Swine flu

Margaret McCartney

I’m pleased to see the WHO acknowledging that there was not enough admission of the “uncertainties” about swine flu.WHO admits shortcomings in handling flu pandemic

If we learn one thing from the experience, surely it should be that we should absolutely accept the unknowns and then start to reduce them – with well-designed, clinical trials.

Margaret McCartney

As stories unfold about piles of unused and nearly out-of-date H1N1 “swine flu” vaccinations, I was interested to come across the Council of Europe’s parliamentary assembly ‘s enquiry into the “pandemic”  – WHO challenged at public hearing on the handling of the Swine Flu pandemic.  

I’m glad to see that some of the concerns I’d written about a few months back – the new definition of “pandemic” being one of them – being brought to light. The conclusions will be published and debated later this year.

My endeavour to find a trial of vaccination against placebo to which I or my under-5 year old could be entered has drawn a blank. As to why it’s important, this commentary -  Why the MRC randomized trials of whooping cough (pertussis) vaccines remain important more than half a century after they were done – from the James Lind Library is about trials for whooping cough vaccine.

Note – immune response from vaccines was independant of clinical response. “i) it is difficult to forecast the field performance of any whole-cell pertussis vaccine without randomized placebo controlled trials using clinical outcome measures; and (ii) it is impossible to extrapolate from the result of an assessment of one type of whole-cell vaccine to reliable assessments of the effects of another vaccine.”

Margaret McCartney

It doesen’t seem to have been the predicted pandemic of swine flu that snarled up the country and caused all sorts of disorganisation, but the far more predictable and treatable snow.

Just an observation, from one yet to have her swine flu jab. And who had great fun sledging most of the weekend.

Margaret McCartney

Those of us who prefer Cochrane reviews for our evidence, and who know that the majority of pharmaceutical companies do not publish all of their research, will not be surprised by this publication in the BMJ today: Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. The lead author is Dr Tom Jefferson, who we’ve interviewed for the blog. Here’s the conclusion, about the impact of neuraminidase inhibitors oseltamivir and zanamivir :

” Neuraminidase inhibitors have modest effectiveness against the symptoms of influenza in otherwise healthy adults. The drugs are effective postexposure against laboratory confirmed influenza, but this is a small component of influenza-like illness, so for this outcome neuraminidase inhibitors are not effective. Neuraminidase inhibitors might be regarded as optional for reducing the symptoms of seasonal influenza. Paucity of good data has undermined previous findings for oseltamivir’s prevention of complications from influenza. Independent randomised trials to resolve these uncertainties are needed.”

Margaret McCartney

The swine flu vaccine has landed, but the case numbers are up again. In the US, Barack Obama has declared a national emergency, and the vaccination queues are stretching round the block. Swine flu is a serious problem worldwide, but it is only a recent semantic twist that sees us name it as a pandemic. The World Health Organisation used to define a pandemic as a new virus that spread quickly, and for which there was no immunity, causing high mortality rates. In 2008, this was changed so that a new strain of a virus already in circulation could qualify as a pandemic. The minimum mortality rate that had to be reached before a pandemic could be declared was also scrapped.

This is important because it weighs heavily on the way governments respond to the problem. In general, I support vaccination. My concern about the swine flu vaccine isn’t that it could be harmful, but that it might not do a lot of good. Indeed, there’s plenty of evidence suggests that the best way to manage influenza is to keep infected people out of contact with non-infected people. This sounds simple in theory, but it is not easy in practice. Even when people feel decidedly flu-ish, they are remarkably reluctant to drop prior commitments; snuffling choristers will sing in a much-anticipated concert; friends will soldier into town for a Christmas lunch.

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Amny.com, New York’s free morning daily paper, brings intriguing killjoy advice to avoid swine flu, which provides an insight into new social practices among students.

Alongside kissing less and not sharing marijuana pipes and hookahs comes a warning against … “beer pong”. The game involves tossing a ping pong ball towards cups full of beer. The lucky “owner” of the cup where it lands drinks it down, along with whatever infections the ball may by then have gathered.

It seems one New York college has already emailed advice to desist, debunking claims that the alcohol would disinfect the flu. No judgmental advice on avoiding alcohol, at least!

Margaret McCartney

In terms of information for parents, this trial from the Oxford Vaccine Group looks quite good: Swine Flu (Novel Influenza A H1N1) Vaccine Study for parents and children, except I can’t see a note that they have registered the trial at controlled-trials.com on their website. However, they clearly have –  it is registered here on the International Standard Randomised Controlled Trial Number Register

It’s a head-to-head trial of two vaccines, their side effects and their antibody response. The one by Baxter is called Celvapan, but GlaxoSmithKline has gone for Pandemrix, which really is a terrible name.

This trial is presumably to help the government choose a vaccine supplier: the trial may not, though, be able to add to the evidence for or against vaccination at all: see my previous interview with Dr Tom Jefferson

Margaret McCartney

Tom Jefferson is a medically trained epidemiologist and Cochrane reviewer who has a specialist research interest in the effectiveness of vaccinations. As the first press releases start to filter through about vaccinations for H1N1, there are numerous questions in my mind as to the usefulness of this vaccine – not just for people in general, but for people at higher risk or who work in the health service and are going to be recommended to have it .

MM: As someone who has examined the evidence on this topic, Tom, I’m wondering what your thoughts are as to the potential role of influenza vaccination in a “pandemic”?

TJ: First, let me say that all our reviews are freely available online at cochrane.org site – click on resources. [Some of the vaccine studies Dr Jefferson has been involved can be found on the Wiley Interscience site]. The question you are really asking is – how effective are seasonal vaccines? And our reviews either show no effect or limited effect, and poor data.

