Читать книгу Bad Pharma: How Medicine is Broken, And How We Can Fix It - Ben Goldacre - Страница 19

So far we’ve established that doctors and patients have been failed by a range of different people and organisations, all of whom we might have expected to step up and fix the problem of missing data, since it harms patients in large numbers around the world. We have seen that governments take no action against those who fail to publish their results, despite the public pretence to the contrary; and that they take no action against those who fail to register their trials. We have seen that medical journal editors continue to publish unregistered trials, despite the public pretence that they have taken a stand. We have seen that ethics committees fail to insist on universal publication, despite their stated aim of protecting patients. And we have seen that professional bodies fail to take action against what is obviously research misconduct, despite evidence showing that the problem of missing data is of epidemic proportions.⁶⁶

While the published academic record is hopelessly distorted, you might hope that there is one final route which patients and doctors could use to get access to the results of clinical trials: the regulators, which receive large amounts of data from drug companies during the approval process, must surely have obligations to protect patients’ safety? But this, sadly, is just one more example of how we are failed by the very bodies that are supposed to be protecting us.

In this section, we will see three key failures. Firstly, the regulators may not have the information in the first place. Secondly, the way in which they ‘share’ summary trial information with doctors and patients is broken and shabby. And finally, if you try to get all of the information that a drug company has provided – the long-form documents, where the bodies are often buried – then regulators present bizarre barriers, blocking and obfuscating for several years at a time, even on drugs that turn out to be ineffective and harmful. Nothing of what I am about to tell you is in any sense reassuring.

One: Information is withheld from regulators

Paroxetine is a commonly used antidepressant, from the class of drugs known as ‘selective serotonin reuptake inhibitors’, or SSRIs. You will hear more about this class of drugs later in this book, but here we will use paroxetine to show how companies have exploited our longstanding permissiveness about missing trials, and found loopholes in our inadequate regulations on trial disclosure. We will see that GSK withheld data about whether paroxetine works as an antidepressant, and even withheld data about its harmful side effects, but most importantly, we will see that what it did was all entirely legal.

To understand why, we first need to go through a quirk of the licensing process. Drugs do not simply come onto the market for use in all medical conditions: for any specific use of any drug, in any specific disease, you need a separate marketing authorisation. So, a drug might be licensed to treat ovarian cancer, for example, but not breast cancer. That doesn’t mean the drug doesn’t work in breast cancer. There might well be some evidence that it’s great for treating that disease too, but maybe the company hasn’t gone to the trouble and expense of getting a formal marketing authorisation for that specific use. Doctors can still go ahead and prescribe it for breast cancer, if they want, because the drug is available for prescription, and there are boxes of it sitting in pharmacies waiting to go out (even though, strictly speaking, it’s only got marketing approval for use in ovarian cancer). In this situation the doctor will be prescribing the drug legally, but ‘off-label’.

This is fairly common, as getting a marketing authorisation for a specific use can be time-consuming and expensive. If doctors know that there’s a drug which has been shown in good-quality trials to help treat a disease, it would be perverse and unhelpful of them not to prescribe it, just because the company hasn’t applied for a formal licence to market it for that specific use. I’ll discuss the ins and outs of all this in more detail later. But for now, what you need to know is that the use of a drug in children is treated as a separate marketing authorisation from its use in adults.

This makes sense in many cases, because children can respond to drugs in very different ways to adults, so the risks and benefits might be very different, and research needs to be done in children separately. But this licensing quirk also brings some disadvantages. Getting a licence for a specific use is an arduous business, requiring lots of paperwork, and some specific studies. Often this will be so expensive that companies will not bother to get a licence specifically to market a drug for use in children, because that market is usually much smaller.

But once a drug is available in a country for one specific thing, as we have seen, it can then be prescribed for absolutely anything. So it is not unusual for a drug to be licensed for use in adults, but then prescribed for children on the back of a hunch; or a judgement that it should at least do no harm; or studies that suggest benefit in children, but that would probably be insufficient to get through the specific formal process of getting marketing authorisation for use in kids; or even good studies, but in a disease where the market is so small that the company can’t be bothered to get a marketing approval for use in children.

