[Dit boek handelt over de 'barriers to refutation' die de farmaceutische industrie oproept bij het ontwikkelen en uittesten en op de markt brengen van medicijnen: er is meestal geen sprake van onafhankelijk onderzoek en de resultaten van het onderzoek door de farmaceutische industrie zelf geven een gemanipuleerd positief beeld van de resultaten van de onderzoeken: negatieve resultaten worden achtergehouden, niet gepubliceerd, terwijl degelijke 'systematic reviews', meta-analyses, blobbogrammen en dergelijke vergelijkende onderzoeken worden tegengewerkt door geen data te verstrekken. De farmaceutische industrie wordt daarin nota bene gesteund door de organen die hen moeten controleren. Op die manier worden artsen misleid en is het moeilijker voor hen om de juiste medicijnen voor te schrijven. Eigenlijk wilde ik vooral duidelijk krijgen hoe het thema van dit boek samenhangt met het economsich systeem, met het kapitalisme, maar Goldacre trekt dat soort lijnen niet nadrukkelijk. Jammer. Ik las een epub-document, ik heb dus geen verwijzingen naar paginanummers.]
"Medicine is broken. And I genuinely believe that if patients and the public ever fully understand what has been done to them – what doctors, academics and regulators have permitted – they will be angry. On this, only you can judge.
We like to imagine that medicine is based on evidence, and the results of fair tests. In reality, those tests are often profoundly flawed. We like to imagine that doctors are familiar with the research literature, when in reality much of it is hidden from them by drug companies. We like to imagine that doctors are well-educated, when in reality much of their education is funded by industry. We like to imagine that regulators only let effective drugs onto the market, when in reality they approve hopeless drugs, with data on side effects casually withheld from doctors and patients.
I’m going to tell you how medicine works, just over the page, in one paragraph that will seem so absurd, so ludicrously appalling, that when you read it, you’ll probably assume I’m exaggerating. We’re going to see that the whole edifice of medicine is broken, because the evidence we use to make decisions is hopelessly and systematically distorted; and this is no small thing. Because in medicine, doctors and patients use abstract data to make decisions in the very real world of flesh and blood. If those decisions are misguided, they can result in death, and suffering, and pain."
[Moet je je voorstellen: de bedoelde en onbedoelde werking van een medicijn kan alleen vastgesteld worden door intensief onderzoek. Op basis van de resultaten daarvan kan een huisarts of een specialist dat medicijn verantwoord voorschrijven. Nu is dat onderzoek voor het grootste deel de verantwoordelijkheid van het bedrijf dat geld wil verdienen met de verkoop van dat medicijn. Liberalen en kapitalisten vertrouwen immers op het bedrijfsleven. Uiteraard roept die situatie bij zo'n bedrijf de neiging op om te liegen over dat product, zoals onder het kapitalisme vrijwel alle verkopers altijd liegen over hun product. Alleen gaat het nu bijvoorbeeld niet over de kuren van een smartphone met slechte software waar een consument last van heeft, maar over een medicijn dat het lichaam van een gebruiker onzichtbaar en onomkeerbaar kan beschadigen. Je zou toch denken dat elk bedrijf dat een medicijn produceert aan intensieve controles is onderworpen en dat elk medicijn met name onafhankelijk en openlijk op zijn werkingen getoetst wordt, zodat artsen met enige gemoedsrust een medicijn kunnen voorschrijven. Maar, nee, niets is minder het geval. Dit is de wereld van het grote geld: overheid en controlerende instanties lopen aan de leiband van de farmaceutische industrie, er is alleen maar schijnregulering. Daarmee lopen ook huisartsen en specialisten aan de leiband van de farmaceutische industrie. Daarom is een gezond wantrouwen tegenover artsen en hun medicijnen verstandig en gerechtvaardigd.]
"Before we get going, we need to establish one thing beyond any doubt: industry-funded trials are more likely to produce a positive, flattering result than independently-funded trials. This is our core premise, and you’re about to read a very short chapter, because this is one of the most well-documented phenomena in the growing field of ‘research about research’. It has also become much easier to study in recent years, because the rules on declaring industry funding have become a little clearer."
