ECDC Public consultation
Expert Opinion on neuraminidase inhibitors for prevention and treatment ofinfluenza – review of recent systematic reviews and meta-analyses
Deadline for comments: Wednesday 16 March 2016 sent to influenza_public_consultation@ecdc.europa.eu.

☒ I am submitting the comments contained in this document on behalf of myself. (All fields mandatory)
First Name

SurnameCountry

E-mail address

Affiliation

Rokuro

Hama

Japan

gec00724@nifty.com

Tom

Jefferson

Italyjefferson.tom@gmail.com

Carl

HenehganUKcarl.heneghan@phc.ox.ac.uk

Director, NPO Japan Institute ofPharmacovigilance
Honorary Research Fellow, Centre forEvidence Based Medicine, Oxford OX2
6GG.
Centre for Evidence-Based Medicine,
Nuffield Department of Primary Care
Health Sciences, University of Oxford

Correspondence: Rokuro Hama M.D., gec00724@nifty.com

Disclosure of conflict of interest.
RH, TJ and CH are co-recipients of a UK National Institute for Health Research grant for the systematic review
discussed in this article (HTA – 10/80/01 Update and amalgamation of two Cochrane Reviews: neuraminidase
inhibitors for preventing and treating influenza in healthy adults and children—
http://www.nets.nihr.ac.uk/projects/hta/108001). This review focused on oseltamivir, manufactured by Roche,and zanamivir, manufactured by GSK.
TJ and CH are co-recipients of a Cochrane Methods Innovations Fund grant to develop guidance on the useof regulatory data in Cochrane reviews.
In addition:
RH wrote two books published in 2008 about the harm of oseltamivir and antipyretics. RH provided scientificopinions and expert testimony on 14 adverse reaction cases related to oseltamivir for the applications by theirfamilies for adverse reaction relief by PMDA (Pharmaceuticals and Medical Devices Agency) and in the lawsuits forrevocation of the PMDA's decision concerning with these reactions. Most of the cases were reported in: IJRSM
2008:20:5-36.
TJ is co-recipient of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory
data in Cochrane reviews. TJ receives royalties from his books. TJ is occasionally interviewed by market researchcompanies about phase I or II pharmaceutical products. In 2011-13, TJ acted as an expert witness in a litigationcase related to oseltamivir and in a labour case on influenza vaccines in healthcare workers in Canada. He has
acted as a consultant for Roche (1997-99), GSK (2001-2), Sanofi-Synthelabo (2003), and IMS Health (2013) and in2014 was retained as a scientific adviser to a legal team acting on oseltamivir. In 2014-15 TJ was a member of two
advisory boards for Boerhinger. He is a member of an independent data monitoring committee for a Sanofi
Pasteur clinical trial.
CH receives payment for running educational courses at the University of Oxford and University of Oxford ISIS
consulting services for external teaching and training. He also receives royalties for books (Evidence Based Toolkit
series by Blackwell BMJ Books).

1Comments on document under public consultation:
Introduction

As ECDC advice has many limitations, we would like to comment on it as the following contents shows:Contents of our comments:
1. On the analysis methods
1.1. On the principles of analysis methods in general
1.2. For the systematic review of treatment
1.2.1. The population: ITT population should be used for efficacy analysis.
1.2.2. Exclusion or inclusion of high dose groups
1.2.3. All hospitalizations
1.2.4. Pneumonia and bronchitis
1.2.5. Note that reduction of antibody production is related to the mechanism of action of symptom relief
1.2.6. Efficacy in non-influenza ILI
1.3. For the systematic review of prophylaxis: Discussions are needed by taking “false negative effect” into
account both for ECDC advice and for our own.
2. On the data of individual results.
2.1. Treatment trials
2.1.1. Efficacy: complication especially on serious events leading to treatment withdrawal and hospitalization.
2.1.2. Harm: antibody production, QT interval, cardiovascular events.
2.1.2.1. Antibody production
2.1.2.2. QT interval and other cardiovascular events
2.1.2.3. Psychiatric events, injury and poisoning
2.2. Prophylaxis trials
2.2.1. Efficacy in prophylaxis trials:
2.2.2. Harm in prophylaxis trials:
2.2.2.1. Psychiatric reactions
2.2.2.2. Injury and poisoning
2.2.2.3. Other adverse reactions
2.2.2.3.1. Renal impairment
2.2.2.3.2. Hyperglycemic of diabetic events, and pain in limbs
2.2.2.3.3. Headaches
3. Evidence from non-randomized studies
3.1. Epidemiological studies suggesting neuropsychiatric adverse reactions to oseltamivir:
3.1.1. Prospective cohort studies and their systematic review and meta-analysis.
3.1.2. Proportional reporting ratio for abnormal behaviours especially of fatal outcome.
3.2. Adverse effects on mortality
3.2.1. Observational studies do not support protective effect on mortality
3.2.2. Epidemiological evidence suggesting sudden deterioration leading to death following oseltamivir use:
3.3. Adverse effect on pregnant women, fetus and newborns
4. No discussion on the mechanisms of action and reactions of oseltamivir
4.1. Oseltamivir act on the central nervous system (CNS) both as depressant and as stimulants.
4.1.1. Juvenile (7-day-old) rats and mature rats (intraduodenally and intravenously)
4.1.2. Oseltamivir has hypothermic effect on animals by inhibiting nicotinic acetylcholine receptor.
4.1.3. Oseltamivir induces abnormal behaviours by inhibiting MAO-A.
4.1.4. Oseltamivir has various other effects on CNS such as impairment of sensory system, impairment ofcognition, impairment of alertness other than respiratory depression.
4.2. Oseltamivir has symptom relieving effects by inhibiting host’s endogenous neuraminidase, not by inhibiting
viral load.
4.2.1 Label of oseltamivir does not state viral load reduction
4.2.2. Experiments indicate inhibition of host’s endogenous neuraminidase, but not viral load
4.3. Inhibiting host’s endogenous neuraminidase may be related with adverse effects of NIs
5. Efficacy and effectiveness in risk groups
6. Conflict of Interest
7. Conclusion

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Note: we cite the reference number, same as in the ECDC report if the document is cited in the ECDC report. We
cited the reference number serially after 51 if they are not referred in the ECDC report.
1. On the analysis methods
1.1. On the methods of systematic review and analysis
On Cochrane’s systematic review, ECDC reported:
267 In 2014, Jefferson et al. published a meta-analysis of study-level data gathered from reports of published and
268 unpublished randomised, placebo-controlled trials and regulatory comments and presented the results in the269 Intervention Review ‘Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children
270 (Review)’ [14-16]. This is the fifth and most extensive review of NAIs by the Cochrane group.
271 The review team identified study reports through trial registries, electronic databases and regulatory archives and272 corresponded with manufacturers to identify all randomised, placebo-controlled trials on adults and children with
273 confirmed or suspected exposure to naturally circulating influenza. Many study reports had, until then, been
274 confidential and available only to respective manufacturer and reviewing regulators. For inclusion, studies were
275 evaluated for quality using CONSORT criteria, and risk of bias in each analyses was quantified using a Cochrane
276 ‘risk of bias’ tool.
277 Data from 46 clinical trial study reports were analysed for time to first alleviation of symptoms, influenza outcomes,
278 complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. The analysis included
279 20 studies which assess oseltamivir with 9 623 participants, and 26 studies which assess zanamivir with 14 628
280 participants.

On the Dobson’s review, ECDC reported:
299 In 2015, Dobson et al. published ‘Oseltamivir treatment for influenza in adults: a meta-analysis of randomised
300 controlled trials’ [17].
301 This report is a meta-analysis of individual adult patient data from twelve randomised placebo-controlled clinical
302 trials with a total of 4 328 participants using the dose of 75 mg twice a day. They report data on an intention to
303 treat population (ITT) as well as on an intention to treat (influenza) infected population (ITT-I).
307 A comparison of clinical trials included in the analyses by Jefferson et al. and Dobson et al. are presented in Table
308 4. These meta-analyses included 11 RCT’s in common.

As ECDC described above, unlike Cochrane systematic reviews [14], Dobson’s report [17](1) did not review prophylaxis trials(2) did not disclose protocol pre-specified at the outset, which the authors should not deviate from, or if they
do should be explained.
(3) did not perform a quality assessment of the evidence, and as such, the Roche funded study doesn’t meetthe criteria for a systematic review.
1.2. For the systematic review of treatment
ECDC compared Cochrane’s review [14] and Dobson’s [17], but picked up only the results that favors
oseltamivir and did not discuss the difference of methodology and rationality of methods.
Dobson’s results [17] are different from our results [14]. It seems the difference is due to(1) The difference of populations analysed,(2) Exclusion or inclusion of high dose groups, and(3) We included all hospitalizations; rather than the availability of individual patient data (IPD).