Regulators have recognised that there is a serious problem with drugs being used in children ‘off-label’, without adequate research, so recently they have started to offer incentives for companies to conduct the research, and formally seek these licences. The incentives are patent extensions, and these can be lucrative. All drugs slip into the public domain about a decade after coming onto the market, and become like paracetamol, which anyone can make very cheaply. If a company is given a six-month extension on a drug, for all uses, then it can make a lot more money from that medicine. This seems a good example of regulators being pragmatic, and thinking creatively about what carrots they can offer. Licensed use in children will probably not itself make a company much extra money, since doctors are prescribing the drug for children already, even without a licence or good evidence, simply because there are no other options. Meanwhile, six months of extra patent life for a blockbuster drug will be very lucrative, if its adult market is large enough.

There’s a lot of debate about whether the drug companies have played fair with these offers. For example, since the FDA started offering this deal, about a hundred drugs have been given paediatric licences, but many of them were for diseases that aren’t very common in children, like stomach ulcers, or arthritis. There have been far fewer applications for less lucrative products that could be used in children, such as more modern medicines called ‘large-molecule biologics’. But there it is.

When GSK applied for a marketing authorisation in children for paroxetine, an extraordinary situation came to light, triggering the longest investigation in the history of UK drugs regulation. This investigation was published in 2008, and examined whether GSK should face criminal charges.⁶⁷ It turned out that what the company had done – withholding important data about safety and effectiveness that doctors and patients clearly needed to see – was plainly unethical, and put children around the world at risk; but our laws are so weak that GSK could not be charged with any crime.

Between 1994 and 2002 GSK conducted nine trials of paroxetine in children.⁶⁸ The first two failed to show any benefit, but the company made no attempt to inform anyone of this by changing the ‘drug label’ that is sent to all doctors and patients. In fact, after these trials were completed, an internal company management document stated: ‘it would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine’. In the year after this secret internal memo, 32,000 prescriptions were issued to children for paroxetine in the UK alone: so, while the company knew the drug didn’t work in children, it was in no hurry to tell doctors that, despite knowing that large numbers of children were taking it. More trials were conducted over the coming years – nine in total – and none showed that the drug was effective at treating depression in children.

It gets much worse than that. These children weren’t simply receiving a drug that the company knew to be ineffective for them: they were also being exposed to side effects. This should be self-evident, since any effective treatment will have some side effects, and doctors factor this in, alongside the benefits (which in this case were non-existent). But nobody knew how bad these side effects were, because the company didn’t tell doctors, or patients, or even the regulator about the worrying safety data from its trials. This was because of a loophole (on which more in a couple of pages’ time): you only had to tell the regulator about side effects reported in studies looking at the specific uses for which the drug has a marketing authorisation. Because the use of paroxetine in children was ‘off-label’, GSK had no legal obligation at the time to tell anyone about what it had found.

People had worried for a long time that paroxetine might increase the risk of suicide, though that is quite a difficult side effect to detect in an antidepressant, because people with depression are at a much higher risk of suicide than the general population anyway, as a result of their depression. There are also some grounds to believe that as patients first come out of their depression, and leave behind the sluggish lack of motivation that often accompanies profound misery, there may be a period during which they are more capable of killing themselves, just because of the depression slowly lifting.

Furthermore, suicide is a mercifully rare event, which means you need a lot of people on a drug to detect an increased risk. Also, suicide is not always recorded accurately on death certificates, because coroners and doctors are reluctant to give a verdict that many would regard as shameful, so the signal you are trying to detect in the data – suicide – is going to be corrupted. Suicidal thoughts or behaviours that don’t result in death are more common than suicide itself, so they should be easier to detect, but they too are hard to pick up in routinely collected data, because they’re often not presented to doctors, and where they are, they can be coded in health records in all sorts of different ways, if they appear at all. Because of all these difficulties, you would want to have every scrap of data you could possibly cobble together on the question of whether these drugs cause suicidal thoughts or behaviour in children; and you would want a lot of experienced people, with a wide range of skills, all looking at the data and discussing it.

