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

there is nothing to be ashamed of in gagging clauses – if companies, and legislators, and academics, and university contracts departments, all believe that they are acceptable – then everything should be out in the open, prominently flagged up, so that everyone outside those systems can decide if they agree.

      1 Until they can be eradicated, where gagging clauses exist, patients should be told, at the time they are invited to participate in a trial, that the company sponsoring it is allowed to hide the results if it doesn’t like them. The consent form should also explain clearly that withholding negative results will lead to doctors and patients being misled about the effectiveness of the treatment being trialled, and so exposed to unnecessary harm. Trial participants can then decide for themselves if they think these contracts are acceptable.

      2 Wherever the sponsoring company has the contractual right to gag publication, even if it doesn’t exercise that right, the fact that a gagging clause existed should be stated clearly: in the academic paper; in the trial protocol; and in the publicly available trial registry entry that goes up before the trial starts. Readers of the trial findings can then decide for themselves if they trust that sponsor and research group to publish all negative findings, and interpret any reported positive findings in that light.

      3 All university contracts should follow the same boilerplate format, and forbid gagging clauses. Failing that, all universities should be forced to prominently declare which contracts with gagging clauses they have permitted, and to publish those clauses online for all to see, so that all can be alerted that the institution is producing systematically biased research, and discount any findings from them accordingly.

      4 In legislation, gagging clauses should be made illegal, with no possibility of quibbles. If there is a dispute about analysis or interpretation between the people running the trial and the people paying for it, it should take place in the published academic literature, or some other public forum. Not in secret.

       Professional bodies

      1 All professional bodies should take a clear stand on unpublished trial data, declare it clearly as research misconduct, and state that it will be handled like any other form of serious misconduct that misleads doctors and harms patients. That they have not done so is a stain on the reputation of these organisations, and on their senior members.

      2 All research staff involved in any trial on humans should be regarded as jointly and severally liable for ensuring that it is published in full within one year of completion.

      3 All those responsible for withholding trial data should have their names prominently posted in a single database, so that others can be made aware of the risk of working with them, or allowing them access to patients for research, in future.

       Ethics committees

      1 No person should be allowed to conduct trials in humans if a research project they are responsible for is currently withholding trial data from publication more than one year after completion. Where any researcher on a project has a previous track record of delayed publication of trial data, the ethics committee should be notified, and this should be taken into account, as with any researcher guilty of research misconduct.

      2 No trial should be approved without a firm guarantee of publication within one year of completion.

      How regulators and journals have failed us

      So far we’ve established that ethics committees, universities and the professional bodies of medical researchers have all failed to protect patients from publication bias, even though the selective non-publication of unflattering data is a serious issue for medicine. We know that it distorts and undermines every decision that researchers, doctors and patients make, and that it exposes patients to avoidable suffering and death. This is not seriously disputed, so you might reasonably imagine that governments, regulators and medical journals must all have tried to address it.

      They have tried, and failed. Worse than simply failing, they have repeatedly provided what we might regard as ‘fake fixes’: we have seen small changes in regulations and practices, announced with great fanfare, but then either ignored or bypassed. This has given false reassurance to doctors, academics and the public that the problem has been fixed. What follows is the story of these fake fixes.

      Registers

      The earliest and simplest solution proposed was to open registers of trials: if people are compelled to publish their protocol, in full, before they start work, then we at least have the opportunity to go back and check to see if they’ve published the trials that they’ve conducted. This is very useful, for a number of reasons. A trial protocol describes in great technical detail everything that researchers will do in a trial: how many patients they’ll recruit, where they’ll come from, how they’ll be divided up, what treatment each group will get, and what outcome will be measured to establish if the treatment was successful. Because of this, it can be used to check whether a trial was published, but also whether its methods were distorted along the way, in a manner that would allow the results to be exaggerated (as described in Chapter 4).

      The first major paper to call for a registry of clinical trial protocols was published in 1986,⁵⁵ and it was followed by a flood. In 1990 Iain Chalmers (we can call him Sir Iain Chalmers if you like^fn2) published a classic paper called ‘Underreporting Research is Scientific Misconduct’,⁵⁷ and he has traced the chequered history of trials registers in the UK.⁵⁸ In 1992, as the Cochrane Collaboration began to gather influence, representatives of the Association of the British Pharmaceutical Industry (ABPI) asked to meet Chalmers.⁵⁹ After explaining the work of Cochrane, and the vital importance of summarising all the trial results on a particular drug, he explained very clearly to them how biased under-reporting of results harms patients.

      The industry’s representatives were moved, and soon they took action. Mike Wallace, the chief executive of Schering and a member of that ABPI delegation, agreed with Chalmers that withholding data was ethically and scientifically indefensible, and said that he planned to do something concrete to prevent it, if only to protect the industry from having the issue forced upon it in less welcome terms. Wallace stepped out of line from his colleagues, and committed to registering every trial conducted by his company with Cochrane. This was not a popular move, and he was reprimanded by colleagues, in particular those from other companies.

      But then GlaxoWellcome followed suit, and in 1998 its chief executive, Richard Sykes, wrote an editorial in the BMJ called ‘Being a modern pharmaceutical company involves making information available on clinical trial programmes’.⁶⁰ ‘Programmes’ was the crucial word, because as we’ve seen, and as we shall see in greater detail later, you can only make sense of individual findings if you assess them in the context of all the work that has been done on a drug.

      GlaxoWellcome set up a clinical trials registry, and Elizabeth Wager, the head of the company’s medical writers group, pulled together a group from across the industry to develop ethical guidelines for presenting research. The ABPI, seeing individual companies take the lead, saw the writing on the wall: it decided to commend GlaxoWellcome’s policy to the whole industry, and launched this initiative at a press conference where Chalmers – a strong critic – sat on the same side of the table as the industry. AstraZeneca, Aventis, MSD, Novartis, Roche, Schering Healthcare and Wyeth began registering some of their trials – only the ones involving UK patients, and retrospectively – but there was movement at last.

      At the same time, there was movement in America. The 1997 FDA Modernization Act created clinicaltrials.gov, a register run by the US government National Institutes of Health. This legislation required that trials should be registered, but only if they related to an application to put a new drug on the market, and even then, only if it was for a serious or life-threatening disease. The register opened in 1998, and the website clinicaltrials.gov went online in 2000. The entry criteria