What did we learn from Tamiflu (Oseltamivir)

Ten years after questions were first raised over its effectiveness, this article charts the fortunes of this blockbuster pill and finds that lack of evidence has not dented its success. (BMJ 2020;368:m626 doi: 10.1136/bmj.m626) .
” Governments cannot calm earthquakes, bottle up volcanoes, or hold back tsunamis—they may not even be able to put out wildfires—but one disaster they do claim to have power over is a flu epidemic. Since the first pandemic scare of this century, H5N1 avian influenza in 2004 (see timeline, box 1), governments have been stockpiling the neuraminidase inhibitors zanamivir (Relenza) and especially oseltamivir (Tamiflu), in vast quantities.

The UK, the US, and many other countries hold enough stocks of these antivirals to offer courses of treatment to a quarter of their population. The practice is almost ubiquitous in rich countries. Of 28 European states that have published a pandemic response plan, all but one (Poland) make oseltamivir the mainstay of their response until a vaccine can be developed.

In the public mind, and the minds of politicians, the flu pandemic problem is one that has been dealt with and prepared for, at least to the best of our ability. This happy state of reassurance has been almost completely unperturbed by the actual state of the evidence on oseltamivir, much of which evaporated on close inspection by a Cochrane review team six years ago.”

In 2009, when the World Health Organization declared the novel type A H1N1 “swine” flu to be a pandemic, and global spending on stockpiling oseltamivir reached $6.9bn, the NHS commissioned a systematic review of the drug from Cochrane. The Cochrane reviewers had already concluded in 2006 that oseltamivir reduced complications such as pneumonia and shortened symptoms in seasonal flu.

They anticipated a simple update, until a Japanese paediatrician, Keiji Hayashi, challenged them to dig deeper. He pointed out that the paper that had driven their 2006 review, a 2003 pooled analysis by Laurent Kaiser and colleagues,3 was based on 10 randomised controlled trials of which only two had been published. Most of the data supporting oseltamivir’s claim to reduce lower respiratory tract complications had never seen the light of day.

A Cochrane review in 2014 that used the newly released data found insufficient evidence to support claims that oseltamivir reduced lower respiratory tract complications or impeded viral transmission.4 The reviewers also raised new questions about the drug’s harm profile.

Meanwhile, one of the Cochrane team members, Thomas Jefferson, has pursued Roche to the present day. Papers unsealed in a US federal court in January showed that he is suing Roche as a whistleblower under the US False Claims Act to recover $1.5bn he says the company wrongfully billed for, by selling oseltamivir to US public health authorities as a pandemic response drug.

It is perhaps worth noting that the shelf life of stockpiled oseltamivir is generally set at about seven years. Hence by delaying disclosure of its trial data from 2009 to 2013 Roche would allow many governments to replenish their first big stockpile, dating from 2004-5, without being troubled by new data. By 2014 global spending on stockpiling oseltamivir had reached $9bn, a trend that has continued untroubled by the conclusions of the Cochrane reviewers that year that the manufacturer’s claims for the drug were not based on evidence. Speaking to The BMJ, Jefferson claimed that oseltamivir could have actually hastened the spread of the 2009 pandemic. This comes down to a disagreement between Cochrane reviewers and Roche as to how the drug works.

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