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Trish Groves: Reader responses to updated Cochrane reviews on Tamiflu and Relenza

23 Apr, 14 | by BMJ Group

trish_grovesIt’s nearly two weeks since The BMJ published two updated Cochrane reviews on the benefits and harms in influenza of the neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza). These research articles were accompanied by The BMJ’s peer review comments and other supplementary files and appendices and several commissioned articles.

It’s good to see some post publication review of these articles via rapid responses. Peter J Flegg, a consultant physician in Blackpool, is worried about throwing out the baby with the bathwater. “I am concerned that The BMJ is conflating the Tamiflu RCT data with its admirable aim of supporting open access to all trials data. The potential benefits of early treatment of influenza have become the first casualty in this ‘political’ war, and I am afraid that patients who are eligible for treatment will wrongly be denied treatment with neuraminidase inhibitors as a result, to their significant potential detriment.” He agrees with the US Centers for Disease Control (CDC) which, despite the updated Cochrane reviews, is continuing to recommend these drugs for reducing mortality in severe influenza.

Jake Dunning, an infectious diseases clinician and influenza researcher from Imperial College London, writes from personal experience  of managing more than 150 patients with severe flu since pandemic H1N1 influenza (pH1N1) emerged in 2009. “Despite the great number of hospitalisations and deaths from influenza, antivirals were prescribed infrequently prior to admission (<3%) in contrast to generous prescription of antibacterial drugs (25% in our series),” he reports.

The latest Cochrane review of neuraminidase inhibitors for influenza was an impressive undertaking, writes Dr Dunning, “but unfortunately addressed the wrong question. It is unable to provide the answers we need…Those responsible for pandemic planning and response had to rely on seasonal flu RCT data to make decisions on stockpiling and licensing.”

He cites the recent systematic review of 78 observational studies which reported significant reductions in mortality in adults “most notably a 50% reduction with early treatment.” He concludes “We will serve patients best by looking at – and scrutinising – all available data, while understanding and accepting the limitations of different methodologies.”

Patrick J Saunders and John Middleton, public health doctors from the University of Staffordshire, bemoan the “rearguard argument that the Cochrane analysis relates to trials undertaken on seasonal flu, not pandemic flu” and argue that this is “a bizarre reinterpretation of history given it was precisely the evidence about seasonal flu trials which was used to determine national policy for pandemic stockpiling.”

They report what it was like in UK public health services during the 2009 pandemic, with “the wanton abandonment of first principles such as isolation, basic control of infection measures and clinical assessment in favour of the stubborn insistence on managing ‘England as a single epidemiological unit’; the irrational maintenance of the ‘containment’ phase which led directly to perverse and damaging interventions and over-reliance on antivirals in mass prophylaxis exercises particularly in schools.” And they warn that “It would be irresponsible for these lessons not to underpin current planning for pandemics and any subsequent responses.”

Peter M English, also from public health in England, was seconded to work in a flu response centre early in the 2009 pandemic. He reminds us that early in the “containment phase,” the health secretary promised that everybody with flu-like symptoms would be given antivirals. But, he explains, “most people, while I was involved, were delivered the antivirals a week after the onset of symptoms. We were unable to prioritise high-risk patients.”

He thinks that the reduction in viral shedding that may plausibly have been a consequence of antiviral treatment slowed the spread of the pandemic, but “there is no reason to believe that antivirals given more than 48 hours after the onset of symptoms had any other benefit.”

Having said that, he says “respiratory physicians tell me they believe it may have had some benefit in the most seriously ill patients.”

Motoi Suzuki and colleagues from Nagasaki University sent us a response from Japan, “the leading NI-consuming country [which] has prescribed 75% of all oseltamivir worldwide.”

Prompted by the Cochrane reviewers’ comments that “laninamivir and peramivir may be more potent as NIs, because their bioavailability is far higher than zanamivir and may affect the host’s endogenous neuraminidase”, these Japanese readers provided a table of published and unpublished clinical trials of laninamivir and peramivir for seasonal influenza in healthy adults in Japan and other East Asian countries. None of these trials showed superiority of the newer NIs over oseltamivir and there were no differences in the risks of complications.

