AFTERWORD: WHAT HAPPENED NEXT?
A lot has happened in the year since Bad Pharma was first published. On the issue of missing trials, there is the beginning of a popular movement that could deliver real change, with your help, as we will see. But first, it may be useful to look at how the book was received. While colourful idiocy makes for fun stories, most reactions have been very sensible (with notable exceptions). Bad Pharma is not an easy book to read if you work in the pharmaceutical industry, or even in medicine; this combative thoughtfulness has been truly encouraging.
From medics and academics – in letters, emails, conversations and at public events – the response has been positive and pragmatic, with a gung-ho approach to fixing the flaws. Those with concerns, for the most part, had few serious objections to the factual content. It would be graceless to address individuals in a book, where they can’t answer back, but I can give you a flavour of their concerns.
Some felt it was wrong to frighten patients by telling them about the problems in medicine. This, I think, is a matter of culture. There are two strands around ‘public engagement’ activity for science. One strand involves telling everyone how fantastic science is, with colourful images of molecules and the galaxy, exciting explosions, and so on. The other is more collaborative: discussing the problems, the shortcomings and challenges, so that an informed public can help us overcome barriers to change. I put myself firmly in the latter category, mainly because – after meeting a lot of them, as a doctor – you know that the public aren’t stupid. This book is a clear description, for a lay audience, of shortcomings in medicine that have been widely discussed and documented in academic journals for many years. I believe we have a duty to share the problems in science, especially when we have failed to fix these problems ourselves; and I believe we need the public’s help to deliver change.
Some objected to the book’s tone, in parts. One extremely senior British doctor, whom I shall not name, asked if it was really necessary to use ‘inflammatory’ terms like ‘avoidable suffering and death’, when the correct words are ‘morbidity and mortality’. This one comment has stayed with me, because it speaks volumes about why the fixable problems described in these pages have remained unaddressed for so long: we have allowed the abstract world of effect sizes, forest plots and primary outcomes to be walled off from the real world of suffering, bereavement and death.
This should come as no surprise. Like many doctors, I was frankly traumatised by some of the experiences I had early on in my career. When you lean over a patient in A&E, trying to bring a dead body back to life, you are entirely focused on the job in hand. On the other side of a thin curtain, you can hear that person’s husband or wife, howling and wailing, knowing that the person they have loved and lived with for fifty years is dying, begging the staff to do all that they can, phoning their children, struggling to speak through tears to form the words and communicate the horror, telling them to come, quickly. I have memories from cubicles that I will never be able to shift, and they upset me even now. But those moments are all about one, single, death.
We learn, in medicine, to block out these feelings, so we can get the job done. With research, we have the opposite challenge: we need to force ourselves to give the numbers the emotional content they deserve. This isn’t just true for the problems set out in this book, it’s also true for teaching evidence-based medicine. Go back to page 15 and look at the forest plot for the Cochrane logo. That abstraction speaks to a horror: parents whose babies struggled to breathe and then died, with all the suffering and horror that entails, the bereavement, the scarred relationships, and the pain. Nobody who is taught that graph in medical school experiences one hundredth of the emotional impact from it that they do from telling one mother that her child is dead: yet that graph is a representation of exactly that suffering, on a grand scale.
This is why, when I talk about avoidable ‘mortality’ and ‘morbidity’ – as a result of shortcomings in our abstract systems for gathering, synthesising, disseminating and implementing evidence – I will always use the better words, ‘suffering’ and ‘death’. Because only they have even a small chance of nudging us towards feeling the feelings we ought to feel. That is how we will overcome complacency, and drive improvement.
Another comment came predominantly from doctors working in the pharmaceutical industry. We should be clear, once again, that these are largely good and thoughtful individuals. They felt wounded, arguing that the book gives too little credit to the people who have tried and failed to fix these problems, especially in the UK, over the past thirty years. On this, I can’t fight the reflex to point to the text: pages 48 to 51 cover some of these failed initiatives, enough for a lay reader, who will soon move on to something more cheerful. The successful passage of primary legislation in the US requiring all results to be posted on clinicaltrials.gov within a year of completion – and the ensuing failure to implement or audit that law – is far more significant than the admirable but failed efforts of some people in the UK in the 1990s. I hope that one day they publish a history of their struggle: I will read it.
Less thoughtful people from the industry sometimes said: ‘How can you say these problems harm patients, when drugs must always be better than placebo if they are to get onto the market?’ This betrays a stunning lack of ambition, but explains, I think, how people have been able to justify promoting mediocre drugs. Let’s imagine there are two treatments: both cost the same amount, but one saves six lives for every hundred people taking it, and the other saves eight lives. Which treatment do you want? They’re both better than nothing. From a bird’s-eye view of the problems, I think that treatments which actively do more harm than good are pretty rare. But again, that’s a very low ambition. We are commonly bounced into giving people the second-best treatment in a class, through a combination of badly designed trials, trials that are never done, missing results, and biased dissemination of evidence through aggressive marketing. Where this happens, patients are harmed. They’re not worse off than if they had been born in the Stone Age – of course they’re not. They’re just worse off than they need to be. If there are eight people tied to a railway track, with a very slow shunter crushing them one by one, and I only untie the first six before stopping and awarding myself a point, you would rightly think that I had harmed two people. Medicine is no different.
The same people sometimes felt I didn’t say often enough that the industry has made some good drugs. I’ll say it again: the industry has made some good drugs.