What is interesting is that there has been extensive manipulations of the visibility of the data. Now, if you take influenza related mortality in the US – deaths related to influenza, bilateral pneumonia and so on – if you take the CDC (Centre for Disease Control and Prevention) data over the past  20 years, the curve is flat. A plateau. That line flattened after the 1950s – but before influenza vaccination started. As in – influenza related mortality crashed for reasons independent of vaccines. But, if you look at the past 20 years, the mean impact factor of journals (how well read, or well cited they are) the line is nearly vertical. These are pharma sponsored studies. But as far as seasonal influenza vaccines go, there is no difference to the level of threat from 20 years ago. But influenza vaccines have become the thing to talk about – they are now the things that journals like to run.

MM: Pandemic flu vaccines are currently in development; do we know much about them?

TJ: I have consulted the meta-register of clinical trials which should contain registration and broad outline of all current, recently closed or about to begin clinical trials on (in this case) H1N1 vaccines. I have found nine studies on H1N1 so-called pandemic vaccines using the search string “influenza H1N1″. However none of these studies are completed (except for H1N1 trials for “FluMist”, which is an error as it is another type of non pandemic vaccine). Some of them have not even started. The ones that have, give a completion date of Dec 2010.

I have also consulted the International Federation of Pharmaceutical Manufacturers & Associations IFPMA clinical trials portal and found a further 8 trials of H1N1 all similarly either ongoing or recruiting. These too have delivery dates of late 2009-2010.  Note that the vast majority of these trials are financed by public money. What we would need to do is to go through each entry tabulating the details to be absolutely certain of the facts.

MM: So what kind of testing should there be on new H1N1 influenza vaccines before they are used widely?

TJ: Do we know they are safe, or what the side effect profile is? No,  we don’t. We rely on forecasting with seasonal influenza vaccine – and some safety things – like injection site marks – and on past performance. The best evidence we have is for use in healthy adults - where there’s limited benefit – and there is none for use in pregnancy, yet.

Do we have a mechanism for dealing with vaccines which perform poorly or not at all? Not evidently. Do we know if these pandemic flu vaccines will do better? We don’t.

MM: A number of questionnnaires in the UK suggest many doctors and nurses will decline to receive any new pandemic flu vaccine against H1N1. But doctor and nurse leaders have asserted that they should have it in order to protect patients. I have seen no evidence that leads me to think that me being vaccinated will make much difference – what do you think?

TJ: There is no evidence, looking at seasonal flu vaccines, that is going to do anything – to benefit the elderly or others. There is evidence that healthcare workers may be prevented from symptoms of the flu, but these workers having the vaccine do not show a decrease in mortality. The data are poor.

MM: Thank you: much appreciated.

There are several podcasts featuring Dr Jefferson on the Cochrane website for further information: Cochrane Influenza Resources

Vaccine manufacturers have been at pains to point out recently that swine flu is a one-off public health issue more than a bonanza that is likely to make them significant money over the long term: Drug groups to reap swine-flu billions

Some have even donated stocks for free or at substantial discounts to the World Health Organisation and developing countries: Sanofi to donate 100m swine flu vaccines , although others have resisted, arguing that they need to recoup their costs in order to provide supplies sustainably: Novartis rejects call for vaccine donations  

But the high-minded debate has not prevented a fierce public relations battle, with Baxter, CSL and other vaccine makers each eager to grab public attention by claiming to be the first to produce the latest pandemic (or even seasonal) doses. In the process, they hope to hype their scientific prowess.

Yet such spin is largely irrelevant. Many of the richest countries have already long made their decisions on which vaccines they will buy. Others are still waiting for answers that the recent pandemic of press releases cannot answer: how much can be produced over what timescale, what the pricing will be, and which vaccines with which chemical adjuvants to boost effectiveness will the data show offer best value for money.

It’s a fair bet there may be a little less triumphalism from some of the loudest corporate shouters when the final evidence – and contracts – come out.

Margaret McCartney

Yesterday the British Medical Journal published a systematic review and meta-analysis on flu drugs (where all trials, published and unpublished, are searched for and combined, making for a more powerful and reliable conclusion) about the effects of antiviral medication in seasonal flu in children.

The conclusions are that “Neuraminidase inhibitors provide a small benefit by shortening the duration of illness in children with seasonal influenza and reducing household transmission. They have little effect on asthma exacerbations or the use of antibiotics. Their effects on the incidence of serious complications, and on the current A/H1N1 influenza strain remain to be determined.”

We have to bear in mind that these antivirals are relatively new drugs, and that children can react in different ways to medicines from adults.

Additionally, the side effects of antivirals in children- vomiting, or nightmares – may well outweigh any small reduction in how long the flu symptoms last.  The Department of Health has reacted to the trial by saying that they will not be changing prescribing policy because they say they are using a ‘safety first approach’ to swine flu.

This makes no sense to me: there are lots of things doctors have prescribed or done over decades which might have seemed to make sense but actually ended up doing far more harm than good. What this paper says to me is that there is pretty strong support for getting a decently sized and powered randomised controlled trial underway so that we have good evidence on how best to treat children should a further wave of H1N1 appear later this year or next.

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Margaret McCartney is a Glasgow-based GP and FT Weekend columnist. She started writing for the Life and Arts section in 2005 and moved to the magazine in 2008. She also has her own blog: www.margaretmccartney.com/blog

Clive Cookson has been a science journalist for the whole of his working life. He joined the FT in 1987. Clive, the FT's science editor, picks out the research that everyone should know about. He also discusses key policy issues, from R&D funding to science education.

Andrew Jack is pharmaceuticals correspondent, covering the industry and public health issues. He has been a journalist with the FT for 19 years, based in London, Paris and Moscow