I want to begin this chapter with a fantasy, one that has a powerful hold in the minds of many. Doctors treat patients using simply the best evidence and their experience. They are not influenced by money or self-interest. Similarly, researchers try to answer the important questions in medicine, specialist societies are concerned only with what is best for a population of patients, and editors of journals publish only what is true and important for medicine. Unlike people who work in the venal worlds of commerce, politics or journalism we in healthcare are untainted by money and ‘the pursuit’, in the words of Sigmund Freud, ‘of fame and the love of beautiful women (or perhaps men)’.
This is of course nonsense. Those who work in healthcare are human beings and just as prone as any other humans to acting in their own interest, responding to economic incentives, and stumbling into frank fraud and corruption. Anybody who has knocked around in the world and read Dante, Juvenal, Balzac and Dickens knows that this is how human beings behave. Yet somehow in medicine we have fallen prey to the fantasy that we are superhuman. We are not. We are exposed to conflicts of interest, like everybody else. Our response should not be to pretend that they don’t exist but rather to acknowledge and disclose them always, and sometimes to accept that they are so extreme that the doctor should not treat a particular patient or an author write an editorial in a medical journal.
Academia and industry are becoming increasingly entangled. In the United States industry support of biomedical research grew from one-third in 1980 to almost two-thirds in 2000 (192). In 1986 just under one-half of life science companies in the United States funded research in academic institutions. This had increased to 92% of them by 1996. About two-thirds of universities in the United States invest in businesses that sponsor research in the same institutions. Meanwhile, pharmaceutical companies spend billions on the influencing, education and entertainment of doctors around the world. The scope for conflicts of interest is vast.
Conflict of interest has been defined as: ‘A set of conditions in which professional judgement concerning a primary interest (such as patients’ welfare or the validity of research) tends to be unduly influenced by a secondary interest (such as financial gain)’ (193). It is important to understand that it is a condition not a behaviour. Many doctors fail to declare a conflict of interest because they are confident that the conflict has not caused them to behave in a different way. This is to misunderstand conflict of interest. It is hard — perhaps impossible — for us to know whether the conflict of interest has caused us to behave in a different way. We do not understand our own motivations. Double blind randomized trials are so important not because researchers are consciously dishonest but because bias is pervasive and unconscious. It is the same, I suggest, with conflicts of interest.
There is a tendency to concentrate on financial conflicts of interest, but the conflicts might be personal, academic, political or religious. Many things may cause conflicts of interest. Once when writing an editorial on animal research in the BMJ, I declared as a conflict of interest that my pet rabbit had been killed by a fox just a few days earlier (194). This might seem absurd, but I strongly suspect that the rabbit’s death influenced what I wrote. It may be that some non-financial conflicts of interest may have more powerful effects than financial conflicts, but they are hard to pin down and define. What’s more, much of the research on conflict of interest has concentrated on financial conflicts, which means that our actions on financial conflicts can be more firmly based on evidence. Policies on conflict of interest thus tend to concentrate on financial conflicts.
At the BMJ when I was the editor we required authors, reviewers and editors to declare financial conflicts of interest but simply encouraged them to declare non-financial conflicts. We had required people to declare all conflicts, including non-financial conflicts, but the policy proved unworkable.
Conflicts of interest may be almost universal. Doctors in many countries are paid at least in part according to what they do. If doctors are paid to perform investigations, to admit patients to particular hospitals or to carry out treatments or investigations, then they have financial conflicts of interest. Similarly if they have lunch bought for them by pharmaceutical companies, are paid as consultants by those companies, or have shares in those companies, then they have conflicts of interest. There are very few doctors who have not been given something by a pharmaceutical company.
A major review in JAMA systematically collected all the evidence on financial conflict of interest in biomedical research and concluded that about one-quarter of researchers have received research funding from the pharmaceutical industry (192). Whether or not people are deemed to have conflicts of interest obviously depends on the definition used, and a survey in 1998 found that nearly one-half of researchers had received ‘research-related gifts’ — materials or money (195). An analysis of 789 articles from major medical journals found that one-third of the lead authors had financial interests in their research — patents, shares or payments for being on advisory boards or working as a director. These conflicts were mostly not disclosed to readers (196).
A study in the New England Journal of Medicine looked at the financial conflicts of interest of authors of 75 pieces in prominent medical journals on calcium channel antagonists (197). They asked the 89 authors of the articles whether they had received from pharmaceutical companies reimbursement for attending a symposium, fees for speaking, fees for organizing education, funds for research, funds for a member of staff or fees for consulting. They also asked about the ownership of stocks and shares in companies. (The questionnaire used in the study and adapted for use by the BMJ can be viewed at http://bmj.com/cgi/content/full/317/7154/291/DC1.) Sixty-nine (80%) of the authors responded, and 45 (63%) had financial conflicts of interest. Yet only two of the 75 pieces disclosed the conflicts of interest. This is despite the fact that the uniform requirements for authors submitting articles to medical journals have required them to declare conflicts of interest since 1993 (198).
A study that I undertook with a medical student looked at 3642 articles in the five leading general medical journals (Annals of Internal Medicine, BMJ, Lancet, JAMA and the New England Journal of Medicine) and found that only 52 (1.4%) declared authors’ conflicts of interest (199). One positive sign was that there was a trend towards more declarations over time.
The journals now have a policy of requiring authors of randomized trials funded by industry (about three-quarters of trials published in the journals (186)) to declare the role of the sponsor in the study and who controlled the decision on publication (200). A study of trials in the same five journals in 2001 showed that only the Annals of Internal Medicine had ever published such a statement (201). Frank Davidoff, former editor of the Annals, explained that he had been sensitized to this issue after one set of authors repeatedly failed to tone down their conclusions despite editorial requests. When Davidoff phoned to ask why, they explained that the unidentified sponsors didn’t want them to do so. An extension of the study looking at whether or not the major journals describe the role of the sponsor found that in only eight of 100 studies funded by industry was the role of the sponsor spelt out — and even when spelt out it often wasn’t clear (202).
Anxiety on this issue has risen steadily, and JAMA not only requires that the role of the sponsor is declared but also that the data are analysed by an independent statistician not employed by the sponsor (201). This policy has been described as both discriminatory and unworkable (‘independent’ statisticians are not easily found) (204), but the editors of JAMA have hit back with an impressive list of cases where studies with commercial sponsors have included serious examples of bias (205).
The picture that emerges is that financial conflicts of interest are very common among authors of studies in medical journals and yet these conflicts have been rarely declared — despite editors saying that they require such declarations. Editors themselves, I must note, hardly ever declare their own conflicts of interest. The BMJ posted competing interest statements for the members of the editorial team, the editorial board and the management team in 2003, but this was several years after it required authors and reviewers to declare their competing interests. A study of 37 general medical journals found that only nine had an explicit policy to deal with the editors’ conflicts of interest and that the BMJ was the only journal that publicly declared the conflicts of interests of its editors and editorial board (206).
Several studies have shown that financial benefit will make doctors more likely to refer patients for tests, operations or hospital admission (207-209), or to ask that drugs be stocked by a hospital pharmacy (210). Caesarean section rates vary dramatically across the world and are higher when women are cared for by private practitioners who are paid for the operation (211, 212). Doctors in Britain performed screening examinations on older people when paid to do so — even though most argued that there was no evidence to support such screening. Dentists in Britain have carried out many unnecessary fillings because they are paid much more to fill teeth than to simply clean them. Doctors, in other words, do respond to financial incentives, and it would be surprising if they didn’t.
The JAMA review found 11 studies that compared the outcome of studies sponsored by industry and those not so sponsored (192). In every study those that were sponsored were more likely to have a finding favourable to industry. When the results were pooled the sponsored studies were almost four times more likely to find results favourable to industry. When we remember that industry sponsors about three-quarters of the randomized trials in the major weekly journals, then we can see that there is substantial room for bias.