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1.2.1. The population: ITT population should be used for efficacy analysis.
One of the most important things that we found during the analysis process of oseltamivir, is the fact that
oseltamivir use affected not only the outcome but also the initial inclusion or exclusion of analysis population byaffecting the diagnosis of influenza, if ITT-I (intention to treat infected) population is used as population for theassessment of efficacy.
This is derived from one of the most important action of oseltamivir on antibody production due tosuppression of host’s endogenous neuraminidase.
We reported that oseltamivir reduced the odds of patients having four-fold antibody rise by almost 20 %[51]. In the recent review [14], we reported RR=0.92 by expressing relative risk. If it is expressed by odds ratio, OR=
0.82 (95%CI: 0.70, 0.95, p= 0.01).
Influenza-infection was diagnosed by the results of antibody testing which is affected by oseltamivir but notby placebo. This means that some influenza patients were miss-classified from the “infected population” to the“non-infected population” in the oseltamivir group due to false negative testing. As a result, the ITT-infected
population is biased: patients with influenza whose antibody response were poor were excluded from the
ITT-infected population in the oseltamivir group leading to greater apparent benefit compared to the
ITT-non-infected population.
51: Jefferson T, Jones MA, Doshi P, Del Mar CB, Heneghan CJ, Hama R et al. Neuraminidase inhibitors for preventing andtreating influenza in healthy adults and children. Cochrane Database Syst Rev. 2012 Jan 18;1:CD008965. doi:
10.1002/14651858.CD008965.pub3

1.2.2. Exclusion or inclusion of high dose groups
The excluded high dose group in WV15671 included four hospitalized patients, while there were two in the
75mg b.i.d group and one in the placebo group. If oseltamivir decreases hospitalization, high dose groups should
exhibit a more beneficial effect but they did not. Moreover, the trends were the reverse.
1.2.3. All hospitalizations
To resolve the confusing number of hospitalizations in the clinical study reports, we obtained the complete
list of hospitalized patients from Roche. In comparison, the numbers in Dobson’s review are generally smaller inthe oseltamivir group. Even if we include the Japanese data (which is the only different RCT that we did not include
because of unavailability of CSRs), we get pooled RR (0.85: 95% CI: 0.53 to 1.34, p= 0.48) compared to Dobson’s
results (RR: 0.61, p>0.05) [17]1.2.4. Complication: Pneumonia and bronchitis
Pneumonia:
The main complication reported was lower respiratory tract complication more than 48 hours after
randomisation requiring antibiotics. However, the Dobson paper confirms that the diagnosis of pneumonia was
not based on a valid measure: “participant report and the investigator’s clinical judgment” and not on objective

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measure such as x-ray. Why these lack of definitions were not originally reported in the earlier papers is a major
issue that has led to confusion amongst those who make clinical decisions.
Bronchitis-antibiotic:
The use of lower respiratory tract complications requiring antibiotics is not a clinically relevant outcome.
Much of the reported effect on this outcome is driven by bronchitis, a condition for which antibiotics are notindicated. Acute bronchitis is often an indicator of respiratory syncytial virus (RSV) not influenza. We know fromthe results of a Cochrane systematic review “There is limited evidence to support the use of antibiotics in acutebronchitis.’ (see Box 1)
Box 1: Antibiotics for acute bronchitis.
Conclusions“There is limited evidence to support the use of antibiotics in acute bronchitis. Antibiotics may have a modest
beneficial effect in some patients such as frail, elderly people with multimorbidity who may not have been
included in trials to date. However, the magnitude of this benefit needs to be considered in the broader context ofpotential side effects, medicalisation for a self-limiting condition, increased resistance to respiratory pathogens
and cost of antibiotic treatment.”
Ref. Smith SM, Fahey T, Smucny J, Becker LA. Cochrane Database Syst Rev. 2014 Mar 1;3:CD000245 [52]Furthermore, the Dobson paper [17] used the same outcome as the Hernan study of “oseltamivir and risk oflower respiratory tract complications in patients with flu symptoms.” This is puzzling as peer review should havepicked up on the similarities of the analysis and that there was nothing new in this current paper, apart from one
important deviation by Dobson, of only reporting complications beyond 48 hours, meaning the study had
deviated from the important principle of intention to treat (see box 2).
Box 2: Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: ameta-analysis of eleven randomized clinical trials.
Hernan methods:“Second, we included endpoints diagnosed during the first 2 days after randomization. These events were
excluded by Kaiser et al because they hypothesized that oseltamivir could have no effect during the first 2 days.
Although reasonable, this approach deviates from the intention-to-treat principle used in many randomized
trials, in which investigators refrain from making assumptions about the timing of effects and thus include all
events after randomization in the analysis.”
Ref. Hernán MA, Lipsitch M. Clin Infect Dis. 2011 Aug 1;53(3):277-9 [53]References
52. Smith SM, Fahey T, Smucny J, Becker LA. Antibiotics for acute bronchitis. Cochrane Database Syst Rev. 2014 Mar
1;3:CD000245. doi: 10.1002/14651858.CD000245.pub3.
53. Hernán MA, Lipsitch M. Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: ameta-analysis of eleven randomized clinical trials. Clin Infect Dis. 2011 Aug 1;53(3):277-9. doi: 10.1093/cid/cir400. Epub
2011 Jun 15.

1.2.5. Note that reduction of antibody production is related to the mechanism of action on symptom relief (asdescribed later in the section 4.2 Oseltamivir has symptom relieving effects by inhibiting host’s endogenous
neuraminidase, not by inhibiting viral load)

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1.2.6. Efficacy in non-influenza ILIECDC report:
381 Neuraminidase inhibitors treatment does not show any efficacy in those with ILI due to pathogens other than
381 influenza virus (non-influenza ILI) [14].

We have no data for adequate assessment of influenza-like illness (ILI) in any treatment CSRs of oseltamivir.
In addition, oseltamivir induce false negative results of influenza testing (antibody production, culture and PCR)
and negative results do not mean “ILI due to pathogens other than influenza virus (non-influenza ILI)”. Hence, it isinappropriate for ECDC to say in the line 380 to 381 “NI treatment does not show any efficacy in those with ILI
due to pathogens other than influenza virus (non-influenza ILI)”.
In subgroup analysis of time to first alleviation of symptoms in adults by infection status, we found noevidence of a difference in treatment effect for zanamivir on the influenza-infected (positive testing) subgroupcompared to the non-influenza-infected (negative testing) subgroup (P = 0.53). The treatment effect was 0.67 days
2

(95% CI 0.35 to 0.99 days, I statistic = 17%) for influenza-infected (positive testing) patients and 0.52 days (95% CI
20.18 to 0.86 days, I statistic = 0%) for non-influenza-infected (negative testing) patients (Analysis 3.69). Zanamivir
did not reduce odds of patients with 4 fold or more rise of antibody production.
Hence, these results suggest that zanamivir show some efficacy in non-influenza ILI. The implications arethat efficacy in reducing time to alleviation of symptoms is independent of the property of neuraminidase
inhibition which is specifically targeted at influenza viruses but is related to the nonspecific inhibition ofneuraminidase (see the section 4.2 Oseltamivir has symptom relieving effects by inhibiting host’s endogenous
neuraminidase, not by inhibiting viral load .
1.3. For the systematic review of prophylaxis: Discussions are needed by taking “false negative effect” into

account both for ECDC advice and for our own.

ECDC does not take into account the property of oseltamivir to reduce antibody production and to conceal
positivity of influenza virus by testing culture and/or PCR.
In the amended protocol published on 16th May 2013 (p539-543 [14]), “Outcome measures for prophylaxis
studies” of the systematic review issued on 10th April 2014, the primary outcome measure for prophylaxis trials isdefined as “Influenza-like-illness” (p542).
There is a note “The main outcome of interest is any symptomatic influenza-like-illness (ILI). However, we will
also conduct separate analyses of influenza (symptomatic and asymptomatic) and non-influenza ILI” (p543 [14]).
“Symptomatic influenza-like-illness” means “symptomatic influenza-like-illness irrespective of positivity oflaboratory testing”.
We would like to emphasize that the protocol was amended to describe the endpoints more clearly after two
feedback comments and our replies (see the feedback from Frederick G. Hayden, M.D., 2 February 2012 andAdditional feedback from Frederick G. Hayden, 10 August 2012 and replies: Cochrane review [14] p520-536).

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The outcome measure of symptomatic influenza-like-illness is biologically relevant, because neuraminidase
inhibitors induce false negative testing results for influenza not only by reducing production of host’s antibody (p25[14]) but also by concealing the positivity of viral culture results by their mechanism of action of reducing viral
shedding but not viral load of the lungs or nasal washings of infected animals (module 2 of WV15670, WV15671[14]) and in mice with experimental mild influenza infection (Wong [54]). This outcome measure is also of primaryinterest for patients wishing to reduce the risk of having symptomatic illness.
Among the CSRs that we included, no oseltamivir study and only one study of zanamivir (NAI 30034) reported
the relevant primary outcome “symptomatic influenza-like-illness irrespective of positivity of laboratory testing”. In
the zanamivir CSR (NAI 30034) no significant reduction was observed (9% versus 10%) (p37 [14]).