[Het is vele malen aangetoond dat farmaceutische bedrijven liegen over de werking van hun medicijnen: de resultaten van hun onderzoek worden opgepoetst, negatieve resultaten worden weggemoffeld, en zo verder. Negatieve resultaten zouden altijd bekend moeten zijn en gerapporteerd moeten worden, maar dat is niet het geval. En op een of andere manier werken onderzoekscentra, universiteiten, controlerende en regulerende instanties, overheden, daar aan mee.]
"To guard against this risk, researchers invented the systematic review. We’ll explore this in more detail soon, since it’s at the core of modern medicine, but in essence a systematic review is simple: instead of just mooching through the research literature, consciously or unconsciously picking out papers here and there that support your pre-existing beliefs, you take a scientific, systematic approach to the very process of looking for scientific evidence, ensuring that your evidence is as complete and representative as possible of all the research that has ever been done.
Systematic reviews are very, very onerous. In 2003, by coincidence, two were published, both looking specifically at the question we’re interested in. They took all the studies ever published that looked at whether industry funding is associated with pro-industry results. Each took a slightly different approach to finding research papers, 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 that had been published in the four years after these two earlier reviews: it found twenty more pieces of work, and all but two showed that industry-sponsored trials were more likely to report flattering results.
I am setting out this evidence at length because I want to be absolutely clear that there is no doubt on the issue. Industry-sponsored trials give favourable results, and that is not my opinion, or a hunch from the occasional passing study. This is a very well-documented problem, and it has been researched extensively, without anybody stepping out to take effective action, as we shall see."
"In the light of all this, the data on what researchers say about their own behaviour is very revealing. In various surveys they have said that they thought there was no point in submitting negative results, because they would just be rejected by journals: 20 per cent of medical researchers said so in 1998; 61 percent of psychology and education researchers said so in 1991; and so on. If asked why they’ve failed to send in research for publication, the most common reasons researchers give are negative results, a lack of interest, or a lack of time.
This is the more abstract end of academia – largely away from the immediate world of clinical trials – but it seems that academics are mistaken, at best, about the reasons why negative results go missing. Journals may pose some barriers to publishing negative results, but they are hardly absolute, and much of the problem lies in academics’ motivations and perceptions.
More than that, in recent years, the era of open-access academic journals has got going in earnest: there are now several, such as Trials, which are free to access, and have a core editorial policy that they will accept any trial report, regardless of result, and will actively solicit negative findings. With offers like this on the table, it is very hard to believe that anyone would really struggle to publish a trial with a negative result if they wanted to. And yet, despite this, negative results continue to go missing, with vast multinational companies simply withholding results on their drugs, even though academics and doctors are desperate to see them.
You might reasonably wonder whether there are people who are supposed to prevent this kind of data from being withheld. The universities where research takes place, for example; or the regulators; or the ‘ethics committees’, which are charged with protecting patients who participate in research. Unfortunately, our story is about to take a turn to the dark side. We will see that many of the very people and organisations we would have expected to protect patients from the harm inflicted by missing data have, instead, shirked their responsibilities; and worse than that, we will see that many of them have actively conspired in helping companies to withhold data from patients. We are about to hit some big problems, some bad people, and some simple solutions."
"Patients and the public participate in clinical trials at some considerable cost to themselves: they expose themselves to hassle and intrusion, because clinical trials almost always require that you have more check-ups on your progress, more blood tests, and more examinations; but participants may also expose themselves to more risk, or the chance of receiving an inferior treatment. People do this out of altruism, on the implicit understanding that the results from their experience will contribute to improving our knowledge of what works and what doesn’t, and so will help other patients in the future. In fact, this understanding isn’t just implicit: in many trials it’s explicit, because patients are specifically told when they sign up to participate that the data will be used to inform future decisions. If this isn’t true, and the data can be withheld at the whim of a researcher or a company, then the patients have been actively lied to. That is very bad news."
"The output of a regulator is often simply a crude, brief summary: almost a ‘yes’ or ‘no’ about side effects. This is the opposite of science, which is only reliable because everyone shows their working, explains how they know that something is effective or safe, shares their methods and their results, and allows others to decide if they agree with the way they processed and analysed the data.
