Japanese paediatricians are studying whether Tamiflu, the drug widely thought to be our best defence against avian flu, might be causing mental instability and suicidal tendencies. An initial study cleared Tamiflu of any link, but that study, as well as a larger one that has just started, are raising concerns about conflicts of interest, as some of the researchers have received large sums of money from the drug's Japanese distributor.

Suicides in Japanese teenagers have raised concerns about Tamiflu's safety. Credit: DAJ/GETTY

Countries around the world have been stockpiling Tamiflu (oseltamivir) since 2004, in case of a pandemic of avian flu. Japan is by far the biggest user of the drug: in 2005, Japanese doctors wrote 9 million prescriptions for Tamiflu, compared with 3 million for all other countries combined. But concerns about the drug's safety, which is made by Roche, have been growing after some unusual deaths in Japanese teenagers who had taken it. Most recently, a 14-year-old girl and a 14-year-old boy died when they jumped from apartment buildings on 16 and 27 February, respectively.

Tokyo-based Chugai Pharmaceuticals, which distributes the drug in Japan, says that it has reported 289 cases of psychoneurotic effects, including three suspicious deaths, to the Japanese health ministry since the drug was launched there in 2001. Chugai now lists the possibility of severe neurological side effects on the drug's labelling and has distributed a warning note to hospitals. The Japanese health ministry insists that there is no clear evidence of a link, however, and points out that flu itself can cause symptoms such as abnormal behaviour. Roche agrees, adding that the number of suspicious deaths is tiny compared to the number of people who have been prescribed the drug.

Tamiflu was cleared initially when seven paediatricians and a statistician looked at the side effects of it and other influenza drugs, as well as at the symptoms of flu itself. The study, which ended in February 2006, followed up 2,846 children aged mostly ten or younger who had been diagnosed with flu. The frequency of abnormal behaviour in children who took Tamiflu was 11.9%, compared with 10.6% in those who didn't take it, which the researchers concluded was not a significant difference.

Shunpei Yokota, head of the study group and a paediatrician at Yokohama City University's Graduate School of Medicine, admits that the study had shortcomings, including a poor definition for the term 'abnormal behaviour'. So in February, at the government's request, Yokota's team launched a larger study, which will trace 10,000 people aged 0–18 years. The team aims to release the results by this autumn.

But Yokota's team has itself come under fire recently. Last week, it emerged that Chugai paid for paediatric research and teaching by at least two members of the study group, including Yokota, and Tsuneo Morishima of Okayama University.

Chugai gave ten million yen (around US$ 85,000) to Yokota between 2001 and 2006 and two million yen to Morishima in 2005, prompting criticisms that the researchers had a conflict of interest. “It's quite natural for the public to imagine any interest may have been involved,” says Masayuki Shibuya, vice-president at Tokushima University, which has developed model guidelines to manage conflicts of interest in clinical research.

Morishima, Yokota and their universities have defended the donations, saying that all funding was approved by the university, and that the money was used for unrelated work and so did not affect the results of the flu study. Tamaki Fushimi, head of drug safety at the Japanese health ministry, says that the ministry was not aware of the funding when it appointed the study group, and that it has not yet decided whether to allow those who received money from Chugai to continue with the study. Masanori Fukushima, professor of clinical-trial design and management at the Kyoto University Graduate School of Medicine, is one of those who think that the researchers should be removed. “The ministry should care about ethical and regulatory issues more properly,” he says.

But Yokota insists he has done nothing wrong. “Tamiflu is an important drug, but we have no standards to tell doctors who can be prescribed it and who can't,” he says. “It is our responsibility as paediatricians to create this measurement.”