Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients (13 page)

Then, in October 2009, the company changed tack: they would like to hand the data over, they explained, but another meta-analysis was being conducted elsewhere. Roche had given them the study reports, so Cochrane couldn’t have them. This was a simple non-sequitur: there is no reason why many groups shouldn’t all work on the same question. In fact, quite the opposite: replication is the cornerstone of good science. Roche’s excuse made no sense. Jefferson asked for clarification, but never received a reply.

Then, one week later, unannounced, Roche sent seven short documents, each around a dozen pages long. These contained excerpts of internal company documents on each of the clinical trials in the Kaiser meta-analysis. This was a start, but it didn’t contain anything like enough information for Cochrane to assess the benefits, or the rate of adverse events, or fully to understand exactly what methods were used in the trials.

At the same time, it was rapidly becoming clear that there were odd inconsistencies in the information on this drug. Firstly, there was considerable disagreement at the level of the broad conclusions drawn by people who apparently had access to different data. The FDA said there were no benefits on complications, while the Centers for Disease Control and Prevention (in charge of public health in the USA – they wear nice naval uniforms in honour of their history on the docks) said it did reduce complications. The Japanese regulator made no claim for complications, but the EMA said there was a benefit. In a sensible world, all these organisations would sing from the same hymn sheet, because all would have access to the same information.

Reflecting this pattern, Roche’s own websites said completely different things in different jurisdictions, depending on what the local regulator had said. It’s naïve, perhaps, to expect consistency from a drug company, but from this and other stories it’s clear that industry utterances are driven by the maximum they can get away with in each territory, rather than any consistent review of the evidence.

Now that their interest had been piqued, the Cochrane researchers also began to notice that there were odd discrepancies between the frequency of adverse events in different databases. Roche’s global safety database held 2,466 neuropsychiatric adverse events, of which 562 were classified as ‘serious’. But the FDA database for the same period held only 1,805 adverse events in total. The rules vary on what needs to be notified to whom, and where, but even allowing for that, this was odd.

In any case, since Roche was denying them access to the information needed to conduct a proper review, the Cochrane team concluded that they would have to exclude all the unpublished Kaiser data from their analysis, because the details could not be verified in the normal way. People cannot make treatment and purchasing decisions on the basis of trials if the full methods and results aren’t clear: the devil is often in the detail, as we shall see in Chapter 4, on ‘bad trials’, so we cannot blindly trust that every study is a fair test of the treatment.

This is particularly important with Tamiflu, because there are good reasons to think that these trials were not ideal, and that published accounts were incomplete, to say the least. On closer examination, for example, the patients participating were clearly unusual, to the extent that the results may not be very relevant to normal everyday flu patients. In the published accounts, patients in the trials are described as typical flu patients, suffering from normal flu symptoms like cough, fatigue, and so on. We don’t do blood tests on people with flu in routine practice, but when these tests are done – for surveillance purposes – then even during peak flu season only about one in three people with ‘flu’ will actually be infected with the influenza virus, and most of the year only one in eight will really have it. (The rest are sick from something else, maybe just a common cold virus.)

Two thirds of the trial participants summarised in the Kaiser paper tested positive for flu. This is bizarrely high, and means that the benefits of the drug will be overstated, because it is being tested on perfect patients, the very ones most likely to get better from a drug that selectively attacks the flu virus. In normal practice, which is where the results of these trials will be applied, doctors will be giving the drug to real patients who are diagnosed with ‘flu-like illness’, which is all you can realistically do in a clinic. Among these real patients, many will not actually have the influenza virus. This means that in the real world, the benefits of Tamiflu on flu will be diluted, and many more people will be exposed to the drug who don’t actually have flu virus in their systems. This, in turn, means that the side effects are likely to creep up in significance, in comparison with any benefits. That is why we strive to ensure that all trials are conducted in normal, everyday, realistic patients: if they are not, their findings are not relevant to the real world.

So the Cochrane review was published without the Kaiser data in December 2009, alongside some explanatory material about why the Kaiser results had been excluded, and a small flurry of activity followed. Roche put the short excerpts it had sent over online, and committed to make full study reports available (it still hasn’t done so).

What Roche posted was incomplete, but it began a journey for the Cochrane academics of learning a great deal more about the real information that is collected on a trial, and how that can differ from what is given to doctors and patients in the form of brief, published academic papers. At the core of every trial is the raw data: every single record of blood pressure of every patient, the doctors’ notes describing any unusual symptoms, investigators’ notes, and so on. A published academic paper is a short description of the study, usually following a set format: an introductory background; a description of the methods; a summary of the important results; and then finally a discussion, covering the strengths and weaknesses of the design, and the implications of the results for clinical practice.

A clinical study report, or CSR, is the intermediate document that stands between these two, and can be very long, sometimes thousands of pages.
⁷⁴
Anybody working in the pharmaceutical industry is very familiar with these documents, but doctors and academics have rarely heard of them. They contain much more detail on things like the precise plan for analysing the data statistically, detailed descriptions of adverse events, and so on.

These documents are split into different sections, or ‘modules’. Roche has shared only ‘module 1’, for only seven of the ten study reports Cochrane has requested. These modules are missing vitally important information, including the analysis plan, the randomisation details, the study protocol (and the list of deviations from that), and so on. But even these incomplete modules were enough to raise concerns about the universal practice of trusting academic papers to give a complete story about what happened to the patients in a trial.

For example, looking at the two papers out of ten in the Kaiser review which were published, one says: ‘There were no drug-related serious adverse events,’ and the other doesn’t mention adverse events. But in the ‘module 1’ documents on these same two studies, there are ten serious adverse events listed, of which three are classified as being possibly related to Tamiflu.
⁷⁵

Another published paper describes itself as a trial comparing Tamiflu against placebo. A placebo is an inert tablet, containing no active ingredient, that is visually indistinguishable from the pill containing the real medicine. But the CSR for this trial shows that the real medicine was in a grey and yellow capsule, whereas the placebos were grey and ivory. The ‘placebo’ tablets also contained something called dehydrocholic acid, a chemical which encourages the gall bladder to empty.
⁷⁶
Nobody has any clear idea of why, and it’s not even mentioned in the academic paper; but it seems that this was not actually an inert, dummy pill placebo.

Simply making a list of all the trials conducted on a subject is vitally important if we want to avoid seeing only a biased summary of the research done on a subject; but in the case of Tamiflu even this proved to be almost impossible. For example, Roche Shanghai 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.
*

There were other odd discrepancies. Why, for example, was one trial on Tamiflu published in 2010, ten years after it was completed?
⁷⁸
Why did some trials report completely different authors, depending on where they were being discussed?
⁷⁹
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.
⁸⁰
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.