In February 2003, GSK spontaneously sent the MHRA a package of information on the risk of suicide on paroxetine, containing some analyses done in 2002 from adverse-event data in trials the company had held, going back a decade. This analysis showed that there was no increased risk of suicide. But it was misleading: although it was unclear at the time, data from trials in children had been mixed in with data from trials in adults, which had vastly greater numbers of participants. As a result, any sign of increased suicide risk among children on paroxetine had been completely diluted away.

Later in 2003, GSK had a meeting with the MHRA to discuss another issue involving paroxetine. At the end of this meeting, the GSK representatives gave out a briefing document, explaining that the company was planning to apply later that year for a specific marketing authorisation to use paroxetine in children. They mentioned, while handing out the document, that the MHRA might wish to bear in mind a safety concern the company had noted: an increased risk of suicide among children with depression who received paroxetine, compared with those on dummy placebo pills.

This was vitally important side-effect data, being presented, after an astonishing delay, casually, through an entirely inappropriate and unofficial channel. GSK knew that the drug was being prescribed in children, and it knew that there were safety concerns in children, but it had chosen not to reveal that information. When it did share the data, it didn’t flag it up as a clear danger in the current use of the drug, requiring urgent attention from the relevant department in the regulator; instead it presented it as part of an informal briefing about a future application. Although the data was given to completely the wrong team, the MHRA staff present at this meeting had the wit to spot that this was an important new problem. A flurry of activity followed: analyses were done, and within one month a letter was sent to all doctors advising them not to prescribe paroxetine to patients under the age of eighteen.

How is it possible that our systems for getting data from companies are so poor that they can simply withhold vitally important information showing that a drug is not only ineffective, but actively dangerous? There are two sets of problems here: firstly, access for regulators; and secondly, access for doctors.

There is no doubt that the regulations contain ridiculous loopholes, and it’s dismal to see how GSK cheerfully exploited them. As I’ve mentioned, the company had no legal duty to give over the information, because prescription of the drug in children was outside of paroxetine’s formally licensed uses – even though GSK knew this was widespread. In fact, of the nine studies the company conducted, only one had its results reported to the MHRA, because that was the only one conducted in the UK.

After this episode, the MHRA and the EU changed some of their regulations, though not adequately, and created an obligation for companies to hand over safety data for uses of a drug outside its marketing authorisation, closing the paroxetine loophole.

This whole incident illustrates a key problem, and it is one that recurs throughout this section of the book: you need all of the data in order to see what’s happening with a drug’s benefits, and risks. Some of the trials that GSK conducted were published in part, but that is obviously not enough: we already know that if we see only a biased sample of the data, we are misled. But we also need all the data for the more simple reason that we need lots of data: safety signals are often weak, subtle and difficult to detect. Suicidal thoughts and plans are rare in children – even those with depression, even those on paroxetine – so all the data from a large number of participants needed to be combined before the signal was detectable in the noise. In the case of paroxetine, the dangers only became apparent when the adverse events from all of the trials were pooled and analysed together.

That leads us to the second obvious flaw in the current system: the results of these trials – the safety data and the effectiveness data – are given in secret to the regulator, which then sits and quietly makes a decision. This is a huge problem, because you need many eyes on these difficult problems. I don’t think that the people who work in the MHRA are bad, or incompetent: I know a lot of them, and they are smart, good people. But we shouldn’t trust them to analyse this data alone, in the same way that we shouldn’t trust any single organisation to analyse data alone, with nobody looking over its shoulder, checking the working, providing competition, offering helpful criticism, speeding it up, and so on.

This is even worse than academics failing to share their primary research data, because at least in an academic paper you get a lot of detail about what was done, and how. 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 discreetly 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. For ‘single technology appraisals’, on one treatment, they ask the company to make available to them the information the company thinks is relevant. For ‘guidelines’ on treatment in a whole area of medicine, they are more vulnerable to what is published in journals. As a result, even NICE can end up working on distorted, edited, biased samples of the data.

