Arguably the world’s foremost debating chamber, the Oxford Union was the scene of this annual event, which always addresses contentious issues for the pharmaceutical industry. After a convivial reception in the Union’s library and garden, where old friends were reacquainted and new introductions made, the party moved into the chamber itself and was welcomed by the chairman, Professor Trevor Jones CBE. He was followed by Candace Kendle, whose eponymous company was the evening’s sponsor. She outlined the huge scale of pharmaceutical R&D, not only in terms of volume but especially in complexity. In recent years the number of investigations per study has risen by some 70%, and the number of eligibility criteria by 60%. These and other factors add up to an expensive and high risk undertaking, with clinical trials currently costing US$124 billion per annum globally.
The Motion
The Motion for this year’s debate was: “
This house believes that there is an unacceptable conflict of interest when pharma conducts trials on its own drugs”.
Speaking for the Motion were:
- Dr Fiona Godlee, Editor in Chief, British Medical Journal
- Dr Ben Goldacre, ‘Bad Science’ columnist, The Guardian
Speaking against the Motion were:
- Dr Robert Ruffolo, Former President of Research, Wyeth
- Professor Vincent Lawton CBE, Health Care Consultant
For the Motion
Dr Fiona Godlee opened for the proposition with candour and realism. She did not expect to win the debate, she declared, and emphasised that the industry was responsible for wonderful achievements. The problem as she saw it, however, was that evaluation of medicines is in the hands of those with the most to gain from favourable results. She challenged the reliability of the published literature, citing a number of now notorious examples. The safety profile of Vioxx was initially based on nine small, short studies, and there was clear conflict of interest among some members of the safety monitoring board. Despite these shortcomings, Merck purchased one million reprints of these articles, and used them to press home the safety message for Vioxx, which we now know was not unblemished. Other examples of distorted safety data are ondansetron, for which several trials were published more than once, and gabapentin, whose marketing recruited influential authors.
Overall, Dr Godlee considered that the literature is littered with lies and distortion. She recognised that some improvements are being made, but these never entirely escape the issue of conflict of interest. She mentioned a significant development in Italy, whereby a 5% tax on drug sales is devoted to independent research, and recommended this for other countries.
Against the Motion
Following the rules of debate, Dr Robert Ruffolo opened for the opposition. He outlined the major impact on public health that has been wrought by modern medicines under the current regulatory system. New drugs have been responsible for half of the 20% increase in life expectancy over the past 20 years. He cited some dramatic examples, including carvedilol. As it has beta-blocking effects, the FDA refused approval of any studies with this drug in heart failure for several years. When such a study was eventually carried out, the benefits were so marked that it was stopped early. Dr Ruffolo showed that the willingness of the industry to take risks leads to major health benefits; for example, HIV is no longer a death sentence and has become a manageable disease.
However, he agreed that control of trials is an issue, but this is addressed by the FDA, MHRA and other regulators, who largely dictate what trials are to be conducted. Where is the expertise for all this? In the USA, the industry spends about $20 billion per annum on clinical trials, while the National Institutes of Health spends $1 billion.
Dr Ruffolo did concede a number of points. He was not in favour of ‘ghost writing’, but disagreed that the literature was generally unreliable. He placed the responsibility on the regulators, reminding us that all Vioxx data went to the FDA. What matters is risk:benefit ratio, but the problem with this is that it is always judged in hindsight. If there were an independent R&D organisation, who would regulate it and who would pay for it? There would be a poor fit with political thinking, which rarely looks beyond the next election, whereas the pharmaceutical industry has a long-term commitment.