Yet for the safety and efficacy of drugs, one of the most important of all analyses done by science, we turn our back on this process completely: 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, and a perfect example of a problem that benefits from many eyes and minds, is carried out alone and in secret.
This perverse and unhealthy secrecy extends way beyond regulators. NICE, the UK’s National Institute for Health and Clinical Excellence, is charged with making recommendations about which treatments are most cost-effective, and which work best. When it does this, it’s in the same boat as you or me: it has absolutely no statutory right to see data on the safety or effectiveness of a drug, if a company doesn’t want to release it, even though the regulators have all of that data. As a result, NICE can be given distorted, edited, biased samples of the data, not just on whether a drug works, but also on how likely it is to have unpleasant side effects."
[Dat is een ander negatief facet van het kapitalisme: elk bedrijf X is gericht op eigenbelang en probeert de markt te veroveren met bepaalde producten die andere bedrijven Y en Z niet kunnen verkopen of in ieder geval niet in de kwaliteit die bedsrijf X levert. Het gevolg van competitite en concurrentie is daarom dat je je onderzoek en je productiemethoden en je boekhouding en zo ver weg houdt van de nieuwsgierige ogen van anderen. Je deelt geen kennis, je werkt op basis van geheimzinnigheid en geheimhouding, je bestrijdt bedrijfsspionage, je legt patenten vast en voert rechtszaken tegen iedereen die die patenten schendt, en zo verder. Wat een verlies aan energie, wat een verspilling van hulpbronnen. Maar dat dat dus ook zo werkt dat zelfs controlerende instanties geen openheid krijgen van de farmaceutische industrie is walgelijk. Hoe kun je de werking van die medicijnen controleren als je niet alle data hebt uit eerdere onderzoeken? Maar de farmaceutische bedrijven weigeren simpelweg om mee te werken en worden er door de liberale overheid niet toe gedwongen. Schokkend vind ik dat.]
"In 2007, researchers from the Nordic Cochrane Centre were working on a systematic review for two widely used diet drugs, orlistat and rimonabant. A systematic review, as you know, is the gold-standard summary of the evidence on whether a treatment is effective. These are life-saving, because they give us the best possible understanding of the true effects of a treatment, including its side effects. But doing this requires access to all of the evidence: if some is missing, especially if unflattering data is deliberately harder to obtain, we will be left with a distorted picture.
The researchers knew that the trial data they were able to find in the published academic literature was probably incomplete, because negative trials are routinely left unpublished. But they also knew that the European Medicines Agency (EMA) would have much of this information, since the manufacturers of drugs are obliged to give the study reports to the regulator when trying to get them onto the market. Since regulators are supposed to act in the interests of patients, they applied to the EMA for the protocols and the study reports. That was in June 2007.
In August, the EMA responded: it had decided not to give out the study reports for these trials, and was invoking the section of its rules which allows it to protect the commercial interests and intellectual property of drug companies. The researchers replied immediately, almost by return of post: there is nothing in the study reports that will undermine the protection of someone’s commercial interests, they explained. But if there was, could the EMA please explain why it felt the commercial interests of the drug companies should override the welfare of patients?
Here we should pause for just one moment, and think about what the EMA is doing. It is the regulator that approves and monitors drugs for the whole of Europe, with the aim of protecting the public. Doctors and patients can only make meaningful decisions about treatments if they have access to all the data. The EMA has that data, but has decided that the drug companies’ interests are more important. Having spoken to a lot of people in regulation, I can offer one small insight into what on earth they might be thinking. Regulators, in my experience, are preoccupied with the idea that they see all the data, and use it to make the decision about whether a drug should go on the market, and that this is enough: doctors and patients don’t need to see the data, because the regulator has done all that work."
"The field of missing data is a tragic and strange one. We have tolerated the emergence of a culture in medicine where information is routinely withheld, and we have blinded ourselves to the unnecessary suffering and death that follows from this. The people we should have been able to trust to handle all this behind the scenes – the regulators, the politicians, the senior academics, the patient organisations, the professional bodies, the universities, the ethics committees – have almost all failed us. And so I have had to inflict the details on you, in the hope that you can bring some pressure to bear yourself."
