Stockpiling of the antiviral drug Tamiflu may be of little use in the event of a influenza pandemic, according to a new comprehensive review of clinical trial data.
The latest updated Cochrane Review, published this week in the BMJ: Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children, challenges the assumption that drugs such as Tamiflu and Relenza are effective in combating influenza.
The BMJ and the Cochrane Collaboration, the independent, global healthcare research network, are calling on government and health policy decision makers to review guidance on use of Tamiflu in light of the findings.
Although the review has confirmed small benefits on symptom relief, there is little to justify any belief that it reduces hospital admission or the risk of developing confirmed pneumonia. Along with the evidence of harms from the medication, it raises the question of whether global stockpiling of the drugs is still justifiable given the lack of reliable evidence to support the original claims of its benefits.
“Our findings do not support the stockpiling of neuramidase inhibitors,” write the authors in the report’s conclusions.
You can read more about the review and access the full document here. A ‘Behind the headlines’ statistical review from the UK SMC is also available below.
The SMC rounded up the following expert commentary.
Dr Vanessa Jordan, New Zealand Cochrane Fellow, University of Auckland, comments:
“This latest publication from the Cochrane library represents another chapter in a story which reads like a sensationalist script for a Hollywood movie. Influenza is the one illness which from time to time may threaten to disrupt our ordered existence. It can affect healthy individuals indiscriminately, the worst epidemics of which have historically decimated populations in centuries past. Swine flu hit New Zealand in the winter of 2009. The report from the Pandemic and Influenza Mortality and Morbidity Review Group, shows that 49 New Zealanders died from this illness that year, the majority of which were under the age of 60.
“The available data in 2009 suggested that antivirals, such as Tamiflu and Relenza, had potential benefits in reducing complications from influenza and as a result the length of hospital stays and ICU admissions. Based on this the New Zealand government (along with governments worldwide) purchased and stockpiled 750,000 doses, the majority of which have subsequently been dumped as they have passed their expiration date. However, this information was incomplete and full trial evidence on the drug’s effectiveness was suppressed by the manufacturers. Through perseverance the Cochrane authoring group have succeeded in obtaining information on 45 unpublished trials. This new synthesized evidence confirms what was previously suspected — that there is currently no support for claims that Tamiflu or Relenza reduces admissions to hospital or complications of influenza. At most you may get back to work half a day earlier but in trade off for this you may also suffer from some of the side effects such as nausea and vomiting.
“Medications are not harmless and we must use the evidence both published and unpublished to determine whether the harms of adverse effects of the medication are justified by the benefits of the treatment. As a result of this latest Cochrane review we can see that there is not a case for widespread use of antivirals for influenza. Pharmaceutical companies should be required to publish all the data related to effectiveness and safety. There is a global effort underway directed by the All Trials Campaign to improve access to data. Members of the European parliament voted on the third of April this month in favour of a new law that will require all drug clinical trials in Europe to be registered and their results reported in a public database. We call on New Zealand to join in support for these global initiatives.”
Dr John Cameron, Clinical Director, ProCare Health Ltd, comments:
“The use of the Neuraminidase Inhibitors (Oseltamivir (Tamiflu) and Zanavimir (Rulenza)) has been an integral part of response planning for a potential novel pandemic or epidemic Influenza virus outbreak in New Zealand. There has always been some concern over potential over reliance on a drug for use in a pandemic event that had not shown dramatic clinical efficacy in routine yearly Influenza epidemics. This report from the Cochrane Collaboration illustrates that the planned role of the Neuraminidase Inhibitors in a pandemic event may not provide a level of reduction in morbidity and mortality that had been expected and places significant questions over the benefit from either patient or government funded or held stocks of these medicines.
“Planning for a national response to a novel infectious agent such as a pandemic influenza virus has been on-going. The data in this study will allow planners to look at more effective management strategies away from the use of Neuraminidase Inhibitors and more to the greater effectiveness of public health processes, infection control programs and the early development and delivery of potentially more effective vaccine agents in the management of any influenza pandemic event.
“It is not a question of “if” but “when” a novel pandemic Influenza virus such as that of the H1N1 1918 Pandemic will arise. The H1N5 “Bird” flu virus is still active with a 50% human mortality but which thankfully has not managed sustained human to human transmission to date. At least now we should be able to reduce the potentially wasteful use of health resources on medications that have not shown to have significant beneficial effects for suffers of current Influenza viruses.”
