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New evidence, same conclusion: Tamiflu only modestly useful for influenza

Tamiflu

Does Tamiflu have any meaningful effects on the prevention or treatment of influenza? Considering the drug’s been on the market for almost 15 years, and is widely used, you should expect this question has been answered after 15 flu seasons. Answering this question from a science-based perspective requires three steps: Consider prior probability, be systematic in the approach, and get all the data. It’s the third step that’s been (until now) impossible with Tamiflu: Some data was unpublished. In general, there’s good evidence to show that negative studies are less likely to be published than positive studies. Unless unpublished studies are included, systematic reviews are more likely to miss negative data, which means there’s the risk of bias in favor of an intervention.

The absence of a full data set on Tamiflu (oseltamivir) and the other neuraminidase inhibitor Relenza (zanamivir) became a rallying point for BMJ and the AllTrials campaign, which seeks to enhance the transparency and accessibility of clinical trials data by challenging trial investigators to make all evidence freely available. (Reforming and enhancing access to trial data was one of the most essential changes recommended by Ben Goldacre in his book, Bad Pharma.) In 2009, Tamiflu’s manufacturer, Hoffman-La Roche committed to making the Tamiflu data set available to investigators. Now after four years of back-and-forth between BMJ, investigators, and Roche, the full clinical trials data set has been made freely available. An updated systematic review was published today in BMJ (formerly The British Medical Journal), entitled “Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments.” This will be a short post covering the highlights. As the entire study and accompanying data are freely available, I’ll await continued discussion in the comments.

What do we already know about influenza and the antiviral drugs?

Influenza is a significant cause of illness and death. While deaths directly attributed to the virus tend to be uncommon, influenza kills through its effects on other diseases, like lung and heart disease, and by causing secondary infections. It doesn’t always discriminate, either – every influenza season we see stories of otherwise healthy adults, pregnant women, and children who died due to influenza. Influenza is an unpredictable killer – seasonal variation and genetic variation make each year’s influenza season slightly different.

It’s been widely acknowledged that we have limited tools to prevent and treat influenza. Beyond the basic infection control processes (e.g., handwashing), there’s the vaccine, and then there’s antiviral drugs. The influenza vaccine can be effective (depending on the antigenic match) but even a well-matched vaccine still has only modest efficacy – especially compared to other vaccines, like smallpox (now eradicated), polio (on its way to being eradicated), and measles (potentially eradicable, but we’re not close yet). For decades, the main drug was amantadine, a drug with little persuasive evidence of efficacy. In the late 1990′s two new antiviral drugs were launched: oseltamivir, an oral capsule marketed as Tamiflu, and zanamivir, an inhaled powder, sold as Relenza. While these drugs were widely marketed when launched, there was very little good evidence to demonstrate that they had meaningful effects in the ambulatory (generally healthy) population that contracted influenza. Evidence suggested that it seemed to only shorten the duration of influenza slightly, though it seemed more useful at preventing its spread. There was also some observational data suggesting a possible mortality benefit. Meta-analysis by groups other than Cochrane suggested some benefit. Guidelines in the 2000′s reinforced the primary role of vaccination and tended to recommend the restriction and use of antiviral products to populations considered more “at-risk”: The hospitalized, those that could not be vaccinated, and those exposed to the virus, particularly in locations like nursing homes, where the risks and consequences of infection were much higher. Despite guidance that was, in some cases, quite limiting, the drugs developed a perception of efficacy, no doubt reinforced by effective marketing, extensive prescribing, and undoubtedly, patient demand.

Despite the modest efficacy of the new antivirals, most governments developed stockpiles of the medications. All public health agencies fear that we may someday see another influenza pandemic like 1919 (which killed millions worldwide), so it’s not surprising that there’s a supply maintained, even when the overall efficacy looked poor. There is evidence for the prevention of spread, and given the unknown virulence of the next virus to circulate, stockpiling is like an insurance policy of unknown value – it might help, and it might not, but if you don’t have any stockpiled, you won’t have anything at all in a pandemic situation. It’s important to reiterate (as we’ll come back to this point) that stockpiles are not for seasonal influenza, they are reserved for pandemics, where infectiousness and virulence may be much greater. Given most of the drug probably expires before it’s ever used, the value-for-money of this strategy isn’t clear and can really only be assessed in retrospect – and in the face of a new pandemic, it will be difficult to assess.

