Response to Uyeki et al.
We thank the nine representatives of the U.S. Centers for Disease Control and Prevention, European Centre for Disease Prevention and Control, UK Department of Health, Public Health England, World Health Organization, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists -- all organizations that have promoted the use and stockpiling of oseltamivir (Tamiflu) over the years -- for taking the time to express their strong disagreement with an editorial published in The BMJ that endorsed WHO’s decision to downgrade the status of oseltamivir on the Essential Medicines List.
In their letter, Timothy Uyeki and colleagues object to the editorial, and feel the evidence base, particularly on oseltamivir, needs clarification. Their argument, however, is weakened by its selective citation of evidence, and the fact that none of their organizations claim to have independently scrutinized the more complete evidence from clinical study reports.
SELECTIVE CITATION OF THE RANDOMISED EVIDENCE
Uyeki et al. criticize the BMJ editorial, stating, “Ebell did not mention the meta-analysis of RCTs in outpatients published by Dobson et al. that reported oseltamivir treatment of adults with laboratory-confirmed influenza versus placebo was associated with a reduction in clinician-diagnosed lower respiratory tract complications requiring antibiotics more than 48 hours after randomization, and fewer hospital admissions for any cause .”
Uyeki et al. however fail to mention the results of two other analyses of the same trials, which came to different conclusions, complicating the story. The first is our Cochrane review, which found the complications result was not trustworthy, and the hospitalizations result was not statistically significant. The second is a short article by Hernan and Lipsitch which reported that oseltamivir reduces the risk of complications but argued it was not possible to assess hospitalizations. (The Hernan and Lipsitch study was conducted pro bono at the request of Roche.)
Uyeki et al. also failed to mention that all authors of the Dobson et al. study are financially linked to the manufacturer (Roche) or patent holder of oseltamivir (Gilead Science), and funding for the Dobson et al. study itself came through the Roche-funded so-called “Multi-party Group for Advice on Science (MUGAS).”[5,6]
SELECTIVE CITATION OF THE NON-RANDOMISED EVIDENCE
Uyeki et al. cite the results of two observational studies that reported that oseltamivir reduces the risk of hospitalization and mortality.[7,8]
Uyeki et al. however fail to mention that both of these studies were conducted by the same group and funded by oseltamivir’s manufacturer, Roche. They also do not cite our published criticism which notes the purported hospitalisation benefit relies on a shaky assumption. Nor do they cite a WHO-funded systematic review of the observational studies that rated the evidence as “low-quality” and “very low-quality.”
Uyeki et al also fail to mention any of the observational studies, including one by our group, that rebut their conclusions about the benefits of antiviral drugs. These include:
Heneghan et al. which stated “After taking account of time-dependent bias and potential confounding variables, competing risks analysis of the IPD showed no evidence that oseltamivir reduced the risk of mortality (HR 1.03, 95% CI: 0.64 to 1.65)”
Wolkewitz and Schumacher, which stated: “There is no direct effect of NI on the hospital death rate; the hazard ratio (HR) of NI was 1.03 (95%-CI: 0.64–1.66)”
Choi et al. which found, among 506 adult patients hospitalized for influenza, that the in-hospital mortality in the 233 patients who received early neuraminidase inhibitor treatment did not differ from those who received later treatment (8/273, 2.9% vs. 8/233, 3.4%; p = 0.75).
The lack of citations is perplexing considering we provided this list of studies to Dr. Uyeki on numerous occasions over the past six months.
Uyeki et al. say that neuraminidase inhibitors “only have activity against influenza viruses, but not other pathogens.” This is manifestly wrong: our Cochrane review showed “in subgroup analysis of time to first alleviation of symptoms in adults by infection status, we found no evidence of a difference in treatment effect for zanamivir on the influenza-infected subgroup compared to the non-influenza-infected subgroup (P = 0.53). The treatment effect was 0.67 days (95% CI 0.35 to 0.99 days, I2 statistic = 17%) for influenza-infected patients and 0.52 days (95% CI 0.18 to 0.86 days, I2 statistic = 0%) for non-influenza-infected patients.” This raises the possibility that neuraminidase inhibitors might exhibit a general effect of on viral illness symptoms separate from any specific antiviral action.
Furthermore, there is reason to doubt the reliability of analyses based on the “intention-to-treat-infected” (ITTI) population. In oseltamivir treatment trials, “the proportion of patients being diagnosed as influenza infected in oseltamivir treatment of adults was significantly lower in the treated group than in the control group.” This was because “the proportion of patients with four-fold increases in antibody titre was significantly lower in the treated group compared to the control group.” This finding implies that the “intention-to-treat-infected” (ITTI) subgroup analyses in oseltamivir treatment trials are not based on comparing equivalent groups, and therefore are unreliable.
RCTS VS. OBSERVATIONAL STUDIES
Uyeki et al. appear to be promoting observational studies over randomised controlled trials because they are better at evaluating “real-world effectiveness.” This shift of focus away from randomised evidence has increased in recent years as it has become clear that the efficacy of oseltamivir is limited -- something the official FDA-approved oseltamivir prescribing information has always made clear -- and evidence for important clinical outcomes such as a reduction in pneumonia and death remains unproven. But it should not be forgotten that numerous governments, including the United States, stockpiled neuraminidase inhibitors under the assumption that randomised evidence showed the drugs reduced complications and hospitalizations. This retrospective attempt to justify stockpiling by selectively citing observational studies would not be needed if, during the 2009 influenza pandemic, large randomised trials powered to answer clinically important questions had been undertaken. They would have cost a fraction of the billions of dollars governments have spent stockpiling the drug.
