Letters

Competing interests and controversy about third generation oral contraceptives

BMJ readers should know whose words they read

Editor's reply

Science is not a dispassionate activity

BMJ readers should know whose words they read

EDITORThe influence of competing interests arising from funding by the pharmaceutical industry is worrying in the controversy about third generation oral contraceptives.¹ At the end of 1998 three major studies without sponsoring from the industry found a higher risk of venous thrombosis for third generation contraceptives, unlike three sponsored studies.² To date, of nine studies without sponsoring, one study found no difference and the other eight found relative risks from 1.5 to 4.0 (summary relative risk 2.4); four sponsored studies found relative risks between 0.8 and 1.5 (summary relative risk 1.1) (references available on the BMJ's website, www.bmj.com). The sponsored study with a relative risk of 1.5 has been reanalysed several times, yielding lower relative risks; after this failed to convince,³ a new reanalysis was sponsored by another company.⁴

In 1995 four studies found the same risk. That evidence was sufficient for public health action since equally reliable pills were available. For at least one company the third generation pill secured more than half its revenue. The companies proclaimed that with almost total certainty everything was the result of bias and confounding. Even for a sceptic at the time, that was an unreasonable position: all four studies were reasonably executed and had withstood criticism from the Committee on Safety of Medicines and reviewers of leading journals. Thus, the companies' position ran the high risk ofdamaging both their product and their credibility. Their behaviour is reminiscent of that described by Barbara Tuchman in 1984 in The March of Folly: from Troy to Vietnam, in which rulers become removed from reality and continuously act against their own best interests despite clear warnings.

Since 1995 three multinational companies have used enormous marketing resources to sow confusion. An avalanche of special symposia and paid supplements convinced outsiders that something had to be wrong with the studies finding the higher risks. Many general practitioners, gynaecologists, and family planners were swayed into accepting methodological arguments that sounded logical because of their legitimate concern with good contraception. However, few are really trained in the intricacies of epidemiological arguments. The companies exerted strong legal pressure on governments. Irresponsible scientists were accused of having caused a pill scare by juxtaposing selected figures without showing longer time trends in unwanted pregnancies. Irrelevant comparisons abounded, as with the risk of thrombosis in pregnancy.

The industry's view on bias and confounding was disproved by the World Health Organisation's scientific committee of leading epidemiologists who were not involved in the controversy.⁵ Given the pervasiveness of the competing interest caused by industry funding, BMJ readers should know whose words they read.

Jan P Vandenbroucke, professor, department of clinical epidemiology. 
vdbroucke{at}mail.medfac.leidenuniv.nl

Frans M Helmerhorst, lecturer, department of obstetrics, gynaecology, and reproductive medicine. 
Frits R Rosendaal, professor, thrombosis and haemostasis research centre. 
Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, Netherlands

Competing interests: Professors Vandenbroucke and Rosendaal have no competing interests except a passion for the integrity of epidemiological reasoning. Dr Helmerhorst has supervised studies sponsored or assigned by various pharmaceutical companies that manufacture oral contraceptives, but none of these companies has funded his research on the comparative merits of second and third generation oral contraceptives.

Editor's reply

Readers might be interested to look at our website and see further debate over competing interest and third generation contraceptive pills.¹ Ledger suggested that the BMJ should not have carried an editorial written by O'Brien, who was advising lawyers acting behalf of women who had developed venous thrombosis while taking third generation contraceptive pills. Lidegaard, who has written for the BMJ on this subject previously,² disagreed with O'Brien's interpretation of the evidence and argued that professionals who were "consultants in legal processes supporting women suffering venous thromboembolic disease" would be inclined to interpret the evidence one way. Neither Ledger nor Lidegaard declared competing interests, but I asked them to do so. Ledger did not reply, but Lidegaard declared several links with pharmaceutical companies. I defended our decision to ask O'Brien to write the editorial, arguing that disclosure is a better policy than a ban because people who are deeply knowledgeable on a subject and wholly independent are vanishingly rare. I also urged authors: "If in doubt, disclose."

Richard Smith, editor. 
BMJ

Science is not a dispassionate activity

EDITORThe need for transparency in matters of competing interests, highlighted by Smith,¹ is amply illustrated by the recent controversy about third generation oral contraceptives. During this debate considerable sums of money have been spent denigrating well conducted studies with both clear hypotheses at the outset and clear analyses, studies which unexpectedly found that newer pills containing desogestrel and gestodene were associated with higher risks of venous thrombosis than older preparations with other progestogens. Often highly personalised attacks have been made to discredit the work of well respected researchers, regulatory authorities, and the World Health Organisation. At the same time studies with non-validated data, subgroup analyses after the event, controls of different ages recruited for another study, and inappropriate statistical adjustments have been promoted as providing robust evidence of an absence of risk. The proponents of such arguments have often been paid consultants of companies manufacturing oral contraceptives, or people receiving large research grants from these companies. Would such efforts have been made if the first studies had found differences in favour of third generation pills rather than against them?

To this mixture of claim and counterclaim has been added the smokescreen of whether particular oral contraceptives have different risks of myocardial infarction. For most women this issue is irrelevant. Most women stop taking the pill before their mid-30s, well before the age when women experience myocardial infarction. Furthermore, women at low riskthat is, those who do not smoke, who do not have hypertension, and who have their blood pressure measured before taking the pillare not at risk of myocardial infarction, regardless of the preparation used.

Science is not a dispassionate activity. Money is a powerful motivator, and, as O'Brien points out in his editorial,² the stakes are high. A desire for fame, an excessive belief in your own work, and jealousy can also distort personal perspectives. The truth might never be established to the satisfaction of all parties, and even in the age of evidence based medicine opinion guides clinical practice. After much time evaluating the various arguments (including time as a paid consultant to the World Health Organisation's scientific group on cardiovascular disease and steroid hormone contraception³), I have concluded, like O'Brien, that all currently available oral contraceptives are safe. I have also concluded that the older formulations have a smaller risk of venous thromboembolism than newer preparations containing desogestrel or gestodene. For this reason, I believe that these older preparations remain the preferred first choice for most women.

Philip Hannaford, director. 
Royal College of General Practitioners Centre for Primary Care Research and Epidemiology, Department of General Practice and Primary Care, University of Aberdeen, Foresterhill Health Centre, Aberdeen AB25 2AY p.hannaford{at}abdn.ac.uk

Competing interests: The RCGP Centre for Primary Care Research and Epidemiology (formerly the RCGP Manchester Research Unit) has received funding for its research and education activities from all manufacturers of oral contraceptives. Professor Hannaford has received lecture fees and hospitality from manufacturers of oral contraceptives and has been a paid consultant to the World Health Organisation and solicitors acting for the defence of the manufacturers.