What new information does this analysis provide?

This new paper is written by Tom Jefferson, Mark Jones, Peter Doshi, Elizabeth A Spencer, Igho Onakpoya, and Carl J. Heneghan, several of whom contributed to the previous version of the same review. Some of these names may be familiar to regular readers of this blog. Tom Jefferson is a vocal critic of the influenza vaccine and his strict approach to data been criticized as “methodolatry” by some epidemiologists. Mark Crislip, this blog’s resident infectious disease specialist, agrees with many of Jefferson’s criticisms of the existing evidence but comes to a different conclusion regarding the vaccine’s effectiveness based on a different interpretation of the data, one that’s pretty consistent with the perspective of David Gorski. The other author who holds strong opinions about influenza is Peter Doshi, who is so stridently anti-vaccine he makes Tom Jefferson look pro-vaccine. Doshi believes that influenza itself is an example of “selling sickness”, and questions the morbidity and mortality estimates of the disease. It is perhaps not surprising, then, to see the authors describe influenza as “benign” in the text of this review. It all depends on the population you study. Lest you think I’m poisoning the well before getting into the data, it’s important to keep the authors’ perspectives on the disease itself in mind, when we discuss what the study results are telling us about the “real world” outside the randomized controlled trial.

The data set the authors used is described as complete, and they suggest that every trial of oseltamivir, both unpublished and published, has been included (83 trials). They included randomized controlled trials of oseltamivir that examined prevention, treatment, and post-exposure prophylaxis (another type of prevention). Patients had to be healthy, or have a chronic illness. Trials that studied the immune-compromised were excluded. The authors also excluded all trials for which they could not access unabridged clinical study reports, creating the strictest inclusion criteria I’ve ever seen in a systematic review. Clinical trial reports can run into the thousands of pages and are the medical equivalent of visiting a sausage factory – the final product looks nothing like the raw ingredients. They admit this was a challenge:

The main limitation of our study is our relative inexperience in dealing with large quantities of information and our lack of familiarity with certain trial documents such as blank case report forms. A further limitation of our review is that the methods we have developed to assess and summarise information from clinical study reports may not apply to non-industry trials (which may not be reported in clinical study reports).

Which is a pretty significant limitation, as non-industry-sponsored trials may have been excluded based on this strict criterion. With the new criteria and dataset, new findings and conclusions were drawn:

Treatment

  • Tamiflu reduces symptoms in adults by about 2/3 of one day, from 7 days to 6.3 days (P<0.001)
  • Tamiflu reduces symptoms in children by over one full day (P=0.001) but not in asthmatic children
  • Tamiflu has no effects on rates of admission to hospital when used for treatment or prophylaxis (prevention)
  • Tamiflu significantly reduced the risk of “investigator mediated” unverified pneumonia (risk ratio 0.55) (NNT=100)
  • There was no reported difference for trials that reported pneumonia differently
  • Tamiflu did not appear to influence the likelihood of pneumonia in pediatric patients

Prevention

  • Tamiflu reduces the risk of symptomatic influenza in individuals by 55% (NNT=33)
  • Tamiflu reduces the risk of symptomatic influenza in households by 80% (NNT=8)
  • Tamiflu has no effects on rates of admission to hospital when used for prophylaxis (prevention)
  • There was no effect on asymptomatic influenza transmission

Post-exposure prophylaxis

  • There was only a single post-exposure trial included in the analysis. The manufacturer concluded the drug was effective; the authors disagree with the trial’s design. No statistics are provided.

Overall, these new findings provide convincing evidence that Tamiflu has a beneficial effect for treating influenza, but the net benefit is small. Moreover, the drug does not seem to prevent complications like hospitalizations. However the drug provides a meaningful benefit in the prevention of influenza, especially in households.