We added our own analysis of oseltamivir for the primary outcome: “in prophylaxis trials
we could not analyse effects on influenza-like illness because of a lack of definition in theclinical study reports. However, using our definition (see methods), oseltamivir did not reduce
influenza-like illness in participants (RR 0.95, 95% CI 0.86 to 1.06)” (p24 [14]).
References

14. Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, Spencer EA, Onakpoya I, Mahtani KR, Nunan D, Howick
J, Heneghan CJ. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane
Database of Systematic Reviews 2014, Issue 4. Art. No.: CD008965. DOI: 10.1002/14651858.CD008965.pub4.
54. Wong ZX, Jones JE, Anderson GP, Gualano RC. Oseltamivir treatment of mice before or after mild influenza
infectionreduced cellular and cytokine inflammation in the lung. Influenza and Other Respiratory Viruses 2011;5(5):343-50.

2. On the data of individual results.
2.1. Treatment trials
2.1.1. Efficacy: complication especially on serious events leading to treatment withdrawal and hospitalization.
See the methods section (1.2. For the systematic review of treatment: 1.2.1.to 1.2.6.)
2.1.2. Harm: antibody production, QT interval, cardiovascular events.
2.1.2.1. Antibody production
Oseltamivir significantly reduced the odds of patients having a 4-fold antibody rise, by 18% (risk ratio by28%), according to a meta-analysis of 8 reports (10 studies) [14, 51]. Heterogeneity was not significant (I =4%).
Attenuation of secretory IgA (sIgA) was more marked [55-58]. Sawabuchi et al. reported that lower
induction of sIgA against the influenza A virus was observed in children treated with oseltamivir in comparison
with children treated without oseltamivir. The odds of a child’s sIgA level increasing more than 5-fold weresignificantly lower in children treated without oseltamivir: OR=0.11 (95%CI: 0.02, 0.61, p=0.008) [55].
Anti-influenza A virus sIgA attenuation was observed in children treated both with oseltamivir or with zanamivir[56].
These findings are consistent with evidence from animal tests using sub-clinical doses of oseltamivir in
influenza A/H1N1 infected mice [57,58]. Non-significant slight reduction of hemagglutinin (HA) specific IgG
antibody in the serum and spleen was reported, while HA specific secretory IgA antibody (s-IgA Ab) in nasal wash7and bronchoalveolar fluids (BALF) was significantly reduced: by approximately 80% on day 12 [57].
In human clinical trials, zanamivir at the usual dosage did not reduce antibody (anti-HA Ab) production [14],but attenuated sIgA antibody significantly [56]. In a double blind, placebo controlled trial with healthy volunteers
designed to investigate the effect of zanamivir treatment (20 mg/day for 14 days) on the humoral immune
response to influenza, the zanamivir group responded with significantly lower antibody titres to the H1N1 [59].
Levels of pro-inflammatory cytokines including IL-6, TNF-α, IFN-γ, and other chemokines were almost completely
suppressed in the viral challenge RCT using a very high dose (600 mg) of intravenous zanamivir before inoculationof influenza virus in human adults [60].
Shinahara et al. [56] reported: “Even under the spread of a new virus subtype in 2009/2010, only 8.6% of
the children of the no-treatment group were re-infected. However, the proportions of children treated theprevious year with oseltamivir and zanamivir who developed re-infection in 2009-2010 were significantly higher at
37.3% and 45.0%, respectively (P<0.01), than those of the no-treatment group.”
Several cases of re-infection with the same influenza virus within one season were reported [61, 62]. Kopel
et al. [61] reported a 13-year-old boy with cerebral palsy who 3 times had episodes of fevering with positive
2009A/H1N1 influenza detected by the RT-PCR method. He was treated with the standard dose (75mg b.i.d for 5days) of oseltamivir at the time of the first episode. A second course of oseltamivir was administered for 10 days
with the dosage adjusted for age and doubled from that of the previous regimen. His HI titres were high, but thelevel of secretory IgA was not determined.
References
55. Sawabuchi T, Suzuki S, Iwase K, Ito C, Mizuno D, Kido H et al (2009) Boost of mucosal secretory immunoglobulin A responseby clarithromycin in paediatric influenza. Respirology 14: 1173-9.
56. Shinahara W, Takahashi E, Sawabuchi T, Arai M, Kido H et al (2013) Immunomodulator clarithromycin enhances mucosaland systemicimmune responses and reduces re-infection rate in pediatric patients with influenza treated with antiviralneuraminidase inhibitors: a retrospective analysis.PLoS One 8: e70060.
57. Takahashi E, Kataoka K, Fujii K, Chida J, Kido H et al (2010) Attenuation of inducible respiratory immune responses byoseltamivir treatment in mice infected with influenza A virus. Microbes and Infection / Institut Pasteur 12: 778-83.
58. Takahashi E, Kataoka K, Indalao IL, Konoha K, Kido H et al (2012) Oral clarithromycin enhances airway immunoglobulin A(IgA) immunity through induction of IgA class switching recombination and B-cell-activating factor of the tumor necrosis
factor family molecule on mucosal dendritic cells in mice infected with influenza A virus. J Virol 86: 10924-34.
59. Cox RJ, Mykkeltvedt E, Sjursen H, Haaheim LR (2001) The effect of zanamivir treatment on the early immune response to
influenza vaccination. Vaccine 19: 4743-9.
50. Fritz RS, Hayden FG, Calfee DP, Cass LM, Straus SE et al (1999) Nasal cytokine and chemokine responses in experimental
influenza A virus infection: results of a placebo-controlled trial of intravenous zanamivir treatment. J Infect Dis 180: 586-93.
61. Kopel E, Mandelboim M, Amitai Z, Grotto I, Hindiyeh M et al (2010) Possible recurrent pandemic (H1N1) 2009 infection,
Israel.Emerg Infect Dis 16: 1321-2.
62. Perez CM, Ferres M, Labarca JA (2010) Pandemic (H1N1) 2009 reinfection, Chile. Emerg Infect Dis 16: 156-7.

2.1.2.2. QT interval and other cardiovascular events
ECDC reported:
367 Cardiovascular events and gastrointestinal events can occur as both an adverse event from medication but also as
368 complications or symptoms of influenza infection. In the Jefferson et al. analysis, oseltamivir use was associated369 with a decrease in ‘cardiac body system adverse events’ (RR 0.49; 95% CI 0.25–0.97) and a decrease in risk of
370 diarrhoea (RR 0.67; 95% CI 0.46–0.98).

In the Cochrane review we report “The cardiac effects of oseltamivir are unclear. Exposure to oseltamivir
2

may reduce cardiac general events compared to placebo (RR 0.49, 95% CI 0.25 to 0.97, I statistic = 0%; RD 0.68%,

8

95% CI 0.04 to 1.00; NNTB = 148, 95% CI 101 to 2509), excluding WV16277 in which ECG was included in the safetyparameters (Analysis 1.27). However, exposure to oseltamivir may increase QTc prolongation (including borderline)
as reported in trial WV16277 (RD 4.0%, 95% CI 0.71 to 7.30; NNTH = 25, 95% CI 14 to 140) compared to placebo
during on-treatment periods.”
Occurrence of QTc prolongation was closely related to the timing of the increase in the concentration ofoseltamivir carboxylate [14]. This is consistent with the findings from animal toxicity tests. Oseltamivir decreased
heart rate in the 9-month repeated toxicity test using marmoset monkeys. The average heart rate during
treatment period with oseltamivir was 328 beats/min, which was an 11% and 16% decrease compared with thecontrol group (368 beat/min) and the average of baseline and recovery phase (392 beat/min), respectively [63].
In an experiment using beagle dogs to test the effects on cardiac functions such as QT time [64], meanbaseline QTc intervals (msec ± SE) were 417±16 in the control (vehicle) group (n=4) and 374±2 in the oseltamivir
carboxylate (OC) group (n=4). This difference was significant (p=0.0372) according to the summary data t-test.
Other evidence suggested that variation was higher in the control group (P=0.005; Bartlett’s test) [65]. The
average ± standard error of QTc interval of anesthetized dogs intravenously infused with 100 mg/kg OC over 30
minutes significantly increased (390±4) compared with that before infusion (376±2). The average QTc recovered(374±6) at 1.5 hours after discontinuation, but the standard error became larger. QTc prolongation is closely
related to the serum concentration of OC [63-65]. The reasons for such large and systemic imbalances are notknown, but they are unlikely to have occurred by chance.
References

63. Japanese SBA (Tamiflu capsule for treatment)：
http://www.pmda.go.jp/drugs/2000/g001202/index.html
64. Marketing Authorization Application, Table of Contents – Volume 81. 1007- Brewster M. Ro 64-0802/002 (GS-4071)
cardiovascular and respiratory evaluation in the anaesthetized dog following intravenous administrations (DHB08601).RR
W-142974. 1999 (disclosed document from EMA)
65. Hama R, Jones M and Jefferson T (2015) Concerns about the randomization in the prophylaxis trials of oseltamivir (rapid
response): Accessed on 30/5/2015, available at:
http://www.bmj.com/content/348/bmj.g2545/rr

2.1.2.3. Psychiatric events, injury and poisoning.
Psychiatric events were more reported in the prophylaxis trials. “Injury and poisoning” may be related to thepsychiatric events and these are discussed in the section for prophylaxis trials (2.2.2. Harms in prophylaxis trials)

2.2. Prophylaxis trials
2.2.1. Efficacy in prophylaxis trials:
We have no data for adequate assessment of influenza-like illness (ILI) in any CSRs of prophylaxis trials ofoseltamivir analyzed. Oseltamivir induce false negative results of influenza testing (antibody production, culture
and PCR) and negative results do not mean “ILI due to pathogens other than influenza virus (non-influenza ILI)”.
For oseltamivir prophylaxis, a Japanese trial which is only available as a published paper (in Japanese,
Kashiwagi et al 2001 [66]) provided the data from which we could report “symptomatic influenza-like-illness

9irrespective of positivity of laboratory testing”. By using these data, “symptomatic influenza-like-illness irrespectiveof positivity of laboratory testing” was compared showing no difference between the oseltamivir (34/155=22%)
and placebo groups (36/153=24%) (Hama 2009 [67]).

