Risk of bias in industry-funded oseltamivir trials published

“As information increased in the document, this increased our assessment of bias. This may mean that risk of bias has been insufficiently assessed in Cochrane reviews based on journal publications.”


The Cochrane risk of bias tool is a prominent instrument used to evaluate potential biases in clinical trials. In three updates of our Cochrane review on neuraminidase inhibitors, we assessed risk of bias on the same trials using different levels of detail: the trials in journal publications, in core reports, and in full clinical study reports. Here we analyse whether progressively greater amounts of information and detail in full clinical study reports (including trial protocols, statistical analysis plans, certificates of analyses, individual participant data listings and randomisation lists) affected our risk of bias assessments.


We used the Cochrane risk of bias tool to assess and compare risk of bias in 14 oseltamivir trials (reported in 10 clinical study reports) obtained from the European Medicines Agency (EMA) and the manufacturer, Roche. With more detailed information, reported in clinical study reports, no previous assessment of ‘high’ risk of bias was reclassified as ‘low’ or ‘unclear’ in the main analysis, and over half (55%, 34/62) of the previous assessments of ‘low’ risk of bias were reclassified as ‘high’. Most assessments of ‘unclear’ risk of bias (67%, or 28/42) were reclassified as ‘high’ risk of bias when our judgements were based on full clinical study reports. The limits of our study were our relative inexperience in dealing with large information sets, sometimes subjective bias judgements and focus on industry trials. Comparison with journal publications was not possible because of the low number of trials published.

CONCLUSIONS: We found that as information increased in the document, this increased our assessment of bias. This may mean that risk of bias has been insufficiently assessed in Cochrane reviews based on journal publications.



Cochrane review A159 published

Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, et al. 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



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


To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments.


We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE,, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database.


Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza.


We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers.