Harms

Like the efficacy data, the harms data are consistent with what’s already known about Tamiflu. When used for treatment of infection, the drug is generally well tolerated with the exception of nausea and vomiting, which are not uncommon (NNH 28 and 22, respectively). However, it reduces the risk of diarrhea (NNT 43) and “cardiac body system events” (NNT 148). There is no evidence to suggest that Tamiflu increase psychiatric side effects while on treatment.

When used for prevention of infection, Tamiflu can cause headache (NNH 32), nausea (NNH 25) and neuropsychiatric adverse effects (NNH 94).

There were insufficient deaths in the dataset to draw conclusions about effects.

What about real-world data?

Accompanying the Jefferson paper is a paper by Freemantle and colleagues, entitled “Oseltamivir: the real world data”, that goes beyond the dataset used in the Jefferson analysis, which was restricted to randomized controlled trials only. The authors note:

  • RCTs tend to include healthier patients that may not reflect the population that receives a drug in the real world.
  • While observational trials don’t randomize (and can be more easily prone to bias) they allow study in populations where RCTs may be ethically impossible (e.g., pregnancy). Some biases can be addressed in part by statistical techniques.

The authors updated a systematic review that was last completed in 2012 examining oseltamivir’s impact on mortality. The search strategy is well described and 18 studies were included:

  • Prevention of death: Three observational studies evaluated the effectiveness of oseltamivir to prevent death. The authors noted design, analysis and reporting issues with the three studies. However all three studies found that oseltamivir reduces mortality, a finding the authors describe as “reasonably consistent evidence which points towards a benefit of oseltamivir in this setting.”
  • Effects in pregnancy: Three observational studies have looked at maternal infant outcomes. No harms have been noted.
  • Neuropsychiatric effects: Three observational studies examine psychiatric and neurological events. The effects are mixed to positive, with one study finding reduced psychiatric effects with treatment.

The authors conclude that Tamiflu has some overall positive effects but also argue that they’re inconclusive, given the quality issues in the data. They argue, justifiably, for more trials, both prospective and observational, in higher-risk populations, where there continues to be a lack of good-quality evidence. This conclusion is largely consistent with another, older, systematic review of observational studies completed in 2012 by Hsu, which cautiously suggested a net benefit in high-risk patients.

Conclusion

The headlines today may suggest Tamiflu is a scam, and there’s no doubt that the beneficial effects have been overstated, particularly in the general population where the risk of serious complications tend to be low. However, the data are more nuanced than the investigators themselves believe. Jefferson and associates argue their findings provide evidence that stockpiling of this drug should end. One question is how generalizable the current evidence base is to a pandemic situation, and how much we’re prepared to invest (to stockpile) given the limited beneficial effects shown as a treatment. The second question is the role of Tamiflu in the seriously ill, and in those at greater risk of flu-related complications and death. What the news coverage and the authors seem to be ignoring is that Tamiflu is demonstrably and meaningfully effective at preventing the spread of the infection. At the same time, there’s some real world evidence (albeit with limitations) that suggests that oseltamivir may provide a slight survival advantage in the very ill. Tamiflu is also well tolerated and has a generally good side effect profile. Overall, this new study reinforces what’s been argued by science-based medicine for years: Antivirals like Tamiflu don’t replace vaccination. It offers little benefit in the routine treatment of influenza in the otherwise-well individual, but may have a role in those with other medical conditions, or when used to prevent influenza’s spread.

Posted in: Clinical Trials, Pharmaceuticals, Public Health

Leave a Comment (30) ↓

30 thoughts on “New evidence, same conclusion: Tamiflu only modestly useful for influenza

  1. goodnightirene says:

    I was reading coverage of this just last night in The Guardian, so it’s a treat for me that you covered it so quickly. It was not possible from the article I read to tell whether or not the UK government had, indeed, wasted millions of pounds on Tamilflu–as the headline claimed. There was too much “balance” for a subject that most readers will never be fully qualified to evaluate. But happily for me, our resident pharmacist came to the rescue. Many thanks.