One extremely senior doctor said, on the topic of missing trials (and I am quoting verbatim): ‘Look here, old boy, we were working well to fix these problems behind closed doors. Was it really necessary to make such a fuss, and frighten the public?’ We were standing, at the time, in an oak-panelled room. Once again, I have to say: we were not fixing this problem behind closed doors. We were not. We needed the help of the public, of lawyers, civil servants, campaigners, politicians, journalists, and more. We are now starting to get that help, and we should be glad of it, because we had failed: we failed to prioritise this problem, and we failed to fix it.
On a related note, you may remember the Ethical Standards in Health and Life Sciences Group, co-chaired by the ABPI and the Royal College of Physicians. They produced the documents discussed on page 357, which claim (quite falsely) that trial results are made available, and so on. An impressive campaign was led by medical students atbadguidelines.org, and the response has been mixed, to say the least: the BMA and theLancet have removed their names, which is reassuring, but others have not; and the two documents have remained online, now marked as ‘under review’, without action, for half a year. All the organisations that signed these documents were approached, and almost all have declined to explain how or why they came to sign up to a series of false statements. I have been clear, throughout this book, that doctors collaborating with the pharmaceutical industry is a good thing (at the very least, you would have to agree that it is inevitable) but there are risks to be managed: there is a clear need for good, evidence-based guidelines, and it is a shame that the most eminent organisations in medicine and academia are still failing to deliver. On an upbeat note, the BMA passed a formal motion at its annual conference this year, declaring unambiguously that non-publication of trial results is research misconduct. I hope others will follow.
Some from industry took offence at the title, though they largely relaxed when they read the book. The pharma industry does harm patients. It’s not all that it does – of course it’s not – but avoidable harm is something we all need to talk and think about. The Francis Report into poor care in British hospitals has shown the harm that can come when medics get caught up in denial and obfuscation. If I regret one thing, though, it is that the focus of Bad Pharma – of the title, at any rate – was too much on the industry. I don’t say this because the title worried people who work in drug companies: I say it because it helped doctors, policymakers, universities and regulators to continue letting themselves off the hook. If I was publishing this book tomorrow, its subtitle would be ‘How Medicine Fails to do the Best for Patients’. My favourite working title before publication, greeted with derision by my publisher, was: ‘The Information Architecture of Medicine has Several Interesting Flaws, Many of Which Inflict Avoidable Harm on Patients, But All of Which are Amenable to Cost-Effective Change, Were There to be Adequate Public and Political Will’. That remains my preferred option.
From industry PR people I expected a slick sop (‘These are important problems that we are working to fix, together with stakeholders’) and a competent kick into the long grass. I predicted in the Conclusion to the first edition of this book that the worst elements would respond in three ways: they would issue personal comments; they would point to mountains of legislation that has been shown to be ineffective, as if that were an answer; and they would say that the problems I have described are all in the past. The response from ABPI itself – the official representative body of the pharmaceutical industry in the UK – did not fall far short.
I should cover the silliness, briefly, but there are more interesting battlegrounds than this. I’ve been shown written comments from Stephen Whitehead, the Chief Executive of the ABPI, that I choose not to reproduce here. They’re unpleasant, and essentially try to frame me as some kind of fringe figure, who is not to be taken seriously: it’s for you to decide whether he’s correct, and whether his behaviour here is stylish, or surprising.
In public, both Stephen Whitehead and Deepak Khanna – president of the ABPI – said things like ‘during the development of Mr Goldacre’s book, the ABPI did try on numerous occasions to make contact with Mr Goldacre, and were disappointed that he did not respond’. You can call me mister all you like, but I am open to discussion with anyone: my email address is on my website, in my Twitter profile, at the foot of five hundred newspaper articles, and in all my books, including this one. There can’t be many more accessible doctors or writers in the world. My email address is ben@badscience.net, I’ve searched back ten years, and I can’t find these numerous approaches anywhere (for total clarity: one generic email from one ABPI press officer, two years ago, to myGuardian email address, saying ‘I just started here a couple of weeks ago and thought I’d introduce myself. I know you cover the subject sometimes, so if you’re ever looking for stats/information/etc relating to the industry let me know’).
Equally baffling – but much more important – was the ABPI’s claim, in a press release on the day of the book’s publication, that the cases were all ‘long-documented’, ‘historical’ and ‘long-addressed’. As a PR strategy, this was unwise, to say the least. Far from being historic, many of the issues discussed are core elements on the medical student curriculum: it would be impossible to pass an undergraduate epidemiology course without knowing about design flaws in clinical trials, or the shortcomings of observational data. The problem of withheld trial results is vast and plainly ongoing. Suggesting that these cases are historic was also optimistic, because every month there are new examples of these ongoing problems. Medicine isn’t perfect, so we document and discuss its imperfections constantly, in an effort to fix them. Follow this asterisk[1] and you will find a 1,200-word-long footnote: it is a brief walk through the academic literature from just the past few months, a small selection of the greatest hits from the newest research about these ongoing problems, which really are the bread and butter of medical academic discourse.
I don’t think the many ethical professionals in the pharmaceutical industry are well served by a representative body that is willing to imply that these cases are all in the past. I also don’t believe that policy-makers – who need to talk to industry – will feel enthusiastic about an industry body that is willing to gloss over live problems. But finally, as explained throughout this book, even if all this shoddy practice had miraculously ceased in August 2012, then we would still need to know about it. This is not for some kind of moral reckoning: it’s because the medicine of today is practised on the evidence of yesterday, of the past year, the past five years, and the past five decades.