Sometimes NICE is able to access some extra unpublished data from the drug companies: this is information that doctors and patients aren’t allowed to see, despite the fact that they are the people making decisions about whether to prescribe the drugs, or are actually taking them. But when NICE does get information in this way, it can come with strict conditions on confidentiality, leading to some very bizarre documents being published. On the opposite page, for example, is the NICE document discussing whether it’s a good idea to have Lucentis, an extremely expensive drug, costing well over £1,000 per treatment, that is injected into the eye for a condition called acute macular degeneration.

As you can see, the NICE document on whether this treatment is a good idea is censored. Not only is the data on the effectiveness of the treatment blanked out by thick black rectangles, in case any doctor or patient should see it; absurdly, even the names of some trials are missing, preventing the reader from even knowing of their existence, or cross referencing information about them. Most disturbing of all, as you can see in the last bullet point, the data on adverse events is also censored: I’m reproducing the whole page here because I worry that it would otherwise be almost too bizarre for you to believe. This level of censorship isn’t an everyday phenomenon; but it illustrates the absurdity of what medicine has come to accept, in professional documents that most people wouldn’t bother to read.⁶⁹

Why shouldn’t we all – doctors, patients and NICE – have access to the information on trials that regulators see? This is something I asked both Kent Woods from the MHRA, and Hans Georg Eichler, Medical Director of the European Medicines Agency, in 2010. Both, separately, gave me the same answer: people outside the agencies cannot be trusted with this information, because they might misinterpret it, either deliberately or through incompetence. Both, separately – though I guess they must chat at parties – raised the MMR vaccine scare, as the classic example of how the media can contrive a national panic on the basis of no good evidence, creating dangerous public-health problems along the way. What if they released raw safety data, and people who don’t know how to analyse it properly found imaginary patterns, and created scares that put patients off taking life-saving medication?

I accept that this is a risk, but I also believe their priorities are wrong: I think that the advantages of many eyes working on these vitally important problems are enormous, and the possibility of a few irrational scaremongers is no excuse for hiding data. Drug companies and regulators also both say that you can already get all the information you need from regulators’ websites, in summary form.

We shall now see that this is untrue.

Two: Regulators make it hard to access the data they do have

When exposed to criticism, drug companies often become indignant, and declare that they already share enough data for doctors and patients to be informed. ‘We give everything to the regulator,’ they say, ‘and you can get it from them.’ Similarly, regulators insist that all you need to do is look on their website, and you will easily find all the data you need. In reality, there is a messy game, in which doctors and academics trying to find all the data on a drug are sent around the houses, scrabbling for information that is both hard to find and fatally flawed.

Firstly, as we’ve already seen, regulators don’t have all the trials, and they don’t share all the ones that they do. Summary documents are available on the early trials used to get a drug onto the market in the first place, but only for the specific licensed uses of the drug. Even where the regulator has been given safety data for off-label uses (following the paroxetine case above) the information from these trials still isn’t made publicly available through the regulator: it simply sits quietly in the regulator’s files.

For example: duloxetine is another drug in fairly widespread use, which is usually given as an antidepressant. During a trial on its use for a completely different purpose – treating incontinence – there were apparently several suicides.⁷⁰ This is important and interesting information, and the FDA holds the relevant data: it conducted a review on this issue, and came to a view on whether the risk was significant. But you cannot see any of that on the FDA website, because duloxetine never got a licence for use in treating incontinence.⁷¹ The trial data was only used by the FDA to inform its internal ruminations. This is an everyday situation.

But even when you are allowed to see trial results held by regulators, getting this information from their public websites is supremely tricky. The search functions on the FDA website are essentially broken, while the content is haphazard and badly organised, with lots missing, and too little information to enable you to work out if a trial was prone to bias by design. Once again – partly, here, through casual thoughtlessness and incompetence – it is impossible to get access to the basic information that we need. Drug companies and regulators deny this: they say that if you search their websites, everything is there. So let’s walk, briefly, through the process in all its infuriating glory. The case I will use was published three years ago in JAMA as a useful illustration of how broken the FDA site has become:⁷² replicating it today, in 2012, nothing has changed.