    It seems the answer is to ban marketing of drugs other than through the release of all data to qualified panels who can evaluate it in as unbiased a manner as possible–and then release the results including areas of disagreement among the qualified.

    1. Andrew says:

      Ban the marketing of all drugs? Do you mean to patients/consumers only? If so, that’s not an unreasonable claim although there is some benefit to better awareness.
      If you’re talking about a ban on marketing to HCPs, that’s perhaps a little over the top don’t you think? While I agree there are many biased or exaggerated marketing claims, that would call for us to tighten the regulation and data that are used to support the claims, not ban the use already.
      If we are to expect doctors and pharmacists to keep up on all of the data of all of the drugs we are in for trouble, especially in rarer diseases.

      1. WilliamLawrenceUtridge says:

        There was a study discussed here, perhaps in a comment? That studied whether advertising and drug reps helped increase the uptake of new drugs, and the finding was that they did. And much as there are me-too drugs, some new drugs are genuine improvements (gleevec anyone?).

        Probably funded by Pfizer :)

  2. CHotel says:

    With this new and comprehensive data regarding the (surprisingly good, to me) benefit in limiting spread, I’d be very interested in seeing a pharmacoeconomic analysis of widespread use in a pandemic situation. Get some computer modelling all up in it. I don’t think that the treatment efficacy data supports the stockpiles we are currently holding, but it would be interesting to see for various WTP/QALY (Willingness to Pay per Quality Adjusted Life Year) thresholds how bad an epidemic would have to be to justify giving it to most of the population to curb such spread.

    (Not that I ever think such a situation would occur, but it would be neat data. I’d do it myself if I had any idea how to)

    Another note: Did the observational studies only include people using it for treatment or was it all use? I haven’t had time to read the whole thing myself yet. Since they do find a modest mortality benefit, I wonder if the prevention of spread rather than efficacy of treatment could have contributed there (ie less people get the flu, therefore less people die of the flu). Seems a longshot, but could be a possible confounder.

  3. Derek Freyberg says:

    One of the issues with Tamiflu has always been the cost. But in the US, the last patent (there are three) expires in June 2017, so in the not too distant future, oseltamivir will be generic and the cost of keeping a stockpile should decline considerably – unless this and other reviews cause governments to decide that they don’t need a stockpile after all. Relenza goes off patent around the end of this year – it will be interesting to see if/when a generic emerges.

  4. Sawyer says:

    So here’s what I don’t understand at all:

    Other people working with the Cochrane Collaboration must have an interest in the evidence behind Tamiflu and the prevention of suffering from influenza. Other scientists surely have the background in epidemiology/pharmacology/virology to do a high quality review. And certainly anyone familiar with Tamiflu has to know about Jefferson and Doshi’s questionable track record on this topic.

    So why can’t Cochrane just get someone else to do the meta analysis on Tamiflu? I admit I don’t know a damn thing about the how most journals are organized, but it seems like it wouldn’t take that much effort to find more qualified researchers to do these reviews. Or at the very least, have a follow-up article that points out some of the more obvious limitations of this type of meta analyses (like how hard it is to measure the spread of influenza instead of just monitoring symptoms)

    Someone on another forum I frequent expressed concern that the Cochrane Collaboration is slowly starting to brand themselves as a “watchdog” organization rather than sticking to their original mission objective. Okay, fine by me. We certainly could use an extra pair of eyes on huge pharmaceutical companies. But just come clean and tell people that’s your new MO. And regardless of their objectives, I still think they can do much better than the ambiguously vague duo of Doshi and Jefferson.

    1. WilliamLawrenceUtridge says:

      The real problem to me seems to always be the interpretation. If you skipped right to the results table, you’d say “oh, that’s modestly effective, there are obviously some possible applications and some follow-up research to conduct”. But if you read the prose, the phrasing is “useless”, “waste of money”, “ineffective”. And if you read interviews with Jefferson at least, he rides the pharmanoia horse and puts it away wet’.