Once again, this is not simply about the pharma industry: it is about a culture of complacency in medicine, an inappropriate lack of urgency about solving the everyday problems we face, and an ‘excuses culture’ that perpetuates them. In the deluge of mail from academics that followed Bad Pharma’s publication, I received endless everyday tales that spoke to this issue. One academic forwarded the response he’d had from a journal editor after submitting a paper documenting clear bad practice. The editor’s comments betray a world view that is holding medicine back from doing the best we can for patients. I reproduce one sentence with permission:
There is nothing unusual about drug manufacturers producing one-sided promotional material, or about there being uncertainty about a medication’s place in therapy because of a scarcity of adequate data, so the indignity expressed in the commentary seems out of proportion to the commonness of the problems.1
Similarly, one reader forwarded a letter from his MEP, who had previously been a clinician, in response to a letter about shortcomings in the evidence for prescribing decisions: ‘The objections you raise do not endanger patient safety in any way, [they] only question clinical efficacy compared to existing similar medicines.’ This reveals, once more, a dangerous lack of ambition in medicine: it is not enough that we prescribe medicines that are better than nothing; we need to ensure that we are prescribing the best treatment. Where we fail to do that, we expose patients to avoidable harm, as surely as if we had inflicted that harm recklessly and directly, through incompetence or malice.
The AllTrials Campaign
There has, however, been some small movement on the key issue of missing trials. Some of this has been triggered by Bad Pharma, but it has acted only as a catalyst (if I’m honest, the outlandish denials from industry have also helped, in some quarters: people love a scrap, and a bad opponent can do a lot to galvanise busy people into action, or remind them that an issue is still alive). But most importantly, while the formal policy units of medical and academic professional bodies had largely neglected the issue of transparency, there was huge pent-up demand for more action in the wider community, going back for at least three decades.
So: last September, an MP and GP called Sarah Wollaston asked me in for a meeting, and then tabled a parliamentary question on missing trial results. These questions are given to the Minister in advance, so as is common, the Health Minister responded in advance, at 7 a.m., in a slot on the BBC Radio 4 Today programme. He explained that the problem simply doesn’t exist: ‘By law, companies must report any adverse reactions experienced in trials, as well as all results both positive and negative, and any abandoned or incomplete studies.’ Five hours later, the formal response in Parliament more closely reflected reality:
“The government support transparency in publishing results of clinical trials, and they recognise that more can, and should, be done… Greater transparency can only serve to further public confidence in the safety of medicines. My Hon. Friend raises absolutely legitimate concerns, which have been raised by others, including Ben Goldacre.”
This turnaround is a microcosm of the battle over missing trial results: outright denials and reassurance, before a slow erosion to more serious engagement. The Minister agreed to meet a group of us, so we went along: Sarah Wollaston MP, Fiona Godlee (editor of the BMJ), Iain Chalmers (co-founder of the Cochrane Collaboration), Carl Heneghan (director of the Centre for Evidence Based Medicine in Oxford), and myself. The meeting was positive, and we organised a letter to The Times, signed by the great and good of British medicine, from the president of the Royal College of GPs, to the editor of the Lancet. You might think these letters are trivial, or pompous, but this one was helpful for two reasons: firstly, it was a line in the sand against widespread denialism, and called for clear action, over an ongoing problem; secondly, it showed a broader front for the issue, which makes it harder to smear the discussion away.
Coverage picked up in all UK newspapers, from the Mail and the Telegraph to theIndependent and others. The House of Commons Science and Technology Select Committee announced an inquiry into the issue (citing this book in its announcement, and also, I’m pleased to say, covering the bureaucratic barriers to getting trials done, which is equally important, as you will know from Chapter 5). This is yet to report its findings, and it is always possible that it might end up holding progress back. However, one important outcome has already been delivered: both MRC and NIHR, major UK academic research funders, have conducted internal audits on their rate of publication – and found that they publish 89 per cent and just under 100 per cent of all trials, respectively. Regardless of the specific numbers, since academic trials, just like industry trials, have been racked by publication bias – and clear public audit is the only way forward – the very existence of these figures is a small victory.
Next, a group of MPs (including David Davis, Sarah Wollaston and Julian Huppert) wrote to the hugely influential Public Accounts Committee, and as a result the National Audit Office is now conducting a formal inquiry into Tamiflu. The Health Select Committee had clear words for NICE and the pharmaceutical industry on ensuring that all results are made available. There were further questions in Parliament, including a Prime Minister’s Question: this was answered with a blasé promise that everything was about to be fixed in Europe. At that point, it became clear that we needed a proper campaign.
The author Simon Singh is shy, and doesn’t want people to know that he had £5,000 to spare, so this is our secret: he very generously gave us the money we needed to cover the costs of an intern at Sense About Science for a few months. Simon and I had both worked with them before, on quackery, bad science reporting, and the incredibly successful Libel Reform campaign. The experience at Sense about Science of lobbying, drawing together interested parties and running a public campaign was exactly what our small group of academics and doctors needed. The AllTrials campaign launched in January 2013, calling for three things: all trials should be registered, all results should be reported, and clinical study reports should be made publicly available. The campaign’s central group includes the BMJ, Cochrane, the Centre for Evidence Based Medicine, patient advocates, and the open-access publisher PLoS. Within a few months, from nothing, the AllTrials campaign has grown to represent the mainstream, normative position in the UK. We now have over 50,000 individual supporters, and more than two hundred organisations have also signed up, including the Medical Research Council, NICE, the Wellcome Trust, and effectively all the major medical and academic faculties, societies, Royal Colleges and so on. There is also extensive international support, from organisations as widespread as the National Physicians’ Alliance in the US to the European Public Health Association. Among the earliest signatories were patient groups, which now number well over a hundred, with eighty signing up on one day alone. This is key, because patients are showing leadership on this issue, helping professionals to find their way. The National Rheumatoid Arthritis Society – which came in for some criticism on page 272 – was one of our earliest supporters, and I am hugely impressed by what I have seen in this whole community (NRAS in particular have now shown real leadership on increasing transparency about their finances, as well as for clinical trials).