So: let’s say we want to find the results from all the trials the FDA has, on a drug called pregabalin, in which the drug is used to treat pain for diabetics whose nerves have been affected by their disease (a condition called ‘diabetic peripheral neuropathy’). You want the FDA review on this specific use, which is the PDF document containing all the trials in one big bundle. But if you search for ‘pregabalin review’, say, on the FDA website, you get over a hundred documents: none of them is clearly named, and not one of them is the FDA review document on pregabalin. If you type in the FDA application number – the unique identifier for the FDA document you’re looking for – the FDA website comes up with nothing at all.

If you’re lucky, or wise, you’ll get dropped at the Drugs@FDA page: typing ‘pregabalin’ there brings up three ‘FDA applications’. Why three? Because there are three different documents, each on a different condition that pregabalin can be used to treat. The FDA site doesn’t tell you which condition each of these three documents is for, so you have to use trial and error to try to find out. That’s not as easy as it sounds. I have the correct document for pregabalin and diabetic peripheral neuropathy right here in front of me: it’s almost four hundred pages long, but it doesn’t tell you that it’s about diabetic peripheral neuropathy until you get to here. There’s no executive summary at the beginning – in fact, there’s no title page, no contents page, no hint of what the document is even about, and it skips randomly from one sub-document to another, all scanned and bundled up in the same gigantic file.

If you’re a nerd, you might think: these files are electronic; they’re PDFs, a type of file specifically designed to make sharing electronic documents convenient. Any nerd will know that if you want to find something in an electronic document, it’s easy: you just use the ‘find’ command: type in, say, ‘peripheral neuropathy’, and your computer will find the phrase straight off. But no: unlike almost any other serious government document in the world, the PDFs from the FDA are a series of photographs of pages of text, rather than the text itself. This means you cannot search for a phrase. Instead, you have to go through it, searching for that phrase, laboriously, by eye.

I could go on. I will. There’s some kind of ‘table of contents’ on the seventeenth page, but it gets the page numbers wrong. I’ve finished now. There is simply no reason for this obfuscation and chaos. These problems aren’t caused by technical issues specific to trials, and they would hardly cost any money at all to fix. This is plainly, simply, unhelpful, and the best we can hope is that it’s driven by thoughtlessness.

That’s a tragedy, because if you can unearth this document, and decode it, you will find that it is full of terrifying gems: perfect examples of situations in which a drug company has used dodgy statistical methods to design and analyse a study, in such a way that it is predestined – from the outset – to exaggerate the benefits of the drug.

For example, in the five trials on pregabalin and pain, lots of people dropped out during the study period. This is common in medical trials, as you will shortly see, and it often happens because people have found a drug to be unhelpful, or have had bad side effects. During these trials you’re measuring pain at regular intervals. But if some people drop out, you’re left with an important question: what kind of pain score should you use for them in your results? We know, after all, that people dropping out are more likely to have done badly on the drug.

Pfizer decided to use a method called ‘Last Observation Carried Forward’, which means what you’d expect: you take the last measurement of pain severity while the patients were on the drug, from just before they dropped out, and then paste that in for all the remaining pain measures that they missed, after they stopped coming to follow-up appointments.

The FDA disapproved of this: it pointed out, quite correctly, that Pfizer’s strategy would make the drug look better than it really is. For a fairer picture, we have to assume that the drop-outs stopped taking the drug because of side effects, so their pain score should reflect the reality, which is that they would never get any benefit from the drug in normal use. The correct level of pain to record for them is, therefore, their pain at the beginning of the study, before they had any kind of treatment (if you’re interested, this is called ‘Baseline Observation Carried Forward’). The analysis was duly redone, properly, and a more modest, more accurate view of the benefits of the drug was produced. In this case, it turns out that using the ‘last observation’ method overestimated the improvement in pain by about a quarter.

Here’s the catch. Four out of five of these trials were then published in the peer-reviewed academic literature, the place where doctors look for evidence on whether a drug works or not (one trial wasn’t published at all). Every single one of the published analyses used ‘Last Observation Carried Forward’, the dodgy method, the one that exaggerates the benefits of the drug. Not one of them acknowledges that ‘last observation’ is a technique that overstates these benefits.