  5. Adam Jacobs says:

    Very nice blogpost, Scott, and broadly in agreement with my own:

    http://dianthus.co.uk/tamiflu-its-a-bit-more-complicated-than-that

    However, I do have one question about something you say. You say that the “accompanying data” are freely available. The link you provide is to all the various analyses the authors do to reach their conclusions. However, to me, the “accompanying data” would mean the Tamiflu study reports from Roche.

    I can’t find those anywhere. I would love to read them for myself, as Roche have alleged that the analysis the Cochrane reviews did is not actually consistent with the data in their reports, and it would be interesting to see if Roche are right about that.

    I did previously ask the Cochrane reviewers to share the reports with me, but they refused. This is a bit odd, when the back story to all this is that they made a big thing of refusing to sign a confidentiality agreement with Roche as a condition of receiving the reports, as they said it would be essential to be able to be transparent and to share them.

    So do you know if the Roche reports are available anywhere?

  6. Lytrigian says:

    The news radio station in San Francisco covered this yesterday, and the spokesman they interviewed (associated with the Cochrane folks somehow; I forget the details) claimed flat-out there was no effect at all on flu transmission from Tamiflu; that it was totally useless for dealing with an epidemic. I wonder why they’re overstating the matter?

  7. Self Skeptic says:

    I think the issue is, that once the Cochrane reviewers painstakingly dissected away the distorted marketing claims around Tamiflu, there was so little apparent benefit left, that they suspect it is within the margin of error, and consistent with the null hypothesis. They could be wrong, of course; anyone can be wrong. But it seems plausible, if not “proven”, to conclude that the drug is most likely useless, and merely functioning as a placeholder fiction, to allay public fear of a flu epidemic (and as a profit-maker for Roche.). Alternatively, there may actually be a small, real, benefit; it’s probably impossible to tell the difference at this point, no matter how much of the (supposedly untainted) original data is laid open to examination.

    In such a case, what is the reasonable thing to do? It seems quite evident to everyone, that exaggerated marketing claims have played a role in convincing the public (i.e. the various governments) into thinking that Tamiflu was effective enough to possibly staunch an epidemic. It seems that once the exaggeration is stripped away, its effects (if they exist) are so modest, a reasonable person might conclude that it probably wouldn’t affect the progress of an epidemic. If this is so, should we keep up the charade, so the public can continue to believe that it has protection from another 1918-style epidemic? (And also perhaps to support the ideology that the pharmaceutical and medical care industries are both unusually honest, and unusually competent among big lucrative industries.)

    There are many examples in medicine, where the final argument for retaining some dubious test or treatment is, “but we don’t have anything better.” I’m assuming there is some compelling medical-culture reason, why that is considered a valid response. In science, fake fixes are considered extremely undesirable. I’ll leave it to you all, to work out why that is so in science, with the hint that it is practical, not due to arbitrary and idealistic scruples. While we’re at it, we should mull over, why medicine seems to need placeholder fictions, despite their significant downside.

    For a scientist like me, it’s pretty hard to think that such large, mainstream, commercial deceptions as the overselling of Tamiflu is better left unexposed. People can avoid CAM; they can’t reasonably avoid participating in Tamiflu and other dubious mainstream medical purchases.

    To me, the complaints about Cochrane’s supposed anti-business bias, and about “pharmanoia,” seem to come from people with a pro-business bias, that has nothing to do with promoting good science-based medicine. Yes, we do need businesses. But if they are going to be so big and wealthy that they can dominate public opinion and actions by saturation-advertising, lobbying, price-fixing, and medical journal and specialty society patronage, then those of us who care about medicine being science-based, need to take some measures that challenge corporations and academic power-players to be more honest, in their claims about what science tells us. Otherwise, science will end up looking, and behaving, like just another scam. There is no Truth Fairy; exaggerated and amplified corporate (or academic) claims that get into the medical literature and become widely accepted, are not distinguishable from physical truth, unless someone does the kind of intellectual heavy-lifting that Cochrane was founded to do. It seems peculiar to me, to complain about Cochrane’s exposing these not-so-trivial scientific fibs.