Then, in March, GlaxoSmithKline signed up to the AllTrials campaign. That is hugely significant: like most other pharmaceutical companies, GSK has received enormous regulatory fines over the past few years, and you will remember some of the stories involving it from earlier in this book. In October 2012 it had already promised to share some individual patient data with individual research groups, behind closed doors, after review by a panel, for trials going back to 2007. By signing up to AllTrials in 2013, GSK has committed to something different: it will make all clinical study reports publicly available within a year of completion of the trial; and it will apply this retrospectively, going back to the beginning of the company. There are several things that make me believe GSK is sincere, rather than merely making a quick PR move. Firstly, in a meeting with chief executive Andrew Witty the week before GSK signed up, he was combative, with specific questions about what information we wanted in the public domain, and why. From the moment the policy was announced, it was clear that GSK had thought through the specifics, such as how to prioritise trial reports for release, and how to redact genuinely confidential patient information. Lastly, the GSK team delivering this commitment has come to AllTrials meetings, presented on progress, and given timelines that are in advance of the suggested minimums. We can judge them by results, next year, but that is my risk assessment so far.
GSK has done something far more than simply promising to share specific pieces of information on its own drugs, though: it has shown leadership, and formally recognised that transparency matters for patient care, at a time when others in the industry are hoping the issue can be dodged. It has shown that delivering on transparency is possible, and has undermined other companies’ claims to the contrary. In fact, GSK commit-ted to share all clinical study reports in the very same week that PhRMA, the US industry body, put out a colourful press release saying that transparency was expensive, impractical, dangerous and impossible.
If AllTrials has had an impact, it is because it has encouraged organisations and companies to make a clear commitment on transparency, and declare where they stand. It has also provided a focus for lobbying activity, and a venue for discussions. Crucially, it has also allowed individuals to feel safe about speaking out. There is one comment we heard from policy staff in certain signatory organisations that I found chilling: we knew that withholding trial data was common, they said, and we knew that it harms patients, but we felt embarrassed to talk about it, because even raising the issue seemed somehow subversive. This is a terrifying state of affairs, and a testament to the power of aggressive lobbying by the industry. It is also, perhaps, a testament to the capture of key opinion leaders, and to the dangers of longstanding inaction at senior levels in the medical establishment. In the UK, we have seen the same phenomena during prominent inquiries into failing hospitals: many senior staff, in numerous organisations, saw a problem, but most were too busy – or too anxious about workplace conflict – to put patients first.
Europe, and Beyond
It was crucial that the campaign grew when it did, because there were several events happening at the same time which needed to be harnessed, and influenced. Here the story becomes so detailed that I can only give an outline: I strongly encourage you, if you are interested, to visit www.alltrials.net and follow it through.
Firstly, the European Union Clinical Trials Regulation was already up for revision, with a Labour MEP, Glenis Willmott, as the ‘lead rapporteur’ (who guides the legislation through the European Parliament). We were able to work with her at a time when she was under phenomenal pressure from hundreds of industry lobbyists in Brussels. She has been excellent, making a clear public commitment to transparency, and introducing several crucial amendments to a deeply flawed piece of legislation. There is the prospect of ensuring that all trials conducted within a European country after 2014 will report results within a year, with a clear audit trail of changes to the protocol, and so on. This is far less than patients need, since it leaves all trials from before 2014 (and all those conducted outside Europe) untouched, but it is at least some small progress. The battle, however, is not yet won, and the key votes will come over the next year, with the second reading in October.
Through AllTrials there have been various meetings in the UK on how to practically deliver transparency. There has also been a series of other meetings, hosted by people like Wellcome, and even the ABPI, although these have often acted more as a noticeboard for opponents of transparency to publicise their objections. Even here there has been progress, though. Roche has announced a policy to share more clinical study reports, and sent some new information to Cochrane that is currently being assessed (though we must remember its previous broken promises – see pp.82–91). At the recent All Party Parliamentary Group meeting, when the Roche representative agreed that ‘transparency is a must’, everybody nodded enthusiastically. Julian Huppert MP (a rare scientist in Parliament) said: ‘Myself and Sarah Wollaston MP are smiling, because there is a stark difference between that accord, and the ABPI meeting we went to, where the discussion was all about how impossible this is.’ Is it now fashionable to say you support more transparency? The answer may be yes: this is why we must judge people on what they deliver.
Some regulators have moved firmly in the right direction. In May 2013 the UK Health Research Authority sent out a groundbreaking set of new proposals to improve transparency around trials conducted in the UK, with a range of impressive and solid practical suggestions (as I said, rather cheesily, in the HRA press release). In July its action plan was announced.
Meanwhile in November 2012 the European Medicines Agency made a remarkable announcement: it is planning to share individual patient data, for all the trials it is given, starting from 2014. There is no doubt about whether the EMA will do this, it explained; the only thing to be discussed is how. The outstanding questions are complex. Sharing individual patient data is fairly common, especially within academia, but unlike clinical study reports, where personal data can be easily redacted, individual patient data poses a genuine risk of reidentification. It is also not clear whether this rule will be imposed retrospectively, or only for trials completing (or maybe even starting) after 2014.