You can see why it is important that we have access to all the information we can possibly get on every drug trial: not only are some whole trials withheld from us, but there are often hidden flaws in the methods used. The devil is in the detail, and there are many dodgy trials, as we shall soon see, with flaws that may not be clear even in the academic papers, let alone in the thin and uninformative summaries from regulators. Furthermore, as we shall also see very shortly, there are often worrying discrepancies between the regulators’ summary documents and what actually happened in the trial.

This is why we need to get hold of a more detailed document on each trial: something called the Clinical Study Report (CSR). These are long pieces of work, sometimes thousands of pages, but they are complete enough for the reader to reconstruct exactly what happened to all the participants; and they will let you find out where the bodies are buried. Drug companies give this study report to the regulator – though still only for formally licensed uses of the drug – so both have a copy, and both should be happy to hand it over.

We will now see what happens when you ask them.

Three: Regulators withhold study reports that they do have

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?

We should pause for just one moment, and think about what the EMA is doing here. 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.

This misunderstands a crucial difference between the decisions made by regulators and the decisions made by doctors. Contrary to what some regulators seem to think, a drug is not either ‘good’ and therefore on the market, or ‘bad’ and therefore off it. A regulator makes a decision about whether it’s in the interests of the population as a whole that the drug should be available for use, at all, ever – even if only in some very obscure circumstance, infrequently and cautiously. This bar is set pretty low, as we shall see, and lots of drugs that are on the market (in fact, the overwhelming majority) are hardly ever used.

A doctor needs to use the same information as that available to the regulator in order to make a very different decision: is this the right drug for the patient in front of me right now? The simple fact that a drug is approved for prescription doesn’t mean it’s particularly good, or the best. In fact, there are complex decisions to be made in each clinical situation about which drug is best. Maybe the patient has failed to get better on one drug, so you want to try another, from a different class of drugs; maybe the patient has mild kidney failure, so you don’t want to use the most popular drug, as that causes very occasional problems in patients with dodgy kidneys; maybe you need a drug that won’t interfere with other drugs the patient is taking.

These complex considerations are the reason we are OK with having a range of drugs on the market: even if some of them are less useful overall, they might be useful in specific circumstances. But we need to be able to see all of the information about them, in order to make these decisions. It is not enough for the regulators to grandly state that they have approved a drug, and therefore we should all feel happy to prescribe it. Doctors and patients need the data just as much as regulators do.

In September 2007 the EMA confirmed to the Cochrane researchers that it wasn’t going to share the study reports on orlistat and rimonabant, and explained that it had a policy of never disclosing the data given as part of a marketing authorisation. A serious problem had emerged. These weight-loss drugs were being widely prescribed throughout Europe, but doctors and patients were unable to access important information about whether they worked, how bad the side effects were, which was more effective, or any of a whole host of other important questions. Real patients were being exposed to potential harm, in everyday prescribing decisions, through this lack of information that was enforced by the EMA.

The researchers went to the European Ombudsman with two clear allegations. Firstly, the EMA had failed to give sufficient reasons for refusing them access to the data; and secondly, the EMA’s brief, dismissive claim that commercial interests must be protected was unjustified, because there was no material of commercial interest in the trial results, other than the data on safety and effectiveness, which doctors and patients obviously need to access. They didn’t know it at the time, but this was the beginning of a battle for data that would shame the EMA, and would last more than three years.

It took four months for the EMA to respond, and over the next year it simply reiterated its position: as far as it was concerned, any kind of information the disclosure of which would ‘unreasonably undermine or prejudice the commercial interests of individuals or companies’ was commercially confidential. The study reports, it said, might contain information about the commercial plans for the drug. The researchers responded that this was unlikely, but was in any case of marginal importance, as part of a much more important and pressing situation: ‘As a likely consequence of [the] EMA’s position, patients would die unnecessarily, and would be treated with inferior and potentially harmful drugs.’ They regarded the EMA’s position as ethically indefensible. More than that, they said, the EMA had a clear conflict of interest: this data could be used to challenge its summary views on the benefits and risks of these treatments. The EMA had failed to explain why doctors and patients having access to study reports and protocols should undermine anyone’s reasonable commercial interests, and why these commercial interests were more important than the welfare of patients.

