blood test result, which we hope is theoretically
associated with a real-world outcome, but not tested against real-world
outcomes such as pain, suffering and death. On top of that, while doctors and
patients sometimes fetishise the new, the evidence is that overall, new drugs
are often no better than the older ones they replace.
If
there is time for shared decision making, when we're prescribing a new drug,
then I think first doctors could maybe say to their patients: "The drug
I'm prescribing has only been tested in a few thousand people for less than six
months, and it's only been shown to improve blood tests, not the real outcomes
in your disease. If you prefer, we also have a tablet that has been around for
10 years, has been taken by millions of people, and that we know has a positive
impact on real-world long-term outcomes – which would you prefer?" Because
I think these are reasonable issues to factor in, when you're making a
treatment decision.
Obs:
And the point about marketing departments influencing trials?
This
is a really interesting area and it's a good illustration of how there is good
and bad in current marketing practices. I think it's really good that somebody
out there listens to what doctors and patients want and need, in order to try
to address those needs. There's a scandalously brief and interesting history of
research on this question in academia. It was only very recently that people
went out and formally asked patients: "What's the most important outcome
to you?" The classic study was one in a rheumatology outpatients' clinic –
they said: "What kind of trials do you think need to be done?" And
the patients said: "We don't think you need any more trials comparing one
pill against another, we want trials to tell us if physiotherapy improves
outcomes, because doing physio is a massive drag and requires a lot of effort
from us." The other thing they said, to everybody's complete astonishment,
was: "We don't think that pain is the most important symptom, it's
actually stiffness." And that amazed everyone. So good quality,
systematic, mixed methods, qualitative and quantitative research, to find out
this sort of stuff is really great and important.
Obs:
Are pharma marketing departments doing that?
Well,
they're probably doing some and a mix of other stuff. The real problems come
when you look at the interplay between market research and the whole process of
publication planning, which is something that many doctors and academics are
completely unaware of. Certainly, I think, the public have very little
knowledge of it. We all like to imagine that the academic literature is
composed of worthy papers by independent academics exploring things on the
basis of interest. We don't, for the most part, realise that there is often a
hidden hand guiding this process. So when a new drug is being brought to
market, especially one that addresses a problem that hasn't been addressed
before, you will often get an elaborate sequence of covertly planned marketing
activity in the academic literature, without any declaration that this is
what's happening.
For
example, companies will set about paying for and planning, and in some cases
ghostwriting, papers saying that the disease their new drug treats is an
underdiagnosed problem, it's much more prevalent than we thought. You might
also start to produce lots of literature about how current interventions aren't
very good, downplay your own side effects, promote off-label uses of your drug,
and so on. That's all before you get anywhere stage-managing the literature
about the actual benefits of your treatments.
So
the interplay between marketing departments and research departments, I think,
is inevitable. It's a mixture of good and bad, but the thing that's most
striking is how ignorant most people are about these things, and how huffy and
upset drug companies get when you start to talk about it. If people really
think it's OK to have commercial medical writers writing papers instead of
academics, then they should put their names clearly and proudly at the top of
the papers. If people really think it's OK to stage-manage the whole programme
of academic journal articles behind the scenes up to the launch of your drug,
they should just mention that in the papers at the bottom: "This is part
of the programme leading up to the launching of drug X. The idea for this paper
came from the marketing department at Y." If they think all this activity
is OK, then that's fine: they should be happy to declare that publicly, and we
can decide for ourselves.
In
your book you appear to be describing situations where companies knowingly
suppress information that shows the products they are selling are ineffective
or worse. My doctorate is in engineering and if we had done that we would have
been liable to a prosecution for fraud. This is quite irrespective of the
regulations pertaining to a specific industry, though we were required to
report any significant deviation to the regulator as soon as we were aware of
it. So, quite simply, why are these pharmaceutical companies not being
prosecuted?
Joseph
Cullen, via email
Well,
it's a huge cultural blind spot. No one, with the exception of the Faculty of
Pharmaceutical Medicine, which is a very small organisation, not one of the
medical and academic bodies have stood up and said: "Selectively
withholding unflattering trial data is research misconduct, and the ultimate end
product is a biased picture of the effectiveness of your intervention."