This has created an outpouring of activity from the industry: the changes have even been raised by PhRMA lobbyists with the US team working on EU/US trade treaty negotiations. At the launch of the new EMA policy, I sat on a discussion panel alongside Peter Gøtzsche of Cochrane and Ginny Barbour from PLoS, up against two representatives from EFPIA, the industry body. EFPIA argued that individual patient data should – at most – only be shared with people who can prove that they have a serious academic question. Crucially, they said that everyone wanting access to data sets should be compelled to disclose their full protocol and statistical analysis plan beforehand. This is a sensible demand to make, in some respects, because where people don’t post their protocol and analysis plan, there is room for them to go on long statistical ‘fishing trips’, changing their analysis until it provides an answer that suits their wishes or preconceptions (as you now know, from reading this book). That is why many of us have asked that everybody running a trial should themselves post their full protocols and statistical analysis plans (and a log of all changes) in public. We need the people running trials to post their analysis plans for their own data, publicly, for all the same reasons that we want outsiders working on other people’s data to do so.
This suggestion was not met with enthusiasm. I was struck most by an industry lawyer, who spoke without a shred of self-doubt, or subsequent regret. Look, he said: we pay for the trial to be done, it should be our choice how that data is used. There was no sharp intake of breath, no sense of astonishment, and I felt very strongly that all of us in that room, in our suits, had become acculturated to accepting some truly remarkable positions. This man was charming and friendly, with no hint of bad intentions. I don’t believe for one moment that he could sit down with a patient at breakfast, and tell them that they had no right to access the most complete possible information about the tablet they were about to swallow. He is, in my view, both the product and a beneficiary of the complexity around this whole area: he was making his case in a room full of people who were no longer shocked by his position, with everyday patients several hours’ reading away from being able to understand its implications. In any case, since then there have been a series of advisory groups on how this should work (with many of us from AllTrials – and fellow travellers – involved, as well as many from industry); in September 2013 the EMA’s draft proposal will go out for consultation, and by November it will be finalised.
All has not been roses in Europe, however. You will remember (pp.77–9) that the EMA was forced to share clinical study reports, after the EU Ombudsman made a ruling of maladministration against the agency. This policy has, in fact, been a quiet success, and over 1.9 million pages of documents were shared up until May 2013, when the programme was forced to a dramatic halt. Many of the applicants for these documents were from industry, and many in industry took objection to this. In my view, companies seeing each other’s trials is good for transparency: if anyone is likely to spot a hole in your claims, it is a competitor, and this is a common phenomenon in complex regulatory areas. Many complaints to the medicines marketing regulator (or rather, self-regulator) come from rival drug companies’ sales reps; and even with the Advertising Standards Authority it’s common to find that the complaint about a technically inaccurate claim from one paint shop was made, in triumph, by the paint shop down the road.
In any case, two companies, InterMune and AbbVie, sued the EMA, demanding that it stop releasing clinical study reports on their drugs. An interim ruling has now been issued by the General Court of the European Union, forcing the EMA to stop. Although the agency initially promised to be combative, and encouraged people to continue applying, the legal advice we received at AllTrials was clear: it would find it impossible to release any further information with this court order hanging over them. Within a month, the first Cochrane request for a clinical study report was rejected. It is now clear that this is one of the most significant backward steps that has ever been seen in the battle for transparency: where briefly CSRs were available, they are now once again kept under lock and key. This is extremely serious, since we now know – from the work done on Tamiflu, but also other work published just this year on a series of gabapentin trials21 – that brief trial reports in academic journals can be incomplete or misleading about the methodological shortcomings in a study’s design. Wealthy industries are fond of saying, with huge, expensive court cases like these, that they simply want clarity on the law. It will take several years for the full hearing to pass through the court system, and during that time, medicine will be gravely held back.
Despite its pivotal role, in testament to the complexity of this area, the AbbVie and InterMune case has received almost no mainstream media coverage. Both PhRMA and EFPIA supported the two companies in their court action, while at the same time proclaiming that they are in favour of transparency. At the same time, while professing to support transparency in principle, the ABPI has campaigned hard against AllTrials, saying, formally and on the record, ‘we will not respond to PR-driven initiatives such as AllTrials’ (a remarkable response to a group supported by over a hundred patient groups, representing over a million people, the very people who participate in trials).
Then, in July 2013, an extraordinary document was leaked: it was an internal PhRMA and EFPIA memo, sent to leaders of major pharma companies around the world, setting out their strategy on transparency.22 Under the heading ‘Advocacy’, it discussed a plan for ‘mobilizing patient groups to express concern about the risk to public health by non-scientific re-use of data’. The notion of using patient groups as an advocacy tool against transparency is one that many people will find abhorrent. Many patient groups – including the European Patients Forum, the European Cancer Patient Coalition and a wide coalition of AIDS charities – were appalled by this notion, and sent out clear statements confirming their commitment to information being made available.23 It will be interesting to see which patient groups – if any – raise objections to greater transparency over the coming year.