[Onderzoeken zijn om allerlei redenen niet representatief en voldoen dus niet aan de regels van een zo objectief mogelijk soort onderzoek. Proefpersonen hebben vaak dezelfde achtergrond, hebben er belang bij dat een onderzoek op een bepaalde manier verloopt, of zijn afkomstig uit hetzelfde land, een land dat niet vergelijkbaar is met de landen waar dat medicijn (ook) op markt gebracht wordt. Resultaten van die onderzoeken zijn dus vertekend en onbetrouwbaar. Goldacre legt dat in dit hoofdstuk uit.]
"That’s an extreme case. But even at best, volunteers come from less well-off groups in society, and this creates a situation where the drugs taken by all of us are tested – to be blunt – on the poor. In the US, this means people without medical insurance, and that raises another interesting issue: the Declaration of Helsinki, the ethics code which frames most modern medical activity, says that research is justified if the population from whom participants are drawn would benefit from the results. The thought behind this is that a new AIDS drug shouldn’t be tested on people in Africa, for example, who could never afford to buy it. But uninsured unemployed people in the US do not have access to expensive medical treatments either, so it’s not clear that they could benefit from this research. On top of that, most agencies don’t offer free treatment to injured subjects, and none give them compensation for suffering or lost wages.
This is a strange underworld that has been brought to light for the academic community by Carl Elliot, an ethicist, and Robert Abadie, an anthropologist who lived among phase 1 participants for his PhD. The industry refers to these participants by the oxymoron ‘paid volunteers’, and there is a universal pretence that they are not paid for their work, but merely reimbursed for their time and travel expenses. The participants themselves are under no such illusions.
Payment is often around $200 to $400 a day, studies can last for weeks or more, and participants will often do several studies in a year. Money is central to the process, and payment is often back-loaded, so you only receive full payment if you complete the study, unless you can prove your withdrawal was due to serious side effects. Participants generally have few economic alternatives, especially in the US, and are frequently presented with lengthy and impenetrable consent forms, which are hard to navigate and understand.
You can earn better than the minimum wage if you ‘guinea pig’ full-time, and many do: in fact, for many of them it’s a job, but it’s not regulated as any other job might be. This is perhaps because we feel uncomfortable regarding this source of income as a profession, so new problems arise. Participants are reluctant to complain about poor conditions, because they don’t want to miss out on future studies, and they don’t go to lawyers for the same reason. They may be disinclined to walk away from studies that are unpleasant or painful, too, for fear of sacrificing income. One participant describes this as ‘a mild torture economy’: ‘You’re not being paid to do a job…you’re being paid to endure.’"
"Clinical research organisations are a very new phenomenon. Thirty years ago, hardly any existed: now there are hundreds, with a global revenue of $20 billion in 2010, representing about a third of all pharma R&D spending. They conduct the majority of clinical trials research on behalf of industry, and in 2008 CROs ran more than 9,000 trials, with over two million participants, in 115 countries around the world.
This commercialisation of trials research raises several new concerns. Firstly, as we have already seen, companies often bring pressure to bear on academics they are funding, discouraging them from publishing unflattering results and encouraging them to put spin on both the methods and the conclusions of their work. When academics have stood up to those pressures, the threats have turned into grim realities. What employee or chief executive of a CRO is likely to stand up to a company which is directly paying the bills, when the staff all know that the CRO’s hope for future business rides on how it manages each demanding client?"
"It would be wrong to imagine that this shift in culture has been driven by a hope that CROs would produce more flattering findings than other options. They are attractive because they’re fast, efficient, focused and cheap. And they’re especially cheap because, like many other industries, they outsource their work to poorer countries. As the former chief executive of GSK explained in a recent interview, running a trial in the US costs $30,000 per patient, while a CRO can do it in Romania for $3,000. That is why GSK aims to move half of its trials to low-cost countries, and it is part of a global trend.
