by Ben Goldacre
3
Bad Regulators
Getting your drug approved
After all the effort and expense of discovering a molecule, and conducting trials, still nobody can prescribe your drug: first you must go to regulators, and get them to approve it for marketing in their territory. Like so much in medicine, this field has been protected from public scrutiny by the complicated nature of the process, and in general even doctors don’t fully understand what regulators do: as just one illustration of this reality, a 2006 survey by Ipsos MORI found that 55 per cent of hospital doctors and 37 per cent of GPs1 had never even heard of the MHRA, the UK medicines regulator.2
In principle, the job of a regulator is simple: it approves a drug in the first place, after seeing trials that show it works; it monitors a drug’s safety once it’s on the market; it communicates risks and hazards to doctors; and it removes unsafe and ineffective medications from sale. Unfortunately, as we shall see, regulators are beset with problems: there are pressures from industry; pressures from government; problems with funding; issues of competence; conflicts of interest within their own ranks; and worst of all, again, a dangerous obsession with secrecy.
Pressures on regulators
Sociologists of regulation – such people exist – talk about something called ‘regulatory capture’.3 This is the process whereby a state regulator ends up promoting the interests of the industry it is supposed to monitor, at the expense of the public interest. It can happen for a number of reasons, and many of them are very human. For example, if you work in the technical business of drug approval and pharmacovigilance, who can you chat to about your day’s work? To your partner, it’s all baffling and pedantic; but the people in the regulatory affairs division of the companies you work with every day, they understand. You have so much in common with them. So industry bodies – not even necessarily the pharmaceutical companies themselves – might offer things as intangible as friendship, and opportunities to socialise.
That is how regulatory capture works, and it has been discussed at length in the academic literature, as well as by those who seek to influence regulators. A disarmingly honest illustration of how industries view this process can be found in a book called The Regulation Game: Strategic Use of the Administrative Process:
Effective lobbying requires close personal contact between the lobbyists and government officials. Social events are crucial to this strategy. The object is to establish long-term personal relationships transcending any particular issue. Company and industry officials must be ‘people’ to the agency decision-makers, not just organisational functionaries. A regulatory official contemplating a decision must be led to think of its impact in human terms. Officials will be much less willing to hurt long-time acquaintances than corporations. Of course, there are also important tactical elements of lobbying…This is most effectively done by identifying the leading experts in each relevant field and hiring them as consultants or advisors, or giving them research grants and the like. This activity requires a modicum of finesse; it must not be too blatant, for the experts themselves must not recognise that they have lost their objectivity and freedom of action. At a minimum, a programme of this kind reduces the threat that the leading experts will be available to testify or write against the interests of the regulated firms.4
Then there is free movement of staff between regulators and drug companies, a revolving door which creates problems that are very hard to monitor and contain. Government regulators tend not to pay very well, and after some time working for the MHRA you might start to notice that the people in the regulatory affairs department at the companies you work with – the ones you socialise with – all seem to have much smarter cars than you. They live in much more expensive areas, and their children go to much better schools. But they do basically the same job as you, just on the other side of the fence. In fact, as somebody with inside knowledge of the regulator, you can be very valuable to a pharmaceutical company, especially since it is a field where the written rules are often lengthy but vague, and many of the details on ‘what you can get away with’ are effectively an oral tradition.
This movement of personnel then creates a further problem: what if people working for a regulator, while still in post, are thinking of their future at a drug company? It’s possible, after all, that they might be reluctant to make decisions that would alienate a potential future employer. This is a very difficult conflict of interest to monitor and regulate, since no declarable current arrangement exists; it’s also hard to predict who will move; and there is little opportunity to impose sanctions retrospectively. Furthermore, if individuals working at a regulator are changing their behaviour based on vague thoughts of future employment, it probably won’t be on the basis of a specific job plan, or a specific exchange of favours, so clear evidence of corruption will be hard to spot. The whole process may not even be conscious, and in any case, all large organisations are like container ships, taking a long time to change direction. Rather, you might see a shift in the spirit of the workers, and a slow, gradual reorientation of priorities and implicit organisational goals.
The clearest illustration of how these problems are managed by the European Medicines Agency comes from the head of the organisation itself. The EMA regulates the pharmaceutical industry throughout the whole of Europe, and has taken over the responsibilities of the regulators in individual member countries. In December 2010 Thomas Lonngren stepped down as its executive director. On the 28th of that month he sent a letter telling the EMA management board that he was going to start working as a private consultant to the pharmaceutical industry, starting in just four days’ time, on 1 January 2011.5
Some places, and some fields, have clear regulations on this kind of thing. In the USA, for example, you have to wait a year after leaving the Defense Department before you can work for a defence contractor. After ten days the chairman of the EMA wrote back to Lonngren saying that his plans were fine.6 He didn’t impose any further restrictions, and nor, remarkably, did he ask for any information on what kind of work Lonngren planned to do.7 Lonngren had said in his letter that there would be no conflict of interest, and that was enough for everyone concerned.