During all this time, evidence on the scale of the problem has continued to mount. The most recent paper, from July 2013, tracked 8,907 trials registered on clinicaltrials.govover three years: for over half of them they could find no evidence of any results.24 This is a huge piece of work, and one of the biggest studies yet. Another group followed hundreds of cancer trials registered at clinicaltrials.gov, and found that only one in five had results available at twelve months, and only half at three years. A BMJ paper surveyed what happens when Cochrane authors try to get unpublished data from trialists: half had their requests rejected.25 Manufacturers were the least helpful, with requests resulting in longer delays, greater difficulties, more frequent follow-up requests, and ultimately, less data. In October 2012 IQWiG – the German equivalent of NICE – published a paper describing how the manufacturer of Exubera (an inhaled insulin) refused to share clinical study reports.26 In the very same week, a New England Journal of Medicine editorial explained: ‘Substantial instances of missing data are a serious problem that undermines the scientific credibility of causal conclusions from clinical trials.’27 The evidence on issues upstream has also continued to flow out. In April PLoS One carried a paper showing that only a third of academic journal reviewers bother to check whether a trial is properly registered when considering it for publication.28
At the same time, the industry has tried desperately to undermine these findings. The data on FDA Amendment Act compliance for posting results at clinicaltrials.gov (only 22 per cent managed to do so) has been challenged, and in bizarre terms that make the need for simple, routine, public audit by the FDA even clearer. The sticking point is that companies can ask for an extension, or argue that their specific trial should be exempt from reporting results at all. This discussion is conducted in secret, and the industry has lobbied against having adjudications in public on clinicaltrials.gov, so nobody can know for sure why a trial hasn’t reported. This broken system has inevitably created chaos and contradiction, where there should be simple clarity. In one interview, the FDA told Nature that the 22 per cent figure is wrong, and that it is only pursuing fifteen cases of overdue results: a tiny proportion. Nature then asked the US government research agency NIH for an informal audit, which found 50 per cent compliance for the industry (and even worse for NIH: it found that it reported only one in five of its own trials). Meanwhile some internal FDA slides being circulated among industry people give the compliance for that period as 65 per cent. The industry brandishes this triumphantly, but a figure of 65 per cent is still abysmal, and furthermore, it comes from a secret audit that has never been published or publicly discussed, available only as some slides, with unknown methods, and no data sharing, from the same organisation that has also claimed that a mere fifteen trials in total are breaching. Alongside this mess, the Prayle audit, published in the BMJ, is fully explicit about the methods it used, and more than that, its entire data set – huge files listing every single trial it looked at, and every individual adjudication it made on compliance – is freely downloadable for anyone who wishes to review it.29 While all studies may have flaws, this is the only audit whose flaws we can see for ourselves, and discuss.
But it has not all been denial and gloom. Some companies have chosen a much more impressive path, alongside GSK, and this is where there is hope. Roche has said that it will look at sharing clinical study reports, though the mechanism is not yet clear, and it has felt unable to join GSK in actively campaigning for transparency throughout the industry by signing up to AllTrials. I hope it will change its mind, and I hope you will encourage it to do so.
Others have gone much further. US company MedTronic has shared individual patient data – on its treatment to improve outcomes in spinal surgery – with a group of researchers from Yale, and very nobly: because the results show that the product has only very limited benefits.30 Was this an act of corporate suicide? I’m not so sure. I’ve always been in favour of one simple, clear regulation, across the board, requiring all companies to share all results, and to compete on a level playing field of high ethical standards. I still believe this is the optimal outcome, but now I can also see that diversity in the market, with respect to transparency, could actively create a financial incentive for companies to do the right thing. It’s easy to see why, if you follow through one example.
Let’s imagine there are two treatments for early dementia, made by two different companies, and both have identical benefits. This is the last bit of maths in the book. Let’s say, for example, that your chances of staying well, without deterioration, are exactly 35 per cent higher if you’re on either of these two drugs than if you get a placebo pill. But next, let’s say that one of these drugs is made by a company with a proven track record of transparency: it doesn’t just say the right things, it has actually delivered full clinical study reports on all the trials it has done (we’re imagining this is in 2016, or later); and it has also made good on promises to share data with outside researchers. The other drug, meanwhile, is made by a company whose staff actively mock and deride the very notion that you should even dare to ask it to share all trial results; it participates in industry dirty tricks to rubbish such calls; it sues and lobbies regulators and governments to prevent it from sharing trial information; and so on.
In that situation, which drug do you want to take? Remember, both have numerically identical benefits: both increase your chances of staying disease-free by exactly 35 per cent. But are those figures really identical? We know there is a background rate of missing trials, and we might reasonably assume that this applies to all trials, across the board, regardless of where they come from. We know that overall, when results go missing, that tends to exaggerate the benefits of treatments. We cannot possibly know for sure that the specific companies lobbying, denigrating, suing and campaigning have themselves hidden any unflattering information. But overall, if we were playing safe, and all other things were equal, would you really want to take a drug manufactured by such a company, in preference to a drug for which there were no such concerns?
I know what I would want.
But really, this can only be fixed by you. After years of appallingly slow progress on missing trials, wider public attention has begun to move things forward. The peculiar smears unloaded onto people daring to share this problem with the public are clear proof, to me, that public engagement is the most powerful approach. The phenomenal progress with patient groups has been truly heartening. But only a united front, and a large public campaign, can put this issue on the agenda for politicians, and fix it for good. So please sign up to the AllTrials campaign. If you are a member of a professional body, or a patient group, or a university, or a company, ask them to do the same. If they have a shred of doubt, ask them to get in touch, through alltrials.net, and we will talk with them.
There is a huge amount happening right now: inquiries in multiple countries, European legislation, a groundswell of popular opinion, a barrage of new research findings, cultural shifts in regulators, isolated individuals in industry showing leadership, and more. But this has all happened before, without delivering success. The window will only open briefly, and there are many, many people trying to wrestle it shut. For the good of patients, for the reputation of medicine, and for the reputation of the pharmaceutical industry, we have one new chance, right now, to deliver real change. I hope you can help us to take it.
Epic Footnote
In the BMJ, to take just three examples from the past few months, you could read an editorial on corporate crime in pharma;2 or a long analysis piece by an eminent diabetes professor on whether several insulin studies were ‘marketing’ rather than research;3 or a paper arguing that we perversely incentivise companies to develop new drugs with few new benefits;4 and so on.
