WHO committee recommend transfer of Tamiflu from the Core to the Complementary Essential   Medicines List “and its use be restricted to severe illness due to confirmed or suspected influenza virus infection in critically ill hospitalized patients” because “there now exists additional evidence of oseltamivir in seasonal and pandemic flu which has reduced the previously estimated magnitude of effect of oseltamivir on relevant clinical outcomes”.

http://www.who.int/selection_medicines/committees/expert/21/en/

http://www.who.int/selection_medicines/committees/expert/21/eml21applications/en/

http://www.who.int/selection_medicines/committees/expert/21/applications/oseltamivir_del/en/

Michael McCarthy: What makes an essential medicine? WHO’s new list focuses on antibiotic resistance, adds expensive drugs, and downgrades Tamiflu. BMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3044 (Published 07 July 2017) Cite this as: BMJ 2017;358:j3044

Mark Ebell: WHO downgrades status of oseltamivir BMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3266 (Published 12 July 2017)

Cite this as: BMJ 2017;358:j3266

Early administration of neuraminidase inhibitors in adult patients hospitalized for influenza does not benefit survival: a retrospective cohort study. Choi SH, Kim T, Park KH, Kwak YG, Chung JW, Lee MS. Eur J Clin Microbiol Infect Dis. 2017 Apr 18. doi: 10.1007/s10096-017-2982-z.

https://link.springer.com/article/10.1007%2Fs10096-017-2982-z

Abstract

Background
Several observational studies reported that Oseltamivir (Tamiflu) reduced mortality in
infected and hospitalized patients. Due to the restriction of observation to hospital stay
and time-dependent treatment assignment, such findings were prone to common types
of survival bias (length, time-dependent and competing risk bias).

Methods
British hospital data from the FLU-CIN study group were used which included 1391
patients with confirmed pandemic influenza A/H1N1 2009 infection. We used a multistate
model approach with following states: hospital admission, Oseltamivir treatment,
discharge and death. Time origin is influenza onset. We displayed individual data, risk
sets, hazards and probabilities from multi-state models to study the impact of these
three common survival biases.

Results
The correct hazard ratio of Oseltamivir for death was 1.03 (95%-CI: 0.64-1.66) and
for discharge 1.89 (95%-CI: 1.65-2.16). Length bias increased both hazard ratios:
HR(death)= 1.82 (95%-CI:1.12-2.98) and HR(discharge)= 4.44 (95%-CI: 3.90-5.05)
whereas the time-dependent bias reduced them: HR(death)= 0.62 (95%-CI:0.39-1.00)
and HR(discharge)= 0.85 (95%-CI:0.75-0.97). Length and time-dependent bias were
less pronounced in terms of probabilities. Ignoring discharge as a competing event for
hospital death led to a remarkable overestimation of hospital mortality and failed to
detect the reducing effect of Oseltamivir on hospital stay.

Conclusions
The impact of each of the three survival biases was remarkable and it can make NI appear
more effective or even harmful. Incorrect and misclassified risk sets were primary
the source of biased hazard rates.

Dunn AG, Zhou X, Hudgins J, Arachi D, Mandl KD, Coiera E, et al. Financial competing interests were associated with favorable conclusions and greater author productivity in nonsystematic reviews of neuraminidase inhibitors. J.Clin.Epidemiol. 2016 Dec;80:43-49

OBJECTIVE: To characterize the conclusions and production of nonsystematic reviews about neuraminidase inhibitors relative to financial competing interests held by the authors. STUDY DESIGN AND SETTING: We searched for articles about neuraminidase inhibitors and influenza (January 2005 to April 2015), identifying nonsystematic reviews and grading them according to the favorable/

STUDY DESIGN AND SETTING: We searched for articles about neuraminidase inhibitors and influenza (January 2005 to April 2015), identifying nonsystematic reviews and grading them according to the favorable/nonfavorable presentation of evidence on safety and efficacy. We recorded financial competing interests disclosed in the reviews and from other articles written by their authors. We measured associations between competing interests, author productivity, and conclusions. RESULTS: Among 213 nonsystematic reviews, 138 (65%) presented favorable conclusions. Financial competing interests were identified for 26% (137/532) of authors; 51% (108/213) of reviews were associated with a financial competing interest. Reviews produced exclusively by authors with financial competing interests (33%; 71/213) were more likely to present favorable conclusions than reviews with no competing interests (risk ratio 1.27; 95% confidence interval 1.03-1.55). Authors with financial competing interests published more articles about neuraminidase inhibitors than their counterparts. CONCLUSION: Half of nonsystematic reviews about neuraminidase inhibitors included an author with a financial competing interest. Reviews produced exclusively by these authors were more likely to present favorable conclusions, and authors with financial competing interests published a greater number of reviews.