One study included in the JAMA review looked at 69 randomized trials of non-steroidal anti-inflammatory drugs which are prescribed on a huge scale for arthritis. All of these trials were sponsored by industry, and the drug being investigated (the sponsor’s drug) was as good as the comparative treatment in three-quarters of the studies and better in one-quarter. In not a single case was the drug being investigated worse than the comparative treatment. This suggests something is wrong. Supposedly researchers conduct trials when they are in a charmed state called ‘equipoise’, which means that they are genuinely uncertain which is the best treatment. If they think that one treatment is better than another then they shouldn’t be conducting the trial. The implication is that the results should half the time favour one treatment and half the time the other. The fact that none of these 69 trials found that the comparison treatment was better suggests that the trials might have been done more for marketing than medical or scientific reasons. Or it could have been that the trials that found against the sponsor’s interest were somehow ‘lost’.
(Richard Lilford, a researcher from Birmingham, has recently made the interesting point that although traditionally it is the researcher who is required to be in equipoise, it is the patients who are receiving the treatments with the possibility of both benefit and harm (214). In a genuinely ‘patient-centred’ world it would [be] the equipoise of patients not doctors that mattered.)
The study I have already quoted on calcium channel antagonists classified 70 articles from major journals as critical of the drugs (23 articles), supportive (30) or neutral (17). Almost all the supportive authors (96%) had financial relationships with manufacturers, compared with 60% of the neutral authors and 37% of the critical authors (197).
An important study from JAMA looked at what characteristics determined the conclusions of review articles on passive smoking (215). The authors identified 106 reviews, with 37% concluding that passive smoking was not harmful and the rest that it was. They then considered all the factors that might mean that authors of reviews reached different conclusions. One was the quality of the review. Perhaps better done reviews reached one conclusion and poorly done ones another. Another factor they considered was whether or not a journal was peer reviewed. It might be that journals that had a peer review system would publish better reviews that reached the same conclusion. Or could it be the year of publication? Perhaps recent studies had changed the direction of the evidence. The authors of the JAMA study expected to find that the quality of the review would be the most important determinant of whether or not authors of reviews found that passive smoking was harmful.
In fact the only factor associated with the review’s conclusion was whether or not the authors were affiliated with the tobacco industry (215). Three-quarters of the articles concluding that passive smoking was not harmful were written by tobacco industry affiliates. The study authors suggest that ‘the tobacco industry may be attempting to influence scientific opinion by flooding the scientific literature with large numbers of review articles supporting its position that passive smoking is not harmful to health’. Again, only a minority of the articles (23%) disclosed the sources of funding for research. The review’s authors had to use their own database of researchers linked with the tobacco industry to determine whether authors had such links (216).
This is a disturbing finding. It suggests that far from conflict of interest being unimportant in the objective and pure world of science where method and the quality of data are everything, it is the main factor determining the result of studies. But the JAMA study was of reviews and concerned the tobacco industry, which is notorious for trying to corrupt science. Could the same thing apply with other sorts of studies and with industries less louche than the tobacco industry?
The systematic review of all studies suggests that the answer to the question is yes (192), and a powerful example comes from studies of whether or not third generation contraceptive pills carry an increased risk of thromboembolic disease. This is a question that matters greatly to women and their doctors. Women who take the contraceptive pill are young and healthy. All medicines have some risks, and those people who have life threatening illnesses are often willing to accept serious and common side-effects. But small risks of side-effects are much more of a problem when millions of healthy people are going to use a drug. Third generation pills were heavily promoted by manufacturers as being an improvement on second generation pills. Many women were switched to the new pills.
New drugs are also important to the companies who make them. It costs hundreds of millions of dollars to bring new drugs to market, and for a new drug to be banned or lose favour in the market can cause companies serious financial damage. Furthermore, some companies have just one or two successful drugs. If just one of those drugs comes under suspicion and loses market share then the whole company may fail, with hundreds or thousands losing their jobs. The incentive is thus enormously strong for companies to conduct studies and interpret their findings in ways that will be favourable to their drugs. There’s also a strong incentive to find ways to undermine any studies that are unfavourable to your products. Researchers who work on studies funded by industry may be handsomely rewarded — in many different ways. It seems not unlikely that the motivations of the companies may be transmitted to the researchers — albeit in ways that stop short of conscious dishonesty.
Drug authorities in Britain issued a warning on the dangers of third generation contraceptive pills increasing the risks of clots before the studies that raised this possibility were published. There was wide media coverage of the warning, and many women stopped taking the new pills immediately (217). Other studies soon appeared — and disturbingly for those who believe in the objectivity of science — studies funded by the pharmaceutical industry found no increased risk, whereas studies funded by public money mostly did (218).
Jan Vandenbroucke, a Dutch epidemiologist and a leading researcher in this area, observed in 2000 that the eight studies that had not been funded by the industry found (when combined) that there was just over twice the chance of developing a clot on the new contraceptive pills compared with the old (218). One study that had not been funded by the industry found no increased risk (219). Three of four studies that had been funded by the industry found no increased risk, but one did. This study has been repeatedly re-analysed by statisticians funded by the industry — until the extra risk disappeared. Another study funded by the industry that found an increased risk was never published — but discovered later by Dutch journalists (219). (I explained in chapter 10 why some argue that failure to publish completed trials is research misconduct.)
If the possible extra risk of third generation contraceptive pills had been high then perhaps all the trials would have found the same result, but the difference was ‘small’. The publicly funded trials found that women on third generation pills had about twice the chance of developing clots when compared with those on older pills. A systematic review of all available trials, including those funded by industry, found the risk to be increased by about 70% (220). Another way to present the results is to say that the chance of a young woman developing a clot in any one year is increased from five per 100,000 person-years (one person taking the drug for one year would be one person year as would two patients taking the drug for six months each) if she is not taking any pill to 15 if she uses the second generation pill and to 25 if she uses the third generation pill. About 1-2% of people who develop a deep venous thrombosis die, which means that the chance of a woman on the third generation pill dying of clots in her lungs is about 2 per million users. In other words the chance of a woman dying from a clot is very low, so an increase in the risk of developing one of 70% seems trivial from the point of view of any individual woman. But when we remember that hundreds of millions of women around the world take these pills, many of them for 10 years or more, then the increased risk if true means a good many dead mothers and motherless children. The risk doesn’t seem trivial to relatives of patients who die and to patients who are affected.
Women who developed clots and relatives of patients who died took legal action against the manufacturers of third generation contraceptive pills. Seven women, one of them aged 16, had died. Of those who survived one had lost part of her leg, one had had a stroke, one had been in a coma for weeks, and one had had much of her bowel removed. Both sides in the case agreed that it would be necessary for the plaintiffs to make a case that the risk of developing clots was doubled by taking the pills. They failed, and the case was dismissed. David Skegg, an epidemiologist from New Zealand and one of the leading researchers on the subject, called the judgement bizarre in an editorial in the BMJ (221).
This case was very interesting to us at the BMJ because the judge was strongly influenced by Ken MacCrae, a first class statistician who had been an adviser to the BMJ. There might be better statisticians than Ken, I don’t know, but I’ve never met one with a better sense of humour and with such an ability to explain complex statistics to people with little or no knowledge of statistics. This ability was obviously invaluable in court cases and made Ken highly desirable as an expert witness. Another characteristic of Ken was a delight in being as politically incorrect as he could and still be amusing. He belonged to the Savage club, a club of heavy drinking wits. Anybody could join who wasn’t a bore or a woman.
The BMJ had reluctantly had to part company with Ken when he agreed to give evidence on behalf of tobacco companies. He would be giving evidence against Sir Richard Doll, Britain’s leading epidemiologists and one of the first scientists to identify smoking as the main cause of lung cancer. Ken’s argument was that he was no different from a barrister. Britain has an adversarial legal system, and each side makes the best case it can. Justice required that the tobacco companies had good statistical advice. Most statisticians wouldn’t dream of advising tobacco companies, but Ken’s delight in political incorrectness meant he would. He would also be very handsomely rewarded, earning in a few weeks what he might earn in a year as an academic.
