The pharma industry has its fair share of critics, but unfortunately for everybody, many are easy to dismiss - shrill, ill-informed campaigners who sometimes bear a grudge or border on being conspiracy theorists.This is unfortunate because an industry as important as pharma needs articulate, rational, and reasoned criticism to keep it on its toes - and to bring about change when it is needed.
Happily, Dr Ben Goldacre fits this description, and frequently highlights serious concerns about the industry’s practices in his Bad Science website, book and weekly columns in The Guardian newspaper.
But Goldacre doesn’t just target pharma, of course - his columns skewer any organisation or individual guilty of peddling dodgy data and bad science - from mumbo jumbo nutritionists; ignorant and scaremongering media; to alternative medicine exponents or even the Catholic church.
A trained doctor and currently a research fellow at the London School of Hygiene and Tropical Medicine, Goldacre frequently gives free lectures to medical students on evidence based medicine, the use of statistics, and the tricks used by the pharma industry.
On a Friday night in September, Goldacre is giving his talk to the wider public as part of the British Festival of Science in Birmingham.
Not prone to hyperbole, Goldacre nevertheless says that he believes concealment of negative data, and the failure of regulators in cases such as Seroxat, Vioxx and Avandia is “the single biggest political scandal of modern times”. Goldacre has decided to make the pharma industry the sole focus of his talk tonight, and engages his audience with an impassioned argument - careful not to be too angry, Goldacre aims to inform and explain, and uses humour to illustrate his point.
He says pharma industry disease mongering has reached ridiculous heights when an antidepressant pill to treat dogs for ‘separation anxiety’ is on the market.
“It’s called Clomicalm. That’s an industry in trouble,” he tells his audience.
Is Big Pharma really evil?Speaking to him before he goes on stage, I put it to him that his description of the pharmaceutical industry as ‘evil’ perhaps doesn’t do the situation justice.
“No, obviously ‘evil’ is an over-simplification and an over-dramatisation - there is no medicine without medicines,” he says. “They have invented countless brilliant molecules and they fund the overwhelming majority of trials, because the individual states choose not to. They make an enormous contribution.”
He adds that the blame must lie first with regulatory failure, secondary at carelessness, and lastly something which follows from regulatory failure, ‘perverse incentives’.
“If your incentive is to make money, and the regulations don’t actively prevent you from doing one thing which would help you do that, big organisations can parcel up jobs so that each individual person feels they are doing the right thing, then obviously no individual agent in this system is evil. But overall, the way drug development and research is organised means we get a very distorted and error-ridden picture.
“I don’t think it has to be like that - it could be fixed very easily with good will from the industry, adequate regulation and lastly more of the public being aware of a few more of the details of what’s wrong with the way the pharmaceutical industry is operating at the moment.
“There is no doubt their stock is really low, everybody thinks they are really dodgy. But because most people don’t understand the specifics of why the industry is dodgy, that leads to these bizarre non-sequiturs - the pharmaceutical industry is evil, therefore MMR causes autism, and therefore homeopathy cures cancer.”
However when I say that the picture must be a bit more complicated than ‘pharma is evil’ Goldacre flashes back: “Hang on, let’s not get too far away from this - there are many individual instances where I would say that bad people did bad things - such as GSK withholding from the MHRA the fact that paroxetine (Seroxat) not only didn’t work in children, but also had these adverse side effects.
“They withheld that information from the MHRA because strictly speaking, by the absolute letter of the law, they weren’t obliged to give it to them because it wasn’t a licensed indication. And in reality we know that nearly all paediatric licensing is off label licensing.
“I think withholding that information - if you were to ask me whether that was evil or not evil - well, I would say that is really bad.”
Goldacre tells his audience: “To me, a regulatory hole that big is a very very broken system. And although I can identify and empathise with the people who work in the pharmaceutical companies - I don’t think they are bad people necessarily - I find it difficult to understand the thoughts and motivations and beliefs of the people who were involved in those decisions.”
AvandiaGoldacre moves on to the case of Avandia (rosiglitazone), which as it turned out, would be suspended from the market a few weeks later.
“GSK knew from their own meta-analysis that rosiglitazone had a higher rate of unwanted cardiovascular problems. In 2004-5 they didn’t tell anybody but the FDA and they [the FDA] didn’t tell anyone either, and I think that’s crazy.”
He adds: “It is strange and I feel strange explaining this to you, and you must be thinking, ‘this man must be wrong, he must mad, or overstating it’, but that’s how it is.