RESULTS: Among 213 nonsystematic reviews, 138 (65%) presented favorable conclusions. Financial competing interests were identified for 26% (137/532) of authors; 51% (108/213) of reviews were associated with a financial competing interest. Reviews produced exclusively by authors with financial competing interests (33%; 71/213) were more likely to present favorable conclusions than reviews with no competing interests (risk ratio 1.27; 95% confidence interval 1.03-1.55). Authors with financial competing interests published more articles about neuraminidase inhibitors than their counterparts. CONCLUSION: Half of nonsystematic reviews about neuraminidase inhibitors included an author with a financial competing interest. Reviews produced exclusively by these authors were more likely to present favorable conclusions, and authors with financial competing interests published a greater number of reviews.

CONCLUSION: Half of nonsystematic reviews about neuraminidase inhibitors included an author with a financial competing interest. Reviews produced exclusively by these authors were more likely to present favorable conclusions, and authors with financial competing interests published a greater number of reviews.

PMID: http://www.ncbi.nlm.nih.gov/pubmed/27460462
DOI: http://dx.doi.org/10.1016/j.jclinepi.2016.07.010

Zhou X et al. Citations alone were enough to predict favorable conclusions in reviews of neuraminidase inhibitors. Journal of Clinical Epidemiology 10/2014; DOI: 10.1016/j.jclinepi.2014.09.014

“Favorable conclusions in reviews about neuraminidase inhibitors can be predicted using only information about the articles they cite. The approach highlights how evidence exclusion shapes conclusions in reviews and provides a method to evaluate citation practices in a corpus of reviews.”

The Alberta College of Family Physicians (ACFP)’s Tools for Practice summarises the evidence (www.acfp.ca) so far:
Biased, poor quality, mostly unpublished evidence demonstrates that oseltamivir and zanamivir shorten the duration of
influenza symptoms by ~1/2 a day. Objectively defined pneumonia or hospitalizations are not decreased.

www.acfp.ca/tools-for-practice

Statisticians Wolkewitz and Schumaker using methods to avoid survival biases on observational data from 1391 patients hospitalised in UK during 2009-2010 fail to find an effect of Tamiflu on mortality but show a shortened duration of hospital stay.

View the paper here.

Cochrane reviewer Mark Jones and intensive care specialist Robert Fowler using simulation and an example demonstrate the impact of immortal time bias on the observational datasets used in Tamiflu influenza survival studies. The use of inappropriate statistical methods shows an effect on mortality which disappears when time-dependent exposures are included as time-dependent variables in the analysis.

http://www.sciencedirect.com/science/article/pii/S0883944116302544

A linked commentary by Tom Jefferson explains the significance of Rokuro Hama’s paper.

Cochrane author Rokuro Hama reviews the evidence of harms on neuraminidase inhibitors with a special focus on the two earliest registered molecules (Zanamivir, Relenza, Glaxo SmithKline and Oseltamivir, Tamiflu Roche). Hama provides what is probably the most extensive review of the evidence of neuaraminidase inhibitor harms ever undertaken. Hama’s evidence comes from a powerful mix of mostly hitherto untapped sources, including regulatory papers, clinical study reports, animal studies and published evidence. The evidence fails to support the mechanism of action mediated through antiviral action put forward by the manufacturers. A linked commentary by Tom Jefferson explains the significance.

No effect of oseltamivir on mortality in patients with 2009A/H1N1 influenza? HTA review

What did we do?

As part of our recently published HTA review we assessed the effect of oseltamivir on mortality in 2009A/H1N1 influenza patients.

(See Chapter 3, page 99 Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data. Health Technol Assess 2016; 20 (42).

To do this we did a systematic review and individual patient data meta-analysis of observational studies.  We included 2009A/H1N1 influenza patients reporting mortality outcomes and exposure to oseltamivir with at least 5% of patients untreated with influenza antivirals and five or more deaths overall.