The same thinking meant that he had always been willing to give evidence on behalf of pharmaceutical companies, and in the case of the third generation contraceptive pills he won the case for the companies. The judge relied primarily on his evidence — despite it being a complex and controversial re-analysis of a study that as published (in the BMJ) showed that the third generation pills did carry a higher risk (222, 223). Hours after giving his evidence Ken, who was around 60, collapsed and died (224).
Discussion of conflict of interest and journals rarely extends beyond authors and reviewers, and the fact that all of us are much more interested in the conflicts of interest of others than our own conflicts means that we have little evidence on the prevalence, extent and effects of editorial conflicts of interest. But the ‘black box’ of peer review leaves huge scope for conflicts of interest to have powerful effects. I will discuss, for example, the problem of editors publishing their own research in their own journals in chapter 12.
But I want to describe here some of the other conflicts than arise. The one that seems to me most stark arises in relation to reprints of articles. Pharmaceutical companies will often spend thousands (and occasionally millions) of dollars buying reprints of single articles from journals. As I described in chapter 2, the company Merck reportedly bought a million reprints of the highly controversial VIGOR trial that suggested that its drug, rofecoxib, had fewer gastrointestinal side-effects than naproxen (46). The companies usually buy reprints of studies that they have funded themselves. Unsurprisingly, they buy them only when the results are positive for their drugs, and they use these reprints as a form of marketing. They are given to doctors, and the prestige of the journal adds to the marketing message.
Editors know which sorts of articles are likely to be purchased as reprints by pharmaceutical companies. If they accept such an article then their journal may receive hundreds of thousands of dollars in income — and these reprints are very profitable. If they reject the article then the money is gone. Some editors are directly responsible for the budgets of their journals, and all editors are concerned about their budgets. A healthy budget means job security, praise from the owners, and often the freedom to expand and innovate. A failing budget means the opposite, and for many journals reprint income is an important source of revenue — sometimes the most important. Editors may be faced with a choice as stark as accepting a study that will bring a substantial income or making some editorial colleagues redundant in order to stay within budget. A million dollar order may mean $600,000 profit, which is the equivalent of several editorial salaries for a year.
Sometimes companies will ring when an article is submitted and make clear that they will purchase reprints if the article is accepted. This is effectively a bribe, and ‘everybody has their price’. A woman from a public relations company once rang me at the BMJ to say that if we accepted a paper then she would ‘take me to the restaurant of my choice’. She was very effusive and stopped just short of saying she would go to bed with me if we took the paper. This was actually the most brazen bribe I was offered in 25 years as an editor. Readers will be relieved to know that the BMJ did not accept the paper.
I don’t know how other editors handle this conflict of interest, but I think that the answer is that they reassure themselves that their judgement is not affected. The evidence that I’ve quoted on conflicts of interest in other contexts suggests that they are wrong. I was somewhat relieved of any conflict in that I rarely attended the meetings where the final decision was taken on which papers to publish. The BMJ was highly unusual (some would say irresponsible) in that the decisions on which original research papers to publish were taken largely by outside advisers. They had no responsibility for the budget, and most (at least until reading this book) were unaware of the money attached to reprints.
Another conflict of interest for editors relates to advertising, a major source of income for many journals. Most of the advertising comes from pharmaceutical companies. Advertisers would always prefer an editorial plug to an advertisement — because they know that readers discount advertising. They want to tie advertising and editorial material as closely together as possible and have various ways to do this, as I discuss in chapter 16. Advertisers may also object to particular studies and withdraw — or threaten to withdraw — their advertising. This may mean death for some journals, and editors may be faced with the stark choice of agreeing not to publish a particular piece or seeing their journal die.
The BMJ faced something close to this with one of its local editions (selections from the weekly BMJ published in around a dozen different countries). The local edition was heavily dependent on advertising and just breaking even. One company which bought advertising threatened to withdraw it if the local edition republished an article that had been published in the weekly BMJ and was critical of the company and one of its products. For the staff, including the business staff, in London this was an easy decision — what the Americans call a ‘no brainer’. If the BMJ succumbed to such pressure there would be no point in publishing the local edition and — worse still — the independence of the weekly edition, perhaps its greatest attribute, would be undermined. It wasn’t so easy for the local publishers, who stood to lose their investment and damage their relationship with an important customer who bought advertising space in their other publications. But the BMJ stood firm and published the article. (The local edition did not die at that point but did later through lack of income from advertising.)
In 2004 the BMJ devoted the whole issue to the relationship between doctors, including their journals, and the pharmaceutical industry (225). The cover of the journal — which summed up the whole issue for many — showed doctors as pigs gorging at a banquet and playing golf with the drug company representatives as lizards; a patient — depicted as a guinea pig — sat amazed at the whole escapade. The BMJ‘s target was more doctors than drug companies, but the companies were very upset and threatened to withdraw £750,000 of advertising. As far as I can tell, they didn’t: it’s impossible to know for sure because you can’t know exactly what they were intending to spend.
For many editors, however, it isn’t so easy to resist the threats and blandishments of the advertisers. If they resist the journal may die, and the owners of the journal — perhaps a specialist society — may be far from pleased. Indeed, the society may be financially dependent on profits from the journal. The Annals of Internal Medicine suffered a severe drop in advertising income after the journal published a study that showed that pharmaceutical advertising was often misleading (226). The episode contributed to the premature departure of the editors, Bob and Suzanne Fletcher, two outstanding editors.
A financial conflict of a different form for editors and journals arises in relation to allowing their studies to be posted on electronic databases — like PubMed Central — that allow everybody free access. If the journals and their owners are primarily interested in advancing science and medicine, as most medical organizations claim to be, then surely the material should be made available for free — particularly as most of the cost of generating it, the research costs, have been met with public money. But making material available for free may cause a loss of subscriptions to the journal — and so reduce profits and perhaps ultimately kill the journal.
Most editors and journals have dealt with this conflict by not recognizing it. Most have stayed with the status quo and declined to make their studies available on PubMed Central. I will discuss this issue further in chapter 17, but this issue illustrates how there is constant conflict between what might be best editorially and financially. This is analogous to the conflict between what doctors and patients might want to do given unlimited resources and what can be afforded. Some argue that the best way to resolve the conflict is for editors (and by analogy doctors) to have no responsibility whatsoever for money. This responsibility should lie with somebody else — owners, publishers or managers.
The trouble with this ‘solution’ is that it leads to constant — and often increasingly bitter — battles. The conflict between editorial (or medical) and financial needs is real. It cannot be avoided. It has to be resolved, and if the conflict is institutionalized in different individuals or parts of the organization it isn’t resolved efficiently and effectively. Rather, much grief is generated. I think it better that one individual (the editor) or one team has responsibility for both editorial quality (or medical excellence) and finance. The conflicts can then be resolved within the individual or team. We are all used to doing this in our daily lives. If I want to make a journey I trade off comfort, speed and cost — and perhaps travel standard class on a train. But if I didn’t have to think at all about cost I might charter a plane or at least travel first class.
So we have expanding evidence that conflicts of interest do affect how doctors treat patients and what conclusions researchers reach in studies, but we have little evidence on the conflicts of interest of editors and journals. This could be a rich area for study.
There has also been little evidence on how statements on conflicts of interest affect readers, but together with others (whom I should confess did most of the work) I have conducted two studies to investigate this (227, 228). We took a letter posted on the BMJ website that reported that the impact of pain from shingles on patients’ daily functioning may be substantial. It came from authors associated with a drug company, and they kindly gave us permission to use a version of the letter in our study.
We sent a random sample of 150 readers the letter with no competing interest declared and another random sample of 150 the letter with a statement that the authors were employees of a fictional company and held stock in the company (227). We asked the readers to score the letters for interest, importance, relevance, validity and believability. We thought that readers might rate as less believable the version that had a conflict of interest statement. In fact the 170 responders (a 52% response rate) rated the version with a competing interest statement lower on every criterion — of interest, importance, relevance, validity and believability.