“The only reason it came out at all was as part of a settlement that they reached after the Seroxat scandal in America. They signed an undertaking to publish all of their trial data on a website. They posted the information eventually, and then eventually the cardiologist Steven Nissen looked at it and found a 50% increase in the risk of cardiovascular problems.”
He says this could have been known four or nearly five years ago, and that enormous numbers of patients were involved.
Post-withdrawal, questions around GSK’s long term safety study of Avandia, RECORD are yet to be resolved.
Goldacre adds his voice to critics who believe GSK were guilty of ‘peeking’ - checking the data during the trial and then breaking clinical trials rules by halting it early in order to produce the desired results (see table below).
The media: scaremongering and ignoranceGoldacre has also criticised the role of journalists and the media in many of the medical scares and scandals of recent years. He devotes an entire chapter in his book to unpicking the role of the media in inflating the MMR scare in the UK, for example. He believes inadequate, and sometimes downright irresponsible reporting of science has got a lot to answer for.
I ask him if it is time for science and medical journalists to pass a training diploma, or even take the equivalent of a Hippocratic oath, pledging to represent the facts fairly and not be fooled by bad science. But he says after having given much thought to the subject, he believes there will always be good and bad journalists.
He adds that specialist health or science correspondents usually have a better grasp and appreciation of the science. But this isn’t guaranteed: “There are some properly bat shit mad health correspondents who write all kinds of ridiculous things in some newspapers. At the same time, there are people who are conscientious and do a good job.”
He argues the worst cases of media distortion exist because of ‘wider institutional pressures,’ because newspapers want sensational stories and that generalist ‘character columnists’ and the political diarists are drafted in to cover big science stories, even though they have the least ability to understand them.
“Editors tend to come from a humanities background, and they care about things like politics, economics and history, there is a bit of an empathy failure in the sense that they don’t realise that there are people who want to know the nerdy details.
“I suspect ultimately the solution is to accept bad science reporting, it will always be there, and then provide an alternative perspective. If mainstream media neglects the interests of nerds, then do it yourself, work around it.”
He says the internet age allows any number of direct and unmediated ways of communicating about science, opening up the exchange of information, through blogs and internet fora, with undergraduates, PhD students and post docs all able to benefit and contribute.
The responsibility of doctorsI challenge Goldacre on the role of doctors in this relationship, saying surely the medical profession must make sure its own house in order. He agrees that doctors must take responsibility for distancing themselves from inappropriate interactions with the industry, but can’t see the situation changing.
“Just as I think there are perverse consequences for the industry, I think the exact same thing has happened with doctors and academics.” He adds that it is ‘plainly problematic’ that doctors must organise their own continuing professional development (CPD) for the rest of their careers, and that they rely on industry funding.
“The idea that we leave CPD in the hands of the industry, and we recognise industry funded teaching as counting for CPD is, to me, ridiculous.
“I think also it won’t change because, what are doctors paid? It is quite a lot, but if you nationalised law or accountancy, there would be an outcry, they would be very unhappy about it. I think it is a situation which inevitably results in people accepting things from the pharma industry.”
True transparency is the keyI ask if reform of ethics committee could be one solution to the problem.
“I think complex regulatory failure only persists because it is happening in a dark shadowy corner of our society, despite the fact that the drugs are being taken by a vast number of people. I am not sure it’s just ethics committees - there is the monitoring committee and the individuals on it - perhaps they had perverse incentives, perhaps they were busy; perhaps they were persuaded by arguments that are really compelling when you are in the room, but that other people wouldn’t agree with.”
He suggests if a sponsor or investigators has trial data from more than two years ago and hasn’t published it, they shouldn’t be allowed to conduct further trials until they do.
“Academics, companies, regulators and ethics committees are all responsible - it is a kind of a failure of vision, and to me it feels like a set of unhappy situations that have grown up very organically and naturally because it has not really been anybody’s job to keep an eye on it. And it is a bit technical and complicated, so the public and the politicians haven’t kept their eye on it.”
He adds: “I am not even convinced that it is in the interests of the pharmaceutical industry except if everybody else is doing it, you need to be doing it too.”
Clinical trials registerIt has long been suggested that compulsory registration of trials on a central register will solve the problem, but Goldacre says this is still not a reality.
First of all, he points out that there is not one, but 58 separate clinical trials registers, which presents its own problems for researchers wishing to find data.
There are also major problems with the European Medicines Agency’s own database EudraCT, which remains confidential.
“The whole idea of a clinical trials registry remember, is transparency - but EudraCT is completely secret. All we know is that 5,000-8,000 new trials are added to it a year, and that there are 20,000-30,000 trials on the database already.”
