Neuraminidase inhibitors for preventing and treating influenza in healthy
adults and children
World Health Organization (WHO) recommendations dating from 2002 have encouraged governments around
the world to spend billions of dollars stockpiling neuraminidase inhibitors such as oseltamivir (TamifluŽ) and zanamivir (RelenzaŽ)
in anticipation of an influenza pandemic. Public health agencies worldwide suggested that these drugs would stop the spread of influenza and reduce the risk
of developing serious complications from influenza such as pneumonia or hospitalisation.
Questions about the accuracy
of these claims and the efficacy of both preparations prompted an international
team of researchers, led by Dr Tom Jefferson, a Cochrane Review author and independent epidemiologist based in Rome, Italy,
to examine newly available evidence and amalgamate two previously published Cochrane Reviews focusing on the efficacy of these
interventions into one comprehensive, updated review, published in the January 2012 issue of
the Cochrane Library.
In carrying out this research, the Cochrane team was reluctant to focus their efforts on published
trial reports available in scientific journals, because while many trials have been conducted around the world, only a few
have been published.
“We identified that a large number of studies, including data from 60% of the people who have been involved in randomised, placebo-controlled phase III treatment trials of oseltamivir, have never been published.
This includes the biggest treatment trial ever undertaken on oseltamivir that on its own included just over 1,400 people of
all ages,” noted Jefferson. "We are concerned that these data remain unavailable for scrutiny by the scientific community."
Following a public pledge by the manufacturer of oseltamivir, Roche, to make full study reports
available to scientific investigators, the Cochrane team decided to focus instead on manufacturers’ clinical study reports
(typically submitted to regulators) and regulators’ comments. They called reports and comments “regulatory information”.
Availability of documents generated by national and regional regulatory bodies during licensing processes in the UK, USA,
continental Europe and Japan, along with partial trial reports from the manufacturer of oseltamivir, Roche, and from the European
regulator European Medicines Agency (EMA), enabled the researchers to verify information from the trials.
When the team compared published data with the more complete unpublished trial records, they found
apparent inaccuracies in the published record of the trials. For example, while unpublished trial reports mentioned serious adverse events (some even classified
as possibly related to oseltamivir), one of the two most cited publications makes no mention of such effects, and the other
states “... there were no drug-related serious adverse events”.
Having pieced together information from more than 16,000 pages of clinical trial data and documents used in the process of licensing oseltamivir, the Cochrane team
raises critical questions about how well the drug works, as well as about its reported safety profile. While the drug did reduce the time to first alleviation of symptoms by
an average of 21 hours, it did not reduce the number of people who went on to need hospital treatment. Results from the reanalysis of data also raise questions about
how the drug works as an influenza virus inhibitor.
The Cochrane Review authors conclude that there is an urgent need for independent research on
both of these drugs. There is continuing uncertainty about their effects beyond the initial reduction in symptoms, mainly
because full access to the data needed has still not been provided. “We believe that until more is known about the mode
of action of neuraminidase inhibitors health professionals, patients and other decision makers need to reflect on the findings
of this review before making any decision about the use of the drug,” concluded Jefferson.
The decision to base the review’s analysis solely on regulatory information, unprecedented
in the history of Cochrane Reviews, marked the team’s concern, increasingly shared by the international community, about
the quality and reliability of published sources of evidence. Research was
funded by the UK National Institute for Health Research Health Technology Assessment (NIHR HTA) programme.
As of February 4, 2006, 39 deaths had been associated with oseltamivir in Japan, 13
of which were of children aged 16 and under.5 Several of
the deaths in children involved falls from high places.6 In 2008 the
FDA and manufacturer Roche issued an advisory warning regarding neuropsychiatric events associated with the use of oseltamivir.
Most of these reports were from Japan and included delirium and abnormal behavior leading to injury, and in some cases resulting