In the past, only 15 per cent of clinical trials were conducted outside the USA. Now it’s more than half. The average rate of growth in the number of trials in India is 20 per cent a year, in China 47 per cent, in Argentina 27 per cent, and so on, simply because they are better at attracting CRO business, at lower cost. At the same time, trials in the US are falling by 6 per cent a year (and in the UK by 10 per cent a year). As a result of these trends, many trials are now being conducted in developing countries, where regulatory oversight is poorer, as is the normal standard of clinical care. This raises a huge number of questions about data integrity, the relevance of findings to developed world populations, and ethics – all issues with which regulators around the world are currently struggling."
"Beyond differences in routine treatment, there will also be a different social context. Are patients diagnosed with depression in China really the same as patients diagnosed with depression in California? And then there are genetic differences. You might know, from drinking with friends, that many Oriental people metabolise drugs, especially alcohol, differently from Westerners: if a drug has few side effects at a particular dose in Botswana, can you really rely on that data for your patients in Tokyo?"
"This is an area of considerable obfuscation and embarrassment, tangled up in complex regulatory frameworks which are starting to change in a worrying direction. In 2009, three researchers wrote in the Lancet drawing attention to one very notable shift. For years, they explained, the FDA had insisted that when a company applied for a marketing authorisation for a drug in the US, all foreign trials given as evidence had to show that they were compliant with the Declaration of Helsinki. In 2008 this requirement changed, but only for foreign trials, and the FDA shifted to the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. These are not terrible, but they are only voted on by members from the EU, the USA and Japan. They are also more focused on procedures, while Helsinki clearly articulates moral principles. But most concerning are the differences in detail, when you consider that GCP is now the main ethical regulation for trials in the developing world.
Helsinki says that research must benefit the health needs of the populations where it is conducted. GCP does not. Helsinki discusses the moral need for access to treatment after a trial has finished. GCP does not. Helsinki restricts the use of dummy placebo sugar pills in trials, where there are effective treatments available. GCP does not. Helsinki also, incidentally, encourages investigators to disclose funding and sponsors, post the study design publicly, publish negative findings, and report results accurately. GCP does not. So this was not a reassuring regulatory shift, specifically for trials conducted outside the US, and specifically in 2008, at a time when studies were moving outside the US and the EU at a very rapid pace.
It’s also worth mentioning that the pharmaceutical industry plays hardball with developing countries over the price of medicines. Like much else we are discussing, this is worthy of a book in its own right, but here is just one illustrative story. In 2007 Thailand tried to take a stand against the drug company Abbott over its drug Kaletra. There are more than half a million people living with HIV in Thailand (many of them can thank Western sex tourists for that), and 120,000 have AIDS. The country can afford first-line AIDS drugs, but many become ineffective with time, through acquired resistance. Abbott had been charging $2,200 a year for Kaletra in Thailand, which was – by morbid coincidence – roughly the same as the gross income per capita.
We give drug companies exclusive rights to manufacture the treatments they have discovered for a limited period of time – usually about eighteen years – in order to incentivise innovation. It’s unlikely that the revenue available from selling drugs in poorer countries will ever incentivise innovation of new treatments to any great extent (we can see this very clearly from the fact that so many medical conditions that occur mainly in developing countries are neglected by the pharmaceutical industry). Because of this there are various international treaties, such as the Doha Declaration of 2001, under which a government can declare a public-health emergency, and start manufacturing or buying copies of a patented drug. One memorable use of these ‘compulsory licences’ was when the US government insisted in the aftermath of the 9/11 attacks that it should be allowed to buy large amounts of cheap ciprofloxacin to treat anthrax, when it was worried that spores were being sent to politicians by terrorists.
So in January 2007 the Thai government announced that it was going to copy Abbott’s drug, only for the country’s poor, to save lives. Abbott’s response was interesting: it retaliated by completely withdrawing its new heat-stable version of Kaletra from the Thai market, and six other new drugs for good measure, and then announced that it would not bring these drugs back to the Thai market until the government promised not to use a ‘compulsory licence’ on its drugs again. It’s hard to think of anything less in keeping with the Doha Declaration. If you want more moral context, the World Health Organization estimates that half of HIV transmissions in Thailand come from contact between sex workers and their clients. There are said to be two million women and 800,000 children under eighteen working in the Thai sex trade, much of which is servicing Western men, some of whom you may know personally."
