Which Review of Tamiflu Data Do You Believe?

Ever since its introduction, there have been skeptics regarding the utility of oseltamivir and other neuraminidase inhibitors for the treatment of influenza.  Roche has profited tremendously off strategic stockpiling by many governments as a response to pandemic influenza – yet, nearly all the data comes from Roche-conducted trials, and the data has been persistently cloaked from independent review.  This past year, after much strife and public shaming, the Cochrane Collaboration received some access to clinical trial reports to conduct an independent review.  This review found, on average, adults receiving early treatment with oseltamivir benefited by reduction in symptom duration from 7 days to 6.3 days.  No benefit was found for reduction in respiratory infectious complications or hospitalization, the truly critical need during influenza outbreaks.

However, a second group also conducted an independent review – the “Multiparty Group for Advice on Science”.  Their results, based on an individual-patient meta-analysis, are published in the Lancet and offer similar – yet wildly different – conclusions.  They find, as did the Cochrane group, approximately a 17-hour reduction in symptoms in the intention-to-treat population across the eight Roche trials evaluated.

Similar to the Cochrane review, they perform secondary analyses for “lower respiratory tract infection”(e.g., bronchitis or pneumonia) and hospitalization, stratified by ITT and ITT-infected populations.  Most prominently emphasized are the results for the ITT-infected population, in which the antibiotics for LRTI were provided to 4.2% in the oseltamivir cohort, compared with 8.7% in placebo.  Likewise, 0.9% of patients were hospitalized for any cause compared with 1.7% of placebo.  The authors therefore conclude oseltamivir use decreased infectious complications of influenza.

These numbers, however, are entirely different from the Cochrane review.  The Cochrane review found a 1.4% hospital admission rate in the oseltamivir cohort and 1.8% in the placebo cohort.  Broken down by trial, the admit rates for the oseltamivir cohort in the MUGAS analysis compared with the Cochrane review:

• M76001: 7/965 vs. 9/965
• WV15670: 1/241 vs. 1/484
• WV15671: 1/210 vs. 6/411
• WV15707: 2/17 vs. 2/17
• WV15812+: 6/199 vs. 9/199
• WV15819+: 6/360 vs. 9/362
• WV16277: 2/226 vs. 2/225

The differences in WV15670 and WV15671 appear to stem, at least in part, due to the MUGAS analysis being restricted to only trial patients taking 75mg twice daily, and not 150mg twice daily.  However, it is otherwise entirely unclear how the Cochrane group found extra hospitalizations in the other trials the MUGAS group did not – particularly considering the hospitalization numbers in the placebo cohorts were essentially identical.  Might it be partly a result of the MUGAS group receiving their data directly from a Roche web portal, while the Cochrane group reviewed the individual clinical study reports?

Rather, might it be revealing to pry into the genesis of the “Multiparty Group for Advice on Science”?  Is it an unbiased, independent clearinghouse for re-analysis of trial data?  Do they have a long track record of respected publications in multiple disciplines?  Unfortunately, neither of these conjectures are true – making it increasingly likely they are a puppet foundation fraught with conflict-of-interest.  MUGAS and the present work were funded by an unrestricted grant from Roche.  Furthermore, MUGAS, along with the European Scientific Working group on Influenza (ESWI), are projects of Semiotics, a scientific branding and communication company specializing in influenza.  The stated goal of Semiotics is promoting corporate science and ensuring its place on top of the policy agenda – and MUGAS is one of their “brands”.  This ought to very clearly demonstrate MUGAS is not a scientific enterprise, and rather an organization tasked with the sort of advocacy as best represents the needs of its sponsors.

Any bias might also be clear just in the style used to present results.  These authors present the tiny absolute differences in hospitalization and infectious complications in forest plot figures using only relative risk, rather than absolute risk.  This serves to inflate the apparent effect size.  Conversely, they present the increased incidence of adverse effects in a table culminating in adjusted absolute risk, with the opposite effect.  This manner of presentation persists in their Discussion, highlighting a “significant 63% reduction in risk of hospitalization”, compared with “absolute increases of 3.7% for nausea and 4.7% for vomiting.”

So – the results of an analysis performed by a “brand”, highlighting results discordant with a prior unbiased analysis.  Where is the peer review vetting such discrepancies?  With so many professional reputations and so much revenue at stake – which report do you believe?

“Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62449-1/abstract

Additional editorial content:
“The BMJ Today: The FDA and CDC’s disagreement over Tamiflu, and the spy who isn’t”
http://blogs.bmj.com/bmj/2015/02/05/the-bmj-today-the-fda-and-cdcs-disagreement-over-tamiflu-and-the-spy-who-isnt/