HARMS OF OSELTAMIVIR
Uyeki et al. state that influenza infections can cause a wide spectrum of neurologic complications, and raise doubts over our Cochrane review’s finding of a statistically significant increase in “psychiatric adverse events.” They say that “it is notable that … Dobson et al did not find any effect on neurological or psychiatric disorders or serious adverse events.”
Uyeki et al. here suggest there is a disagreement when there isn’t. Our finding related to prophylaxis studies, and Dobson et al. did not study prophylaxis.
Furthermore, Uyeki et al. further attempt to undermine our finding by noting that it included adverse events that took place on days when no drug was received. Such a statement suggests a fundamental lack of understanding of clinical trial methodology which should include data collected during the follow-up period; adverse events do not necessarily only occur on days when a drug is consumed.
WE NEED BETTER THERAPIES
Uyeki et al. would have us believe the randomised evidence supports a conclusion that oseltamivir reduces complications and hospitalizations, and the non-randomised evidence supports a conclusion that the drug reduces the risk of mortality. If this were true, these would be impressive public health drugs. But do Uyeki et al. themselves believe the studies they presented?
Despite all this supposedly supportive data, the authors argue that “we also need much better therapies with different mechanisms of action than oseltamivir.” Why do we need better therapies if the evidence is already so compelling?
Uyeki et al. say that they agree with Ebell that data from “all trials be published, and that individual patient data be made available for independent re-analysis.”
However Uyeki et al. do not mention why not a single one of the organizations that they represent have conducted such an independent re-analysis, despite our group having made the full trial data freely available (around 150,000 pages worth) on the web since 2014 (http://datadryad.org/resource/doi:10.5061/dryad.77471). This is something we have called on the CDC to do. They have never addressed the point, suggesting they have no interest in conducting their own independent re-analysis, and their letter to BMJ suggests they are happy to cite Roche-sponsored analyses that support their position, and have no interest in citing analyses that do not support their position.
WHO’S DOWNGRADING OF OSELTAMIVIR
Lost in the detail of Uyeki et al.’s reply is any attention given to the ramification of the WHO decision to downgrade oseltamivir’s status on the Essential Medicines List. By removing oseltamivir from the core list, and to suggest its new use be “restricted to severe illness due to confirmed or suspected influenza virus infection in critically ill hospitalized patients,” WHO undercut the very basis for stockpiling.
Stockpiling across the world has aimed to achieve coverage for significant portions of the general population. This is what pushed the bill in the range of hundreds of millions of dollars (and in some countries like the United States, over a billion dollars).
If governments were to actually act on WHO’s new position, stockpiles would be for hospitalized patients only. As such, governments could cut their stockpiles by a factor of 100 or more, since hospitalization is a rare complication of influenza. While the drug’s clinical benefits may still not outweigh its harms in a pandemic, it would at least save taxpayers billions of dollars.
Chris Del Mar
1. Ebell MH. WHO downgrades status of oseltamivir. BMJ. 2017 Jul 12;358:j3266.
2. Uyeki T, Penttinen P, Waton J, Bernstein H, Beigi R, Pavia A, et al. Re: WHO downgrades status of oseltamivir [Internet]. 2017 [cited 2017 Oct 31]. Available from: http://www.bmj.com/content/358/bmj.j3266/rr-7
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13. Choi S-H, Kim T, Park K-H, Kwak YG, Chung J-W, Lee MS. Early administration of neuraminidase inhibitors in adult patients hospitalized for influenza does not benefit survival: a retrospective cohort study. Eur J Clin Microbiol Infect Dis [Internet]. 2017 Apr 18; Available from: http://dx.doi.org/10.1007/s10096-017-2982-z
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15. Doshi P, Mandl K, Bourgeois F. Tamiflu For All? Evidence Of Morbidity In CDC’s Antiviral Guidelines. Health Affairs Blog [Internet]. 2016 Mar 31; Available from: http://www.healthaffairs.org/do/10.1377/hblog20160331.054240/full/
Competing interests: We are co-authors of the letter requesting neuraminidase inhibitors be deleted from the WHO EML (http://www.who.int/selection_medicines/committees/expert/21/applications/oseltamivir_del/en/). In addition, we are all co-recipients of a UK National Institute for Health Research grant (HTA 10/80/01 Update and amalgamation of 2 Cochrane Reviews: neuraminidase inhibitors for preventing and treating influenza in healthy adults and children - https://www.journalslibrary.nihr.ac.uk/programmes/hta/108001). PD and MJ are also in receipt of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews. PD received €1500 from the European Respiratory Society in support of his travel to the society’s September 2012 annual congress in Vienna, where he gave an invited talk on oseltamivir. PD has received funding support ($11,000) from the American Association of Colleges of Pharmacy for a study to analyze written medical information regarding the possible harms of statins. PD is also an associate editor of The BMJ and an unpaid member of the IMEDS steering committee at the Reagan-Udall Foundation for the FDA, which focuses on drug safety research. PD also leads the RIAT Support Center, funded by the Laura and John Arnold Foundation. Carl Heneghan has received expenses from the WHO, and holds grant funding from the NIHR, the NIHR School of Primary Care Research, The Wellcome Trust and the WHO. Chris Del Mar has held grants from the NIHR, WHO, and NHMRC, and holds grants from the NHMRC, on related topics.