Moreover, 29 persons with negative testing ILI weresignificantly more observed in oseltamivir group (29/155=18.7%) than in the placebo group (15/153=9.8%)(OR=2.18; 95% CI: 1.09, 4.13, p=0.026). These may be the results derived by the oseltamivir’s false negative effects
on the laboratory testing.
Figure1:

Japanese RCT for influenza prophylaxis (adults: 75 mg o.d, 42 days)

Total percent of persons with flu symptoms who had positive testing and negative testing and those withdrawn were 23.5 %for placebo group and 23.9 % for the Tamiflu 75mg o.d. group (for 42 days): no difference between both groups.
#1: ILI (Influenza-like illness): if one or more of the following symptoms were seen
1）fever 37.5℃ or more, 2)respiratory symptoms, 3)general symptoms#2: Positive testing: if virus was detected from nasal swab by culture or hemagglutination inhibition (HI) antibody titerincreased 4-fold or more.

This is consistent with the results of NAI 30034 and our own analysis of oseltamivir trials. In additional analysisof the oseltamivir prophylaxis trials we found fever is reduced (RR 0.62, 95% CI 0.42 to 0.93), proportion withlaboratory confirmation is reduced (RR 0.59, 95% CI 0.41 to 0.85) but symptoms other than fever are not reduced(RR 0.96, 95% CI 0.86 to 1.07). These results suggest oseltamivir suppresses fever, reduces antibody response andviral shedding but does not reduce the risk of symptomatic illness.
References
66. Kashiwagi S, Kudoh S, Watanabe A, Yoshimura I. Efficacy and safety of the selective oral neuraminidase inhibitor
oseltamivir for prophylaxis against influenza: placebo-controlled double-blind multicenter phase III trial. Kansenshogaku
Zasshi. 2000 Dec;74(12):1062-76. (in Japanese).
67. Hama R. Neuraminidase inhibitors for prophylaxis and outcome measure: How efficacy claimed? What can we learn fromthe Japanese study? Rapid response (on 24th Dec 2009) to Jefferson T et al. “Neuraminidase inhibitors for preventing andtreating influenza in healthy adults: systematic review and meta-analysis” BMJ 2009; 339
http://www.bmj.com/content/339/bmj.b5106?tab=responses

2.2.2. Harms in prophylaxis trials:
ECDC report:
359 The Expert Group concluded that on the basis of their review of the evidence presented, oseltamivir or zanamivir
360 use was not associated with an increase in serious adverse events or events leading to withdrawal from treatment
361 or prophylaxis among previously healthy adults or children [14,17].

We challenge this conclusion.

10

2.2.2.1. Psychiatric reactions
ECDC might ignore our important findings indicating that oseltamivir may induce 1.8 times more psychiatric
symptoms than placebo group in prophylaxis trials. The psychiatric symptoms include hallucination, aggravation ofschizophrenia, psychosis, aggression and depressions and so on. Aren’t these serious enough?
We reported in the Cochran systematic review that
“Figure 11 (Analysis 2.54) shows that in prophylaxis trials of oseltamivir there was a significant increase in patients2with psychiatric adverse events over the on- and off-treatment periods (RR 1.80, 95% CI 1.05 to 3.08, I statistic =0%; RD 1.06%, 95%CI 0.07 to 2.76; NNTH = 94, 95% CI 36 to 1538). Initial analysis of patients with psychiatricadverse events in the on-treatment period showed a borderline statistically significant result (P = 0.06), hence we
conducted sensitivity analysis using Peto’s method (P = 0.05) as well as the analysis reported in Figure 11.

Table

15 shows a summary of all psychiatric adverse events in oseltamivir prophylaxis trials. Of particular note was anoseltamivir patient in study WV15825 who had severe confusion on day 27 and was hospitalised. On day 28 thepatient was taken off medication and the event resolved. On day 29 the patient was discharged from hospital andsubsequently resumed medication. However, confusion reappeared on day 32. The initial event was misclassified in
the clinical study report as ”mental impairment“ but has since been corrected in an erratum published in the samejournal that published the original trial manuscript (Gravenstein 2013; Peters 2001).”
In the treatment RCTs of oseltamivir and zanamivir, definition of adverse event was defined “any adversechange from the subject’s baseline (pre-treatment) condition, which occurred during the course of the study after
treatment had started, whether considered related to treatment or not”. This is different from the ordinary
definition of the International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) E2D guideline
As a consequence, adverse events that are similar to the symptoms of influenza (such as headache, mild
gastrointestinal adverse events and mild psychiatric events) tend to be excluded from the treatment trials.
However, we found that :“there was a dose-response effect in the two ”pivotal“ treatment trials. In the identically designed trials WV15670
and WV15671 there were two active treatment groups: 150 mg (standard dose) and 300 mg (high dose)
oseltamivir per day. In the dose-response analysis there was an increased risk of psychiatric body system adverse
events over the entire follow-up period (P = 0.038 based on likelihood ratio test). In trial WV15670, the event rates
were: 1/204, 1/206 and 4/205 in the placebo, 75 mg and 150 mg arms respectively, whereas trial WV15671 had
rates of 2/235, 0/242 and 5/242, respectively.”
Is it appropriate to state that there were

“no serious adverse effects”?

2.2.2.2. Injury and poisoning
Although, oseltamivir increased “injury and poisoning” in the treatment trials, we discuss here, because it may
be related to the psychiatric reactions.

11

In the Dobson review [17], risk of “injury and poisoning” was higher in the oseltamivir group than in theplacebo group: RR 3·37 (95% CI 1·08 to 10·47) P=0·036.” (see table 2 in the Dobson’s paper [17]) .
By our own analysis excluding Japanese trial, we have similar results:
Pooped relative risk (by Random effects, DerSimonian-Laird) = 3.04 (95% CI = 1.02 to 9.05, p=0.046. As many zero
cells were reported especially in the placebo group, we conducted some sensitivity analyses:
Pooled odds ratio (by Fixed effects, conditional maximum likelihood) = 6.54 (95% CI = 1.51 to 59.34, P = 0.0051),
Pooled odds ratio (by Peto’s method) = 4.08 (95% CI = 1.55 to 10.71, P = 0.0043).
Although, the risk did not increase dose-dependently (in WV15670 and WV15671 trials) and was not evident
in the prophylaxis trials, most of the events of “injury and poisoning” reported in the treatment trials were “injury”
and these might occur as accidents. Considering the relation between abnormal behaviours and accidents, theseshould not be ignored.

2.2.2.3. Other adverse reactions
Other than psychiatric events, we reported in the Cochrane review that oseltamivir increased renal, diabetic

or hyperglycemic events, pain in limbs and headaches, but that zanamivir did not. However, ECDC ignored
these findings.
2.2.2.3.1. Renal impairment
Renal event was marginally non-significant by random effects (DerSimonian-Laird) (RR= 3.17 [95% CI= 0.96,
10.49, p=0.058] but significantly different by Fixed effects (Mantel-Haenszel, Rothman-Boice: RR= 3.47 [95% CI =1.06, 11.32, p=0.039]) and by Peto’s methods (OR = 2.93 [95% CI = 1.16 to 7.43, p=0.023]) as sensitivity analysis.
We also noticed two patients in oseltamivir groups who experienced renal failure prior to death [14]: one intrial WV15825 and on in trial WV15708. The two participants who died in the oseltamivir arms both experienced
acute renal failure while on-treatment, although only one of those events was listed as an adverse event. The
unlisted event was in a 91-year old female who was withdrawn from the study on Study Day 15 because her
estimated creatinine clearance was less than 30 mL/min. The screening laboratory examinations that werecarried out 10 days before the start of study treatment were normal [14].
Moreover, while assessing the evidence in individual patient data in prophylaxis trials, we found significant
and serious imbalance of baseline renal disorders between the oseltamivir and placebo groups [68]. We
independently extracted the data on baseline creatinine level and concomitant renal and urinary tract diseases(renal/UTD) for five studies in total: two in adults (WV15673/WV15697), two in the elderly (WV15708; WV15825)
and one in households (WV15799).
Participants with high baseline creatinine level (154μmol/L or more) were significantly less reported in the2

oseltamivir group than in the placebo group: pooled odds ratio was 0.29 (95% CI = 0.12 to 0.69, P = 0.005, I = 0%).
In trial WV15708 which was never published, participants with high baseline creatinine level (154μmol/L or more)12were significantly less reported (OR 0.23; 95％CI: 0.06, 0.82、P = 0.0168). Participants with concomitant renal/UTD
were less reported (OR 0.38; 95%CI: 0.14, 0.93, p=0.0269). In trial WV15708, Proportions of participants with highbaseline creatinine level and/or concomitant renal/UTD were 5.8% (11/190) and 16.5% (30/182) for oseltamivirgroup and placebo group respectively: odds ratio 0.31 (95%CI = 0.14 to 0.67, P = 0.0014).
We don’t know the reason why such large and systemic imbalances occurred, but they are unlikely to haveoccurred by chance [68].
References