Prof Kurt Krause, Director Webster Centre for Infectious Diseases, University of Otago, comments:
“It’s long been known that the clinical improvements that most people will experience from taking Tamiflu are modest, and only accrue for the most part when it is begun within 48 hours of the onset of symptoms. The types of side effects reported here, i.e. mostly gastrointestinal related, are also well-known. The concern expressed by the Cochrane report on publication bias are worth noting and again well known. The idea that tamiflu is acting through an as yet unexplained mechanism, is new to me and counter-intuitive given the nature of the association between tamiflu and its target the influenza neuraminidase protein. However, it may be an issue amenable to study directly given modern laboratory methods of assessing viral replication.”
The following commentary was collected by our colleagues at the AusSMC:
Professor Peter Collignon is an Infectious Diseases Physician and Microbiologist at Canberra Hospital, Associate Executive Director of ACT Pathology and Professor of Medicine at the Australian National University. He comments:
“The earlier paper published in The Lancet Respiratory Medicine suggests that, if patients were NOT on neuraminidase inhibitors (i.e. Tamiflu) there was a 9.2 per cent death rate (959/10,431) but if they were given Tamiflu the death rate was slightly higher at 9.7% (1825/18,803).
“Yet the conclusion was the opposite of this. They concluded that neuraminidase inhibitors save lives.
“Looking at comments on the Lancet paper in the BMJ, the statistics that were done to reach that conclusion likely have major methodological issues.
“In contrast, the new Cochrane review says there is no evidence to show that Tamiflu saves lives based on studying a similar number of patients but with much better methodology, as the patients they included were part of controlled trials (even if Roche did not let the reviewers see all the data).”
Professor Nikolai Petrovsky is Director of Endocrinology at Flinders Medical Centre with a conjoint position as Professor of Medicine at Flinders University, and Research Director at Vaxine Pty Ltd. he comments:
“New data supports the need for greater government investment in influenza vaccine strategies and less investment in stockpiling of anti-influenza drugs such as Tamiflu and Relenza.
“Benefits of anti-influenza drugs such as Tamiflu and Relenza are modest at best and most recent data suggests they may not reduce influenza mortality or hospitalisation.
“Unlike anti-influenza drugs, influenza vaccines have proven benefits in reducing influenza hospitalisations and deaths.
“Next generation influenza vaccines, such as those being developed by Adelaide company Vaxine Pty Ltd., offer potential for even greater levels of protection, but their development is not currently supported by Australian health funding agencies.”
Declaration of interests: Professor Petrovsky is the founder of Vaxine Pty Ltd, where he is Research Director.
Associate Professor Jodie McVernon, Senior Research Fellow in the Melbourne School of Population Health at the University of Melbourne, comments:
“This latest Cochrane review finds (again) that NAIs are associated with only modest benefits in the treatment of mild-moderate seasonal influenza infection among healthy individuals participating in clinical trials. However, the study cannot tell us anything about the effects of Tamiflu in seriously ill patients who are already in hospital. During a pandemic, these are the patients of greatest concern, so we should be careful in our interpretation of this latest Cochrane Review. NAIs are also known to be effective in preventing the spread of symptomatic disease among contacts of infected patients, so they can help stop health services being overwhelmed during a pandemic, although they may still allow asymptomatic infection.
“So, are these new findings informative for governments considering the appropriate use of NAIs to reduce clinical cases, health sector burden and death during pandemic events, in which heightened morbidity and mortality are anticipated?
“The limitations of the randomised controlled trial are evident from synthesis of ‘real world’ studies conducted during the 2009 H1N1 pandemic, demonstrating that early treatment of hospitalised patients with NAIs significantly reduced ICU admissions and deaths, particularly among those with underlying poor health. In other words, the trial populations studied here just weren’t sick enough to see an effect.
“The usefulness of NAIs in prevention of secondary disease when given to household contacts of cases was further supported by observational studies during the 2009 pandemic, such as the UK’s analysis of the ‘first few hundred’ cases. Should we be concerned that asymptomatic secondary infections might occur? Not if our aim is to reduce disease burden on the health care sector and society.
“Randomised controlled trials are a ‘model system’ like any other, and necessarily fail to encompass many real world complexities of importance. Caution should be taken in extrapolating their findings without appropriate context.”
The UK Science Media Centre gathered the following expert commentary:
Prof Peter Openshaw, Director of the Centre for Respiratory Infection, Imperial College London, said:
“The latest analysis of antiviral trial data by the Cochrane Collaboration adds little to the author’s previous conclusions.