[Regulerende instanties zijn niet onafhankelijk. Vaak werken er mensen die eerst in de farmaceutische industrie werkten, en daarnaast betaalt de farmaceutische industrie vaak de mensen die bij die instanties werken. Gevolg: medicijnen worden niet met elkaar vergeleken, er wordt niet gezocht naar het beste medicijn, de enige vraag is of een medicijn op de markt gebracht mag worden en het antwoord daarop is al gauw 'ja'.]
"In principle, the job of a regulator is simple: it approves a drug in the first place, after seeing trials that show it works; it monitors a drug’s safety once it’s on the market; it communicates risks and hazards to doctors; and it removes unsafe and ineffective medications from sale. Unfortunately, as we shall see, regulators are beset with problems: there are pressures from industry; pressures from government; problems with funding; issues of competence; conflicts of interest within their own ranks; and worst of all, again, a dangerous obsession with secrecy."
"A man who was previously overseeing the approval of new medicines now advises companies on how to get their drugs approved, having given the EMA four days’ notice of this plan, between Christmas and New Year, and nobody in the organisation regards that as a problem, even though it represents a staggering conflict of interest. In fact, this is not so unusual: the Corporate Europe Observatory recently produced a report detailing fifteen similar cases of senior EU officials passing through the revolving door between government and industry."
"In both the United States and the European Union, regulators are paid for almost entirely by drug companies, through the fees that are paid to pass regulatory hurdles. Until a few years ago, when approval was centralised to the EMA, this was a particular source of concern in Europe, because drug companies could choose which country they would seek approval in, and this created something of a competition. Overall this payment model has created an impression that the companies are the customer, but this is not simply because they write the cheques: this change in funding was brought in specifically to improve approval times for industry."
"As we have seen, drugs regulators don’t require that new drugs are particularly good, or an improvement on what came before; they don’t even require that drugs are particularly effective. This has interesting consequences on the market more broadly, because it means that the incentives for producing new drugs that improve patients’ lives are less intense. One thing is clear from all the stories in this book: drug companies respond rationally to incentives, and when those incentives are unhelpful, so are drug companies."
"These are not stories that can leave anyone feeling actively impressed. But there is a more important problem behind our ethical concerns about how companies behave in situations like this: we have allowed ourselves to be left – as prescribers, as patients, and as the people paying for health care – without clear evidence comparing different treatments against each other. We have no idea which treatments are best, and by extension, we have no idea which are harmful. If you die from getting the third-best treatment, then you have died needlessly and avoidably, and have every right to be angry in your grave."
"So ‘comparative effectiveness research’, as this is called, is vitally important, but it has only recently been embraced. To give you an illustration of how slow and arduous this journey is: in 2008, shortly after being elected President, Barack Obama demonstrated to many academics and doctors that he had a clear understanding of the deep problems in health care, by committing to spend $1 billion on head-to-head trials of commonly used treatments, in order to find out which is best. In return he was derided by right-wing critics as ‘anti-industry’."
[Negentig procent van alle onderzoek naar medicijnen wordt door de farmaceutische industrie gesponsord. Het gevolg is dat die onderzoeken meestal niet deugen, zodat ze ongevaarlijke resultaten voortbrengen. Er wordt onderzoek gedaan bij gezonde proefpersonen, maar als de medicijnen eenmaal op de merkt zijn worden ze voorgeschreven aan personen met allerlei andere ziekten waarvoor ze allerlei andere medicijnen. Er is meestal niets bekend over de interacties tussen al die medicijnen en over de relatie tussen al die ziekten en al die medicijnen.]
"We should also remember that many bad trials (including some of the ones discussed in the pages to follow) are conducted by independent academics. In fact, overall, as the industry is keen to point out, where people have compared the methods of independently-sponsored trials against industry-sponsored ones, industry-sponsored trials often come out better. This may well be true, but it is almost irrelevant, for one simple reason: independent academics are bit players in this domain. Ninety per cent of published clinical trials are sponsored by the pharmaceutical industry. They dominate this field, they set the tone, and they create the norms."