68. Hama R, Jones M, Jefferson T. Concerns about the randomization in the prophylaxis trials of oseltamivir.
http://www.bmj.com/content/348/bmj.g2545/rapid-responses

2.2.2.3.2. Hyperglycemic of diabetic events, and pain in limbs
Hyperglycaemic adverse events (aggravated diabetes mellitus or hyperglycaemia) were also more common in
the oseltamivir arms, with eight events in total (one in WV15673/WV15697, two in WV15708 and five in
WV15825) compared to none in the corresponding placebo arms. These data are only presented descriptively as
they are too few (< 10) to meta-analyse formally, as prespecified in our analysis plan [14].
2.2.2.3.3. Headaches

Oseltamivir caused headaches and psychiatric harms in adult prophylaxis trials. Headaches are one of themost prominent harms of oseltamivir. There is evidence of a dose-response effect in prophylaxis trials
WV15673/WV15697 (P = 0.013), in which headaches were observed in 202/519, 225/520 and 242/520 participantsin the placebo, oseltamivir 75 mg once daily and 75 mg twice daily arms, respectively [14].
It should be emphasised that in the published report of trial WV15673/WV15697 [69], the authors did not
mention the dose-response increase of headaches but denied the difference and wrote that: “The most commonly
reported adverse event was headaches, which occurred in similar proportions in the three groups (39 to 47
percent).”
Headaches may be related to the increased intra-cranial pressure except in infants less than 1 year-old, inwhom it may induce bulging of fontanelle. A typical case with increased intra-cranial pressure was reported as aspontaneous report from Japan that was reported to the Food and Drug administration [70]. A 5-month-old maleinfant who was treated with oseltamivir for prophylaxis vomited one and a half hours after receiving the drug. His
mother noticed that his fontanel bulged repeatedly throughout the treatment period of eight days.
References
69. Hayden FG, Atmar RL, Schilling M, Johnson C, Poretz D, Paar D, Huson L, Ward P, Mills RG. Use of the selective oral
neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med 1999 October 28;341(18):1336-43.
70. Edwards Et and Truffa MM (2005) (Division of Drug Risk Evaluation: DDRE) One-Year Post Pediatric Exclusivity
Postmarketing Adverse Events Review (Drug: Oseltamivir phosphate): Department of Health and Human Services, Public
Health Services, Food and Drug administration: Center for Drug Evaluation and Research=FDA CDER. Accessed on
28/5/2015 available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4180b_06_01_Tamiflu%20AE_reviewed.pdf

3. Evidence from non-randomized studies

13

3.1. Epidemiological studies suggesting neuropsychiatric adverse reactions to oseltamivir:
3.1.1. Prospective cohort studies and their systematic review and meta-analysis.
A systematic review and meta-analysis of three prospective cohort studies of neuropsychiatric adverse events(NPAEs) in Japanese children show a pooled odds ratio for abnormal behaviours due to oseltamivir exposure of
1.55 (95% CI 1.21 to 1.98; P = 0.0005) without significant heterogeneity [71] [14].
The largest prospective cohort study among the tree was conducted by Fujita et al (2011) [72] but theresults were first reported by Hirota Y et al [73] referred by Yorifuji et al [74]. It was conducted in the winter of
2006–2007 to assess the relationship between oseltamivir use and abnormal behaviors. An interim report was
released on 10 July 2008 [73]. In the report, the research group concluded that no positive associations weredetected between oseltamivir use and abnormal behaviors. However, the analytic method used in the study was
flawed. A correct analysis (based on person-time) shows a rate ratio of 1.57 (95% confidence interval 1.34, 1.83,
p<0.0001). Abnormal behaviours were reported in 889 among 25844 person-days (3.4 per 100 person day or 13.8%)
in oseltamivir taker and 187 were reported among 8516 person days (2.2 per 100 person-days or 8.8%) in no
oseltamivir takers [74].
Reanalysis of this study population, focusing on delirium and unconsciousness, also showed a significant
association between oseltamivir and neuropsychiatric events, especially in the very early phase of the illness
within a day of commencement of fever [70]. For example, the risk ratio for delirium associated with oseltamivir
use was up to 7.0 about 12 hours after commencement of fever or multivariate hazard ratio during 21:00 to 24:00
was up to 5.58 (95% CI: 1.94, 16.06), while the overall hazard ratio was 1.51 (p=0.084) by multivariate analysis.
These indicate that prospective and intentional collection with this scale of participants may be necessary intreatment RCTs.
References

71. Hama R. Jones M, Hayashi K, Yanagi T, Sakaguchi K. Oseltamivir: A systematic review and meta-analysis of adverse effects inprospective cohort studies (a preliminary report was presented at the 16th JSPE and 5th ACPE joint meeting Tokyo 29-30th
2010 Tokyo).
72. Fujita T. Fujii Y, Watanabe Y, Mori M, Yokota S. A Pharmacoepidemiological Study on the Relationship between
Neuropsychiatric Symptoms and Therapeutic Drugs after Influenza Infection. Jap J Pharmacoepidemiol 2010; 15: 73-92.
Available from: http://www.jstage.jst.go.jp/article/jjpe/15/2/73/_pdf
73. Hirota Y. Interim report of investigations about the frequency of associated symptoms with influenza (in Japanese).
Available at: http://www.mhlw.go.jp/shingi/2008/07/dl/s0710-6ak.pdf. Accessed July 23, 2008
74. Yorifuji T, Suzuki E, Tsuda T. Oseltamivir and abnormal behaviors: true or not? Epidemiology 2009; 20(4): 619-21.

3.1.2. Proportional reporting ratio for abnormal behaviours especially of fatal outcome.
Association of age and gender with neuropsychiatric adverse events (NPAEs) in patients treated with
oseltamivir was analysed by reporting odds ratio (ROR) using a logistic regression model (after duplicates were
excluded) [75]. NPAE data were obtained from the U.S. Food and Drug Administration Adverse Event Reporting
System (2004 to 2013).
Adjusted ROR of “abnormal behavior” was 96.4 (95% CI, 77.5–119.9) in male patients aged 10–19 years
treated with oseltamivir [75].
If we use data of FDA from Rxisk.org [76] that may contain duplicates, number of reports and PRRs ofabnormal behavior were 1140, 31.3 for oseltamivir and 753, 61.7 for zanamivir. However all reports of zanamivir

14

were from Japan only. In addition, abnormal behaviours with fatal outcome were 30 reports for oseltamivir andnone for zanamivir. Odds ratio of fatal case among abnormal behaviours from oseltamivir compared with zanamivir
was 41.39 (95%CI: 2.53, 677.9, p<0.0001). These data mean abnormal behaviour leading to death may be inducedby oseltamivir but not by zanamivir.
References
75. Ueda N, Umetsu R, Abe J, Kato Y, Nakayama Y, Kato Z, Kinosada Y, Nakamura M. Analysis of Neuropsychiatric Adverse
Events in Patients Treated with Oseltamivir in Spontaneous Adverse Event Reports. Biol Pharm Bull. 2015;38(10):1638-44.