We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628 participants). Inadequate reporting put most of the zanamivir studies and half of the oseltamivir studies at a high risk of selection bias. There were inadequate measures in place to protect 11 studies of oseltamivir from performance bias due to non-identical presentation of placebo. Attrition bias was high across the oseltamivir studies and there was also evidence of selective reporting for both the zanamivir and oseltamivir studies. The placebo interventions in both sets of trials may have contained active substances. Time to first symptom alleviation. For the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P < 0.0001). This represents a reduction in the time to first alleviation of symptoms from 7 to 6.3 days. There was no effect in asthmatic children, but in otherwise healthy children there was (reduction by a mean difference of 29 hours, 95% CI 12 to 47 hours, P = 0.001). Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days, P < 0.00001), equating to a reduction in the mean duration of symptoms from 6.6 to 6.0 days. The effect in children was not significant. In subgroup analysis we found no evidence of a difference in treatment effect for zanamivir on time to first alleviation of symptoms in adults in the influenza-infected and non-influenza-infected subgroups (P = 0.53). Hospitalisations. Treatment of adults with oseltamivir had no significant effect on hospitalisations: risk difference (RD) 0.15% (95% CI -0.78 to 0.91). There was also no significant effect in children or in prophylaxis. Zanamivir hospitalisation data were unreported. Serious influenza complications or those leading to study withdrawal. In adult treatment trials, oseltamivir did not significantly reduce those complications classified as serious or those which led to study withdrawal (RD 0.07%, 95% CI -0.78 to 0.44), nor in child treatment trials; neither did zanamivir in the treatment of adults or in prophylaxis. There were insufficient events to compare this outcome for oseltamivir in prophylaxis or zanamivir in the treatment of children. Pneumonia. Oseltamivir significantly reduced self reported, investigator-mediated, unverified pneumonia (RD 1.00%, 95% CI 0.22 to 1.49); number needed to treat to benefit (NNTB) = 100 (95% CI 67 to 451) in the treated population. The effect was not significant in the five trials that used a more detailed diagnostic form for pneumonia. There were no definitions of pneumonia (or other complications) in any trial. No oseltamivir treatment studies reported effects on radiologically confirmed pneumonia. There was no significant effect on unverified pneumonia in children. There was no significant effect of zanamivir on either self reported or radiologically confirmed pneumonia. In prophylaxis, zanamivir significantly reduced the risk of self reported, investigator-mediated, unverified pneumonia in adults (RD 0.32%, 95% CI 0.09 to 0.41); NNTB = 311 (95% CI 244 to 1086), but not oseltamivir. Bronchitis, sinusitis and otitis media. Zanamivir significantly reduced the risk of bronchitis in adult treatment trials (RD 1.80%, 95% CI 0.65 to 2.80); NNTB = 56 (36 to 155), but not oseltamivir. Neither NI significantly reduced the risk of otitis media and sinusitis in both adults and children. Harms of treatment. Oseltamivir in the treatment of adults increased the risk of nausea (RD 3.66%, 95% CI 0.90 to 7.39); number needed to treat to harm (NNTH) = 28 (95% CI 14 to 112) and vomiting (RD 4.56%, 95% CI 2.39 to 7.58); NNTH = 22 (14 to 42). The proportion of participants with four-fold increases in antibody titre was significantly lower in the treated group compared to the control group (RR 0.92, 95% CI 0.86 to 0.97, I(2) statistic = 0%) (5% absolute difference between arms). Oseltamivir significantly decreased the risk of diarrhoea (RD 2.33%, 95% CI 0.14 to 3.81); NNTB = 43 (95% CI 27 to 709) and cardiac events (RD 0.68%, 95% CI 0.04 to 1.0); NNTB = 148 (101 to 2509) compared to placebo during the on-treatment period. There was a dose-response effect on psychiatric events in the two oseltamivir “pivotal” treatment trials, WV15670 and WV15671, at 150 mg (standard dose) and 300 mg daily (high dose) (P = 0.038). In the treatment of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75 to 10.29); NNTH = 19 (95% CI 10 to 57). There was a significantly lower proportion of children on oseltamivir with a four-fold increase in antibodies (RR 0.90, 95% CI 0.80 to 1.00, I(2) = 0%). Prophylaxis. In prophylaxis trials, oseltamivir and zanamivir reduced the risk of symptomatic influenza in individuals (oseltamivir: RD 3.05% (95% CI 1.83 to 3.88); NNTB = 33 (26 to 55); zanamivir: RD 1.98% (95% CI 0.98 to 2.54); NNTB = 51 (40 to 103)) and in households (oseltamivir: RD 13.6% (95% CI 9.52 to 15.47); NNTB = 7 (6 to 11); zanamivir: RD 14.84% (95% CI 12.18 to 16.55); NNTB = 7 (7 to 9)). There was no significant effect on asymptomatic influenza (oseltamivir: RR 1.14 (95% CI 0.39 to 3.33); zanamivir: RR 0.97 (95% CI 0.76 to 1.24)). Non-influenza, influenza-like illness could not be assessed due to data not being fully reported. In oseltamivir prophylaxis studies, psychiatric adverse events were increased in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07 to 2.76); NNTH = 94 (95% CI 36 to 1538) in the study treatment population. Oseltamivir increased the risk of headaches whilst on treatment (RD 3.15%, 95% CI 0.88 to 5.78); NNTH = 32 (95% CI 18 to 115), renal events whilst on treatment (RD 0.67%, 95% CI -2.93 to 0.01); NNTH = 150 (NNTH 35 to NNTB > 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to 9.51); NNTH = 25 (95% CI 11 to 116).


Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence.

Independent drug Bulletin “Med Check The Informed Prescriber” (Japanese)

Introduces the Cochrane team’s critical comments on the ECDC experts’ draft advice on neuraminidase inhibitor use.

Med Check TIP in English. Cochrane team criticises the ECDC experts’ draft advice on oseltamivir use: in No 4 (April 2016) | PDF

Eficacy and harm of oseltamivir: ECDC’s draft “Expert Opinion” misinterpret Cochrane’s systematic review results “Med Check The Informed Prescriber” in Japanese 2016: 16(65): 6668.

Peter Doshi and colleagues challenge the CDC

They challenge the evidence base used by the CDC to make recommendation on the use of Oseltamivir and their lack of transparency.

Tamiflu For All? Evidence Of Morbidity In CDC’s Antiviral Guidelines.

Peter Doshi, Kenneth Mandl, and Florence Bourgeois. March 31, 2016

The Centers for Disease Control and Prevention (CDC) has boiled down its public health campaign against influenza to a single slogan: “Take 3.” Vaccines, everyday preventive actions like handwashing, and influenza antivirals.