A pre publication protocol outlining our proposed study was also registered at Prospero.

Why did we do this?

• There have only been five deaths in Phase II/III Randomised trials of oseltamivir;
• None of the deaths was in a patient with confirmed influenza.
• Previous reviews of observational studies of influenza 2009A/H1N1 have shown protective effects of NIs on mortality (see here, here and here)
• Case series have suggested increased mortality.(See here and here)

What did we find?

We found insufficient evidence from 30 observational studies to support oseltamivir having a protective effect on 2009A/H1N1 influenza patients for mortality.

• From a total of 1117 studies we included 30 observational studies of hospitalised patients including 11,013 patients.
• Overall there were 1,301 deaths (12%);
• The percentage of deaths receiving oseltamivir was similar to that of survivors (83% vs. 82%).
• We found evidence of time-dependent bias in the summary data and the IPD.
• IPD came from four studies including 3,071 patients and 242 (8%) deaths.

After taking account of time-dependent bias, potential confounding variables, and the competing risk of hospital discharge, analysis of IPD showed  oseltamivir did not reduce the risk of mortality,  HR 1.03 (95% CI 0.64 to 1.65).

Results showed no effect of age group (p=0.40) or severity of illness (p=0.38), but evidence of aneffect of log-odds of death (p=0.024) when, as odds of death increases, the treatment effect in favour ofoseltamivir increases, and log-odds of treatment (p=0.003), when, as odds of treatment increases, the treatment effect in favour of oseltamivir increases.

These effects appear to be independent as p-values in multivariable analysis are 0.031 and 0.006, respectively.

What were the limitations?

Although all 30 studies classified patients by treatment exposure, only two defined it: one as ‘at least one dose of oseltamivir’ and the other as ‘at least one day of treatment’

• A number of studies had missing information on mortality status and/or treatment status,
• Missing data were more common in patients with less-severe disease, whereas other studies reported complete information.
• A number of the included studies conducted analyses adjusting for potential confounding variables, such as patient comorbidities, they used logistic regression or standard survival analysis, which may not be appropriate for observational studies in which treatment exposure is time dependent.
• This type of analysis misallocates the time from initiation of the study (e.g. hospital admission) to start of antiviral treatment and leads to time-dependent bias. See Beyersmann et al. for more on this important methodological issue.

See also  Appendix 15 (page 229)  “Illustration of time-dependent bias using individual patient data from the Canadian study”for a detailed description and example of time-dependent bias.

• The percentages of missing data were smaller for the deaths than the survivors (0.4% vs. 36% for time to death/discharge for example), suggesting that data collection was more thorough for patients who died.
• Reasons for non-treatment with antivirals were not provided and none of the studies described a policy or criteria used for selecting patients for treatment.
• We were able to obtain IPD for only four of the included studies, thus limiting the amount of statistical power that we had for our IPD analysis
• There were missing data for time to death/discharge and time to treatment (33% and 10% missing, respectively) in the four studies for which we had IPD. The majority of missing data for time to death/discharge was due to one study that did not report date of discharge for survivors.

What does this mean?

• The HTA systematic review found insufficient evidence that oseltamivir is associated with a reduced risk of mortality.
• Analysis of all 30 included observational studies using summary data showed evidence of time-dependent bias that had an increasing effect with increasing odds of treatment thus undermining any attempts to estimate treatment effects if it is not taken into account

Figures see chapter 3 page 99,  Health Technol Assess 2016; 20 (42).

read  blog post by Mark Jones on Oseltamivir and mortality: Why does Muthuri et al (2014) conclusions differ from Heneghan et al (2016)

HTA review reports Oseltamivir has no protective effect on mortality among patients with 2009A/H1N1 influenza and Oseltamivir and zanamivir cause small reductions in the time to first alleviation of influenza symptoms in adults.

Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data

Authors: Heneghan CJ, Onakpoya I, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, Spencer EA, Mahtani KR, Nunan D, Howick J, Jefferson T.

Journal: Health Technology Assessment Volume: 20 Issue: 42

Publication date: May 2016

DOI: http://dx.doi.org/10.3310/hta20420

Abstract

Background: Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide.