"In the real world, patients are often complicated: they might have many different medical problems, or take lots of different medicines, which all interfere with each other in unpredictable ways; they might drink more alcohol in a week than is ideal; or have some mild kidney impairment. That’s what real patients are like. But most of the trials we rely on to make real-world decisions study drugs in unrepresentative, freakishly ideal patients, who are often young, with perfect single diagnoses, fewer other health problems, and so on."
"One thing that’s likely to make your new treatment look good is testing it against something that doesn’t work very well: this might sound absurd, or even cruel, so we’re lucky that a researcher called Daniel Safer has pulled together a large collection of trials using odd doses specifically to illustrate this problem."
"But whatever we do about early stopping in medicine, it will probably pollute the data. A review from 2010 took around a hundred truncated trials, and four hundred matched trials that ran their natural course to the end: the truncated trials reported much bigger benefits, overstating the usefulness of the treatments they were testing by about a quarter. Another recent review found that the number of trials stopped early has doubled since 1990, which is probably not good news. At the very least, results from trials that stop early should be regarded with a large dose of scepticism. Particularly since these same systematic reviews show that trials which stop early often don’t properly report their reasons for doing so."
"So, we have established that there are some very serious problems in medicine. We have badly designed trials, which suffer from all kinds of fatal flaws: they’re conducted in unrepresentative patients, they’re too brief, they measure the wrong outcomes, they go missing if the results are unflattering, they get analysed stupidly, and often they’re simply not done at all, simply because of expense, or lack of incentives. These problems are frighteningly common, both for the trials that are used to get a drug on the market, and for the trials that are done later, all of which guide doctors’ and patients’ treatment decisions. It feels as if some people, perhaps, view research as a game, where the idea is to get away with as much as you can, rather than to conduct fair tests of the treatments we use.
However we view the motives, this unfortunate situation leaves us with a very real problem. For many of the most important diseases that patients present with, we have no idea which of the widely used treatments is best, and, as a consequence, people suffer and die unnecessarily. Patients, the public, and even many doctors live in blissful ignorance of this frightening reality, but in the medical literature, it has been pointed out again and again."
"The manifesto implicit in this paper was very straightforward: wherever there is genuine uncertainty about which treatment is best, we should conduct a randomised trial; medicine should be in a constant cycle of revision, gathering follow-up data and improving our interventions, not as an exception, but wherever that is possible.
There are technical and cultural barriers to doing this kind of thing, but they are surmountable, and we can walk through them by considering a project I’ve been involved in, setting up randomised trials embedded in routine practice, in everyday GP surgeries. These trials are designed to be so cheap and unobtrusive that they can be done whenever there is genuine uncertainty, and all the results are gathered automatically, at almost no cost, from patients’ computerised notes."
[Er wordt meer geld uitgegeven aan de marketing van medijnen dan aan het onderzoek naar de werking ervan. Ook dat is typisch voor het kapitalisme: het gaat om het verkopen en het geld verdienen, de kwaliteit van je producten is secundair. Dokters worden door artsenbezoekers bezocht, dokters worden uitgenodigd voor cursussen en symposia en alle reis- en verblijfkosten worden betaald. Die 'opvoeding' van artsen wordt begeleid door een reeks artikelen in de bladen, geschreven door mensen die door de farmaceutische industrie worden betaald.]
"If we can’t manage rational prescribing decisions even for these incredibly common medicines, then that is good evidence that prescription is a haphazard affair, where clear information is not efficiently disseminated to the people making the decisions, on either effectiveness or cost-effectiveness. I can honestly say, if I were in charge of the medical research budgets, I would cancel all primary research for a year, and only fund projects devising new ways to optimise our methods for disseminating information, ensuring that the evidence we already have is summarised, targeted and implemented. But I am not in charge, and there are some much more powerful influences out there.
Now let’s think through a doctor’s prescribing decision from the perspective of a drug company. You want the doctor to prescribe your product, and you will do everything you can to make that happen. You might dress this up as ‘raising awareness of our product’, or ‘helping doctors make decisions’, but the reality is, you want sales. So you will advertise your new treatment in medical journals, stating the benefits but downplaying the risks, and leaning away from unflattering comparisons. You will send out ‘drug reps’ to meet doctors individually, and talk up the merits of your treatment. They will offer gifts, lunches, and forge personal relationships that may be mutually beneficial later.
