A major controversy about the efficacy of the antiviral agent Tamiflu in treating influenza has erupted in the online version of BMJ, formerly known as the British Medical Journal. A team from the prestigious Cochrane Review says that its analysis of published data about clinical trials of the drug, known generically as oseltamivir, shows that the drug is able to reduce the course of an influenza infection by a day but that they are unable to conclude that the drug is effective at reducing complications and hospitalizations caused by flu because they do not have access to key data from eight clinical trials sponsored by the drug's manufacturer, Roche Laboratories Inc. In a commentary accompanying the report, BMJ editor Fiona Godlee said, "Governments around the world have spent billions of pounds on a drug that the scientific community now finds itself unable to judge."
In a response, Roche officials said that the data from the eight trials simply duplicated the results from published trials and did not provide enough new information to justify publication. The company also said that all of the data were submitted to the Food and Drug Administration and other regulatory agencies when the company sought approval to market the drug and that those agencies found it convincing. Roche also said it would post the eight disputed trials on a pasword-protected website so that researchers would have access to it — although that has not occurred yet.
Although the controversy involves trials of the drug against seasonal influenza, the debate has particular significance now because Tamiflu is the primary tool used in combating pandemic H1N1 influenza in the face of poor availability of the swine flu vaccine. In response to the new findings, both the World Heatlh Organizaton and the Centers for Disease Control and Prevention said they would continue to stand by their guidelines for use of the drug, arguing that it is not a good tool for prophylaxis against the swine flu virus but that it does provide benefit in reducing complications.
The Cochrane Review is a nonprofit British organizaton that specializes in independently reviewing published trials on drug efficacy to determine whether the medications are effective. In a 2005 review of Tamiflu and a 2008 update, a group headed by Tom Jefferson of the Cochrane Collaboration's Acute Respiratory Infections Group in Rome concluded that the drug was effective in reducing influenza complications. But a letter from Japanese pediatrician Keiji Hayashi this summer questioned its conclusion, arguing that the team had not actually seen much of the data on which they were basing its conclusion. Hayashi was concerned about the side effects of the drug, which include insomnia, nausea, bad dreams, abdominal pain, headache and a rare neuropsychiatric disease that caused some users to attempt to harm themselves. Such side effects might be tolerated if the drug was effective, but not otherwise. Hayashi was particularly concerned because Japan consumes more than 60% of the world production of the drug.
Under Cochrane rules, the team had six months to respond to Hayashi.
Jefferson attempted to obtain data from the trials, but the situation took a strange turn when the request was made through England's Channel 4 News, which was also investigating the efficacy of Tamiflu. Eventually, Roche agreed to provide the data, providing Jefferson would sign a confidentiality agreement preventing its publication. He refused, and negotiations reached an impasse. Meanwhile, the six-month deadline was nearing its expiration, and Jefferson's team decided to publish its findings without considering the data from the eight studies. And without those studies, they could not reach any conclusions about the effectiveness of the drug.
Roche also provided BMJ with some data about observational studies of Tamiflu, which the group forwarded to Dr. Nick Freemantle and Dr. Melanie Calvert of the University of Birmingham. Reviewing the data, they concluded that "oseltamivir may reduce the risk of pneumonia in otherwise healthy people who contract flu. However, the absolute benefit is small, and side effects and safety should also be considered."
Jefferson's team and BMJ had other concerns about the clinical studies, including original documents that cited Roche employees whose names did not appear on the final papers and the use of professional writers to help produce published papers. Roche made a point-by-point response to their concerns in an online statement. The company also noted that it was standard industry practice 10 years ago, when the studies appeared, not to publish all results from clinical trials and to employ professional writers whose names did not appear on published reports. The company said that its policies have since changed and that it now publishes all new data online and acknowledges all contributions to written reports.
The final conclusions from the brouhaha: It probably doesn't hurt to treat patients with severe flu complications with Tamiflu, and it may help. But the drug should not be used in an effort to prevent infection among people who have been exposed to the virus or in those who have only very mild infections.
— Thomas H. Maugh II