Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients (23 page)

To try to manage these problems, for the past few years companies have been required by the EMA to produce something called a Risk Management Plan (RMP) on their drug, and here our problems begin again. These documents are written by the company, and explain the safety studies it has agreed with the regulator; but for absolutely no sane reason that I can imagine, the contents are kept secret, so nobody knows exactly what studies the companies have agreed to conduct, what safety issues they are prioritising, or how they are researching them.

A brief summary is available to doctors, academics and the public, and just recently academics have begun to publish papers assessing their contents, with damning findings.
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After explaining that changes in risk identified from the RMP were communicated unpredictably and inadequately to doctors, one concludes: ‘The main limitation of this study is the lack of publicly available data regarding the most significant aspects.’ The researchers were simply deprived of information about the studies that were conducted to monitor drug safety. A similar study, given slightly better access, looked at the safety studies that
were
discussed in RMPs.
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For about half of these studies, the RMP gave only a short description, or a commitment to conduct some kind of study, but no further information. In the full RMP document, where you would expect to have found full study protocols, the researchers found not one, for any of the eighteen drugs they looked at.

If these Risk Management Plans are drawn up in secret, and their contents are poorly communicated, but at the same time they are the tool used to get drugs to market with a lower threshold of evidence, then we have a serious and interesting new problem: it’s possible that they are being used as a device to reassure the public, rather than to address a serious issue.
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When it comes to the secrecy of regulators, it is clear that there is an important cultural issue that needs to be resolved. I’ve spent some time trying to understand the perspective of public servants who are clearly good people, but still seem to think that hiding documents from the public is desirable. The best I can manage is this: regulators believe that decisions about drugs are best made by them, behind closed doors; and that as long as they make good decisions, it is OK for these to then be communicated only in summary form to the outside world.

This view, I think, is prevalent; but it is also misguided, in two ways. We have already seen many illustrations of how hidden data can be a cloak for mischief, and how many eyes are often valuable for spotting problems. But the regulators’ apparent belief that we should have blind faith in their judgements also misses a crucial point.

A regulator and a doctor are trying to make two completely different decisions about a drug, even though they are using (or in doctors’ case would
like
to use) the same information. A regulator is deciding whether it’s in the interests of society overall that a particular drug should ever be available for use in its country, even if only in some very obscure circumstance, such as when all other drugs have failed. Doctors, meanwhile, are making a decision about whether they should use this drug right now, for the patient in front of them. Both are using the safety and efficacy data to which they have access, but they both need access to it in full, in order to make their very different decisions.

This crucial distinction is not widely understood by patients, who often imagine that an approved drug is a safe and effective one. In a 2011 US survey of 3,000 people, for example, 39 per cent believed that the FDA only approves ‘extremely effective’ drugs, and 25 per cent that it only approves drugs without serious side effects.
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But that’s not true: regulators frequently approve drugs that are only vaguely effective, with serious side effects, on the off-chance that they might be useful to someone, somewhere, when other interventions aren’t an option. They are used by doctors and patients as second-best options, but we need all the facts to make safe and informed decisions.

Some would argue that cracks are appearing in this secrecy, with some new pharmacovigilance legislation coming into force for Europe in 2012 which is supposed to improve transparency.
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But at best, this legislation is a very mixed bag. It does not give access to Risk Management Plans, but it does state that the EMA should publish the agendas, recommendations, opinions and minutes of various scientific committees, which are currently completely secret. We can only judge this small promised change on how it is implemented, if ever, and as we have seen, previous performance from the EMA does not inspire confidence. Even if we set aside the EMA’s astonishing and perverse behaviour over CSRs for orlistat and rimonabant, which you will remember from
Chapter 1
, we should also recall that it has been mandated to provide an open clinical trials register for many years, but has simply failed to do so, still keeping much of that trials data secret to this very day.

In any case, this legislation has several serious flaws.
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The EMA is being set up as the host of a single database for drug safety data, for example, yet this information will still be kept secret from health professionals, scientists and the public. But the most interesting shortcoming of this new legislation is an organisational one.

Many had called for a new ‘drug safety agency’ to be set up, monitoring risks after a drug came to market, as a stand-alone organisation, with its own powers and staff, completely separate from the organisation in charge of approving a drug when it first comes to market.
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This may sound like a dull organisational irrelevancy, but in fact it speaks to one of the most disappointing problems that has been identified in the operations of regulators around the world: regulators that have approved a drug are often reluctant to take it off the market, in case that is seen as an admission of their failure to spot problems in the first place.

That is not idle pontification on my part. In 2004 the epidemiologist from the US Office of Drug Safety who led the review on Vioxx told the Senate Finance Committee: ‘My experience with Vioxx is typical of how CDER [the FDA’s Center for Drug Evaluation and Research] responds to serious drug safety issues in general…the new drug reviewing division that approved the drug in the first place, and that regards it as its own child, typically proves to be the single greatest obstacle to effectively dealing with serious drug safety issues.’ Chillingly, in 1963, half a century ago, an FDA medical officer called John Nestor told Congress almost exactly the same thing: previous approval decisions were ‘sacrosanct’, he said. ‘We were not to question decisions made in the past.’