This study suggested that doctors, although not inclined to declare their own conflicts of interest, do believe that such conflicts are important. They discount in every way studies where authors have substantial conflicts of interest.
We then repeated the study, but this time the competing statement declared that one of the authors was a recipient of funding for studentships and research grants from the fictional company (228). This statement did not lead readers to judge the study any differently from the version that had no competing interest statement.
In the second study we also investigated whether different statements would affect readers’ judgement of a non-clinical study — one on the use of problem lists in letters between hospital doctors and general practitioners (228). The statements were analogous to those in our first study: no statement; a statement that one of the authors was an employee of the company making the software and held stock options within the company; and a statement that one of the authors was a recipient of funding for studentships and research grants from the company making medical management software. Each statement was sent to a random sample of 150 readers. This time — with a 66% response rate — there was no difference in how readers rated the interest, importance, relevance, validity and believability of the three versions.
We are at the beginning of understanding how competing interest statements alter the readers’ judgement of papers, but it looks as if they do discount studies where there is a ‘strong’ conflict of interest. A ‘strong’ conflict is when the authors are employed by an organization that might benefit from the results of the study, although this didn’t seem to be true in the second case where the software company might have benefited from the positive results associated with its software. Perhaps doctors are more sensitized to conflicts of interest associated with pharmaceutical companies.
The greatest difficulty with conflict of interest is to know how to respond. It is impossible to eradicate conflicts of interest. They are part of life. The New England Journal of Medicine did try to have its editorials written only by doctors without any conflicts of interest. One result was that the editors had great difficulty finding authors to write on some subjects. Within some medical specialties — rheumatology and dermatology, for example — it is impossible to find anybody who doesn’t have a conflict of interest. The BMJ once snootily dismissed a television programme by saying that it was full of people with vested interests. The producer wrote and, rightly, pointed out that the only people who don’t have vested interests are those who don’t know anything about a subject — and what would be the point of having them on the programme. (This always reminds me of another correct aphorism that ‘the only people who don’t have personality disorders are people who don’t have personalities’.)
Another result of the policy of the New England Journal of Medicine was that sometimes editorials were written by people with conflicts of interest but readers — and editors — didn’t know. The editors were embarrassed when the Los Angeles Times published a piece entitled, ‘Medical journal may have flouted own ethics 8 times’ (229). The journalist had identified eight cases where editorials had been written by authors with undeclared conflicts of interest. The journal has now changed its policy and allows editorials from authors who have a financial conflict below $10,000 (230). The policy states:
‘The key provision of the definition sets an upper limit on the annual sum that a person may receive before a relationship is automatically considered significant (the limit, currently $10,000, is referred to as the de minimis level). We also regard as a significant interest any holding in which the potential for profits is not limited, such as stock, stock options and patent positions.’
This too, I fear, will be hard to enforce. Measuring the size of a financial conflict is hard. But to its credit the journal has tried to grasp the nettle of defining when a conflict is so large that the person must be excluded. The BMJ had not done that in my time as editor.
A more common policy is to ask people to declare conflicts of interest. Those sitting on government committees must declare conflicts. In some circumstances doctors treating patients are required to declare conflicts — for example, telling patients that they are receiving a payment for entering them into a post-marketing trial of a drug, or that they have a financial interest in the hospital to which they are referring them. Mostly, however, doctors do not declare conflicts of interest to patients. Increasingly, I suspect, they will be required to. The Declaration of Helsinki, which is written by the World Medical Association, now requires researchers to tell participants about their conflicts of interest (231). Why should the same not apply in everyday medical practice?
Most journals are moving towards asking authors and reviewers to declare conflicts of interest. The BMJ asks all authors and reviewers to complete a questionnaire on conflicts of interest, and authors’ statements are published (232). As mentioned above, the journal requires people to declare financial conflicts of interest and encourages them to declare non-financial conflicts. This is not because the journal thinks non-financial conflicts of interest unimportant. Indeed, many would say that non-financial conflicts — personal, academic or religious — may be more powerful than financial conflicts.
The BMJ concentrated on financial conflicts of interest for three main reasons. First, they are easier to define. Second, most of the research on conflicts of interest has looked at financial conflicts. Third, the journal editors thought it more likely to be able to persuade people to declare conflicts of interest if it began by concentrating on financial conflicts of interest.
The journal did used to require authors and reviewers to declare both financial and non-financial conflicts of interest but had little success (233). The editors sent everybody a form describing what they meant by conflicts of interest and asking authors to let them know if they had any. Few people declared conflicts of interest, as the research showed. But research also showed that most people had them. Why were they not being declared?
One reason is that the culture was not to declare them. It wasn’t an issue that doctors thought important. That is now changing. People also didn’t declare conflicts of interest because they were confident that they were not influenced by them — in the same way that most of us, and certainly most doctors, are confident that we are not influenced by advertising. ‘Other people must be — otherwise advertisers wouldn’t bother — but I’m not.’ I suspect too that authors and reviewers thought that it was in some way ‘naughty’ to have a conflict of interest. By declaring a conflict you suggested that you had been ‘bought’. I believe that it is by no means naughty to have a conflict of interest but it is not to declare one.
The BMJ changed its policies in order to try and get more authors and reviewers to declare conflicts of interest. First, it changed the phrase from ‘conflicts of interest’ to ‘competing interests’. This, the editors hoped, would reduce the feeling of ‘naughtiness’. Second, the journal abandoned requiring people to declare non-financial conflicts. Third, authors and reviewers were sent a specific questionnaire that authors have to complete. The form was derived from that used in the study on calcium channel blockers (197), and it asks specifically about shares, employment, reimbursement for attending a meeting, fees for speaking, and funds for a member of staff, research, consulting or organizing education.
Whatever the reason, many more authors and reviewers do now declare a competing interest (234). The culture seems to have changed, and it has become acceptable and normal — at least within the BMJ — to declare competing interests. The journal started with original papers but slowly extended the practice to every part of the journal. Letters to the editor — for the BMJ and other journals — have been a hotbed of conflict of interest. Many authors who described themselves simply as doctors had close links with pharmaceutical companies and were often prompted by the companies to write. Almost all letters to the editor to the BMJ now arrive electronically, and the software will only allow submission of the letter if authors either declare a competing interest or click to say they don’t have one.
The BMJ‘s policy is ‘if in doubt, declare’. Problems rarely flow from declaring conflicts of interest, but problems do arise when they are discovered to exist when not declared. We live in a world, whether we like it or not, where what is not transparent is assumed to be biased, corrupt or incompetent until proved otherwise.
Disclosure alone cannot solve the problem of conflict of interest. Clearly some conflicts are so extreme that they preclude a person from writing or reviewing. Thus a journal would not commission an editorial on a drug from somebody employed by the manufacturer of the drug. Nor would a journal ask an author to review his sister’s book. But where is the cut-off point? Most journals have not been explicit about where it is — but they surely should be.
And what about the problem that not a single study on non-steroidal anti-inflammatory drugs has findings unfavourable to the manufacturers or that almost every study funded by manufacturers finds no increase in clots in women taking third generation contraceptive pills? Disclosure won’t solve what seems to be a deep bias. Something more is needed, and that something seems to be beyond the power of editors and journals. The answer might be that there need to be many more large, publicly funded trials where drugs are compared directly with each other.
It might even be that we need a completely different way of publishing trials, as I have argued elsewhere with Ian Roberts, a triallist and professor at the London School of Hygiene and Tropical Medicine (235). We argue that trials should not be published in journals, where they are ‘spun’. Instead, the whole process should be conducted openly on the World Wide Web. First, there should be a systematic review showing which questions need answering — because so many trials don’t need doing scientifically but are done for marketing. Second, the protocol should be placed on the web for scrutiny and the trial registered. This would allow the wider world to agree that the trial needed doing and that the methods would allow a confident conclusion. It would also mean that authors could not drift from the protocol without adequate justification and prevent the suppression of results that proved unfavourable to the sponsor. Third, the full data would be posted on the web, preventing selective publication of results and allowing detailed critique of the results. There would be no discussion of the results — because often this proves to be simply spin.