Alongside the analysis of these problems that one would routinely expect – all very much alive – there was also a steady drip of new findings, setting out just how and why these are all such huge problems.
March 2013 saw an excellent round-up of the harms inflicted on patients by our over-reliance on surrogate outcomes – rather than real-world outcomes like death – in clinical research (this you will remember from pp.133–6).5 The problem of trials comparing new drugs against hopeless existing treatments, in order to get an impressive result, continues to be widely discussed, both by academics online6 and in the academic literature.7 This practice is important: it creates uninformative evidence, but it also exposes trial participants to unnecessary harm. One editorial, accompanying further research on the topic, was unambiguous: ‘In fifty-six out of sixty-three trials involving patients with highly active rheumatoid arthritis, potentially helpful treatments were withheld from 9,224 out of 13,095 patients randomized to the control arms. Why? Because placebos or treatments known to be ineffective were used as controls.’ The title of this editorial was unusually direct about the impact on patient care: ‘Blood on Our Hands: Seeing the Evil in Inappropriate Comparators’. The ABPI’s public response to this paper was to say that the industry is very well regulated.8 Everyone else, mercifully, has continued to have an informed conversation about fixable flaws in the design and analysis of clinical trials.
The problem of drugs being tested in small, brief trials continues as before. A paper inPLoS Medicine from March 2013 puts hard figures on this. From a representative sample of two hundred newly approved medicines, each was studied on average in only 1,708 people before approval; and one in five drugs for long-term use failed to meet the guidelines’ recommendations.9 These guidelines, to be clear, are weak in themselves, requiring only that three hundred people should be followed up on the drug for more than six months: for effectiveness on long-term outcomes, this is plainly inadequate.
As well as tiny studies, patients also continue to suffer because of research that is simply never done: a paper published in August 2013, as this chapter went to press, explains that for half of all the recommendations in the current major cardiology guidelines, the level of evidence is only ‘grade C’.10 This is astoundingly poor for one of the biggest specialties in medicine.
In July 2013 the team running ClinicalTrials.gov wrote an influential editorial in Annalsabout the harm that arises from the ongoing problem of trials switching their primary outcomes.11 A paper from one month earlier looked at trials in surgery, and found that half weren’t registered before they began, while half of all primary outcomes were either switched, omitted or changed.12
Notably, none of these papers received significant mainstream media attention, and that illustrates one clear reason why such issues remain unresolved. Huge fuss and effort is deployed on writing newspaper stories about any single ‘rogue surgeon’, but there can be no doubt that our tolerance of poor data – which quietly undermines the quality of clinical decision-making throughout the world – permits far more avoidable suffering and death than any one individual could ever match. Discussion of this problem gets little airtime, because it requires background knowledge about how evidence is created and used; eliciting any outrage around that subject takes more time and imagination than ‘bad surgeon hurts patient’.
Research into biased dissemination of evidence through marketing has also continued, as one would expect it to, regardless of implausible industry denials. One paper from May 2013 – it happens to be on my desk – found that 34 per cent of all industry adverts in Sweden breached that country’s voluntary code of practice.13
In April 2013 a paper was published in the Journal of General Internal Medicine, reporting on a survey of 255 doctors, in four different countries, describing 1,692 visits from drug reps.14 Less than 2 per cent of visits gave ‘minimally adequate safety information’, and at only 6 per cent of visits were serious adverse events mentioned, even though 45 per cent of promotions were for drugs with ‘black box’ warnings. In the same month, President Barack Obama was attacked for his ‘Academic Detailing’ initiative in the USA. This is a new project, designed to run in parallel to the system of ‘drug reps’ (called ‘detailing’ in the US): clinician consultants visit doctors, nurses and pharmacists, disseminating unbiased summaries of evidence about which treatments work best. Pfizer CEO Ian Read said – with no shred of irony – that the Academic Detailing project is a waste of public money, because government has a ‘conflict of interest’ when it disseminates evidence to clinicians.15
Stories and court cases from whistleblowers about kickbacks and aggressive marketing continue, similarly, at the usual pace.16 A paper in May 2013 found that fewer than 6 per cent of biomedical journals have detection and response procedures in relation to ghostwriting.17 If you read the accompanying editorial – although it’s behind the usual paywall, which obstructs popular discussion of all science – you’ll find all the arguments from this book.18 That’s not because anyone has copied anyone: it’s because these issues are entirely mainstream, and routinely discussed behind the paywall.
The Journal of Medical Ethics carried a fascinating description, in June 2013, of an industry-supported medical-school lecture series on opioid prescribing for pain management, with questionable content, undeclared conflicts of interest and more. The course was only stopped after individuals in the medical school protested.19 Senior staff in medical institutions should remember that this kind of action, by junior staff, is risky, brave, and beneficial to patients.
June 2013 brought a remarkable article in JAMA Internal Medicine by a whistleblower, who had himself engaged in ‘disease-mongering’, not just in the academic literature, but also directly to the public, writing in everyday supermarket consumer magazines:
‘Low T’ (low testosterone level, aka hypogonadism) is high-profile these days. Sales of testosterone replacement therapies (TRTs) for Low T have more than doubled since 2006 and are expected to triple to $5 billion by 2017, according to forecasts by Global Industry Analysts. Driving these sales is a sophisticated marketing effort to define low testosterone level as a disease for which the treatment is TRT. I know this because, as a professional medical writer, I have helped craft that message for transmission in a range of media to both physicians and consumers.