Last year, because of a mismatch between the vaccine and circulating virus, the message was reduced to—essentially—“Take 1,” as the CDC emphatically promoted oseltamivir (Tamiflu) for treating disease. The agency has stated: “Antiviral flu medicines are underutilized. If you get them early, they could keep you out of the hospital and might even save your life.”

The CDC is one of the nation’s most powerful voices when it comes to public health recommendations. That’s why it’s so important that its advice be scientifically sound and independently derived. Unfortunately, the CDC’s advice on Tamiflu is neither. Here we explain why — and offer suggestions for what to do about it. Read More

Cochrane reviewers respond to ECDC consultation

Hama R, Jefferson T, Heneghan C .

Cochrane reviewers’ comments on the ECDC draft preliminary Scientific Advice paper “Expert Opinion on neuraminidase inhibitors for prevention and treatment of influenza – review of recent systematic reviews and metaanalyses”




Table of contents:

As ECDC advice has many limitations, we would like to comment on it as the following contents
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. Antibody production QT interval and other cardiovascular events Psychiatric events, injury and poisoning
2.2. Prophylaxis trials
2.2.1. Efficacy in prophylaxis trials:
2.2.2. Harm in prophylaxis trials: Psychiatric reactions Injury and poisoning Other adverse reactions Renal impairment Hyperglycemic of diabetic events, and pain in limbs 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 of
cognition, 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

ECDC launches consultation

ECDC PRELIMINARY SCIENTIFIC ADVICE Expert Opinion on Neuraminidase Inhibitors for prevention and treatment of influenza.

pdf draft scientific advice

A consultation with European and international public health experts was convened to review data presented in newly conducted systematic reviews and meta-analyses regarding influenza antivirals, in order to develop an ECDC Expert Opinion.

In line with ECDC’s commitment to openness and transparency, and in order to receive comments from the scientific community and stakeholders, ECDC is launching a public consultation on the ‘Expert Opinion on neuraminidase inhibitors for prevention and treatment of influenza – review of recent systematic reviews and meta-analyses’.

5 of the acknowledged (2 in the expert group, both presenters and one ECDC representative) are past or present members of ESWI.

This report of the European Centre for Disease Prevention and Control (ECDC) was coordinated by Pasi Penttinen and Kari Johansen.
Contributing authors: Emmanuel Robesyn, Eeva Broberg, Piotr Kramarz.
Expert group: Barbara Michiels (University of Antwerp); Kari S. Lankinen (Finnish Medicines Agency); Regine Lehnert (German Federal Agency for Drugs and Medical Devices); Darina O’Flanagan (Health Protection Surveillance Centre Ireland); Anders Tegnell (Public Health Agency of Sweden); Johan Giesecke (KarolinskaInstitutet); Peter Horby (University of Oxford); John Watson (UK Department of Health); Angela Campbell (U.S.Centers for Disease Control and Prevention); Frederick Hayden (University of Virginia School of Medicine); Filip Josephson (Medical Products Agency of Sweden).
Observers: Manuela Mura (European Medicines Agency); Nikki Shindo (WHO); Caroline Brown (WHO Regional Office for Europe).
Presenters external to expert group: Arnold Monto (University of Michigan School of Public Health); Jonathan Nguyen-Van-Tam (University of Nottingham);
ECDC representatives: Mike Catchpole; Piotr Kramarz; Pasi Penttinen; Angus Nicoll; Kari Johansen; Emmanuel Robesyn; Eeva Broberg; René Snacken; Cornelia Adlhoch; Brenna Deckert; Luciana Muresan.

Independent drug bulletin Prescrire summarises story

“Over a 15-year period, Roche, the company that markets Tamiflu, has hampered independent analysis of the assessment data on oseltamivir in the treatment of influenza. Worse yet, drug regulators and international organisations have been complicit in this data retention.”

In the February issue of Prescrire International. Oseltamivir (Tamiflu°): over 15 years of data retention and systematic stonewalling


Prescrire link

Oseltamivir was authorised in the EU in 2002 for the prevention and treatment of influenza. Despite widespread belief in its efficacy, cleverly orchestrated by the drug’s manufacturer and other organisations, a number of independent teams were not convinced and went on a hunt for missing data. They discovered that the available trial results were neither complete nor clinically relevant and provided only weak evidence.