This radical proposal is unlikely to happen anytime soon because it would work against the interests of both sponsors, who would have less room for marketing, and journals, whose income and scientific credibility depend on publishing such trials.
Problems remain even with the policy of disclosure (234). Reviewers’ conflicts are not published because reviewers are not named in most journals. The BMJ was planning to do so when I left and then it would have disclosed reviewers’ competing interest. But the BMJ remains highly unusual with its policy of open review, and it would seem odd to disclose the reviewers’ conflicts of interest if their names were not disclosed. Next, journals usually give no information on the scale of the financial competing interest. It might be that an author was bought a cheese sandwich by a company or that he has a sizeable vineyard funded from consulting fees. I think it likely that the scale of the competing interest is important, but it would be a bold step to require it — especially in Britain where people find it even more difficult to talk about their financial affairs than their sex lives. Then, journals should surely at some time try again with requiring people to declare non-financial competing interests.
Conflicts of interest are common in healthcare, and yet until recently they have rarely been declared. We have increasing evidence that conflicts of interest affect behaviours like the referral of patients and the interpretation of the results of studies. Editorial conflicts of interest may be particularly stark, and yet they are largely unstudied. Readers seem to discount studies where conflicts of interest are declared, but much more research is needed to understand this more fully. The best response to conflicts of interest seems to be disclosure rather than attempted eradication, but sometimes conflicts of interest will be so strong that they will rule people out from actions like referring patients or writing editorials. The bigger problem of profound bias within trials conducted by pharmaceutical companies cannot be solved by journals.
More From The Trouble With Medical Journals
- Introduction: Medical Journals Are Probably a Force for Good but Need Considerable Reform
- Why Bother With Medical Journals and Whether They Are Honest?
- What and Who Are Medical Journals For?
- Can Medical Journals Lead or Must They Follow?
- What Are and What Should Be the Values of Medical Journals?
- The Complexities and Confusions of Medical Science
- The Death of the Author and the Birth of the Contributor
- Publishing Too Much and Nothing: Serious Problems Not Just Nuisances
- Wakefield AJ, Murch SH, Linnell AAJ et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis and pervasive developmental disorder in children. Lancet 1998;351:637-41.
- Laumann E, Paik A, Rosen R. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999;281:537-44 (published erratum appears in JAMA 1999;281:1174).
- Moynihan R. The making of a disease: female sexual dysfunction. BMJ 2003;326:45-7.
- Hudson A, McLellan F. Ethical issues in biomedical publication. Baltimore: Johns Hopkins University Press, 2000.
- Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Clinical epidemiology: a basic science for clinical medicine. London: Little, Brown, 1991.
- Haynes RB. Where’s the meat in clinical journals? ACP Journal Club 1993;119:A23-4.
- Altman DG. The scandal of poor medical research. BMJ 1994;308:283-4.
- Shaughnessy AF, Slawson DC, Bennett JH. Becoming an information master: a guidebook to the medical information jungle. J Fam Pract 1994;39:489-99.
- Bartrip P. Mirror of medicine: a history of the BMJ. Oxford: British Medical Journal and Oxford University Press, 1990.
- Chen RT, DeStefano F. Vaccine adverse events: causal or coincidental? Lancet 1998;351:611-12.
- Pobel D, Viel JF. Case-control study of leukaemia among young people near La Hague nuclear reprocessing plant: the environmental hypothesis revisited. BMJ 1997;314:101.
- Horton R. A statement by the editors of the Lancet. Lancet 2004;363:820-1.
- Murch SH, Anthony A, Casson DH et al. Retraction of an interpretation. Lancet 2004;363:750.
- Smith R. The discomfort of patient power. BMJ 2002;324:497-8.
- Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high risk patients. BMJ 2002;324:71-86.
- Cleland JGF. For debate: Preventing atherosclerotic events with aspirin. BMJ 2002;324:103-5.
- Bagenal FS, Easton DF, Harris E et al. Survival of patients with breast cancer attending Bristol Cancer Help Centre. Lancet 1990;336:606-10.
- Fox R. Quoted in: Smith R. Charity Commission censures British cancer charities. BMJ 1994;308:155-6.
- Richards T. Death from complementary medicine. BMJ 1990;301:510.
- Goodare H. The scandal of poor medical research: sloppy use of literature often to blame. BMJ 1994;308:593.
- Bodmer W. Bristol Cancer Help Centre. Lancet 1990;336:1188.
- Budd JM, Sievert ME, Schultz TR. Phenomena of retraction. Reasons for retraction and citations to the publications. JAMA 1998;280:296-7.
- McVie G. Quoted in: Smith R. Charity Commission censures British cancer charities. BMJ 1994;308:155-6.
- Smith R. Charity Commission censures British cancer charities. BMJ 1994;308:155-6.
- Feachem RGA, Sekhri NK, White KL. Getting more for their dollar: a comparison of the NHS with California’s Kaiser Permanente. BMJ 2002;324:135-41.
- Himmelstein DU, Woolhandler S, David DS et al. Getting more for their dollar: Kaiser v the NHS. BMJ 2002;324:1332.
- Talbot-Smith A, Gnani S, Pollock A, Pereira Gray D. Questioning the claims from Kaiser. Br J Gen Pract 2004;54:415-21.
- Ham C, York N, Sutch S, Shaw R. Hospital bed utilisation in the NHS, Kaiser Permanente, and the US Medicare programme: analysis of routine data. BMJ 2003;327:1257-61.
- Sanders SA, Reinisch JM. Would you say you ‘had sex’ If…? JAMA 1999;281:275-7.
- Anonymous. lfs over, Debbie. JAMA 1988;259:272.
- Lundberg G. ‘lfs over, Debbie,’ and the euthanasia debate. JAMA 1988;259:2142-3.
- Smith R. Euthanasia: time for a royal commission. BMJ 1992;305:728-9.
- Doyal L, Doyal L. Why active euthanasia and physician assisted suicide should be legalised. BMJ 2001;323:1079-80.
- Emanuel EJ. Euthanasia: where The Netherlands leads will the world follow? BMJ 2001;322:1376-7.
- Angell M. The Supreme Court and physician-assisted suicide-the ultimate right N Eng J Med 1997;336:50-3.
- Marshall VM. lfs almost over — more letters on Debbie. JAMA 1988;260:787.
- Smith R. Cheating at medical school. BMJ 2000;321:398.
- Davies S. Cheating at medical school. Summary of rapid responses. BMJ 2001;322:299.
- Ewen SWB, Pusztai A. Effects of diets containing genetically modified potatoes expressing Galanthus nivalis lactin on rat small intestine. Lancet 1999;354:1353-4.
- Horton R. Genetically modified foods: ‘absurd’ concern or welcome dialogue? Lancet 1999;354:1314-15.
- Kuiper HA, Noteborn HPJM, Peijnenburg AACM. Adequacy of methods for testing the safety of genetically modified foods. Lancet 1999;354:1315.
- Bombardier C, Laine L, Reicin A et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Eng J Med 2000;343:1520-8.
- Curfman GD, Morrissey S, Drazen JM. Expression of concern: Bombardier et al., ‘Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis.’ N Eng J Med 2000;343:1520-8. N Eng J Med 2005;353:2813-4.
- Curfman GD, Morrissey S, Drazen JM. Expression of concern reaffirmed. N Eng J Med 2006;354: 1193.
- Laumann E, Paik A, Rosen R. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999;281:537-44 (published erratum appears in JAMA 1999;281:1174).
- Smith R. In search of ‘non-disease.’ BMJ 2002;324:883-5.
- Hughes C. BMJ admits ‘lapses’ after article wiped £30m off Scotia shares. Independent 10 June 2000.
