Multisystem failure: the story of anti-influenza drugs

Dunning questions the relevance of our systematic review, suggesting that any research data – no matter its quality -- that tests the effect of neuraminidase inhibitors on non-pandemic influenza answers the wrong question. As all randomized trial evidence is on non-pandemic influenza, he argues we must look elsewhere and highlights non-randomized observational studies which conclude the drugs provide great benefit, contrary to the conclusions which can be drawn from randomized trials.

This line of argument has been made elsewhere (1, 2), and there are several problems with it.

First, Dunning's description of the 2009 H1N1 influenza as "severe influenza, or in illness caused by pH1N1" assumes that so-called pandemic H1N1 influenza is by definition severe and non-pandemic influenza is not. Certainly seasons classed as "pandemic" get more media attention than non-pandemics, and certainly the 1918 influenza was severe, but all other so-called pandemics (1957, 1968, and 2009) had mortality comparable with non-pandemic influenza (3, 4) The randomized trial evidence does answer important questions.

Second, we are unconvinced we were wrong to exclude observational studies. We published our methodology in 2010, stating that we would focus on randomized trials. Since 2010 no experts or peer-reviewers questioned this approach.

Third, funding matters. And Dunning omits mentioning that the “systematic review” he cites as demonstrating “significant reductions in mortality in adults” was funded by Roche, oseltamivir’s manufacturer. Nor does Dunning hypothesize how a drug which confers modest benefit on what Dunning considers mild seasonal influenza could produce such stunning benefits against severe influenza. If anything, the reverse would be true.

Fourth, context. In 2003, Roche authored a paper claiming that the randomized trial data demonstrated oseltamivir reduces complications and hospitalizations. Authorities trusted Roche’s word and did not vet these data themselves. Had they done so, as we did in our review, they may have realized that the data did not support Roche’s conclusions. Knowing this, authorities might have even supported properly assessing oseltamivir in a randomized trial during the so-called pandemic of 2009. Clinical trials are ethical and the only way to answer the question Dunning says is important, unless you are seeking to defend a decision already made.

References:

1. http://www.newscientist.com/article/dn25397-is-stockpiling-pandemic-flu-...

2. http://www.nature.com/news/tamiflu-report-comes-under-fire-1.15091

3. Doshi P, AM Trends in Recorded Influenza Mortality: United States, 1900–2004. Am J Public Health. 2008 May; 98(5): 939–945. doi: 10.2105/AJPH.2007.119933

4. Doshi P. The 2009 influenza pandemic. The Lancet Infectious Diseases - 1 March 2013 ( Vol. 13, Issue 3, Page 193 )
DOI: 10.1016/S1473-3099(12)70342-0