If
I deleted half the data points in one study to make my treatment look better
than it really is, everybody would say that was research misconduct. But for
some reason when I delete half of the trials from my clinical trials programme
and only publish half of them, that is not regarded as research misconduct.
It's
a cultural blind spot that comes about, I think, because the misconduct arises
from a slightly diffused network of failure. So in some cases there will be
obsessive, evil people at the centre, with full panoramic knowledge of
everything that's happening, stage managing it. In other cases, you'll have
individuals in organisations, maybe quite junior, they've got a trial with a
negative result, nobody's enthusiastic about putting it out there, and to that
one researcher, not publishing a paper intuitively doesn't feel the same as
deleting some data points in a study, even if the end product is the same, in
terms of the impact on doctors' and patients' knowledge of the risks and
benefits.
That's
why I think it's really disappointing that nobody, not the Royal Colleges, the
Academy of Medical Sciences, the British Pharmacology Society, the British
Medical Association, none of these organisations have stood up and said:
selective non-publication of unflattering trial data is research misconduct,
and if you do it you will be booted out. And I think they really urgently
should.
I
have to say, for a lot of the things I cover in the book, I honestly believe
this stuff has been protected from public scrutiny for many years by a wall of
tedium, or if you like, by a wall of modest scientific complexity. It's behind
closed doors but not locked doors, it's all hiding in plain sight. I think it's
very likely that this will turn out to be like MPs' expenses or phone hacking
journalists. The people involved in these small communities have all convinced
one another that what they do is completely normal and fine. But it's not. I
think that when the public come to see what has been going on, they might be
appalled.
I
work for an institutional shareholder of many large pharmaceutical companies.
Do you think there are any pharmaceutical companies that stand out in terms of
transparency of trial results? And at the other end of the scale, are there any
companies that consistently fail to publish negative trials?
Laura
Foll, analyst, Henderson Global Investors
No.
I have no reason to believe that any one is any better than the other. If you
have bad regulations, incoherently enforced, then everybody does what they have
to do, to succeed in the marketplace.
Considering
we have to discuss and explain population-based risk to the
individual we are treating, and the way we discuss risk biases the response,
how do you discuss risk in simple terms, for example, in primary prevention?
Tariq
Hussain, GP
This
is an amazingly interesting area, and I think it is the next horizon in
medicine. If you put me in charge of the medical research budget I would cancel
all primary research, I would cancel all new trials, for just one year, and I
would spend the money exclusively on making sure that we make the best possible
use of the clinical evidence that we already have. This means first devising
better ways of communicating risk to patients, and engaging in a process of
shared decision-making wherever appropriate. Second, I would put the money into
a better information architecture for evidence-based medicine. I would put the
money into researching and implementing better systems to get the right
information to the right doctor at the right time, to collate and then to
disseminate the information that we have.
Obs:
We had quite a few questions from readers who, faced with difficult decisions
about changing drugs or trying a new drug, were reading trials and studies
themselves…
That's
a real mistake, actually. As I say in the book, I don't think it's a good
idea for individuals to try to pick and choose their drugs, or stop their
drugs. I think it's a very dangerous business. I don't say that because I want
to protect any special status in the medical profession, I just think it takes
a really long time to acquire the skills and knowledge to do that. People often
say: "What do I do for me? For my treatment decision right here and
now?" And the best advice I can ever give is to find a good doctor and
talk to them about it, and anybody who tells you that they can give good advice
about your medical problems in a newspaper article, or on the internet, or
in some silly magazine, should be regarded with infinite suspicion, no matter
how big a bouffant or how deep a perma-tan they have – I'm not thinking of
anyone in particular, I don't really know that scene. I don't do readers'
health advice and I think these things are best discussed with your doctor.
Patients
often resort to saying: "Doctor, if it were you, what would you do?"
Or "If it were your child…?"
I
think that's a reasonable question to ask. Often decision making is a
complicated business, weighing lots of risks and benefits against one another,
often it can't be operationalised. But I think the important thing is that
doctors have all of the information that they need in order to make informed
decisions. First, because it's not hidden from them, and second because it is
competently disseminated to them, and patients should have the choice to engage
with that, but there's nothing compulsory about it. I think data on how good
your local school is should be available to you, but equally I recognise that
the overwhelming majority of parents never look at it, and that's normal. I
wouldn't judge them. I just think the information needs to be available.