- Hettiaratchy S, Clarke J, Taubel J, Besa C. Burns after photodynamic therapy. BMJ 2000;320:1245.
- Bryce R. Burns after photodynamic therapy. Drug point gives misleading impression of incidence of burns with temoporfin (Foscan). BMJ 2000;320:1731.
- Richmond C. David Horrobin. BMJ 2003;326:885.
- Enstrom JE, Kabat GC. Environmental tobacco smoke and tobacco related mortality in a prospective study of Californians, 1960-98. BMJ 2003;326:1057-60.
- Roberts J, Smith R. Publishing research supported by the tobacco industry. BMJ 1996;312:133-4.
- Lefanu WR. British periodicals of medicine 1640-1899. London: Wellcome Unit for the History of Medicine, 1984.
- Squire Sprigge S. The life and times of Thomas Wakley. London: Longmans, 1897.
- Bartrip PWJ. Themselves writ large: the BMA 183~1966. London: BMJ Books, 1996.
- Delamothe T. How political should a general medical journal be? BMJ 2002;325:1431-2.
- Gedalia A. Political motivation of a medical joumal [electronic response to Halileh and Hartling. Israeli-Palestinian conflict]. BMJ 2002. http://bmj.com/cgi/eletters/324173331361#20289 (accessed 10 Dec 2002).
- Marchetti P. How political should a general medical journal be? Medical journal is no place for politics. BMJ 2003;326:1431-32.
- Roberts I. The second gasoline war and how we can prevent the third. BMJ 2003;326:171.
- Roberts IG. How political should a general medical journal be? Medical journals may have had role in justifying war. BMJ 2003;326:820.
- Institute of Medicine. Crossing the quality chasm. Anew health system for the 21st century. Washington: National Academy Press, 2001.
- Oxman AD, Thomson MA, Davis DA, Haynes RB. No magic bullets: a systematic review of 102 trials of interventions to improve professional practice. Can Med Assoc J 1995;153:1423-31.
- Grimshaw JM, Russell IT. Effect of clinical guidelines on medical practice: a systematic review of rigorous evaluations. Lancet 1993;342:1317-22.
- Grol R. Beliefs and evidence in changing clinical practice. BMJ 1997;315:418-21.
- Smith R. What clinical information do doctors need? BMJ 1996;313:1062-8.
- Godlee F, Smith A, Goldman D. Clinical evidence. BMJ 1999;318:1570-1.
- Smith R. The BMJ: moving on. BMJ 2002;324:5-6.
- Milton J. Aeropagitica. World Wide Web: Amazon Press (digital download), 2003.
- Coulter A. The autonomous patient ending paternalism in medical care. London: Stationery Office Books, 2002.
- Muir Gray JA. The resourceful patient. Oxford: Rosetta Press, 2001.
- World Health Organization. Macroeconomics and health: investing in health for economic development. Report of the commission on macroeconomics and health. Geneva: WHO, 2001.
- Mullner M, Groves T. Making research papers in the BMJ more accessible. BMJ 2002;325:456.
- Godlee F, Jefferson T, eds. Peer review in health sciences, 2nd edn. London: BMJ Books, 2003.
- Reiman AS. Dealing with conflicts of interest. N Eng J Med 1984;310:1182-3.
- Hall D. Child protection: lessons from Victoria Climbié. BMJ 2003;326:293-4.
- McCombs ME, Shaw DL. The agenda setting function of mass media. Public Opin Q 1972;36:176-87.
- McCombs ME, Shaw DL. The evolution of agenda-setting research: twenty five years in the marketplace of ideas. J Commun 1993;43:58-67.
- Edelstein L. The Hippocratic oath: text, translation, and interpretation. Baltimore: Johns Hopkins Press, 1943.
- www.pbs.org/wgbhlnova/doctors/oath_modem.html (accessed 8 June 2003).
- Weatherall DJ. The inhumanity of medicine. BMJ 1994;309:1671-2.
- Smith R. Publishing information about patients. BMJ 1995;311:1240-1.
- Smith R. Informed consent: edging forwards (and backwards). BMJ 1998;316:949-51 .
- Calman K. The profession of medicine. BMJ 1994;309:1140-3.
- Smith R. Medicine’s core values. BMJ 1994;309:1247-8.
- Smith R. Misconduct in research: editors respond. BMJ 1997;315:201-2.
- McCall Smith A, Tonks A, Smith R. An ethics committee for the BMJ. BMJ 2000;321:720.
- Smith R. Medical editor lambasts journals and editors. BMJ 2001;323:651.
- Smith R, Rennie D. And now, evidence based editing. BMJ 1995;311:826.
- Weeks WB, Wallace AE. Readability of British and American medical prose at the start of the 21st century. BMJ 2002;325:1451-2.
- O’Donnell M. Evidence-based illiteracy: time to rescue ‘the literature’. Lancet 2000;355:489-91 .
- O’Donnell M. The toxic effect of language on medicine. J R Coli Physicians Lond 1995;29:525-9.
- Berwick D, Davidoff F, Hiatt H, Smith R. Refining and implementing the Tavistock principles for everybody in health care. BMJ 2001;323:616-20.
- Gaylin W. Faulty diagnosis. Why Clinton’s health-care plan won’t cure what ails us. Harpers 1993;October:57-64.
- Davidoff F. Reinecke RD. The 28th Amendment. Ann Intern Med 1999;130:692-4.
- Davies S. Obituary for David Horrobin: summary of rapid responses. BMJ 2003;326: 1089.
- Butler D. Medical journal under attack as dissenters seize AIDS platform. Nature 2003;426:215.
- Smith R. Milton and Galileo would back BMJ on free speech. Nature 2004;427:287.
- Carr EH. What is histoty? Harmondsworth: Penguin, 1990.
- Popper K. The logic of scientific discovery. London: Routledge, 2002.
- Kuhn T. The structure of scientific revolutions. London: Routledge, 1996.
- www.guardian.co.uklnewsroomlstory/0,11718,850815,00.html (accessed 14 June 2003).
- Davies S, Delamothe T. Revitalising rapid responses. BMJ 2005;330:1284.
- Morton V, Torgerson DJ. Effect of regression to the mean on decision making in health care. BMJ 2003;326:1 083-4.
- Horton R. Surgical research or comic opera: questions, but few answers. Lancet 1996;347:984-5.
- Pitches D, Burls A, Fry-Smith A. How to make a silk purse from a sow’s ear — a comprehensive review of strategies to optimise data for corrupt managers and incompetent clinicians. BMJ 2003;327:1436-9.
- Poloniecki J. Half of all doctors are below average. BMJ 1998;316:1734-6.
- Writing group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-33.
- Shumaker SA, Legault C, Thai L et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2651-62.
- Yusuf S, Collins R, Peto R. Why do we need some large, simple randomized trials? Stat Med 1984;3:409-22.
- Leibovici L. Effects of remote, retroactive intercessory prayer on outcomes in patients with bloodstream infection: randomised controlled trial. BMJ 2001;323:1450-1.
- Haynes RB, McKibbon A, Kanani R. Systematic review of randomised trials of interventions to assist patients to follow prescriptions for medications. Lancet 1996;348:383-6.
- Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408-12.
- Altman DG, Schulz KF, Moher D et al., for the CONSORT Group. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001;134:663-94.
- Moher D, Jones A, Lepage L; CONSORT Group (Consolitdated Standards for Reporting of Trials). Use of the CONSORT statement and quality of reports of randomized trials: a comparative before-and-after evaluation. JAMA 2001;285:1992-5.
- Garattini S, Bertele V, Li Bassi L. How can research ethics committees protect patients better? BMJ 2003;326:1199-201.
- Sackett Dl, Oxman AD. HARLOT pic: an amalgamation of the world’s two oldest professions. BMJ 2003;327:1442-5.
- loannidis JPA. Why most published research findings are false. PLoS Med 2005;2:e124.
- Greenhalgh T. How to read a paper. London: BMJ Books, 1997.