76. http://rxisk.org/drugs-a-z/

accessed on March 9 2016

3.2. Adverse effects on mortality
Line number 520 to 537: ECDC report describes as follows:
520

Mortality

521 In the individual patient level meta-analysis done by Muthuri et al. (2014) in patients hospitalised with influenza
522 A(H1N1)pdm09 virus infection, decreased mortality was associated with the use of NAIs among hospitalised
523 patients (OR 0.81; 95% CI 0.70–0.93) [18]. Among adults, treatment was associated with a 25% reduction in
524 likelihood of death, irrespective of the timing of treatment (OR 0.75; 95% CI 0.64–0.87); among children under the
525 age of 16, a similar association was observed but the reduction was not significant (OR 0.82; 95% CI 0.58–1.17).
526 Similar results were observed when restricting the analysis to adult critical care patients
527 (OR 0.72; 95% CI 0.56-0.94) and pregnant women (OR 0.46; 95% CI 0.23–0.89). Late treatment (started after 48
528 hours of symptom onset) was associated with reduced risk of death only among adult critical care patients
529 (OR 0.65; 95% CI 0.43-0.93).
530 For patients for whom exact timing of NAI treatment from symptom onset was available, when antiviral use was
531 modelled as a time-dependent covariate to overcome potential immortal time bias (i.e. survivor bias), NAI
532 treatment was significantly associated with decreased hazard rate of mortality within 30 days of illness onset
533 (adjusted HR 0·51 [95% CI 0·45–0·58], p<0·0001) as compared with no antiviral treatment. Among treated cases,
534 there was an increase in the hazard with each day’s delay in initiation of treatment up to day five as compared with
535 treatment initiated within two days of symptom onset (HR 1.23 [95% CI 1.18–1.28], p<0·0001 for the increasing
536 HR with each day’s delay). The unadjusted and adjusted survival curves comparing survival by time to treatment
537 initiation are shown in Figure 2.

3.2.1. Observational studies do not support protective effect on mortality
Raw data of the study by Muthuri et al [18] shows that 959/10,431 (9.2%) died without treatment while
1825/18,803 (9.7%) died after exposure to NAI treatment. The effect size is, however reported as a Relative risk,
RR, of 0.81 without taking account of time-dependent treatment exposure and as a Hazard Ratio, HR, of 0.51 after
taking account of time-dependent treatment exposure. Including treatment as a time-dependent treatment
exposure must move the treatment effect estimate in the opposite direction to that shown. This is because thetime from initiation of follow up to initial treatment exposure is incorrectly allocated to the treatment group in ananalysis that incorrectly includes treatment exposure as time-independent. This makes the estimates of mortality
over time too low for the treatment group and too high for the non-treatment group [77].
To examine the effects of oseltamivir on 2009A/H1N1 influenza mortality, we included observational studies
with at least 5% of patients untreated and five or more deaths overall. We requested individual patient data (IPD)from corresponding authors of all included studies.
Analysis of summary data of 30 studies as well as IPD of four studies showed evidence of time-dependentbias. After adjusting for time-dependent bias and potential confounding variables, competing risks analysis of the15

IPD showed insufficient evidence that oseltamivir reduced the risk of mortality (HR 1.03, 95% CI: 0.64 to 1.65)[78]. In conclusion, oseltamivir has no protective effect on mortality among 2009A/H1N1 influenza patients [78].
References

77. Jones M, Del Mar C, Hama R. Statistical and methodological concerns about the beneficial effect of neuraminidase
inhibitors on mortality. Lancet Respir Med. 2014 Jul;2(7):.

78. Heneghan CJ, Onakpoya I, Jones M, Doshi P, Del Mar CB, Hama R, Thompson MJ, Spencer EA, Mahtani KR,
Nunan D, Howick J and Jefferson T. Neuraminidase inhibitors for influenza: a systematic review andmeta-analysis of regulatory and mortality data. Health Technology Assessment. 2016 (in press)
3.2.2. Epidemiological evidence suggesting sudden deterioration leading to death following oseltamivir use:
Comparative mortality analysis by Hama et al (2011) [79].

Hama et al [79] conducted a comparative mortality study utilizing all disclosed data of died persons with
influenza 2009A/H1N1 during 09/10 winter season and consumption data of oseltamivir and zanamivir during theseason. Age stratified mortality was calculated and compared between oseltamivir prescribed people andzanamivir prescribed people. Of 119 deaths after Tamiflu was prescribed, 38 deteriorated within 12 hours (28within 6 hours), while of 15 deaths after Relenza, none deteriorated within 12 hours. Pooled OR for early
deterioration was 5.88 (95% CI: 1.30 to 26.6, p = 0.014) (Pooled OR of overall death was 1.91, p = 0.031). Baselinecharacteristics including risk factors did not contribute to early deterioration after Tamiflu use [79].
References
79. Hama R. Jones M, Hayashi K, Sakaguchi K. Oseltamivir and early deterioration leading to death. International Journal of Risk
& Safety in Medicine 2011; 23: 201–15. (accessed on 27/5/1013.
http://iospress.metapress.com/content/5257410g24403m68/fulltext.pdf (note, this is not a proportional mortality study but
comparative mortality study)

3.3. Adverse effect on pregnant women, fetus and newborns
ECDC report state as follows on pregnant women:
548 Severe outcomes in pregnant women
549 Pregnancy is a known risk factor for severe influenza disease, as also noted for the 2009 influenza A(H1N1)pdm09
550 pandemic, and a systematic review published by Mosby et al in 2011 was drawn to the attention of the group by
551 one of the experts [24]. This systematic review identified five observational studies, in which neuraminidase
552 inhibitors administered within 48 hours from onset of symptoms compatible with influenza, conferred decreased
553 risk of severe disease [24]. No meta-analysis was conducted, but in the identified studies Louie et al. in 2010
554 reported an increased risk of being admitted to the intensive care unit (ICU) or to die if treatment was initiated555 later than 48 hours from onset of symptoms (RR 4.3 95% CI 1.4–13.7) [33]. Creanga et al. reported 3.3% of
556 pregnant women who received oseltamivir treatment within two days of symptom onset had severe illness
557 compared with 21.4% and 44.4% pregnant women who started treatment three to four days and five days,
558 respectively or more after symptom onset (P=.002 for trend) [34]. Siston et al. reported that pregnant women who
559 had treatment initiated more than four days from onset of symptoms were more likely to be admitted to the ICU
560 (RR 6.0 05% CI 3.5–10.6) [35].

The reports above (Louie et al [33]. Creanga et al [34] and Siston et al[35]) did not consider the time dependentbias (immortal time bias) and have flaws as pointed out in the mortality section (3.2.1 Observational studies do
not support protective effect on mortality).
Analysis of FDA’s data from Rxisk.org (accessed on November 16 2012) shows increased proportions of16

abortion related reactions (especially of abortion missed), intra-uterine fetal death and complicated delivery(Figure 2), still birth and neonatal death or asphyxia (Figure 3) related to Tamiflu but not to Relenza. Note that a
proportional reporting ratio of 2 or more indicates at least a doubling in the proportion of those ADRs reported
for the drug in question (e.g. oseltamivir) compared to all other drugs in the FDA database. A PRR of 2 or greater
is a signal that the drug in question may cause these types of reactions.
Figure 2: abortions and delivery complications (Analysis of FDA’s spontaneous ADR reports)

abortions and delivery complications(Comparison of PRR between TF and RL)

abortion missed 0
intra-uterine death 0.0
abortion

5.8
4.4

0

abortion induced

Tamiflu(TF)
Relenza (RL)

2.5

0.7

abortion spontaneous

8.7

1.8

0.8

11.0

arrested labour 0premature rupture of…
0.0
membranepremature delivery

5.4
4.9

0

3.2

premature labour 0

0

2

4

6

8

PRR: Proportional reporting ratio

1012"0": no report, "0.0" : there were some but PRR was not provided by the system

Based on the data from RxISK.org (https://www.rxisk.org/Default.aspx) accessed on Nov 16 2012
Figure 3:

Stillbirth and neonatal complications (Analysis of FDA’s spontaneous ADR reports)

Stillbirth and Neonatal complications(Comparison of PRR between TF and RL)
11.4

Neonatal asphyxia 0
Death neonatal

6.2

0

5.5

Still birth 0.0
Neonatal respiratory…

2.0

0.0

0

Tamiflu(TF)
Relenza (RL)

2

4

6

8

PRR: Proportional reporting ratio

1012"0": no report, "0.0" : there were some but RRR was not provided by the system

Based on the data from RxISK.org (https://www.rxisk.org/Default.aspx) accessed on Nov 16 2012
In addition these findings are all supported by animal toxicity tests. Hence, it may be harmful to use
oseltamivir for pregnant women with influenza infection.
Therefore, ECDC should reconsider the recommendation of oseltamivir to use in pregnant women with
influenza infection or at least express caution in its use.

17

4. No discussion on the mechanisms of action and reactions of oseltamivir
ECDC report did not discuss on the mechanisms of actions and reactions of oseltamivir. Here we briefly
summarise them.
4.1. Oseltamivir act on the central nervous system (CNS) both as depressants and as stimulants.
4.1.1. Juvenile (7-day-old) rats [80-84] and mature rats (intraduodenally and intravenously) [85] dieddose-dependently after one dose of oseltamivir as shown in Figure 4. They die from respiratory arrest
followed by cardiac arrest as shown in Figure 5 [85].
Figure 4:

Dose of oseltamivir and mortality trend in juvenile (7-day-old) rats

Data from ref [80-84].
In the TK tests, the proportion ofdeaths is underestimated because
rats
were
withdrawnfordetermination of plasma and brain
concentration. The results showthat for each additional dose of
100 mg/kg, the odds of death
more than double (OR = 2.26, 95%
CI: 2.01 - 2.54, P<0.0001).