But it goes deeper than this. Doctors need ongoing education: they practise for decades after they leave medical school, and looking back from today, medicine has changed unrecognisably since, say, the 1970s, which is when many currently practising doctors came out of medical training. This education is expensive, and the state is unwilling to pay, so it is drug companies that pay for talks, tutorials, teaching materials, conference sessions, and whole conferences, featuring experts who they know prefer their drug.
All of this is built on the back of a published academic evidence base that drug companies have carefully nurtured, through selective publication of flattering results and judicious use of design flaws, to give a flattering picture of their product. But those aren’t the only tools available to companies for influencing what appears in journals. They pay professional writers to produce academic papers, following their own commercial specifications, and then get academics to put their names to them. This acts as covert advertising, and will get more academic publications on their drug, more rapidly. It also aggrandises the favoured experts’ CVs, and helps doctors friendly to the company get the kudos and veneer of independence that comes from a university post.
The company can also give money to patient groups, if those groups’ views and values help it sell more drugs, and so give them greater prominence, power and platform. On top of all this, it can then pay academic journals to accept papers, with advertising revenue and ‘reprint’ orders, and with these academic papers it can foreground the evidence showing that its treatment works, and even expand the market for its drug, by producing work that helpfully shows that the problem it treats is actually much more widespread than people realise.
All of this sounds very expensive, and it is: in fact, the pharmaceutical industry overall spends about twice as much on marketing and promotion as it does on research and development."
"If I tell you that Katie Price did not necessarily write every word of her best-selling autobiography, then this is probably not a revelation to you. But then, nor is it a problem: you want something entertaining, and everyone knows that celebrities don’t write their own books. That is the culture and tradition of this kind of publication, and it’s an open secret.
From doctors and academics we have higher expectations. The reader of an academic journal reasonably assumes that what they are reading is an independent academic’s study, or review article, or opinion in an editorial. But this is quite wrong. In reality, academic articles are often covertly written by a commercial writer employed by a pharmaceutical company, with an academic’s name placed at the top to give it the imprimatur of independence and scientific rigour. Often these academics have had little or no involvement in collecting the data or drafting the paper.
What’s more, while the publication might look like a spontaneous project from an independent academic, it’s generally part of a carefully choreographed timetable of publications, all running to the marketing schedule for one company’s product. So, papers will appear before a new drug’s launch describing cross-sectional survey data which reveals that the prevalence of a medical condition is much higher than previously thought; others will review the field, and say that current treatments are widely regarded as ineffective and dangerous; and so on. By this mechanism, the entire academic literature, used by doctors to guide decisions – the only tool we have – is ghost managed, behind the scenes, to an undeclared agenda."
Tot slot de algemene conclusie van Goldacre:
"For me, missing data is the key to this whole story. Bad behaviour in marketing departments is unpleasant, but it’s the one thing that has already received public condemnation, because the issues are tangible, with covert payments, misleading messages, and practices that are obviously dishonest, even to the untrained eye. But for all that they may be disappointing, these distortions can be overcome by any good doctor. If you go straight to the real evidence, and read systematic reviews of good-quality trials, then all the distortions and spin of drug reps and ‘key opinion leaders’ are nothing more than wasteful, irrelevant noise.
Missing data is different, because it 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 that we use. Nobody can work around this, and there is no expert doctor with special access to a secret stash of evidence. With missing data, we are all in it together, and we are all misled. I will say this only once more, but I think it bears repeating: evidence in medicine is not an abstract academic preoccupation. Evidence is used to make real-world decisions, and when we are fed bad data, we make the wrong decision, inflicting unnecessary pain and suffering, and death, on people just like us."
"We need clear regulations, with clear public auditing, to ensure that compliance is tested, and documented. And we need it to be applied muscularly, to everyone, without exception. We should remember, after all, that drug companies compete against each other, and they play by the rules we set as a society. If the rules permit dodgy practices, then companies are practically compelled to play dirty, even if the personnel know that their actions are morally wrong, and even if they want to do the right thing."