Then, almost two years into this process, the EMA changed tack. Suddenly, it began to argue that study reports contain personal data about individual patients. This argument hadn’t been raised by the EMA before, but it’s also not true. There may have been some information in some whole sections of the study reports that gave detail on some individual participants’ odd presentations, or on possible side effects, but these were all in the same appendix, and could easily be removed.

The EU Ombudsman’s conclusions were clear: the EMA had failed in its duty to give an adequate or even coherent explanation of why it was refusing access to this important information. He made a preliminary finding of maladministration. After doing that, he was under no obligation to offer any further opinion on the weak excuses offered by the EMA, but he decided to do so anyway. His report is damning. The EMA had flatly failed to address a serious charge that its withholding information about these trials was against the public interest, and exposed patients to harm. The Ombudsman also described how he had gone through the study reports in detail himself, and had found that they contained neither any commercially confidential information, nor any details about the commercial development of the drugs. The EMA’s claims that answering the request would have put it under an inappropriate administrative burden were untrue, and it had overestimated the work this would have involved: specifically, he explained, removing any personal data, where it did sometimes appear, would be easy.

The Ombudsman told the EMA to hand over the data, or produce a convincing explanation of why it shouldn’t. Amazingly, the EMA, the drugs regulator covering the whole of Europe, still refused to hand over the documents. During this delay, people certainly suffered unnecessarily, and some possibly also died, simply for want of information. But the behaviour of the EMA then deteriorated even further, into the outright surreal. Any scrap of the company’s thinking about how to run the trial, it argued, which could be intuited from reading the study reports and protocols, was commercially sensitive with respect to its thoughts and plans. This was true, the EMA said, even though the drugs were already on the market, and the information was from final clinical trials, at the very end of the commercial drug-development process. The researchers responded that this was perverse: they knew that withheld data is often negative, so if anything, any other company seeing negative data about these drugs would be less likely to try to get a competitor to market, if it appeared that the benefits of the drugs were more modest than had been thought.

That wasn’t the end of it. The EMA also grandly dismissed the idea that lives were at risk, stating that the burden of proof was on the researchers to demonstrate this. To me this is – if you can forgive me – a slightly contemptuous attitude, especially given what happens in the next paragraph. It’s plainly true that if doctors and patients are unable to see which is the best treatment, then they will make worse decisions, exposing patients to unnecessary harm. Furthermore, it is obvious that larger numbers of academics making transparent judgements about publicly accessible trial data are a much more sensible way of determining the risks and benefits of an intervention than a brief blanket ‘yes or no’ edict and summary from a regulator. This is all true of drugs like orlistat and rimonabant, but it’s also true of any drug, and we will see many cases where academics spotted problems with drugs that regulators had missed.

Then, in 2009, one of the two drugs, rimonabant, was taken off the market, on the grounds that it increases the risk of serious psychiatric problems and suicide. This, at the same time that the EMA was arguing that researchers were wrong to claim that withholding information was harming patients.

And then the EMA suddenly claimed that the design of a randomised trial itself is commercially confidential information.

In case it needs reiterating, let me remind you that the first trial appears in the Bible, Daniel 1:12, and although the core ideas have certainly been refined over time, all trials are essentially identical experiments, generic across any field, with the basics of a modern trial sketched out at least half a century ago. There is absolutely no earthly sense in which anyone could realistically claim that the design of a randomised controlled trial is a commercially confidential or patentable piece of intellectual property.

This was now a farce. The researchers opened all barrels. The EMA was in breach of the Declaration of Helsinki, the international code of medical ethics, which states that everyone involved in research has a duty to make trial findings public. The researchers knew that published papers give a flattering subset of the trial data, and so did the EMA. Patients would die if the EMA continued to withhold data. There was nothing of serious commercial value in there. The EMA’s brief public summaries of the data were inaccurate. The EMA was complicit in the exploitation of patients for commercial gain.