My concern here is not Thomas Lonngren – although I think we would all struggle to be impressed by his behaviour, since we are all, in Europe at any rate, his former employers. This story is interesting, rather, for what it tells us about the EMA and its casual approach to these kinds of problems. A man who was previously overseeing the approval of new medicines now advises companies on how to get their drugs approved, having given the EMA four days’ notice of this plan, between Christmas and New Year, and nobody in the organisation regards that as a problem, even though it represents a staggering conflict of interest. In fact, this is not so unusual: the Corporate Europe Observatory recently produced a report detailing fifteen similar cases of senior EU officials passing through the revolving door between government and industry.8
But regulator employees aren’t the only people operating with a conflict of interest (a notion I’ll examine more in Chapter 6). Many of the patient representatives who sit on boards at the EMA, including the two on their management board, come from organisations heavily funded by pharmaceutical companies. This is despite EMA rules stating that ‘members of the Management Board…shall not have financial or other interests in the pharmaceutical industry which could affect their impartiality’.
The same problem exists among the scientific and medical experts advising the agencies, and sitting on their boards. In the USA, at the FDA meeting on how to manage controversial cox-2 painkiller drugs like Vioxx, ten out of thirty-two members of the panel had some kind of conflict of interest, and nine of those ten voted to keep the drugs on the market, compared with the 60/40 split among the remainder of the committee. Research reviewing a long series of FDA votes found that experts are slightly more likely to vote in a company’s interest if they have a financial tie to that company.9
There are en
dless stories of conflicts of interest at the FDA, and regulatory decisions that have been distorted by political pressure. I don’t find these kinds of stories very interesting (though I’m glad others document them), because they’re often more soap opera than science, but there’s plainly a problem,10 and it’s not a new one. In the 1950s, US Senator Estes Kefauver ran a series of hearings into the activities of the FDA. He noted that drugs were often approved despite offering no new benefits. Along with many other changes, he recommended that drugs should be licensed, and then be subject to rigorous subsequent reviews for renewal once they were on the market, but FDA officials opposed him, and medical officers there complained extensively of industry influence. One possible explanation for this odd situation comes from the payments that were uncovered: the head of one division had received $287,000 from drug companies, which is over $2 million in today’s money.11
Today, a troubling sense of distorted priorities can still be detected in anonymous surveys of people working at the regulators, though the influences appear to be political rather than financial. The fabulously named ‘Union of Concerned Scientists’ recently surveyed 1,000 scientists working at the FDA and found that 61 per cent said they knew of cases where ‘Department of Health and Human Services or FDA political appointees have inappropriately injected themselves into FDA determinations or actions’. A fifth said that they themselves ‘have been asked, for non-scientific reasons, to inappropriately exclude or alter technical information or their conclusions in a FDA scientific document’. Only 47 per cent thought the FDA ‘routinely provides complete and accurate information to the public’.12 If you’re worried about a think tank conducting a survey, the US Department of Health and Human Services had conducted a similar one two years earlier: again, a fifth of those surveyed said they had been pressured to approve a drug despite reservations about efficacy and safety.13
Then there are testimonies from within the organisation. During the withdrawal of Vioxx from the market, several questionable decisions were made by the FDA. Afterwards, David Graham, Associate Director for Science and Medicine in the Office of Drug Safety, told the US Senate Committee on Finance: ‘The FDA has become an agent of industry. I have been to many, many internal meetings, and as soon as a company says it is not going to do something, the FDA backs down. The way it talks about industry is “our colleagues in industry”.’
Various suggestions have been made, over the years, on how to manage the problem of regulatory experts with industry ties. One, of course, is to exclude them from the decision-making process completely, though this can introduce new problems, if it is hard to find anyone with no such ties. This is not because academics are all corrupt or money-grabbing, but rather because university staff have been energetically encouraged to work collaboratively with industry for over two decades, by governments around the world, in the belief that this will stimulate innovation and reduce costs for the public sector. Having actively created this situation, it would be bizarre if we now had to seriously consider excluding some of our best academics from being able to inform us on issues of efficacy and safety. The question, then, becomes how we can monitor and contain the conflicts of interest that arise.
A second suggestion is that the membership and voting of these panels should be open. On this, the FDA is far ahead of the EMA, where membership, voting and comments have been secret since its inception, with some promises of greater transparency being made in the past year (you will know from what you have already read not to judge a promise from the EMA at face value, but to wait and see what actually happens). It’s worth saying here that while I don’t think it should change anyone’s mind about transparency, there is one argument for secret meetings with unattributed comments: people may be more candid if they know they are speaking off the record, unattributably. ‘I shouldn’t tell you this,’ a professor might say to a room full of people he trusts, ‘but everyone at MGB knows that drug is rubbish, and the latest unreported trial is looking bad too.’
