Wyeth suppresses research on pill, programme claimsBMJ 2001; 322 doi: https://doi.org/10.1136/bmj.322.7286.571 (Published 10 March 2001) Cite this as: BMJ 2001;322:571
A Dutch radio broadcast has reopened the debate on the venous thromboembolic risks of the third generation of oral contraceptive pills. The broadcast, by an investigative team from the radio station VPRO, looked into the industrial tactics to keep these drugs in the market.
The team, known as Argos, claimed that the pill manufacturer Wyeth had shelved a 1997 study said to indicate clear increases in the risks of developing deep venous thrombosis in several third generation pills. The Argos team recently came into possession of the summary, key findings, and conclusions of the Wyeth study.
When the team sought further comment, the company refused to disclose the full report on the grounds that it “did not add anything” to existing knowledge of the subject.
On further inquiry, it emerged that Wyeth had in fact submitted the study results to the European Medicines Evaluation Agency in 1999, after a legal suit was mounted in Germany concerning third generation contraceptives. The results, however, remain unpublished. Wyeth tried to prevent Argos from broadcasting its programme last week, threatening to take legal action.
The Dutch broadcast comes at a crucial moment because the European Medicines Evaluation Agency is reviewing the next market authorisation of third generation contraceptives.
Since the 1995 World Health Organization's collaborative study on cardiovascular side effects of the pill in women in developing countries—which contained the finding that European women taking third generation pills were developing higher incidences of deep venous thrombosis—these pills have come under increasing scrutiny.
Although the 1995 pill scare subsided in part due to a political and legal offensive by the three main companies concerned (Wyeth, Schering, and Organon), observers have noticed a continued discrepancy between industry sponsored surveys of the side effects of third generation pills and the research findings of independent scientists. Sixteen major studies have appeared so far, of which four were sponsored by the industry. Unambiguously, the independent studies have shown a significant increase in the risks of developing venous thromboembolic incidents.
For their broadcast, the Argos journalists interviewed independent scientists, such as Ron Herings, director of the Utrecht Pharmo Institute, who claimed that they had been given a difficult time by the drug companies when they had published critical findings.
The team also referred to the commotion that surrounded last year's publication in the BMJ of Dr Richard Farmer's conclusions on the subject, based on the UK general practice research database (GPRD). This study presented itself as additional proof that the risk of venous thromboembolism compared with oral contraceptives with levonorgestrel was negligible (BMJ 2000; 321:477-479). After publication, however, the study came under fire from statistical experts, which led to a formal apology by the BMJ's editor, Richard Smith, last November (BMJ 2000;321:1172).
In the Argos broadcast, epidemiologist Alexander Walker of the Harvard School of Public Health in the United States aired further criticism of the methodology used in Dr Farmer's study, and more generally warned against the growing dangers of academics being subjected to industrial pressures.
“Academics are not at all equipped to deal with the interests involved in such cases,” Dr Walker maintained. He had no problem understanding industrial motivations. “Even clinically insignificant distinctions make a big difference in sales,” he stated. But Dr Walker emphasised that such considerations could never be an excuse for suppressing disadvantageous research outcomes.
Meanwhile, the European Medicines Evaluation Agency finds itself in a predicament. It has postponed its judgment on the new market authorisation of third generation pills until next May or June. It has invited industrial officials to attend a special hearing in London this April to defend their case once more.
Dr Allison Jeynes, medical director of Wyeth UK, explaining why the study was not submitted for publication, said: “The data from the third generation oral contraceptive study in question was submitted to the Committee for Proprietary Medicinal Products, the Food and Drugs Administration and regulatory agencies in several other countries.
“The study was not submitted for publication because it was felt that the study did not offer any new scientific information (it was the third study conducted with the GPRD database regarding the risk of deep vein thrombosis with oral contraceptive use) and because the study was found to have several flaws after having undergone external scientific review.
Specifically, it was discovered that there were problems with the study design and study execution. Problems with the study design included the fact that current users in the study were defined as users within the last six months; cases/controls were not matched by practice; patients who had had recent deliveries or surgery (both known causes of clots) were included in the study as well as patients with arterial events.
Due to these factors, it was recommended by the external reviewer that the results should be interpreted with caution.”