Seconding the Motion
Readers of Ben Goldacre’s Guardian column and of his blog will have expected a forthright speech, and they were not disappointed. He supported his opening claim of a distorted literature, with evidence that an industry-funded study is four times as likely to have a positive result as an unsponsored one. He defined two main causes of this: distorted methodologies and distorted publications. Dr Goldacre drew on his experience in neuropsychiatry, explaining that seven randomised controlled trials of atypical antipsychotics used a 20 mg dose of haloperidol as the control, higher than is normally given. Not surprisingly, the atypical drugs emerged as better tolerated. He also pointed out that some information on suicidal thoughts associated with Seroxat was withheld from publication. Indeed, the problem of selective publication extends to meta-analyses and systematic reviews: even Cochrane reviewers cannot always obtain all study data from companies. Overall, Dr Goldacre thought that eliminating these problems would require only relatively modest changes, and that the industry should have no problem in supporting them.
Supporting the Opposition
Professor Vincent Lawton was formerly the chief executive of MSD in the UK, and repeated the mantra of his erstwhile boss: “Medicines are for people, not for profit”. But, as he pointed out, if they work for people you get the profit anyway. Pharmaceutical research and development in the UK spends some £4 billion and employs about 60,000 people, and there have been many landmark studies emerging from that, for example the well-known 4S study on coronary heart disease. Such trials are designed in academia and not in secret, and are of course overseen by ethics committees. It is the most highly regulated industry in the world. Alongside such exemplary studies, we have publicly-funded ones which are not always above reproach. The Women’s Health Study, funded by the US National Institutes of Health, did not achieve statistical significance for its primary endpoint, but the news media liked other outcomes better so the ones reported were changed post hoc.
Much has been done to ensure publication of studies, including trial registries. An emerging benchmark is that all trials should be published within a year of completion. The industry is making efforts, but there is little recognition of related problems in the public sector. NICE denies patients the benefits of some effective medicines, and does not recognise its own conflict of interest as it is sponsored by the Department of Health, the payer. In many ways, the government hides behind NICE when it wants to save money.
Professor Lawton reiterated that publicly-funded trials are of no better quality than commercially sponsored ones, so it would not be reasonable for companies to pass their intellectual property to the public sector. In any case there is a perennial friction between drug development and politics, with the latter having a time horizon that usually stops at the next election.
Discussion & summing up
It was predictable, given the nature of the audience, that speakers from the floor would not be evenly divided. Some good points were made on both sides, notably that the industry has to seize this opportunity to put its house in order. It was conceded by the opposition that a conflict of interest does exist, but the key question was whether this could be mitigated and made acceptable. Unlike last year’s debate, the proposition ran out of support from the floor and the debate moved on to summaries from the leading speakers.
Dr Ruffolo for the opposition denied that trial methodologies are distorted, and asserted that these are for the most part dictated by the regulators. He did agree, though, that duplicate publications are common and that we could do much better. However, the same applies to public sector trials, and he referred again to the Women’s Health Study which spun off 14 papers from the primary one. It is also worth remembering that no innovative drugs emerged from the USSR. Publicly funded trials commonly fail to show clear benefits. His conclusion was that yes, a conflict of interest does exist, but that it is manageable.
Dr Godlee for the proposition maintained that the acknowledged conflict of interest has a malign effect, in that the industry is unable to provide objective evaluation of medicines. The question of which bodies will provide funding and evaluation needs to be addressed, and she proposed a ‘pool of expertise’ drawn from industry, academia, and related areas.
Conclusion
Following a short conclusion from Professor Jones, the house divided. After dinner at Exeter College it was announced that the motion had been defeated by 95 votes to 22. This, of course, was hardly surprising. Informal debate continued into the small hours in the cellar bar, demonstrating a far from acrimonious relationship between the two sides. There was clear agreement that there is a risk of bias when pharmaceutical companies conduct their own research, but nobody could think of any other industry that gets someone else to do its R&D.
The responsibility seems to fall squarely on regulation, and in informal discussion there was not much confidence in ethics committees. In my view, the medical journals also have a heavy responsibility. Perhaps next year’s debate should consider the conflict of interest they have, when they can make a million pounds by selling reprints of papers they agree to publish.