- Sterne JAC, Davey Smith G. Sifting the evidence: what’s wrong with significance tests? BMJ 2001;322:226-31.
- Le Fanu J. The rise and fall of modem medicine. New York: Little, Brown, 1999.
- Lock S. A difficult balance: editorial peer review in medicine. London: Nuffield Provincials Hospital Trust, 1985.
- Rennie D. Guarding the guardians: a conference on editorial peer review. JAMA 1986;256:2391-2.
- Martyn C. Slow tracking for BMJ papers. BMJ 2005;331:1551-2.
- Hwang WS, Roh Sl, Lee BC et al. Patient-specific embryonic stem cells derived from human SCNT blastocysts. Science 2005;308:1777-83.
- Normile D, Vogel G, Holden C. Stem cells: cloning researcher says work is flawed but claims results stand. Science 2005;310:1886-7.
- Jefferson T, Alderson P, Wager E, Davidoff F. Effects of editorial peer review: a systematic review. JAMA 2002;287:2784-6.
- Godlee F, Gale CR, Martyn CN. Effect on the quality of peer review of blinding reviewers and asking them to sign their reports: a randomized controlled trial. JAMA 1998;280:237-40.
- Schroter S, Black N, Evans S et al. Effects of training on quality of peer review: randomised controlled trial. BMJ 2004;328:673.
- Peters D, Ceci S. Peer-review practices of psychological journals: the fate of submitted articles, submitted again. Behav Brain Sci 1982;5:187-255.
- McIntyre N, Popper K. The critical attitude in medicine: the need for a new ethics. BMJ 1983;287:1919-23.
- Horton R. Pardonable revisions and protocol reviews. Lancet 1997;349:6.
- Rennie D. Misconduct and journal peer review. In: Godlee F, Jefferson T, eds. Peer review in health sciences. London: BMJ Books, 1999.
- McNutt RA, Evans AT, Fletcher AH, Fletcher SW. The effects of blinding on the quality of peer review. A randomized trial. JAMA 1990;263:1371-6.
- Justice AC, Cho MK, Winker MA, Berlin JA, Rennie D, the PEER investigators. Does masking author identity improve peer review quality: a randomized controlled trial. JAMA 1998;280:240-2.
- van Rooyen S, Godlee F, Evans S et al. Effect of blinding and unmasking on the quality of peer review: a randomized trial. JAMA 1998;280:234-7.
- Fabiato A. Anonymity of reviewers. Cardiovasc Res 1994;28:1134-9.
- Fletcher RH, Fletcher SW, Fox R et al. Anonymity of reviewers. Cardiovasc Res 1994;28:1340-5.
- van Rooyen S, Godlee F, Evans S et al. Effect of open peer review on quality of reviews and on reviewers’ recommendations: a randomised trial. BMJ 1999;18:23-7.
- Lock S. Research misconduct 1974-1990: an imperfect history. In: Lock S, Wells F, Farthing M, eds. Fraud and misconduct in biomedical research, 3rd edn. London: BMJ Books, 2001.
- Rennie D, Gunsalus CK. Regulations on scientific misconduct: lessons from the US experience. In: Lock S, Wells F, Farthing M, eds. Fraud and misconduct in biomedical research, 3rd edn. London: BMJ Books, 2001.
- Royal College of Obstetricians and Gynaecologists. Report of the independent committee of inquiry into the circumstances surrounding the publication of two articles in the British Journal of Obstetrics and Gynaecology in August 1994. London: RCOG, 1995.
- Lock S. Lessons from the Pearce affair: handling scientific fraud. BMJ 1995;310:1547.
- Pearce JM, Manyonda IT, Chamberlain GVP. Tenn delivery after intrauterine relocation of an ectopicpregnancy. Br J Obstet Gynaecol 1994;101:716-17.
- Pearce JM, Hamid RI. Randomised controlled trial of the use of human chorionic gonadotrophin in recurrent miscarriage associated with polycystic ovaries. Br J Obstet Gynaecol 1994;101:685-8.
- Wilmshurst P. Institutional corruption in medicine. BMJ 2002;325:1232-5.
- Smith R. What is research misconduct? In: Nimmo WS, ed. Joint Consensus Conference on Research Misconduct in Biomedical Research. J R Coli Phys Edin 2000;30 (Suppl 7): 4-8.
- Integrity and misconduct in research. Report of the Commission on Research Integrity to the Secretary of Health and Human Services, the House Committee on Commerce, and the Senate Committee on Labor and Human resources. 3 November 1995. gopher.faseb.org/opar/cri.html (accessed 10 July 2003).
- Office of Science and Technology Policy, Executive office of the President. Federal policy on research misconduct. Federal Register 6 December 2000, pp 76260-4. frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=2000_register&docid=00-30852-filed (accessed 10 July 2003).
- Nylenna M, Andersen D, Dahlquist G et al. on behalf of the National Committees on Scientific Dishonesty in the Nordic Countries. Handling of scientific dishonesty in the Nordic countries. Lancet 1999;354:57-61.
- Joint Consensus Conference on Misconduct in Biomedical Research. Consensus statement. 28 and 29 October 1999. www.rcpe.ac.uk/esd/consensuslmisconduct_99.html (accessed 10 July 2003).
- Zuckerman H. Scientific elite: Nobel laureates in the United States. New York: Free Press, 1977.
- Rennie SC, Crosby JR. Are ‘tomorrow’s doctors’ honest? Questionnaire study exploring medical students’ attitudes and reported behaviour on academic misconduct. BMJ 2001;322:274-5.
- Lock S. Misconduct In medical research: does it exist In Britain? BMJ 1988;297:1531-5.
- Smith R. Draft code of conduct for medical editors. BMJ 2003;327:1010.
- Stoa-Birketvedt G. Effect of cimetidine suspension on appetite and weight in overweight subjects. BMJ 1993;306:1091-3.
- Rasmussen MH, Andersen T, Breum L et al. Cimetidine suspension as adjuvant to energy restricted diet in treating obesity. BMJ 1993;306:1093-6.
- Garrow J. Does cimetidine cause weight loss? BMJ 1993;306:1084.
- White C. Suspected research fraud: difficulties of getting at the truth. BMJ 2005;331:281-8.
- Smith R. Investigating the other studies of a possibly fraudulent author. BMJ 2005;331 :288-91.
- Chandra RK. Effect of vitamin and trace-element supplementation on cognitive function in elderly subjects. Nutrition 2001;17:709-12.
- Chandra RK. Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. Lancet 1992;340:1124-7.
- Meguid M. Retraction of: Chandra RK. Nutrition 2001;17:709-12. Nutrition 2005;21:286.
- Carpenter RK, Roberts S, Sternberg S. Nutrition and immune function: a 1992 report. Lancet 2003;361:2247.
- Shapiro OW, Wenger WS, Shapiro MF. The contributions of authors to multiauthored biomedical research papers. JAMA 1994;271:438-42.
- Goodman N. Survey of fulfilment of criteria of authorship in published medical research. BMJ 1994;309:1482.
- Flanagin A, Carey LA, Fontanarosa PB et al. Prevalence of articles with honorary authors and ghost authors in peer-reviewed medical journals. JAMA 1998;280:222-4.
- Horton R. The signature of responsibility. Lancet 1997;350:5-6.
- International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals: writing and editing for biomedical publication. www.icmje.org/ (accessed 15 April 2006).
- Bhopal R, Rankin J, McColl E et al. The vexed question of authorship: views of researchers in a British medical faculty. BMJ 1997;314:1009.
- Wilcox LJ. Authorship. The coin of the realm. The source of complaints. JAMA 1998;280:216-17.
- Eysenbach G. Medical students and scientific misconduct: survey among 229 students. www.bmj.com/cgi/eletters/322/7281/274#12443, 3 February 2001.
- Rennie D, Yank V, Emanuel L. When authorship fails: a proposal to make contributors accountable. JAMA 1997;278:579-85.
- Horton R. The hidden research paper. JAMA 2002;287:2775-8.
