Читать книгу Bad Pharma: How Medicine is Broken, And How We Can Fix It - Ben Goldacre - Страница 14

By now, you will, I hope, share my view that withholding results from clinical trials is unethical, for the simple reason that hidden data exposes patients to unnecessary and avoidable harm. But the ethical transgressions here go beyond the simple harm inflicted on future patients.

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.

So what are the formal arrangements between patients, researchers and sponsors? In any sensible world, 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, quite the opposite is true: it is entirely normal for researchers and academics conducting industry-funded trials to sign contracts subjecting them to gagging clauses which forbid them to publish, discuss or analyse data from the trials they have conducted, 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, as we shall now see.

In 2006 a paper was published in JAMA 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.⁴⁷ 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, and the bizarre secrecy that shrouds this world: the researchers applied elsewhere without success, and were specifically refused access to data in the UK.⁴⁸) These trials were overwhelmingly sponsored by the pharmaceutical industry (98 per cent), and the rules governing the management of the results tell a story which walks the now-familiar line between frightening and absurd.

For sixteen of the forty-four trials the sponsoring company got to see the data as it accumulated, and in a further sixteen they 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. As we will see later (early stopping, breaking protocols, pp.186, 202), this distorts a trial’s results with unnecessary and hidden biases. For example, if you stop a trial early because you have been peeking at the preliminary results, then you can either exaggerate a modest benefit, or bury a worsening negative result. Crucially, the fact that the sponsoring company had this opportunity to introduce bias wasn’t mentioned in any of the published academic papers reporting the results of these trials, so nobody reading the literature could possibly know that these studies were subject – by design – to such an important flaw.

Even if the study was allowed to finish, the data could still be suppressed. There were constraints on publication rights in forty of the forty-four 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, and in fact, none of the protocols or papers said that the sponsor had full access to all the data from the trial, or the final say on whether to publish.

It’s worth taking a moment to think about what this means. The results of all these trials were subject to a bias that will significantly distort the academic literature, because trials that show early signs of producing a negative result (or trials that do produce a negative result) can be deleted from the academic record; but nobody reading these trials could possibly have known that this opportunity for censorship existed.

The paper I’ve just described was published in JAMA, one of the biggest medical journals in the world. Shortly afterwards, a shocking tale of industry interference appeared in the BMJ.⁴⁹ Lif, the Danish pharmaceutical industry association, responded to the paper 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. Then Lif wrote to the Danish Committee on Scientific Dishonesty, accusing the Cochrane researchers of scientific misconduct. We can’t see the letter, but the Cochrane 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, because in academia people like to do things properly, and assume that all complaints are made in good faith. Peter Gøtzsche, the director of the Cochrane centre, told the BMJ that only Lif’s third letter, ten months into this process, made specific allegations that could be investigated by the committee. Two months later 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 said that they 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. So, researching in this area is not easy: it’s hard to get funding, and the industry will make your work feel like chewing on a mouthful of wasps.

Even though the problem has been widely recognised, attempts to fix it have failed.⁵⁰ The International Committee of Medical Journal Editors, for example, stood up in 2001, insisting that the lead author of any study it published must sign a document stating that the researchers had full access to the data, and full control over the decision to publish. Researchers at Duke University, North Carolina, then surveyed the contracts between medical schools and industry sponsors, and found that this edict was flouted as a matter of routine. They recommended boilerplate contracts for the relationship between industry and academia. Was this imposed? No. Sponsors continue to control the data.

Half a decade later, a major study in the New England Journal of Medicine investigated whether anything had changed.⁵¹ Administrators at all 122 accredited medical schools in the US were asked about their contracts (to be clear, this wasn’t a study of what they did; rather it was a study of what they were willing to say in public). The majority said contract negotiations over the right to publish data were ‘difficult’. A worrying 62 per cent said it was OK for the clinical trial agreement between academics and industry sponsor to be confidential. This is a serious problem, as it means that anyone reading a study cannot know how much interference was available to the sponsor, which is important context for the person reading and interpreting the research. Half of the centres allowed the sponsor to draft the research paper, which is another interesting hidden problem in medicine, as biases and emphases can be quietly introduced (as we shall see in more detail in Chapter 6). Half said it was OK for contracts to forbid researchers sharing data after the research was completed and published, once again hindering research. A quarter said it was acceptable for the sponsor to insert its own statistical analyses into the manuscript. Asked about disputes, 17 per cent of administrators had seen an argument about who had control of data in the preceding year.