“Most of the antiviral trials they included looked at previously healthy adults infected with seasonal influenza strains. The biggest problem is the continuing failure of the group to recognise that we now face new challenges: since the 2009 pandemic, most of the flu we have seen has been caused by a different virus with unique features, especially its tendency to cause severe illness and death in younger adults and children.
“In planning for a pandemic we have to rely on findings from seasonal flu trial data. We have learnt so much from antiviral treatment during the recent pandemic and it would be dangerous to apply the findings of the latest Cochrane review of antiviral trials for seasonal flu to the current situation or to future outbreaks.
“Given the possibility that next time things might be worse, we have to ask ourselves: would we prefer to have no reserves of antivirals, when we have nothing else available with which to treat a novel pandemic flu virus? Since data from the 2009 pandemic clearly show that antivirals do save lives, it seems very sensible to have an adequate supply of these medicines.
“There were no randomised trials of antivirals for H1N1 flu, but observational data from the pandemic clearly show that antivirals are beneficial and safe in those who were hospitalised. We also know that the earlier treatment is given, the less likely someone will die from flu or require intensive care. Taking this into account, it is compelling to expect that antivirals given before admission to hospital might improve outcomes even more, although we don’t have – and are unlikely to have – studies to prove this. Therefore, we have to be pragmatic and work with the data we have. If you end up in hospital with severe flu, that’s a different matter; the overwhelming observational evidence for H1N1 is that antivirals reduce the risk of progressive illness and death and they should be given as soon as flu is suspected.
“Given all of the attention over antivirals, it is interesting that antibiotics – which have no activity whatsoever against the flu virus – are given out more frequently to people with mild flu-like illness, yet remarkably, no one has scrutinised their benefits or risks in flu patients with such dogged determination. In an average winter, the money we spend on flu antivirals will be far less that the money that’s spent on “best-guess” antibiotics for flu-like illness. We also know that side effects of antibiotics are common and can be significant – probably more so than with antivirals.
“In a previous review by Jefferson et al Vaccines for preventing influenza in the elderly (Cochrane Database Syst Rev 2010) confirmed vaccine safety, but found no convincing evidence for effectiveness against disease undermining campaigns to vaccinate the elderly. In a re-review of the same evidence using sophisticated epidemiological and statistical methods, effectiveness against influenza-related fatal and non-fatal complications was found to be ?30%, influenza-like illness was reduced by ?40% and confirmed influenza infection was reduced by ?50%. When influenza was circulating the overall vaccine efficacy against infection was ?60% (Beyer et al Cochrane re-arranged: Support for policies to vaccinate elderly people against influenza, Vaccine 2013). This type of analysis is very technical, demanding and time-consuming. By not doing a thorough and detailed analysis it is possible (even probable) that important effects can be missed. The new Cochrane review on antivirals should be subjected to a similar reanalysis, but this will take a lot of time and detailed work. At present, I cannot say how reliable it is.
“The conclusions of the Cochrane Collaboration and the publicity by the BMJ will be listened to by many, but their findings are open to misinterpretation. The release of previous Cochrane reviews during the midst of a pandemic was seen by some as being irresponsible. We now know that antivirals saved lives during the pandemic and we risk losing one of the few weapons we have because of overly negative publicity. We should demand better-designed clinical trials and greater transparency, but we should not put lives at risk by ignoring the overwhelming body of evidence accumulated over the past 5 years that supports the use of antivirals.”
Prof Wendy Barclay, Chair in Influenza Virology, Imperial College London, said:
“Treating influenza is a challenge. For most people it is an acute disease, lasting less than one week. The virus replicates in the respiratory tract, peak virus replication occurs in the first days after a person gets infected, but they might not feel ill straight away. Severe influenza disease is associated with higher virus replication so it had always made sense that a drug that targets the virus should help to control symptoms. But getting the drug to the patient in time is difficult because often patients present late, some days after the virus replication has peaked. This difficulty in timing may explain why often these drugs have a bigger effect when given as prophylactics (before the person even catches the virus) than as treatments (Cochrane report says both Tamiflu and Relenza given as prophylaxis reduced the risk of symptomatic influenza). In other words it’s not that the drugs don’t work, it’s just difficult to use them to their best effect.
