Bad Pharma: How Medicine is Broken, And How We Can Fix It. Ben Goldacre

informed the Cochrane group of one large trial (ML16369), but Roche Basel seemed not to know of its existence. But by setting out all the trials side by side, the researchers were able to identify peculiar discrepancies: for example, the largest ‘phase 3’ trial – one of the large trials that are done to get a drug onto the market – was never published, and is rarely mentioned in regulatory documents.^fn3

      There were other odd discrepancies. Why, for example, was one trial on Tamiflu published in 2010, ten years after it was completed?⁸² Why did some trials report completely different authors, depending on where they were being discussed?⁸³ And so on.

      The chase continued. In December 2009 Roche had promised: ‘full study reports will also be made available on a password-protected site within the coming days to physicians and scientists undertaking legitimate analyses’. This never happened. Then an odd game began. In June 2010 Roche said: Oh, we’re sorry, we thought you had what you wanted. In July it announced that it was worried about patient confidentiality (you may remember this from the EMA saga). This was an odd move: for most of the important parts of these documents, privacy is no issue at all. The full trial protocol, and the analysis plan, are both completed before any single patient is ever touched. Roche has never explained why patient privacy prevents it from releasing the study reports. It simply continued to withhold them.

      Then in August 2010 it began to make some even more bizarre demands, betraying a disturbing belief that companies are perfectly entitled to control access to information that is needed by doctors and patients around the world to make safe decisions. Firstly, it insisted on seeing the Cochrane reviewers’ full analysis plan. Fine, they said, and posted the whole protocol online. Doing so is completely standard practice at Cochrane, as it should be for any transparent organisation, and allows people to suggest important changes before you begin. There were few surprises, since all Cochrane reports follow a pretty strict manual anyway. Roche continued to withhold its study reports (including, ironically, its own protocols, the very thing it demanded Cochrane should publish, and that Cochrane had published, happily).

      By now Roche had been refusing to publish the study reports for a year. Suddenly, the company began to raise odd personal concerns. It claimed that some Cochrane researchers had made untrue statements about the drug, and about the company, but refused to say who, or what, or where. ‘Certain members of Cochrane Group involved with the review of the neuraminidase inhibitors,’ it announced, ‘are unlikely to approach the review with the independence that is both necessary and justified.’ This is an astonishing state of affairs, where a company feels it should be allowed to prevent individual researchers access to data that should be available to all; but still Roche refused to hand over the study reports.

      Then it complained that the Cochrane reviewers had begun to copy journalists in on their emails when responding to Roche staff. I was one of the people copied in on these interactions, and I believe that this was exactly the correct thing to do. Roche’s excuses had become perverse, and the company had failed to keep its promise to share all study reports. It’s clear that the modest pressure exerted by researchers in academic journals alone was having little impact on Roche’s refusal to release the data, and this is an important matter of public health, both for the individual case of this Tamiflu data, and for the broader issue of companies and regulators harming patients by withholding information.

      Then things became even more perverse. In January 2011 Roche announced that the Cochrane researchers had already been given all the data they need. This was simply untrue. In February it insisted that all the studies requested were published (meaning academic papers, now shown to be misleading on Tamiflu). Then it declared that it would hand over nothing more, saying: ‘You have all the detail you need to undertake a review.’ But this still wasn’t true: it was still withholding the material it had publicly promised to hand over ‘within a few days’ in December 2009, a year and a half earlier.

      At the same time, the company was raising the broken arguments we have already seen: it’s the job of regulators to make these decisions about benefit and risk, it said, not academics. Now, this claim fails on two important fronts. Firstly, as with many other drugs, we now know that not even the regulators had seen all the data. In January 2012 Roche claimed that it ‘has made full clinical study data available to health authorities around the world for their review as part of the licensing process’. But the EMA never received this information for at least fifteen trials. This was because the EMA had never requested it.

      And that brings us on to our final important realisation: regulators are not infallible. They make outright mistakes, and they make decisions which are open to judgement, and should be subject to second-guessing and checking by many eyes around the world. In the next chapter we will see more examples of how regulators can fail, behind closed doors, but here we will look at one story that illustrates the benefit of ‘many eyes’ perfectly.

      Rosiglitazone is a new kind of diabetes drug, and lots of researchers and patients had high hopes that it would be safe and effective.⁸⁴ Diabetes is common, and more people develop the disease every year. Sufferers have poor control of their blood sugar, and diabetes drugs, alongside dietary changes, are supposed to fix this. Although it’s nice to see your blood sugar being controlled nicely in the numbers from lab tests and machines at home, we don’t control these figures for their own sake: we try to control blood sugar because we hope that this will help reduce the chances of real-world outcomes, like heart attack and death, both of which occur at a higher rate in people with diabetes.

      Rosiglitazone was first marketed in 1999, and from the outset it was a magnet for disappointing behaviour. In that first year, Dr John Buse from the University of North Carolina discussed an increased risk of heart problems at a pair of academic meetings. The drug’s manufacturer, GSK, made direct contact in an attempt to silence him, then moved on to his head of department. Buse felt pressured to sign various legal documents. To cut a long story short, after wading through documents for several months, in 2007 the US Senate Committee on Finance released a report describing the treatment of Dr Buse as ‘intimidation’.

      But we are more concerned with the safety and efficacy data. In 2003 the Uppsala Drug Monitoring Group of the World Health Organization contacted GSK about an unusually large number of spontaneous reports associating rosiglitazone with heart problems. GSK conducted two internal meta-analyses of its own data on this, in 2005 and 2006. These showed that the risk was real, but although both GSK and the FDA had these results, neither made any public statement about them, and they were not published until 2008.

      During this delay, vast numbers of patients were exposed to the drug, but doctors and patients only learned about this serious problem in 2007, when cardiologist Professor Steve Nissen and colleagues published a landmark meta-analysis. This showed a 43 per cent increase in the risk of heart problems in patients on rosiglitazone. Since people with diabetes are already at increased risk of heart problems, and the whole point of treating diabetes is to reduce this risk, that finding was big potatoes. His findings were confirmed in later work, and in 2010 the drug was either taken off the market or restricted, all around the world.

      Now, my argument is not that this drug should have been banned sooner, because as perverse as it sounds, doctors do often need inferior drugs for use as a last resort. For example, a patient may develop idiosyncratic side effects on the most effective pills, and be unable to take them any longer. Once this has happened, it may be worth trying a less effective drug, if it is at least better than nothing.

      The concern is that these discussions happened with the data locked behind closed doors, visible only to regulators. In fact, Nissen’s analysis could only be done at all because of a very unusual court judgement. In 2004, when GSK was caught out withholding data showing evidence of serious side effects from paroxetine in children, the UK conducted an unprecedented four-year-long investigation, as we saw earlier. But in the US, the same bad behaviour resulted in a court case over allegations of fraud, the settlement of which, alongside a significant payout, required GSK to commit to posting clinical trial results on a public website.

      Professor Nissen used the rosiglitazone data, when it became available, found worrying signs of harm, and published this to doctors, which is something that the regulators had never done, despite having the information