It was now August 2009, and the researchers had been fighting for more than two years for access to data on two widely prescribed drugs, from the very organisation that is supposed to be protecting patients and the public. They weren’t alone. The French ‘prescribers’ bulletin’ Prescrire was trying at the same time to get the EMA’s documents on rimonabant. It was sent some unhelpful documents, including the rather remarkable ‘Final Assessment Report’, from the Swedish agency that had handled the drug’s approval much earlier. You can read this PDF in full online. Or rather, you can’t. On the following page you can see exactly what the scientific analysis of the drug looked like – the document the EMA sent to one of France’s most respected journals for doctors.⁷³ I think it tells a rather clear story, and to add to the insult, there are sixty pages of this in total.

In the meantime, the Danish Medical Authority had handed over fifty-six study reports to Cochrane (though it still needed more from the EMA); a complaint from the drug company about this had been rejected by the Danish government, which had seen no problem with commercial information (there was none), nor administrative hassle (it was minimal), nor the idea that the design of a randomised trial is commercial information (which is laughable). This was chaos. The EMA – which you may remember was responsible for EudraCT, the transparency tool that is held in secret – was going out on a very peculiar limb. It seemed that it would do anything it could to withhold this information from doctors and patients. As we shall see, sadly, this level of secrecy is its stock in trade.

But now we come to the end of this particular road for the EMA. It handed the full, final study reports over to the Ombudsman, reminding him that even the table of contents for each was commercial. Once he had had these documents in his hand, his final opinion came swiftly. There was no commercial data here. There was no confidential patient information here. Hand it over to the public, now. The EMA, at glacial pace, agreed to set a deadline for delivering the data to the researchers, doctors and patients who needed it. The Ombudsman’s final ruling was published at the end of November 2010.⁷⁴ The initial complaint was made in June 2007. That is a full three and a half years of fighting, obstruction and spurious arguments from the EMA, during which one of the drugs had to be removed from the market because it was harming patients.

After this precedent had been set, things had to shift at the EMA; it was forced to revise its approach, and study reports were briefly made more widely available under a new policy (this window has just been shut down, in 2013, as you will read in the Afterword). But even this policy of sharing reports did not solve the problem of access to all information about a trial: the EMA often doesn’t hold all the modules, of all the reports, for all the uses of all the medicines it has approved. And it only holds records for the most recent few years, which is hopelessly incomplete, since in medicine we use treatments that have come on the market over the past few decades. In fact, this loophole is illustrated by the very first request made by the Cochrane researchers who won this great breakthrough with the Ombudsman. They applied for documents on antidepressants: a good place to start, since these drugs have been the focus of some particularly bad behaviour over the years (though we should remember that missing trial data pervades every corner of medicine). What happened next was even more bizarre than the EMA’s three-year battle to withhold information on orlistat and rimonabant.

The researchers put in their request to the EMA, but were told that the drugs had been approved back in the era when marketing authorisations were given out by individual countries, rather than by the EMA centrally. These local authorisations were then ‘copied’ to all other nations. The MHRA, the UK drugs regulator, held the information the researchers wanted, so they would have to approach it for a copy. The researchers dutifully wrote to the MHRA, asked for the reports on a drug called fluoxetine, and then waited patiently. Finally the answer came: the MHRA explained that it would be happy to hand over this information, but there was a problem.

The documents had all been shredded.⁷⁵

This was in keeping, it explained, with the agency’s retention policy, which was that such documents were only kept if they were of particular scientific, historical or political interest, and the files didn’t meet those criteria. Let’s just take a moment to think through what the criteria must be. The SSRI antidepressant drugs have seen many scandals on hidden data, and that should be enough on its own, but if you think back to the beginning of this chapter, one of them – paroxetine – was involved in an unprecedented, four-year-long investigation into whether criminal charges could be brought against GSK. That investigation into paroxetine was the largest investigation that the MHRA has ever conducted into drug safety: in fact, it was the largest investigation the MHRA has ever conducted, of any kind, ever. Quite apart from that, these original study reports contain vitally important data on safety and efficacy. But the MHRA shredded them all the same, feeling that they were not of sufficient scientific, historical or political interest.⁷⁶

I can only leave you there.