“Most of the trials on the neuraminidase inhibitors drugs that have been re-analysed by Cochrane were conducted on previously healthy adults, infected with a seasonal influenza virus. Influenza viruses vary considerably in their severity year on year. The rates of influenza-like illness reported by GPs were low through the period (1990s and 2000s) when most of the drug trials were happening, and so the trials might only pick up ‘moderate’ effects of drug treatment, particularly when patients begin treatment several days into the infection and after virus replication has peaked. Despite that the report concludes that the drugs did shorten the time to when adults felt better by about one day (16 hours) and in healthy children this was also the case (29 hours). Although one day does not sound like a lot, in a disease that lasts only 6 days, it is. In the community this gets people back to work and school, and having the drugs available also serves as a safety net to treat people who get sick enough to go to hospital.
“Many of the criticisms in the new report seem to be levelled at trial design. It may well be that trials can be done better in the future. But we should be careful about the message that is now sent to doctors and to the public. Influenza virus infections can lead to death. We have only two drugs with which we can currently treat influenza patients and there is some data to suggest they can save lives. It would be awful if, in trying to make a point about the way clinical trials are conducted and reported, the review ended up discouraging doctors from using the only effective anti-influenza drugs we currently have. This might be particularly important in a pandemic before a vaccine is available.
“Most of the controversy surrounding these drugs is about whether they should be stockpiled for pandemics. The Cochrane group themselves cite this as a reason for their review, but it should be noted that most of the data they have re-analysed was not collected in a pandemic situation. The situation in a pandemic is very different to what we encounter each year with seasonal flu: many more people suffer severe influenza, and raised influenza awareness means they are more likely to present early. One can fairly extrapolate that the rather moderate beneficial effects of NAIs (neuraminidase inhibitors) during seasonal influenza in the 1990s and early 2000s would translate into more apparent positive benefits during a severe and widespread outbreak. Indeed retrospective observational studies published last month in Lancet Respiratory Medicine overwhelmingly support a beneficial effect for early treatment with NAIs in hospitalized patients, including pregnant women, during the swine flu pandemic in 2009/2010. This suggests that stockpiling of these drugs was prudent.
“If another pandemic came tomorrow, and the government had no drug with which to treat thousands of influenza infected patients, I imagine there would be a public outcry. It may be that we can do better at designing clinical trials, and at licensing the next era of drugs but this will take time and meanwhile, this new report, taken alongside a lot of other data collected in different settings, does not convince me that the risks of taking Tamiflu or Relenza would outweigh the benefits.”
Prof David Spiegelhalter, Winton Professor of the Public Understanding of Risk, University of Cambridge, said:
“This is a ground-breaking review. Since important studies have never been published, the reviewers have had to go back to clinical trial reports comprising over 100,000 pages: the effort to obtain these is a saga in itself. The poor quality of these reports clearly made extracting relevant data a massive struggle, with many pragmatic assumptions having to be made, but the final statistical methods are standard and have been used in hundreds of Cochrane reviews. Let’s hope that in future high-quality data can be routinely obtained and this type of review becomes unnecessary.”
Dr John McCauley, Director of the WHO Collaborating Centre for Influenza, MRC National Institute for Medical Research (NIMR), said:
“Recent work by Prof Nguygen-Van-Tam at the University of Nottingham, using data collected from collaborators around the world, reached the conclusion that during the 2009-2010 influenza pandemic (H1N1, swine flu) early initiation of treatment with neuraminidase inhibitors reduced the likelihood of severe outcomes from infection compared with no treatment or delayed treatment. The work done by Jefferson et al had a different design and was based on clinical trials. It is clear then that the differing conclusions reached by the two groups need to be carefully examined.”
Prof Patrick Wolfe, Professor of Statistics, UCL, said:
“This review attempts to assess the evidence from 99 manufacturer-sponsored trials of the drugs oseltamivir (Tamiflu) and zanamivir (Relenza) for the treatment and prevention of seasonal and pandemic influenza in adults and children. The authors discuss their decision not to include published trial reports – i.e., data from journal articles – but instead to use manufacturers’ reports to regulators (which they term “clinical study reports”) and regulator comments as part of their assessment. They also discuss why an additional 8 trials were in their view unsuitable for inclusion in the analysis, and they describe a method for rating the risk of included trials for selection bias or other problems.
“The report concurs that there is evidence “both oseltamivir and zanamivir reduce the time to symptomatic improvement in adults (but not asthmatic children) with influenza-like illness” and that “Using either drug as prophylaxis reduces the risk of developing symptomatic influenza”. However, the authors posit that “these drugs do not have an influenza-specific effect” and that based on their findings, “there is little support for their use as prophylactic agents, for example, during influenza epidemics”. Overall, the authors note that their analysis “agrees with the conservative conclusions on both drugs drawn by the US Food and Drug Administration (FDA)”, which “described the overall performance of both drugs as ‘modest’.”