- MAST-I Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 1995;346:1509-14.
- Tognoni G, Roncaglioni MC. Dissent: an alternative interpretation of MAST-I. Lancet 1995;346:1515.
- Docherty M, Smith R. The case for structuring the discussion of scientific papers. BMJ 1999;318:1224-5.
- Gotzsche PC. Multiple publication of reports of drug trials. Eur J Clin Pharmacol 1989;36:429-32.
- Waldron T. ls duplicate publishing on the increase? BMJ 1992;304:1029.
- Tramer MR. Reynolds DJM, Moore RA, McQuay HJ. Impact of covert duplicate publication on meta-analysis: a case study. BMJ 1997;315:635-40.
- Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B. Evidence b(i)ased medicine — selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ 2003;326:1171-3.
- Chalmers I. Underreporting research is scientific misconduct. JAMA 1990;263:1405-8.
- Dickersin K. The existence of publication bias and risk factors for its occurrence. JAMA 1990;263:1385-9.
- Dickersin K, Min Yi. Publication bias: the problem that won’t go away. Ann N Y Acad Sci 1993;703:135-46; discussion 146-8.
- Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34.
- Olson CM, Rennie D, Cook D et al. Publication bias in editorial decision making. JAMA 2002;287:2825-8.
- Egger M, Bartlett C, Juni P. Are randomised controlled trials in the BMJ different? BMJ 2001;323:1253.
- Lexchin J, Bero LA, Djulbegovic 8, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003;326:1167-70.
- Kjaergard LL, Als-Nielsen B. Association between competing interests and authors’ conclusions: epidemiological study of randomised clinical trials published in the BMJ. BMJ 2002;325:249.
- Saunders MC, Dick JS, Brown IM et al. The effects of hospital admission for bed rest on duration of twin pregnancy: a randomised trial. Lancet 1985;11:793-5.
- Smith R, Roberts I. An amnesty for unpublished trials. BMJ 1997;315:622.
- De Angelis C, Drazen JM, Frizelle FA et al. Is this clinical trial fully registered? A statement from the International Committee of Medical Journal Editors.
- Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research. Asystematic review. JAMA 2003;289:454-65.
- Thompson DF. Understanding financial conflicts of interest. N Engl J Med 1993;329: 573-6.
- Smith R. Animal research: the need for a middle ground. BMJ 2001;322:248-9.
- Campbell EG, Louis KS, Blumenthal D. Looking a gift horse in the mouth: corporate gifts supporting life sciences research. JAMA 1998;279:995-9.
- Krimsky S, Rothenberg LS, Stott P, Kyle G. Scientific journals and their authors’ financial interests: a pilot study. Sci Eng Ethics 1996;2:395-410.
- Stelfox HT, Chua G, O’Rourke K, Detsky AS. Conflict of interest in the debate over calcium channel antagonists. N Engl J Med 1998;338:101-5.
- International Committee of Medical Journal Editors. Conflict of interest. Lancet 1993;341:742-3.
- Hussain A, Smith R. Declaring financial competing interests: survey of five general medical journals. BMJ 2001;323:263-4.
- Davidoff F. DeAngelis CD, Drazen JM et al. Sponsorship, authorship, and accountability. N Engl J Med 2001;345:825-6.
- Smith R. Journals fail to adhere to guidelines on conflicts of interest. BMJ 2001;323:651.
- Gross CP, Gupta AR, Krumholz HM. Disclosure of financial competing interests in randomised controlled trials: cross sectional review. BMJ 2003;326:526-7.
- Fontanarosa PB, Flanagin A, DeAngelis CD. Reporting conflicts of interest, financial aspects of research, and role of sponsors in funded studies. JAMA 2005;294:110-11.
- Rothman KJ, Evans S. Extra scrutiny for industry funded trials. BMJ 2005;331:1350-1.
- Fontanarosa PB, DeAngelis CD. Conflicts of interest and independent data analysis in industry-funded studies-reply. JAMA 2005;294:2576-7.
- Haivas I, Schroter S, Waechter F, Smith R. Editors’ declaration of their own conflicts of interest. Can Med Assoc J 2004:171:475-6.
- Wilkinson P. ‘Self referral’: a potential conflict of interest. BMJ 1993;306:1083-4.
- Hillman BJ, Joseph CA, Mabel MR et al. Frequency and costs of diagnostic imaging in office practice: a comparison of self referring and radiologist referring physicians. N Engl J Med 1990;323:1504-8.
- Hillman AI, Pauly MV, Kerslein B. How do financial incentives affect physicians’ clinical decisions and the financial performance of health maintenance organizations. N Engl J Med 1989;321:86-92.
- Chren MM, Landefeld CS. Physicians’ behaviour and their interactions with drug companies. JAMA 1994;271:684-9.
- Murray SF. Relation between private health insurance and high rates of Caesarean section in Chile: qualitative and quantitative study. BMJ 2000;321:1501-5.
- Roberts CL, Tracy S, Peat B. Rates for obstetric intervention among private and public patients In Australia: population based descriptive study. BMJ 2000;321:137-41 .
- Rochon PA, Gurwitz JH, Simms RW et al. A study of manufacturer supported trials of non-steroidal anti-inflammatory drugs in the treatment of arthritis. Arch Intern Med 1994;154:157-63.
- Lilford RJ. Ethics of clinical trials from a bayesian and decision analytic perspective: whose equipoise is it anyway? BMJ 2003;326:98Q-1.
- Barnes DE, Bero LA. Why review articles on the health effects of passive smoking reach different conclusions. JAMA 1998;279:1566-70.
- Barnes DE, Bero LA. Industry funded research and conflict of interest an analysis of research sponsored by the tobacco Industry through the Center for Indoor Air Research. J Health Policy Law 1996;21:515-42.
- Hope S. 12% of women stopped taking their pill immediately they heard CSM’s warning. BMJ 1996;312:576.
- Vandenbroucke JP. Competing interests and controversy about third generation oral contraceptives. BMJ 2000;320:381.
- Sheldon T. Research on third generation pill remains unpublished. BMJ 2001 ;322:1086.
- Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ 2001;323:131.
- Skegg DCG. Oral contraceptives, venous thromboembolism, and the courts. BMJ 2002;325:504-5.
- Spitzer WO, Lewis MA, Heinemann LAJ et al. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. BMJ 1996;312:83-8.
- Lewis MA, MacRae KD, Kuhi-Habich D et al. The differential risk of oral contraceptives: the impact of full exposure history. Hum Reprod 1999;14:1493-9.
- Wright J. Kenneth David MacRae. BMJ 2002;324:1041.
- Abbasi K, Smith A. No more free lunches. BMJ 2003;326:1155-6.
- Wilkes MS, Doblin BH, Shapiro MF. Pharmaceutical advertisements in leading medical journals: experts’ assessments. Ann Intern Med 1992;116:912-19.
- Chaudhry S, Schroter S, Smith R, Morris J. Does declaration of competing interests affect reader perceptions? A randomised trial. BMJ 2002;325:1391-2.
- Schroter S, Morris J, Chaudhry S et al. Does the type of competing interest statement affect readers’ perceptions of the credibility of research? Randomised trial. BMJ 2004;328:742-3.
- Monmaney T. Medical journals may have flouted own ethics 8 times. Los Angeles Times 21 October 1999.
- Drazen JM, Curfman GO. Financial associations of editors. N Engl J Med 2002;346:1901-2.
- World Medical Association. Declaration of Helsinki. Ethical principles for medical research involving human subjects. http://www.wma.net/e/policylb3.htm (accessed 25 June 2006).
- Smith R. Beyond conflict of interest. BMJ 1998;317:291-2.
- Smith R. Conflict of interest and the BMJ. BMJ 1994;308:4.
- Smith R. Making progress with competing interests. BMJ 2002;325:1375-6.
- Smith R, Roberts I. Patient safety requires a new way of publishing trials. PLoS Clinical Trials 2006;1:e6 DOI: 10.1371journal.pctr.0010006.