Figure 5: Effect of intraduodenal injection of oseltamivir phosphate (OP) on
respiration and blood pressure in rats (Kimura’s Figure 3 on p4)

Figure 3 (of ref [85]): intraduodenal
injection of oseltamivir phosphate (OP)at higher doses (500–1000 mg/kg)
provoked ventilatory arrest followed bycardiac arrest in spontaneously
breathing anaesthetized rats. Traces oftracheal airflow (TA) and blood pressure(BP) were taken before (pre) andseveral times (min.) after the injectionof OP. Thin arrows indicate the time lag
between ventilatory arrest and cardiac
arrest.

References

80. Chugai Pharm Co. SBA of Tamiflu dry syrup 2002: accessed on 09/06/2015 :http://www.pmda.go.jp/drugs/2002/P200200011/index.html

18

81. Chugai Pharm Co. SBA of Tamiflu capsule 75 for prophylaxis 2004: accessed on 09/06/2015:
http://www.pmda.go.jp/drugs/2004/P200400015/index.html
82. Freichel C, Prinssen E, Hoffmann G, Gand L, Beck M et al. Oseltamivir is devoid of specific behavioral and other central
nervous system effects in juvenile rats at supratherapeutic oral doses. International Journal of Virology 2009; 5: 119-30.
83. F. Hofman-La-Roche, Ltd (2007). An oral (gavage) toxicity study of Tamiflu (oseltamivir phosphate) in juvenile rats: disclosed
via FOIA
84. F. Hofman-La-Roche, Ltd (2007). Toxicokinetic phase report for the final study report of Tamiflu (oseltamivir phosphate) injuvenile rats: disclosed via FOIA
85. Kimura S, Niwa Y, Iwajima Y, Nagano Y, Yamamoto S, Ohi Y, Maeda Y, Kurono Y, Ono H, Haji A. High doses of oseltamivir
phosphate induce acute respiratory arrest in anaesthetized rats.. Basic Clin Pharmacol Toxicol 2012; 111(4): 232-9.

4.1.2. Oseltamivir has hypothermic effect [86-89] on animals by inhibiting nicotinic acetylcholine receptor [89].

4.1.3. Oseltamivir induces abnormal behaviours [80-93] by inhibiting MAO-A [93].
4.1.4. Oseltamivir has various other effects on CNS such as impairment of sensory system, impairment ofcognition, impairment of alertness other than respiratory depression [82, 83].

Figure 6: Proportion of rats lacking olfactory orientation at 2 hours after dosing oseltamivir

Odds of lacking olfactory
orientation in 500 mg/kg
group are higher thancontrol: OR=7.43 (95%CI:
1.78-31.04, P=0.004).
Dose-response is clear.
(Chi² for linear trend:
31.08, P < 0.0001).
Data from ref [80,81].

Figure 7: Cliff aversion, arousal at 2 hours after dosing, and proportion of death at 24 hours
1. “Arousal” means “rats without
low or very low arousal”; these
decreased dose-dependently in the
600 mg/kg or higher groups.
Most animals with low arousal were
found dead by 24 hours after dosing.
Odds of death were significantly
higher in rats with low arousal than
without: odds ratio was 12.33 (95%
CI: 3.07, 49.5, p <0.0001).
Dead rats at 2 hours after dosing
were considered “rats with very low
arousal”. Same as for “cliff aversion”.
2. More than half in control group
averted cliff, but proportion
decreased dose-dependently (Chisquare for linear trend: 24.0,
p<0.0001). Data from ref. [80,81]

19

References
86. Ono H, Nagano Y, Matsunami N, Sugiyama S, Yamamoto S, Tanabe M. Oseltamivir, an anti-influenza virus drug, produces
hypothermia in mice. Biological and Pharmaceutical Bulletin 2008; 31(4): 638-42.
87. Ono H, Iwajima Y, Nagano Y, Chazono K, Maeda Y, Ohsawa M, et al. Reduction in sympathetic nerve activity as a possible
mechanism for the hypothermic effect of oseltamivir, an anti-influenza virus drug, in normal mice. Basic & ClinicalPharmacology & Toxicology 2013; 113(1): 25-30.
88. Freichel C, Breidenbach A, Hoffmann G, Körner A, Gatti S, Donner B et al. Absence of central nervous system andhypothermic effects after single oral administration of high doses of oseltamivir in the rat. Basic Clin Pharmacol Toxicol.
2012; 111(1): 50-7.
89. Muraki K, Hatano N, Suzuki H, Muraki Y, Iwajima Y, Maeda Y, Ono H. Oseltamivir Blocks Human Neuronal Nicotinic
Acetylcholine Receptor-Mediated Currents. Basic Clin Pharmacol Toxicol. 2015; 116(2): 87-95.
90. Izumi Y, Tokuda K, O'dell KA, Zorumski CF, Narahashi T. Neuroexcitatory actions of Tamiflu and its carboxylate metabolite.
Neurosci Lett. 2007: 426(1):54-8. Epub 2007 Sep 1.
91. Izumi Y, Tokuda K, O'Dell K, Zorumski C, Narahashi T. Synaptic and behavioral interactions of oseltamivir (Tamiflu) withneurostimulants. Hum Exp Toxicol. 2008: 27(12): 911-7
92. Suzuki M, Masuda Y. Effect of a neuraminidase inhibitor (oseltamivir) on mouse jump-down behavior via stimulation of
dopamine receptors. Biomed Res. 2008: 29(5): 233-8.
93. Hiasa M, Isoda Y, Kishimoto Y, Saitoh K, Kimura Y, and Kuzuhara T et al. Inhibition of MAO-A and stimulation of behaviouralactivities in mice by the inactive prodrug form of the anti-influenza agent oseltamivir. Br J Pharmacol. 2013; 169(1):115-294.2. Oseltamivir has symptom relieving effects by inhibiting host’s endogenous neuraminidase, not by
inhibiting viral load.

4.2.1 Label of oseltamivir does not state viral load reduction
It may be generally believed that oseltamivir most likely reduces symptom duration by reducing viral load,and via the spread and release of cytokines [94]. However, the full prescription information of oseltamivir (revisedin April 2010) states “The concentrations of oseltamivir carboxylate required for inhibition of influenza virus in cell
culture were highly variable depending on the assay method used and the virus tested. (…) The relationshipbetween the antiviral activity in cell culture, inhibitory activity in the neuraminidase assay, and the inhibition of
influenza virus replication in humans has not been established” [95].

4.2.2. Experiments indicate inhibition of host’s endogenous neuraminidase, but not viral load.
A significant but slight reduction of the proportion with serum antibody (mostly hemagglutination inhibition(HAI) antibody) titre rise by four-fold or more among those who were tested was shown in the Cochran review [14].
These findings are also consistent with the evidence on the mode of action of oseltamivir from animal models(Module 2 of most of the CSRs including WV15670 and WV15671 and from viral challenge, randomised,
placebo-controlled studies in humans [94].Pro-inflammatory cytokines, including interleukin 6 (IL-6), tumour
necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ ), were completely suppressed by oseltamivir
administered 28hours after the experimental inoculation of influenza virus, while the reduction of viral titre innasal lavages was partial [94].
There is decisive evidence that administration of oseltamivir in animals challenged by respiratory syncytial
virus (RSV) that lacks a neuraminidase gene showed a symptom-relieving effect (decreased weight loss) andinhibition of viral clearance [96]. These effects were accompanied by a decreased CD+8 T cell surface
sialoglycosphingolipid GM1 level, which is regulated by the endogenous sialidase/neuraminidase in response to20

viral challenge along with suppression of cytokine expression [96].They are consistent with those findings from thepharmaceutical company and their investigators. The findings of the study by Moore2007 [96] suggest a risk ofinfection and exacerbation of infection by pathogens other than influenza virus in spite of the apparent reductionof symptoms from infection [14].
in a study by Wong et al. [54] using mice infected with mild influenza (inoculated with a non-lethal dose of
influenza virus), which is a better model for testing the effects of oseltamivir in human seasonal influenza, aclinically compatible dose of oseltamivir (10 mg/kg=approximately 0.8 mg/kg as HED) administered (in 3 different
experiments) at 4 hours before inoculation, 24 hours after inoculation, or 48 hours after inoculation showed nosignificant effect on viral titres at day 5 post-inoculation.
Wong et al [54] observed that oseltamivir markedly and significantly reduced lung inflammatory cell response
and induction of pro-inflammatory cytokines and chemokines such as TNF-α, IL-1β, IL-6, granulocyte–macrophagecolony-stimulating factor (GM-CSF), keratinocyte-derived chemokine (KC), Macrophage inflammatory protein-1α(MIP-1α), and Monocyte chemotactic protein-1 (MCP-1) whether administered prophylactically or therapeutically.
However, these were accompanied by small non-significant effects on viral titres. Based on these findings, theresearchers discussed the possibility of intrinsic anti-inflammatory effects of oseltamivir [54].
No animal study has been conducted of the infection model with mild and non-lethal doses of the influenza
virus for zanamivir, laninamivir, or peramivir. Only animal studies of the infection model using lethal doses of theinfluenza virus are available.
References
94. Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF et al (1999) Use of the oral neuraminidase inhibitor oseltamivir inexperimental human influenza: randomized controlled trials for prevention and treatment. JAMA 282: 1240–6.
95. Full prescription information of oseltamivir (revised in April 2010) accessed on 09/06/2015 available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021087s057lbl.pdf
96. Moore ML, Chi MH, Zhou W, Goleniewska K, Peebles RS Jr et al (2007) Cutting edge: oseltamivir decreases T cell GM1
expression and inhibits clearance of respiratory syncytial virus: potential role of endogenous sialidase in antiviral immunity.
Journal of Immunology 178: 2651-4.