    No doubt, things look different, to those immersed in business culture, or in the medical profession/industry. I see that Scott Gavura has an MBA,
    and Adam Jacobs has his own business focused on crafting big and small pharma communications:
    http://dianthus.co.uk/our-people
    http://dianthus.co.uk/about-us
    Presumably anyone who writes for Lilly, Pfizer, Sanofi, and Wyeth has found a way to accommodate the needs of such organizations. (I’m not saying anyone here is being intentionally dishonest; just that we all have biases, and the best we can do is to try to become aware of our own, and try to recognize those of others.)

    These business concerns may help account for some of the difference between Gavura and Jacobs’ biases, and mine. I’m just giving you one research scientist’s overall impression. My perception is that there is overwhelming evidence that the biggest pharmaceutical companies habitually overstep the limit at which marketing-motivated claims should be self-restrained, in the interests of scientific accuracy. So far, regulatory fines levied when they are caught, are seen as a mere cost of doing business. It’s a serious, and (so far) barely mitigated, burden on public health and economics.

    1. Windriven says:

      “So far, regulatory fines levied when they are caught, are seen as a mere cost of doing business. It’s a serious, and (so far) barely mitigated, burden on public health and economics.”

      Without getting too far into the weeds,

      First, your observation argues for more – and more rigorous – science based medicine.

      Second, there is growing concern in some economic circles that capitalism – at least as it has evolved in the last 60 years – has about lived out its usefulness. The model has yielded impressive results but only by ignoring many of the costs. It has arguably created a hamster wheel of increased consumption (and the concomitant waste and pollution) of frequently unnecessary and often crappy products. Moreover it has elevated wealth to be an end in itself rather than a means to achieve an end. This is crystallized in the sophomoric mantra of the wealth-obsessed: “he who dies with the most toys wins.”

      1. Self Skeptic says:

        Windriven,

        “First, your observation argues for more – and more rigorous – science based medicine.”

        Yes, absolutely. More rigorous science. More appropriate modesty in making conclusions. Less unwarranted generalization. Less hype, whether it be motivated by careerism, or money.

    2. weing says:

      “My perception is that there is overwhelming evidence that the biggest pharmaceutical companies habitually overstep the limit at which marketing-motivated claims should be self-restrained, in the interests of scientific accuracy. So far, regulatory fines levied when they are caught, are seen as a mere cost of doing business. It’s a serious, and (so far) barely mitigated, burden on public health and economics.”
      Wow. You figured it out all by your lonesome. I would never have guessed this about pharma. (Place irony icon here) I wonder if the same goes for weapons systems that are supposed to protect us from foreign threats? Airport security? EHRs? Archimedes Healthcare Simulator? Obamacare? Republican alternatives?

      1. Self Skeptic says:

        Weing,
        Whew, glad to see that I am indeed stating the obvious. I was actually getting concerned that someone was going to claim that big drug companies are part of a fine upstanding industry that would never think of tampering with data or making exaggerated claims of effectiveness. And that therefore, we don’t need Cochrane teams, to spend months, or sometimes years, trying to get at the truth, as much as one can.

        But, as you say, that would clearly be a ridiculous claim. So we can assume that no one will make it, and that we all know about the need for independent, Cochrane-style analysis. Even if it’s embarrassing, when they rock the boat.

        1. Andrey Pavlov says:

          I was actually getting concerned that someone was going to claim that big drug companies are part of a fine upstanding industry that would never think of tampering with data or making exaggerated claims of effectiveness.

          Yet another bit of evidence that you do not know enough about the field at large to be yammering on the way you do. This exact topic has been written about before. And I, as well as at least some of the editors and contributors here that I know of, are part of the Open Trials campaign.

    3. Sawyer says:

      You claim to be a scientist – have you ever done research on neurominidase inhibitors? Published papers on influenza? Do you understand how to make a robust, reliable model for the spread of an infectious disease, and to predict the strain that will be circulating next year?