Objectives: To (1) describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports (CSRs) of published and unpublished randomised, placebo-controlled trials and regulatory comments; and (2) determine the effect of oseltamivir (Tamiflu^®, Roche) treatment on mortality in patients with 2009A/H1N1 influenza.

Methods: We searched trial registries, electronic databases and corresponded with regulators and sponsors to identify randomised trials of NIs. We requested full CSRs and accessed regulators’ comments. We included only those trials for which we had CSRs. To examine the effects of oseltamivir on 2009A/H1N1 influenza mortality, we requested individual patient data (IPD) from corresponding authors of all included observational studies

Results: Effect of oseltamivir and zanamivir (Relenza^®, GlaxoSmithKline) in the prevention and treatment of influenza: Oseltamivir reduced the time to first alleviation of symptoms in adults by 16.8 hours [95% confidence interval (CI) 8.4 to 25.1 hours]. Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days). Oseltamivir reduced unverified pneumonia in adult treatment [risk difference (RD) 1.00%, 95% CI 0.22% to 1.49%]; similar findings were observed with zanamivir prophylaxis in adults (RD 0.32%, 95% CI 0.09% to 0.41%). Oseltamivir treatment of adults increased the risk of nausea (RD 3.66%, 95% CI 0.90% to 7.39%) and vomiting (RD 4.56%, 95% CI 2.39% to 7.58%). In the treatment of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75% to 10.29%). Both oseltamivir and zanamivir prophylaxis reduced the risk of symptomatic influenza in individuals (oseltamivir RD 3.05%, 95% CI 1.83% to 3.88%; zanamivir RD 1.98%, 95% CI 0.98% to 2.54%) and in households (oseltamivir RD 13.6%, 95% CI 9.52% to 15.47%; zanamivir RD 14.84%, 95% CI 12.18% to 16.55%). Oseltamivir increased psychiatric adverse events in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07% to 2.76%) and the risk of headaches while on treatment (RD 3.15%, 95% CI 0.88% to 5.78%). Effect of oseltamivir on mortality in patients with 2009A/H1N1 influenza: Analysis of summary data of 30 studies as well as IPD of four studies showed evidence of time-dependent bias. After adjusting for time-dependent bias and potential confounding variables, competing risks analysis of the IPD showed insufficient evidence that oseltamivir reduced the risk of mortality (hazard ratio 1.03, 95% CI 0.64 to 1.65).

Conclusions: Oseltamivir and zanamivir cause small reductions in the time to first alleviation of influenza symptoms in adults. The use of oseltamivir increases the risk of nausea, vomiting, psychiatric events in adults and vomiting in children. Oseltamivir has no protective effect on mortality among patients with 2009A/H1N1 influenza. Prophylaxis with either NI may reduce symptomatic influenza in individuals and in households. The balance between benefits and harms should be considered when making decisions about use of NIs for either prophylaxis or treatment of influenza.

Study registration: This study is registered as PROSPERO CRD4201200224

Funding: The National Institute for Health Research Health Technology Assessment programme.

We now know the government’s Tamiflu stockpile wouldn’t have done us much good in the event of a flu epidemic. But the secrecy surrounding clinical trials means there’s a lot we don’t know about other medicines we take.

Ben Goldacre, The Guardian:  What the Tamiflu saga tells us about drug trials and big pharma

Today we found out that Tamiflu doesn’t work so well after all. Roche, the drug company behind it, withheld vital information on its clinical trials for half a decade, but the Cochrane Collaboration, a global not-for-profit organisation of 14,000 academics, finally obtained all the information. Putting the evidence together, it has found that Tamiflu has little or no impact on complications of flu infection, such as pneumonia.

That is a scandal because the UK government spent £0.5bn stockpiling this drug in the hope that it would help prevent serious side-effects from flu infection. But the bigger scandal is that Roche broke no law by withholding vital information on how well its drug works. In fact, the methods and results of clinical trials on the drugs we use today are still routinely and legally being withheld from doctors, researchers and patients. It is simple bad luck for Roche that Tamiflu became, arbitrarily, the poster child for the missing-data story.

And it is a great poster child. The battle over Tamiflu perfectly illustrates the need for full transparency around clinical trials, the importance of access to obscure documentation, and the failure of the regulatory system. Crucially, it is also an illustration of how science, at its best, is built on transparency and openness to criticism, because the saga of the Cochrane Tamiflu review began with a simple online comment. (Read More)