The challenges of regulating trials in the developing world continue to be discussed widely, though not so much in the UK. In July 2013, India’s Economic Times (you’ve probably never heard of it, but it has a readership of 800,000) wrote: ‘Many desperate and poor people in India are unwittingly taking part in clinical trials for drugs by Indian and multinational pharmaceutical companies that outsource the work to unregulated research organisations.’20
I could go on. For the ABPI to even suggest that this stuff is historical, and all long addressed, is absurd, but is also dangerous. We need to recognise that these problems exist, so we can work – together or apart – to address them.
NOTES
1 The citation here is, for obvious reasons, ‘personal communication’. The email from the academic continued: ‘From my perspective, I don’t think we should be anything but indignant!’
2 Davis C, Abraham J. Is there a cure for corporate crime in the drug industry? BMJ. 2013;346:f755.
3 Gale EAM. Post-marketing studies of new insulins: sales or science? BMJ. 2012;344:e3974.
4 Light DW, Lexchin JR. Pharmaceutical research and development: what do we get for all that money? BMJ. 2012;345:e4348.
5 Svensson S, Menkes DB, Lexchin J. Surrogate Outcomes in Clinical Trials: A Cautionary Tale. JAMA Intern Med.
2013;173(8):611–612.
6 “JAMA, Integrity, Accessibility, and Social vs. Scientific Peer Review”. Emergency Medicine Literature of Note, Feb 26, 2013.
7 Abbasi, K. Blood on our hands: seeing the evil in inappropriate comparators. J R Soc Med. 2013 January;106(1): 1.
8 Inside Health, BBC Radio 4, January 2013.
9 Duijnhoven RG, Straus SMJM, Raine JM, de Boer A, Hoes AW, et al. (2013) Number of Patients Studied Prior to Approval of New Medicines: A Database Analysis. PLoS Med 10(3): e1001407. doi:10.1371/journal.pmed.1001407
10 Ioannidis JPA. How Many Contemporary Medical Practices Are Worse Than Doing Nothing or Doing Less? Mayo Clinic Proceedings. 2013 Aug;88(8):779–81.
11 Zarin DA, Tse T. Trust but Verify: Trial Registration and Determining Fidelity to the Protocol. Ann Intern Med. 2013;159(1):65–67.
12 Rosenthal R, Dwan K. Comparison of randomized controlled trial registry entries and content of reports in surgery journals. Ann Surg. 2013 Jun;257(6):1007–15.
13 Zetterqvist AV, Mulinari S (2013). Misleading Advertising for Antidepressants in Sweden: A Failure of Pharmaceutical Industry Self-Regulation. PLoS ONE 8(5): e62609. doi:10.1371/journal.pone.0062609
14 Mintzes B, Lexchin J, Sutherland JM, Beaulieu M-D, Wilkes MS, Durrieu G, et al. Pharmaceutical Sales Representatives and Patient Safety: A Comparative Prospective Study of Information Quality in Canada, France and the United States. J Gen Intern Med. 2013 Apr 5.
15 dailycaller.com/2013/04/27/critics-see-conflict-ofinterestas- obama-admin-advises-doctors-on-prescriptions/ 16 www.propublica.org/article/pay-to-prescribe-twodozendoctors- named-in-novartis-kickback-case
17 Bosch X, Hernández C; Pericas JM, Doti P. Ghostwriting Policies in High-Impact Biomedical Journals: A Cross-Sectional Study. JAMA Intern Med. 2013;173(10):920–921.
18 Nancarrow, CM. Editorial Policies to Ensure Honesty and Transparency: Comment on “Ghostwriting Policies in High- Impact Biomedical Journals: A Cross-Sectional Study”. JAMA Intern Med. 2013;173(10):921–922.
19 Persaud N. Questionable content of an industry-supported medical school lecture series: a case study. J Med Ethics. doi:10.1136/medethics-2013-101343
20 India’s poor duped into clinical drug trials. Economic Times, 7th July 2013.
21 Vedula SS, Li T, Dickersin K. Differences in Reporting of Analyses in Internal Company Documents Versus Published Trial Reports: Comparisons in Industry-Sponsored Trials in Off-Label Uses of Gabapentin. PLoS Med. 2013 Jan 29;10(1):e1001378.
22 Sample, Ian. Big pharma mobilising patients in battle over drugs trials data. Guardian, 21st July 2013.
24 Huser V, Cimino JJ (2013) Linking ClinicalTrials.gov and PubMed to Track Results of Interventional Human Clinical Trials. PLoS ONE 8(7): e68409. doi:10.1371/journal.pone.0068409
25 Schroll JB, Bero L, Gøtzsche PC. Searching for unpublished data for Cochrane reviews: cross sectional study. BMJ 2013;346:f2231.
26 Wieseler B, McGauran N, Kerekes MF, Kaiser T. Access to regulatory data from the European Medicines Agency: the times they are a-changing. Syst Rev. 2012 Oct 30;1:50.
27 Little RJ, D’Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, et al. The Prevention and Treatment of Missing Data in Clinical Trials. N Engl J Med. 2012; 367:1355–1360.
28 Mathieu S, Chan A-W, Ravaud P (2013) Use of Trial Register Information during the Peer Review Process. PLoS ONE 8(4): e59910. doi:10.1371/journal.pone.0059910
29 Prayle AP, Hurley MN, Smyth AR (2012) Data from: Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study. Dryad Digital Repository.doi:10.5061/dryad.j512f21p
30 Simmonds MC, Brown JVE, Heirs MK, Higgins JPT, Mannion RJ, Rodgers MA, et al. Safety and Effectiveness of Recombinant Human Bone Morphogenetic Protein-2 for Spinal Fusion: A Meta-analysis of Individual-Participant Data. Ann Intern Med. 2013;158(12):877–889.
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