      The science behind Tamiflu is actually super complicated, and the difference between “mild benefit” and “no benefit” is not necessarily trivial to people that specialize in this field. You don’t get to just assert that the drug does nothing unless you have the evidence and expertise to back it up. I don’t blindly trust Roche’s depiction of how their drug works, but I also don’t understand why I should trust speculation and conspiracy mongering from those with an ax to grin (primarily Jefferson and Doshi).

      Self Skeptic, you keep intermixing reasonable statements that everyone already agrees with (drug companies overhype their products) with unfounded speculation and arrogant rants that you are way smarter than everyone else here. You’ve been told numerous times that this is NOT the way to have an honest discussion about science and medicine. Yet you keep doing it.

      I also don’t know who the hell is claiming Tamiflu is going to prevent another 1918 flu pandemic. Every public health expert I have listened to gravely admits we still do not possess the tools needed to combat this magnitude of an outbreak. Where on Earth did you come up with that one?

      1. Sawyer says:

        *neuraminidase

        I really need to install a medical dictionary for my browser.

    4. WilliamLawrenceUtridge says:

      The difference between Scott’s bias and yours appears to be that Scott recognizes the nuance of the research, and the risks faced by public health. You seem to think that there is a Truth Fairy and that recognizing the difficulties of this particular aspect of science means irredeemable bias.

      Incidentally, how much do you know about business? Have you ever thought that knowing something about businesses might actually be helpful, since it allows you to recognize the incentives involved, and how to best align business’s ability to produce goods with societies needs for public goods? I’ve learned just enough about business and economics to see how meeting public health needs with private industry presents considerable dangers to both public and industry. It’s not simple.

    5. Andrey Pavlov says:

      n such a case, what is the reasonable thing to do? It seems quite evident to everyone, that exaggerated marketing claims have played a role in convincing the public (i.e. the various governments) into thinking that Tamiflu was effective enough to possibly staunch an epidemic. It seems that once the exaggeration is stripped away, its effects (if they exist) are so modest, a reasonable person might conclude that it probably wouldn’t affect the progress of an epidemic. If this is so, should we keep up the charade, so the public can continue to believe that it has protection from another 1918-style epidemic?

      Once again you fail in your analysis by demanding a false dichotomy. Our choices are not “keep up the placeholder fiction” or “ditch it entirely.” There is evidence that it can indeed help impede the spread of of influenza. Not particularly well in typical situations, not well enough to warrant many (if any) individuals scripts for the average Joe and Jane, but enough that should a serious flu epi/pandemic arise it will still be helpful . Is it particularly good? No. Does it still have evidence of some efficacy? Yes. Does a serious flu pandemic mean millions of people sick and thousands if not tens of thousands dead? Yes. So does even a modestly effective drug to help stem that – even just a tiny bit – make sense? Of course it does. Because that modest effect still translates to lives saved. And yes, that is precisely why the answer of “it’s the best we’ve got” is perfectly reasonable.

      You seem fundamentally incapable of realizing that digging down and finding greatly less efficacy than we’d believed (and hoped) does not equate to throwing out our petri dishes and reagents, retracting a paper or two, and starting over to find something better. There are actual lives in the real world at play here.

      There are many examples in medicine, where the final argument for retaining some dubious test or treatment is, “but we don’t have anything better.” I’m assuming there is some compelling medical-culture reason, why that is considered a valid response.

      So that “compelling medical-culture reason” is because in our business people fracking die. And therefore, if we haven’t anything better, but at least some reason to believe that it actually has utility and could help, it is still worth trying. Tamiflu still has legitimate evidence of efficacy in some situations and a reasonable prior plausibility that it would be the case. Even if that means the NNT is 1000 instead of 100 that still means lives saved. It is completely different from say, homeopathy or reiki or acupuncture that have no evidence for efficacy, plenty against them, incredibly bad prior probability, and will almost certainly be a complete waste of time in all scenarios.

