Research News

Study claiming Tamiflu saved lives was based on “flawed” analysis

BMJ 2014; 348 doi: (Published 19 March 2014) Cite this as: BMJ 2014;348:g2228
  1. Zosia Kmietowicz
  1. 1BMJ

A study that found that neuraminidase inhibitors reduced the risk of death among adults treated in hospital during the 2009-10 H1N1 flu pandemic was based on a flawed analysis, a statistician has claimed.

Mark Jones, a senior research fellow in the School of Population Health at the University of Queensland in Brisbane, told the BMJ that “a crude analysis of the data shows an increased risk of mortality associated with neuraminidase inhibitor treatment,” suggesting that the finding of a reduced risk of death was incorrect.

He has called for the authors of the meta-analysis to release their data so that a full independent analysis could be done. Jones is working on a study to answer the same research question.

For the study, researchers analysed data on 29 234 patients worldwide who were admitted to hospital with suspected or confirmed H1N1 flu between January 2009 and March 2011 and treated with a neuraminidase inhibitor, mainly oseltamivir (marketed as Tamiflu).

The study was funded by Roche, the manufacturer of oseltamivir, and published this week in Lancet Respiratory Medicine.1

The researchers reported that, in a comparison with placebo, neuraminidase inhibitors reduced the risk of death by 19% in adults treated in hospital for flu (adjusted odds ratio 0.81 (95% confidence interval 0.70 to 0.93); P=0·002). They also said that their data provided evidence that treatment within two days of the onset of symptoms halved the risk of death in adults in comparison with later treatment (adjusted odds ratio 0.48 (0.41 to 0.56); P<0·0001). They found no reduced mortality risk in children treated with neuraminidase inhibitors.

However, when Jones looked at the data presented in the paper he found that slightly more patients treated with neuraminidase inhibitors died (1825 of 18 803 (9.7%)) than those who were not treated (959 of 10 431 (9.2%)).

He concluded, “The crude relative risk is 1.06 (95% confidence interval 0.98 to 1.14), suggesting a non-significant increased risk of mortality due to neuraminidase inhibitor treatment.”

He added, “The complex analysis does not take into account time-dependent bias. The analysis that is reported to include NAI [neuraminidase inhibitor] treatment as a time-dependent exposure is incorrect, because the result is impossible, and the survival curves indicate a standard Cox regression has been fitted.”

Jones is working with Cochrane researchers on their analysis of full clinical trial data held by Roche on oseltamivir and by GlaxoSmithKline on its drug, zanamivir (Relenza). The companies released the complete summary reports of published and unpublished clinical trials of the drugs last year after a protracted campaign by the researchers, the BMJ, and others.2 Their independent analysis is expected to be published in the next few weeks. It will be the first evaluation of a drug class that is based on all the available evidence.

The authors of the Lancet Respiratory Medicine study claimed that their findings vindicated the spending of billions of pounds on stockpiling oseltamivir and other neuraminidase inhibitors during the H1N1 pandemic. Last year the UK National Audit Office, which scrutinises public spending, said that the government spent £560m (€670; $930m) on antivirals between 2006 and 2013: £424m on oseltamivir and £136m on zanamivir.3

Jonathan Nguyen-Van-Tam, from the University of Nottingham and an author of the meta-analysis, said that the evidence from the study was “likely to be the best that is available.”

He added, “Treatment guidance policies should emphasise that NAI treatment should be started as soon as possible for any hospitalised adult who presents with influenza that is suspected or confirmed. The same applies to adults in the community who are appreciably unwell with influenza-like illness or who have underlying risk conditions.”

Nguyen-Van-Tam is one of the members of the Multiparty Group for Advice on Science, which is funded by an unrestricted grant from Roche and which was set up in 2013 to review the data on oseltamivir, identify any gaps, and decide on an analysis plan.3


Cite this as: BMJ 2014;348:g2228