This is a universal problem in the politics and management of regulators, and it can be seen in the organisational structures: around the world, the departments in charge of monitoring safety and removing drugs from the market are much smaller and less powerful than the departments that approve drugs, which makes institutions reluctant to impose suspensions. Since we are discussing matters of line management and organ-isational structure, and you might suspect that this is merely a vague, handwaving assertion, let me tell you that it is also the verdict of every serious study of regulators,
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from the Institute of Medicine
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to the semi-official biography of the FDA,
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various academics,
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and people from within the organisations.

That is the reason there were so many calls for the EU to create a new Drug Safety Agency, and that is why it’s so concerning that these calls have been ignored. In fact, the same old models have been put back in place, only under different names. The EMA’s Pharmacovigilance Risk Assessment Committee, which decides on whether to remove an approved drug from the market, still reports to the Committee for Medical Products for Human Use, which is the one that approves them in the first place. This perpetuates all of the old problems about removal being difficult, more lowly than approval, and an embarrassment to the approvers.

So what steps can a regulator take when it has established that there is a problem? In very extreme cases it can remove a drug from the market (although in the US, technically drugs usually stay on the market, with the FDA advising against their use). More commonly it will issue a warning to doctors through one of its drug safety updates, a ‘Dear Doctor’ letter, or by changing the ‘label’ (confusingly, in reality, a leaflet) that comes with the drug. Drug-safety updates are sent to most doctors, though it’s not entirely clear whether they are widely read. But, amazingly, when a regulator decides to notify doctors about a side effect, the drug company can contest this, and delay the notice being sent out for months, or even years.

In February 2008, for example, the MHRA published a small piece in its bulletin
Drug Safety Update
, which is read by all too few people. The article stated that the agency was planning a change to the drug label for all statins, a class of drug given to reduce cholesterol and prevent heart attacks, following a review of clinical trial data, spontaneous reports of suspected adverse drug reactions, and the published literature. ‘Product information for statins is being updated to reflect a number of different side-effects as class effects of all statins.’ It explained: ‘Patients should be made aware that treatment with any statin may sometimes be associated with depression, sleep disturbances, memory loss, and sexual dysfunction.’ The agency also planned a new warning that – very rarely – statin therapy might be associated with interstitial lung disease, a serious medical condition.

The decision to add these new side effects to the label was made in February 2008, but it took until November 2009 for an announcement that the change was finally being made. This is a delay of almost two years. Why did it take so long? The
Drugs and Therapeutics Bulletin
discovered the reason: ‘One of the innovator MA [marketing authorisation] Holders was not in agreement with this wording.’
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So, a drug company was able to delay the inclusion of safety warnings on a whole class of drugs prescribed to four million people in the UK for twenty-two months because it didn’t agree with the wording.

But what good would have come of changing the label in any case?

This is the final component of our story. It’s difficult for doctors and patients to get a clear, up-to-date picture of the risks and benefits of drugs, from any source, but since the regulators have privileged access to information, we should expect them to do a particularly clear job of communicating what they have, as there is by definition no competition for providing information here, and no opportunity to shop around: the regulators are the only people with access to all of the data.

Drug labels are lauded by regulators as a single, awesome repository of information, by which prescribers and patients alike can be educated and informed. In reality, they are chaotic and not very informative. They often discuss trials, but give no reference to enable you to find out more, or even to work out which trial they’re discussing. Sometimes the basic elements of a trial are so bizarrely different in the regulator document and the published paper that it’s hard to match them up even if you try, and even if the trial has been published. What’s more, most labels feature long lists of hundreds of side effects, with poor information as to how common they are, even though most of them are very rare, and are not even confidently associated with the drug anyway. Too much information, communicated chaotically, is every bit as unhelpful as too little information.

Some US researchers have been campaigning for over a decade to add a simple ‘drug facts box’ to the information given to doctors and patients alongside the rather dense and confusing ‘label’. This box would be a summary document giving clear, quantitative information on the risks and benefits of the drug, using evidence-based strategies for communicating statistical information to lay people. There is randomised controlled trial evidence showing that patients given this drug facts box have better knowledge of the benefits and risks of their drugs.
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The FDA has suggested that it will think about using them. I hope that one day it will, and that it will make these boxes itself.

So you can see the difference for yourself, below is the drug facts box for a sleeping pill called ‘Lunesta’.

This drugs fact box is briefer than the official label for the same drug, which appears after it: I think it’s also much more informative. It doesn’t solve all the problems of secrecy, or even all the problems of poor communication. But it does demonstrate very clearly that regulators have neither earned nor respected their special status when it comes to assessing and communicating risk.

Solutions

We have established that there are some very serious problems here, both in how we approve drugs, and in how we monitor their safety once they become available. Drugs are approved on weak evidence, showing no benefit over existing treatments, and sometimes no benefit at all. This gives us a market flooded with drugs that aren’t very good. We then fail to collect better evidence on them once they’re available, even when we have legislative power to force companies to do better trials, and even when they’ve promised to do so. Lastly, side-effects data is gathered in a slightly ad hoc fashion, behind closed doors, with secret documents and ‘risk management plans’ that are hidden from doctors and patients for no good reason. The results of this safety monitoring are communicated inconsistently, through mechanisms that are uninformative and are therefore used infrequently, and which are, in any case, vulnerable to spectacular delays imposed by drug companies.