      1. Dave says:

        “You seem fundamentally incapable of realizing that digging down and finding greatly less efficacy than we’d believed (and hoped) does not equate to throwing out our petri dishes and reagents, retracting a paper or two, and starting over to find something better. There are actual lives in the real world at play here. ”

        “So that “compelling medical-culture reason” is because in our business people fracking die”

        Precisely. Very few medications have 100% efficacy. From a public health standpoint, a medication with a high NNT may still save substantial numbers of lives if given for a disease which affects hundreds of thousands of people. The concept that numerous people must be treated to help a few is not a concept that goes down well, but that is in fact sometimes the best we have.
        If that’s all you have, that’s what you will use until something better comes along.

        I found as a madical student is was pretty easy to have strong opinions on “futile care” and “dnr” orders. It suddenly becomes a lot harder when you are the one responsible for those orders and a person’s life might depend on them. If you develop a severe case of influenza, SS, you will be offered therapy. You can always refuse to take it.

        As part of the infection control committee at my hospital I’ve seen the official predictions of what would happen in our county in the hypothetical scenario of the highly lethal asian avian flu developing the ability to be easily transmitted human-to-human and becoming pandemic. The number of critically ill patients would far exceed the capacity of our hospitals to handle them, and there is an estimate that a significant percentage of the health care workers would either sicken/die or refuse to come to work in such a scenario, increasing the problem. Let’s hope that never happens or we get an effective remedy beforehand.

    6. Self Skeptic says:

      I’m not seeing anything in these replies, that require any clarifying input or correction from me, regarding my viewpoint. So I’ll leave my original comment to stand, as is. Thanks for helping me to understand how you all are thinking and feeling about this.

  8. regularreader says:

    OFF TOPIC

    Ack!

    http://www.nytimes.com/2014/04/13/fashion/dr-mark-hyman-clintons-health.html?hp&_r=0

    Mark Hyman (Dr. Functional Medicine) is best buds with the Clintons.

    He accuses Michelle Obama of being in bed with BigFood because she is taking a “mainstream” path on childhood obesity.

    1. David Gorski says:

      Heheh.

      Tune in tomorrow…

  9. I was glad to see that all the clinical trials were made available for this study. I think all clinical trials should be publicly available for the good of all.

    It appears there are benefits to Tamiflu but it leaves a lot to be desired in our battle against the flu virus. I think this is especially true for the elderly and those who have other health issues.

  10. jon g says:

    Wasn’t there a study that showed that expiration dates of most meds were basically “made up” and no one really knew when their effectiveness would deteriorate?

    In any event (and not condoning the profits made in this case), there was a valuable psychological benefit to the population of knowing that these drugs were available should a pandemic hit. If the drugs were not so expensive, I might agree that they were worth the cost just in that aspect alone. Keeping the population from panicking in the event of a flu epidemic might turn out to be as dangerous as the epidemic.

    1. WilliamLawrenceUtridge says:

      Not sure about a study, but SBM’s own Scott Gavura has discussed this in the past:

      http://www.sciencebasedmedicine.org/the-drug-expiry-date-a-necessary-safety-measure-or-yet-another-big-pharma-conspiracy/

  11. Trish Groves says:

    Interesting questions.

    The datasets (ie the full CSRs) for the two Cochrane reviews of Tamiflu and Relenza are now freely available here: http://datadryad.org/resource/doi:10.5061/dryad.77471

    and the peer review comments are here: http://www.bmj.com/content/suppl/2014/04/09/bmj.g2545.DC1/jeft017746.ww8_default.pdf

    along with a bunch of other supplementary documents for the BMJ papers:
    http://www.bmj.com/content/suppl/2014/04/09/bmj.g2545.DC1

    We’d welcome postpublication peer review of The BMJ’s articles on Tamiflu and Relenza (http://www.bmj.com/tamiflu) via bmj.com Rapid Responses (eletters).

    Since 1998 The BMJ has published nearly 100,000 Rapid Responses to articles in The BMJ, many of them comprising substantive postpublication review. Yet the recent articles on neuraminidase inhibitors have had only a handful of Rapid Responses.

    Why the silence?

    Trish Groves
    Head of Research, The BMJ

    tgroves@bmj.com
    Twitter/trished

    Competing interests: I chair The BMJ’s weekly research committee meetings, including the one where we accepted the Cochrane reviews on neuraminidase inhibitors

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