4.3. Inhibiting host’s endogenous neuraminidase may be related with adverse effects of NIs
ECDC cites our results only on the findings that oseltamivir use was associated with adverse events asfollows:
363 Oseltamivir is associated with an increased absolute risk of 3.66% for nausea (RR 1.57; CI 1.14–2.15 in the
364 Jefferson et al. analysis and RR 1.60; 95% CI 1.29–1.99 in the Dobson et al. analysis) and 4.56% for vomiting
365 (RR 2.43; 95% CI 1.75–3.38 in the Jefferson et al. analysis, and RR 2.43; 95% CI 1.83–3.23 in the Dobson et al.
366 analysis) among adults in the RCTs [14].
367 Cardiovascular events and gastrointestinal events can occur as both an adverse event from medication but also as
368 complications or symptoms of influenza infection. In the Jefferson et al. analysis, oseltamivir use was associated369 with a decrease in ‘cardiac body system adverse events’ (RR 0.49; 95% CI 0.25–0.97) and a decrease in risk of
370 diarrhoea (RR 0.67; 95% CI 0.46–0.98).

However, as shown in 2.1.2.2. Cochrane review also reported that renal events, hyperglycemia/worseningof diabetes, pain in extremities and QT prolongation were more reported in oseltamivir group than placebo group.
About half of the “cardiac body system adverse events” were tachycardia or palpitations and these effects may be21

associated with decreased heart rate observed in the animal toxicity tests. These are also related with inhibitionof host’s endogenous neuraminidase by oseltamivir and QT prolongation, because QT prolongation was observed
closely related with the serum concentration of oseltamivir carboxylate both in animal experiments [14, 61, 62]
and in humans (WV16277). During high fever people need high cardiac output, hence less increase of heart rateshould be considered as adverse effect as QT prolongation is.
Decreased incidence of diarrhoea (RR 0.67;95% CI 0.46–0.98) may be the same effect: apparent beneficial
effects but may even an adverse effects induced by inhibition of host’s endogenous neuraminidase.

7. Efficacy and effectiveness in risk groups
ECDC report:
779 Efficacy and effectiveness in risk groups
780 The limited evidence available on the treatment or prophylaxis of risk groups with underlying chronic conditions is
781 discouraging, as these are the groups who are known to develop severe disease and would most need to be
782 protected from severe outcomes of influenza. It is unlikely that more RCTs will be conducted due to the expiry of
783 patents for oseltamivir and zanamivir, and the unavailability of public funding for such studies. It is also unlikely
784 that ethical boards would approve randomised placebo-controlled trials, given the existing evidence for efficacy.
785 Well-designed prospective observational studies among specific risk groups would be a useful addition to the786 knowledge base. Funding for such observational trials is also an issue and needs more attention. These studies
787 should include longer term follow-up in order to confirm reports on reduced late sequelae (MI, stroke) in
788 oseltamivir-treated persons compared to no treatment.

On the list at p32/39 pdf, ECDC recommend as follows:
Risk group adults including immunocompromised and pregnant women – 18 years and older:
For “Treatment of patients with medically attended influenza-like illness (ILI)*” and “Treatment of patients withlaboratory-confirmed influenza”,
Expert Opinion is “Although limited evidence is available from clinical trials for treatment recommendations of thisvulnerable group, treatment during seasonal influenza epidemics should be recommended.”
Our comments:
High risk group for complicating influenza include elderly, infants, diabetes, renal, hepatic, cardiovascular,
respiratory, neurological and immunocompromised patients. However, oseltamivir may worsen these diseases
and may be harmful for patients with these conditions.
Has ECDC considered this point?

6. Conflict of Interest
In 2014 in the Annals of Internal Medicine, 7 out of 8 studies involving researchers with financial conflicts ofinterest came to positive conclusions about the effectiveness of neuraminidase inhibitors. [97] But, only 5 of the
29 studies conducted by scientists who did not receive money had favorable outcomes. It is time we took
seriously the effects conflicts of interest have upon the reporting of clinical findings and looked purely beyond
the spin to the important outcomes that make a difference to patients.
Reference2297. Dunn AG, Arachi D, Hudgins J, Tsafnat G, Coiera E, Bourgeois FT. Financial conflicts of interest and conclusions about
neuraminidase inhibitors for influenza: an analysis of systematic reviews. Ann Intern Med. 2014 Oct 7;161(7):513-8. doi:
10.7326/M14-0933.

7. Conclusion
As ECDC advice and expert opinion on neuraminidase inhibitor have many limitations including
misunderstanding of the most important findings of our systematic review, meta-analysis and discussions.
We strongly recommend that our Cochrane review be re-read .
Findings from epidemiological studies should be taken into account.
Findings from basic sciences are also important to understand the mechanism of efficacy and harm fromneuraminidase inhibitors:
Inhibition of host’s neuraminidase followed by impaired functions of various cell such as immune,
metabolic, renal, cardiac and neuronal cells by neuraminidase inhibitors is closely related not only to thesymptom relief but also many adverse effects on various organs.
Central nervous system depressing and stimulating actions of oseltamivir but not zanamivir may be closely
related to abnormal behaviours and sudden death from respiratory failure after oseltamivir use.
Finally, we find it strange that a public body would dismiss the findings of our Cochrane review and align its
conclusions with a pharmaceutically-sponsored meta-analysis for which neither protocol nor assessment of riskof bias seems to exist.
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hypothermia in mice. Biological and Pharmaceutical Bulletin 2008; 31(4): 638-42.
87. Ono H, Iwajima Y, Nagano Y, Chazono K, Maeda Y, Ohsawa M, et al. Reduction in sympathetic nerve activity as a possible
mechanism for the hypothermic effect of oseltamivir, an anti-influenza virus drug, in normal mice. Basic & ClinicalPharmacology & Toxicology 2013; 113(1): 25-30.

24

88. Freichel C, Breidenbach A, Hoffmann G, Körner A, Gatti S, Donner B et al. Absence of central nervous system andhypothermic effects after single oral administration of high doses of oseltamivir in the rat. Basic Clin Pharmacol Toxicol.
2012; 111(1): 50-7.
89. Muraki K, Hatano N, Suzuki H, Muraki Y, Iwajima Y, Maeda Y, Ono H. Oseltamivir Blocks Human Neuronal Nicotinic
Acetylcholine Receptor-Mediated Currents. Basic Clin Pharmacol Toxicol. 2015; 116(2): 87-95.
90. Izumi Y, Tokuda K, O'dell KA, Zorumski CF, Narahashi T. Neuroexcitatory actions of Tamiflu and its carboxylate metabolite.
Neurosci Lett. 2007: 426(1):54-8. Epub 2007 Sep 1.
91. Izumi Y, Tokuda K, O'Dell K, Zorumski C, Narahashi T. Synaptic and behavioral interactions of oseltamivir (Tamiflu) withneurostimulants. Hum Exp Toxicol. 2008: 27(12): 911-7
92. Suzuki M, Masuda Y. Effect of a neuraminidase inhibitor (oseltamivir) on mouse jump-down behavior via stimulation of
dopamine receptors. Biomed Res. 2008: 29(5): 233-8.
93. Hiasa M, Isoda Y, Kishimoto Y, Saitoh K, Kimura Y, and Kuzuhara T et al. Inhibition of MAO-A and stimulation of behaviouralactivities in mice by the inactive prodrug form of the anti-influenza agent oseltamivir. Br J Pharmacol. 2013; 169(1):115-2994. Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF et al (1999) Use of the oral neuraminidase inhibitor oseltamivir inexperimental human influenza: randomized controlled trials for prevention and treatment. JAMA 282: 1240–6.
95. Full prescription information of oseltamivir (revised in April 2010) accessed on 09/06/2015 available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021087s057lbl.pdf
96. Moore ML, Chi MH, Zhou W, Goleniewska K, Peebles RS Jr et al (2007) Cutting edge: oseltamivir decreases T cell GM1
expression and inhibits clearance of respiratory syncytial virus: potential role of endogenous sialidase in antiviral immunity.
Journal of Immunology 178: 2651-4.
97. Dunn AG, Arachi D, Hudgins J, Tsafnat G, Coiera E, Bourgeois FT. Financial conflicts of interest and conclusions about
neuraminidase inhibitors for influenza: an analysis of systematic reviews. Ann Intern Med. 2014 Oct 7;161(7):513-8. doi:
10.7326/M14-0933.

25