There are other quirks that lead regulators to feel – perhaps – disoriented as to where their allegiances lie. Up until 2010, for example, the EMA sat in the European Commission’s Enterprise and Industry Directorate, rather than under health, which might make you worry that political oversight was more focused on the economic benefits of a friendly relationship with the $600 billion pharmaceutical industry than on the interests of patients.14
In both the United States and the European Union, regulators are paid for almost entirely by drug companies, through the fees that are paid to pass regulatory hurdles. Until a few years ago, when approval was centralised to the EMA, this was a particular source of concern in Europe, because drug companies could choose which country they would seek approval in, and this created something of a competition. Overall this payment model has created an impression that the companies are the customer, but this is not simply because they write the cheques: this change in funding was brought in specifically to improve approval times for industry.
Approving a drug
So what do regulators mean by ‘effective’ when they measure the benefits of a new drug? The specific details for each drug are often a matter of ad hoc negotiation, and in the dark arts of getting a drug approved, inside knowledge and oral tradition are often as valuable as knowing the rules: for example, research has shown that applications from large companies, which have greater experience of the regulatory process, pass through to approval faster than those from smaller companies. In general, however, a company would expect to have to provide two or three trials, with a thousand or more participants, showing that its drug works.
This is where the smoke and mirrors begin. Although the notion of a simple randomised trial should be straightforward, in reality there are all kinds of distortions and perversions that can come into play, in the comparisons that are made, and the outcomes that are measured for success. For me, ‘What works?’ is the most basic practical question that every patient faces, and the answer isn’t complicated. Patients want to know: what’s the best treatment for my disease?
The only way to answer this question when a new drug comes along is by comparing it against the best currently available treatment. But that is not what drug regulators require of a treatment for it to get onto the market. Often, even when there are effective treatments around already, regulators are happy for a company simply to show that its treatment is better than nothing – or rather, better than a dummy placebo pill with no medicine in it – and the industry is happy to clear that low bar.
‘Better than nothing’
This raises several serious problems, the first of which is ethical. It’s obviously wrong to put patients in a trial where half of them will be given a placebo, if there is a currently available option which is known to be effective, because you are actively depriving half of your patients of treatment for their disease. Remember, these are not healthy volunteers, giving their bodies over for financial reward: these are real patients, often with serious medical problems, hoping for treatment and exposing themselves to some inconvenience (but hopefully no more than that) in order to advance the state of medical knowledge for other sufferers in the future.
What’s more, if patients participate in a trial that uses a placebo instead of a currently available effective treatment, they are suffering a double sting. In all likelihood, the trial they’re taking part in is not attempting to answer a clinically meaningful question, relevant to medical practice. Because doctors and patients aren’t interested in whether a new drug is better than nothing, except as a matter of the most abstract and irrelevant science. We’re interested in the practical question of whether it’s better than the best currently available option, and when a drug is approved, at the very least we’d expect to see trials which answer this question.
That is not what we get. A paper from 2011 looked at the evidence supporting every single one of the 197 new drugs approved by the FDA between 2000 and 2010, at the time they were approved.15 Only 70 per
cent had data to show they were better than other treatments (and that’s after you ignore drugs for conditions for which there was no current treatment). A full third had no evidence comparing them with the best currently available treatment, even though that’s the only question that matters to patients.
As we have seen, the Declaration of Helsinki is pretty hot on patients not being exposed to unnecessary harm in trials. It started to get hot on the misuse of placebos in a 2000 amendment which says that the use of dummy pills is only acceptable when
for compelling and scientifically sound methodological reasons [placebo] is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo…will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option.
You will be interested to note that this amendment marked the beginning of the process by which the FDA distanced itself from Helsinki as its main source of regulatory guidance, especially for trials conducted outside the USA (as we discussed earlier, in the section on CROs).16
This same perverse problem of inadequate comparators also exists in the EU.17 To get a licence to market your drug, the EMA does not require you to show that it is better than the best currently available treatment, even if that treatment is universally used: you simply have to show that it is better than nothing. A study from 2007 found that only half the drugs approved between 1999 and 2005 had been studied in comparison with other treatments at the time they were allowed onto the market (and, shamefully, only one third of those trials were published and publicly accessible to doctors and patients).18
Many researchers have argued for this problem of ‘Better than what?’ to be flagged up as prominently as possible, ideally on the leaflet that patients receive in the packet, since this is the only part of the marketing and communications process on which the regulators can exert clear, unambiguous control. One recent paper suggested some plain, simple wording: ‘Although this drug has been shown to lower blood pressure more effectively than placebo, it has not been shown to be more effective than other members of the same drug class.’19 It has been ignored.