Sometimes, disputes over access to such data can cause serious problems in academic departments, when there is a divergence of views on what is ethical. Aubrey Blumsohn was a senior lecturer at Sheffield University, working on a project funded by Procter & Gamble to research an osteoporosis drug called risedronate.⁵² The aim was to analyse blood and urine samples from an earlier trial, led by Blumsohn’s head of department, Professor Richard Eastell. After signing the contracts, P&G sent over some ‘abstracts’, brief summaries of the findings, with Blumsohn’s name as first author, and some summary results tables. That’s great, said Blumsohn, but I’m the researcher here: I’d like to see the actual raw data and analyse it myself. The company declined, saying that this was not their policy. Blumsohn stood his ground, and the papers were left unpublished. Then, however, Blumsohn saw that Eastell had published another paper with P&G, stating that all the researchers had ‘had full access to the data and analyses’. He complained, knowing this was not true. Blumsohn was suspended by Sheffield University, which offered him a gagging clause and £145,000, and he was eventually forced out of his job. Eastell, meanwhile, was censured by the General Medical Council, but only after a staggering delay of several years, and he remains in post.

So contracts that permit companies and researchers to withhold or control data are common, and they’re bad news. But that’s not just because they lead to doctors and patients being misled about what works. They also break another vitally important contract: the agreement between researchers and the patients who participate in their trials.

People participate in trials believing that the results of that research will help to improve the treatment of patients like them in the future. This isn’t just speculation: one of the few studies to ask patients why they have participated in a trial found that 90 per cent believed they were making a ‘major’ or ‘moderate’ contribution to society, and 84 per cent felt proud that they were making this contribution.⁵³ Patients are not stupid or naïve to believe this, because it is what they are told on the consent forms they sign before participating in trials. But they are mistaken, because the results of trials are frequently left unpublished, and withheld from doctors and patients. These signed consent forms therefore mislead people on two vitally important points. Firstly, they fail to tell the truth: that the person conducting the trial, or the person paying for it, may decide not to publish the results, depending on how they look at the end of the study. And worse than that, they also explicitly state a falsehood: researchers tell patients that they are participating in order to create knowledge that will be used to improve treatment in future, even though the researchers know that in many cases, those results will never be published.

There is only one conclusion that we can draw from this: consent forms routinely lie to patients participating in trials. This is an extraordinary state of affairs, made all the more extraordinary by the huge amounts of red tape that everyone involved in a trial must negotiate, closely monitoring endless arcane pieces of paperwork, and ensuring that patients are fully informed on the minutiae of their treatment. Despite all this regulatory theatre, which hinders good research on routine practice (as we shall see – p.232), we allow these forms to tell patients outright lies about the control of data, and we fail to police one of the most important ethical problems in the whole of medicine. The deceit of these consent forms is, to me, a good illustration of how broken and outdated the regulatory frameworks of medicine have become. But it also, finally, poses a serious problem for the future of research.

We desperately need patients to continue to believe that they are contributing to society, because trial recruitment is in crisis, and it is increasingly hard to persuade patients to participate at all. In one recent study, a third of all trials failed to reach their original recruitment target, and more than half had to be awarded an extension.⁵⁴ If word gets out that trials are often more promotional than genuinely scientific, recruitment will become even more difficult. The answer is not to hide this problem, but rather to fix it.

So universities and ethics committees may have failed us, but there is one group of people we might expect to step up, to try to show some leadership on missing trial data. These are the medical and academic professional bodies, the Royal Colleges of General Practice, Surgery and Physicians, the General Medical Council, the British Medical Association, the pharmacists’ organisations, the bodies representing each sub-specialty of academia, the respiratory physiologists, the pharmacologists, the Academy of Medical Sciences, and so on.

These organisations have the opportunity to set the tone of academic and clinical medicine, in their codes of conduct, their aspirations, and in some cases their rules, since some have the ability to impose sanctions, and all have the ability to exclude those who fail to meet basic ethical standards. We have established, I hope, beyond any doubt, that non-publication of trials in humans is research misconduct, that it misleads doctors and harms patients around the world. Have these organisations used their powers, stood up and announced, prominently and fiercely, that this must stop, and that they will take action?

One has: the Faculty of Pharmaceutical Medicine, a small organisation of doctors – largely working in the industry – with 1,400 members. And none of the others have bothered.

Not one.