“Caveats to bear in mind: As the authors state, “Our decision not to use published evidence as a basis for trial appraisal and data extraction meant that we had to reconcile and synthesise information from multiple unpublished sources”. Moreover, “We are still uncertain whether the complete study reports represent an exhaustive and coherent source of trial narrative and data”.
“If nothing else, this report shows the importance of making full clinical trial, methods, and procedural data available for independent evaluation.”
Before The Headlines – From the UK SMC
COMMENTARY
Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Updated Cochrane Review, to be published in the Cochrane Library, April 2014.
Claim supported by evidence?
Neither the Cochrane review nor the press release claims that these drugs (Tamiflu and Relenza) are ineffective. The claims are that they shorten the symptoms of influenza but only by between a day and half a day, that there is some evidence of increases in some adverse effects in people taking the drugs, and that there is no good evidence to support claims that the drugs reduce admissions to hospital or complications of influenza. In my view these claims are all broadly justified by the data and the analyses in the Cochrane review, though there are some issues of detail, dealt with below. (But you must bear in mind that having no good evidence to support a claim does not mean that the claim is false – perhaps not enough evidence has yet been collected.)
Summary
- A major review of data from clinical trials, published and unpublished, which allows evaluation of almost all the available evidence.
- Some important questions about Tamiflu and Relenza cannot be answered from this work.
- The review raises important questions about how decisions on drugs should be made, but in itself it cannot answer those questions.
Study Conclusions
The review is about two different antiviral drugs, Tamiflu (oseltamivir) and Relenza (zanamivir), and considers their use in both adults and children, both to treat flu-like symptoms in people who already have the disease, and to try to prevent influenza in people who do not yet have it. But it is important to note that the title refers to preventing and treating influenza in healthy adults and children. It (mostly) does not review data on the use of these drugs in specific groups of people that are vulnerable because of some pre-existing disease, for instance.
The key difference between this review and other systematic reviews is that it is based on data in the form of ‘clinical study reports’, made available by the drug manufacturers, which were originally produced for internal purposes and for submission to the authorities in the US, Europe and Japan who decide whether the drugs can be licensed. The review is also based on comments made by the regulators. Systematic reviews are more usually based on reports of clinical trials published in medical journals.
Many of the conclusions in the review are strongly justified by the data and analyses.
I will consider separately the two major types of study, for treatment of influenza when symptoms already exist, and for prevention of influenza in healthy people. First, treatment.
1. TREATMENT IN PEOPLE WITH INFLUENZA
1.1. Symptoms
The conclusion that taking one of these drugs reduces the time taken until flu-like symptoms are relieved, in adults, is clearly justified. The conclusions on the size of this reduction are also reasonably secure, but one must take into account that the reductions are averages and are subject to some uncertainty. (For instance, the average reduction with Tamiflu is about 17 hours, somewhat more than half a day, but the review also states that the average may be somewhat more or less than that (plausibly between 8 hours and 25 hours), and the reduction in an individual patient could in any case be a lot more or less than this average.)
The review and press release describe this reduction as ‘just half a day’ and ‘small’. This is a value judgement about the size of the reduction that cannot be supported or refuted by the data.
The press release says that the effect on the length of time that symptoms were apparent was ‘more uncertain’ in children. In fact this is really the only situation where the review separates out patients with a particular risk factor for analysis. They did find a significant reduction in time for alleviation of symptoms, with Tamiflu, in children who did not have chronic asthma, but they did not find evidence of a reduction in children with chronic asthma. (They found no effect on duration of symptoms with Relenza in children.)
1.2 Hospital admissions and complications
The reviewers found very little evidence that taking Tamiflu to treat influenza reduces admissions to hospital. They also found very little evidence that taking either drug reduced complications of influenza. However, in this respect, lack of evidence for a reduction cannot immediately be taken to mean that there is no reduction in the complications.
There are two problems in studying complications. First, according to the review, most of the trials were not very precise or reliable in how they defined and recorded the complications. Second, most of these complications are relatively uncommon. Even with the large number of patients included in all the trials under review, the great majority of patients had no such complication whether they were taking the drug or a placebo, so that there were sometimes too few of these complications to allow any statistically clear conclusion to be drawn.