He says this goes against the ‘implicit moral contract’ that trial volunteers and patients want to contribute by adding to a pooled knowledge of medicines.
“Regulators cannot be relied on to police this adequately, so other people have tried to step into the breach, but that is plainly unsatisfactory too,” says Goldacre.
In 2006, the International Committee of Medical Journal Editors (ICMJE), ruled that from 2007, no trial could be published in a medical journal unless it was registered on a clinical trials database.
He cites a 2009 study by Doug Altman, (the statistician and founder and director of Centre for Statistics in Medicine) which examined all the trials published in the 10 biggest medical journals in each different speciality.
The study found of the 323 trials surveyed, less than half were adequately registered, and 89 (more than 25%) were entirely unregistered.
‘A fairy tale’Goldacre says a debate he had on Radio 4’s Today programme in December 2009 about publication bias with Vincent Lawton, previously of Merck and now a non-executive director at the MHRA, illustrated how things still need to change.
“He said the problems had all been fixed, but that simply isn’t true. That is like a fairly tale we tell each other about how we fixed it.”
Goldacre says it’s not surprising the ICMJE hasn’t been able to change things. “Of course an ad hoc agreement by a group of academic medical journal editors who only meet very occasionally, isn’t sufficient to police probably one of the biggest industries in the world. And to imagine that it is [sufficient] is ludicrous.
“And all of our efforts to stop these problems don’t work, and the illusion and the fantasy that something has been done is worse than just being honest and saying, ‘nothing has been done’.
“I think it is understandable why these situations have come about, but they can’t go on forever.”
GOLDACRE’S GUIDE TO MANIPULATING DATA TO GET THE RESULTS YOU WANTChoose an unrepresentative group
Goldacre says trials in one Cox-II inhibitor drug were conducted in an entirely unrepresentative group - people in their thirties and forties.
Younger patients are often more likely to respond positively to treatment, and less likely to show up any side effects such as cardiovascular problems.
Choose an ‘odd’ dose for your comparator drug
Specifically, use an abnormally high or low dose of the comparator to go against your drug ‘and hope that nobody notices’. Goldacre says there are numerous examples of this in studies of atypical antipsychotics.
Ignore side effects
Studies of SSRI antidepressants ignored the startling but clear sexual side effect seen in some patients taking the drugs - anorgasmia - the inability to have an orgasm. Goldacre says everyone surely agrees this is a serious side effect: “Wars have been fought, essentially, for the sensation of an orgasm.”
Peeking and stopping early
“It goes without saying that you have pre-specified critieria for stopping early and there are lots of situations where you would want to stop early,” says Goldacre.
“But that is very different to ‘peeking’ where you just have a look every now and then and if you see the results you want, you stop the trial and write it up in a hurry.”
He adds: “You could make a bit of a case that this happened with the [Avandia] RECORD trial - that is certainly Steven Nissen’s argument - and not just his actually. There is a huge debate around whether the RECORD trial broke its stopping rules and was written up inappropriately, and, in response to work that was casting doubt on whether rosiglitazone was a good idea.”
Reference: J Am Coll Cardiol. 2010 Feb 2;55(5):428-31.
Randomized trials, statistics, and clinical inference.
Stone GW, Pocock SJ.
Ignore drop outs
These trial participants are more likely to have done badly in the trial, and more likely to have had side effects. Goldacre says trial sponsors still ignore them, and do not follow up on these cases or include them in their final results.
Clean up the data
Pruning unfavourable ‘outliers’ in the data will help clear up ambiguity in the data, so the temptation to exclude them is strong.
Torture the data
Sub-group analyses will eventually yield positive results.
Bury bad data
A 2008 paper published in the NEJM uncovered large amounts of negative data on SSRIs which had gone unpublished, altering the perception of the drug.
Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy
Produce duplicates of positive trials
Tramer (BMJ 1997; 315 : 635).
BEN GOLDACREBen Goldacre studied medicine at Magdalen College, Cambridge and is currently a research fellow at the London School of Hygiene and Tropical Medicine.
He has written the weekly Bad Science column in The Guardian since 2003, tackling subjects as diverse as the Catholic church’s opposition to condoms, the MMR scandal, self-appointed nutrionist Gillian McKeith, and of course, dubious practices in the pharmaceutical industry.
His Bad Science book (published by 4th Estate) has sold 240,000 copies, reached No.1 in the paperback non-fiction charts, and has been published in 18 countries.
He is currently working on a follow-up to the Bad Science book, and is interested in taking part in a lively public debate with the pharmaceutical industry.
He can be contacted at: firstname.lastname@example.org