David A Cameron, an oncologist in Edinburgh, admonished us for presenting only the BMJ Pico one page summaries of the Cochrane reviews in our print journal, finding it “rather bizarre that this very important, and rather controversial, topic has more pages of comment than research data in the printed version of The BMJ. We have a 1 page summary of the important paper from the Cochrane review, but 4 pages of editorial/news, and 5 pages of further comment under “open data”.” Should we have “let the intelligent reader make their own judgement on the hard data by publishing the full article in the paper version to be read and considered at length?” They would, however, have taken up all or nearly all of that week’s print journal.

 

Competing interests: I chaired the research manuscript committee meeting where we accepted the updated Cochrane reviews on oseltamivir and zanamivir. Last year I observed and blogged about a key meeting of the Multiparty Group for Advice on Science (MUGAS). On behalf of The BMJ I am an active participant in the AllTrials campaign and the Ottawa Group’s IMPACT study, have contributed to several working groups that led to revision of the EU Clinical Trials Directive, and regularly act as an advocate for and give talks on data sharing and particularly on increasing transparency in the reporting of clinical trials.

Trish Groves is deputy editor and head of research, The BMJ

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  • Andreea Steriu

    Dear Editor

    Thank you for this easy to read summary on the light
    which has been shed on one of the most important R&D drug discussion
    to date.

    The entire debate on NI antivirals for the prophylaxis
    of influenza is haunting the public health community and puzzles many
    fellow clinicians. I am still reading the latest Cochrane Review (April
    2014). The Cochrane Collaboration published a few reviews over the
    years, but this time, courtesy to those battling the transparency quest
    on behalf of many of us we hope we got one step closer in finding those
    pragmatic answers to the big question:

    When flu strikes, what
    can we do and to whom (who is the population at risk) to minimise any
    disruption from the viral infection?

    Tamiflu was tested for
    safety and efficacy and passed those tests long time ago. The World
    Health Organisation recommends it as an ‘essential’ drug for the
    treatment of flu. Yet we are no closer in being able to use any of the
    information in what counts most at policy level: opportunity costs. We
    still wonder:

    Will Tamiflu be effective next time around in the ‘at risk’ population in countries ‘A’ and ‘B’ against a pandemic strain HxNy?

    Answers
    presuppose that treatment administration protocols are to be followed.
    Administration during 48h- post onset of symptoms vs prophylaxis for
    contacts are also to be accurately recorded as good medical practice
    dictates. That is if we want to have a better measure of effects.

    Furthermore, would the stockpiling be cost-effective?
    Assume
    that at the start of the next pandemic the drug is given to symptomatic
    individuals and asymptomatic contacts in country ‘A’ where drug is
    stockpiled vs. drug also being given to symptomatic individuals and
    asymptomatic contacts in country ‘B’, where the drug is not stockpiled.
    What remains is to measure costs. But first more assumptions:

    Assuming
    that differences are not significant in clinical outcomes (the drug’s
    clinical effects on symptomatic vs asymptomatic individuals are
    ‘equal’), it finally comes down to the measurement of opportunity costs:
    for country ‘A’ and for country ‘B’.

    What I learn from these hypothetical exercises raises a further question:

    Where
    does one start and stop looking into the ‘cost issues’ as costs, which
    by the time the drug leaves the manufacturer’s premise the drug is not
    sold at a cost, but at a price?

    Reflecting on the affordability,
    whether the drug is stockpiled (country ‘A’) or not (country ‘B’), this
    process may actually ‘make or break’ at that point:

    (1) the drug’s cost-effectiveness (when compared on effects of paracetamol for example) and/or
    (2)
    either or both countries’ health budgets (although ‘developing’ and
    ‘developed’ economies may have to be looked into separately)

    I
    have no practical conclusion to share on this. However, when we say
    ‘everything comes at a price’, I believe that this is another example
    which fits the picture when we all look at our cash strapped health
    budgets and we are indecissive in how to share ‘the cake’: to stockpile
    or not? That is most likely the question now.

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