1.3 Harms
Finally on the treatment trials, the reviewers considered whether the drugs had raised levels of adverse effects, compared to placebo. Here the evidence is mixed. As the press release says, Tamiflu increased somewhat the level of nausea and vomiting, though the press release does not add that it decreased the risk of diarrhoea in adults. Both the press release and the review point out that there is evidence of a small increased risk of psychiatric events. In fact this risk was not statistically significant, and the main basis for the claim appears to be an increase of psychiatric adverse events in two trials, only in patients who were given a larger than standard dose of Tamiflu.
2. PROPHYLAXIS / PREVENTION
2.1 Symptoms
I now turn to trials for prevention. The reviewers and the press release point out that both drugs reduce the risk of people suffering symptomatic influenza. The press release does not say how large these reductions are; the position is complicated, depending on whether influenza is present in the family of the person being studied.
2.1 Harms
The risk of harms from preventive treatment was also considered. With Tamiflu, there was statistically significant evidence of an increased risk of headache and nausea when taking the drug. The review and the press release also report an increased risk of renal (kidney) adverse events, and psychiatric adverse events. However, the evidence for these increases is weak. The difference between those on the drug and those on the placebo was not quite statistically significant for renal events, in the main statistical analysis. The difference for psychiatric events was significant only when the reviewers included events that occurred while the patients were being studied but not actually taking the drug, as well as events when they were taking it. These events were in any case not common, and most (though not all) of them were not severe, but this may well be another situation where there is not enough data from the trials to be conclusive.
2.3 Transmission
Finally, the review and press release state that it is unproven that Tamiflu can stop people carrying the virus and transmitting it to others. The basis for this conclusion is rather different from the others. The review found that one important reason for the claim was not in fact supported by the evidence. Furthermore, the researchers discovered a statement by the FDA (the Food and Drugs Administration, which regulates drugs in the USA) that a claim of interruption of person-to-person transmission was not justified by the data presented to them.
Strengths/Limitations
Strengths
Compared to reviews based on published work, this review is much more comprehensive in covering almost all of the clinical trials that have been done on these drugs, and is also based on much more comprehensive data on each trial than would typically appear in a paper in a medical journal. This is a major strength. In addition to simply making more of the usual kinds of data available, the reviewers had access to information that would never be in published trial reports, such as comments made by the regulatory authorities in response to the information provided by the drug manufacturers. This Cochrane review is a revised version of previous reviews based (mainly) on published data, which found evidence of publication bias – that is, the published studies did not fairly represent the conclusions one would draw from the results of all trials. This new review corrects this important problem.
A further strength is that the information from different trials is aggregated by standard statistical meta-analysis methods for this kind of review, and that the detailed results of all these meta-analyses are presented in the Cochrane review report (one of the reasons why it is 558 pages long).
Limitations
One limitation, made very clear by the reviewers, is that previous systematic reviews have not used the same kind of data source (clinical study reports and regulator comments), and that they had to develop new methods of working with the resulting huge quantity of data. The reviewers are assiduous about describing how they approached this enormous task, and in my opinion they did use appropriate methods, but it is impossible to be certain that this approach did not lead to any biases or miss important information. I have no reason to believe that it did suffer from any such flaws, but really we will be able to tell whether the methodology is entirely appropriate only after it has been more widely applied.
Arguably, a limitation is that the review, huge as it is, is based only on data from randomised clinical trials. As mentioned above, despite the size of the trials, there were simply insufficient data on complications of influenza and on some possible adverse effects of the drugs, because the complications and adverse effects are rare. It is sometimes possible to get further data on these rare events from other types of study (observational studies in very large groups of people who have used the drugs, for instance), though such studies are difficult to interpret and can be subject to serious biases. There have been some such studies, and indeed reviews of them, but the conclusions so far have generally been inconclusive. It would not have been appropriate for this particular review to use data from such studies, but those making public health decisions on the drugs may wish to take them into account, where possible.
One concern is that, in their summarised conclusions, the authors describe the reductions in time to alleviation of symptoms after taking Tamiflu as small in adults and non-existent in asthmatic children, without mentioning that they do also exist in children without asthma. Furthermore, they do not describe the increases in risk of adverse effects as small, even though at least some of them arguably are small, a few of them are arguably not statistically significant, and some show evidence of a reduced risk in those taking the drug.
Before The Headlines is a service provided to the SMC by volunteer statisticians: members of the Royal Statistical Society (RSS), Statisticians in the Pharmaceutical Industry(PSI) and experienced statisticians in academia and research. A list of contributors, including affiliations, is available at http://www.sciencemediacentre.org/working-with-us/for-journalists/headlines-for-journalists/