  • Over a 15-year period, Roche, the company that markets Tamiflu° (oseltamivir), has hampered independent analysis of the assessment data on oseltamivir in the treatment of influenza.
  • Worse yet, drug regulators and international organisations have been complicit in this data retention.
  • These 15 years of stonewalling represent a lost opportunity for patients and the medical community, while providing the company with an unfair advantage after successfully bringing oseltamivir to the market on the basis of unverified data.
Download the full review
Pdf, free
Further information:
Oseltamivir and influenza: still no robust data.
Prescrire Int 2016:
25 (168): 52-55.
Pdf, subscribers only
Oseltamivir for influenza, from birth: no more useful than in adults.
Prescrire Int 2016:
25 (168): 53.
Pdf, subscribers only

JAMA viewpoint on using observational studies

The authors judge the randomized controlled trial (RCT) evidence as inadequate as RCTs have not been carried out in “high risk
populations” which they defined as including children and elderly.


Louie JK, Lampiris H. Treating Influenza With Neuraminidase Inhibitors: What Is the Evidence? JAMA Intern Med. 2015 Oct 19;1.

“In conclusion, the available evidence suggests that the effect of neuraminidase inhibitors on morbidity and mortality from influenza depends on the population being treated and the setting. The findings from the Cochrane reviews are important,but the trials were performed with a specific population (healthy outpatients) and a different outcome (duration of symptoms rather than assessment of pneumonia or mortality) in mind”.

Doshi P, Jefferson T. Treating Influenza With Neuraminidase Inhibitors: What Is the Evidence?

Concerns about this article Posted on October 28, 2015

Dear editor, we are writing with concerns about what we think are inaccurate and misleading statements in the Viewpoint on influenza antivirals by Louie and Lampiris (Louie 2015). We summarize our concerns below.

Louie and Lampiris define “high risk” populations as including young children and the elderly, and state that randomized controlled trials (RCTs) have not been carried out in high-risk populations. This is false. Multiple RCTs analyzed in our Cochrane review (Jefferson 2014) were in such populations (e.g. trials WV15708, WV15825, WV15758, and WV15759/WV15871). In addition, elderly patients participated in trials such as M76001. Based on RCTs alone, Roche wrote in 2003 that oseltamivir treatment reduces complications and hospitalizations in “at-risk” adults (Kaiser 2003).

Louie and Lampiris describe a Roche funded study published in 2015. They note: “Of the four authors, one reported receiving fees from Roche and another company outside the submitted work, and another reported receiving travel funding from Roche.” This is incomplete. In fact, not two but all four authors have financial conflicts of interest. One author (RJW) does not inform readers that Gilead Sciences is the patent holder for oseltamivir; another (JD) declares \”no competing interests” but her salary was supported by Roche while she carried out the analysis; a third (SP) declares “no competing interests” but Stuart Pocock told The BMJ (Lenzer 2015) that he received research funds from Gilead and Genentech. These facts have been documented for months in the following places: (Read More)

Doshi P, Jefferson T. Neuraminidase Inhibitors and Influenza Infection. JAMA Intern Med. 2016;176(3):415-416. doi:10.1001/jamainternmed.2016.0016.

To the Editor As authors of articles cited by Louis and Lampiris,1 we have a different view of the evidence that should inform recommendations about treating influenza with neuraminidase inhibitors.

Louis and Lampiris champion conclusions from observational studies. They judged the evidence from randomized clinical trials as inadequate because such trials have not been carried out in high-risk populations, which they defined as including children and the elderly. However, we analyzed 13 such placebo-controlled randomized clinical trials in our Cochrane review.2

Based on randomized clinical trials, the manufacturer of oseltamivir (Tamiflu; Roche Pharmaceuticals) has claimed that treatment reduces complications and hospitalizations in at-risk adults.3 Our review, however, found this claim unsubstantiated in the elderly population and in children.2 In children with asthma, oseltamivir did not shorten the duration of symptoms. Our review found that oseltamivir may impede the production of influenza antibodies and cause renal and psychiatric harms. Because of flaws in trial design, there is no convincing evidence it can interrupt person-to-person spread of influenza virus.

Louie JK, Lampiris H. Neuraminidase Inhibitors and Influenza Infection—Reply. JAMA Intern Med. 2016;176(3):416-417. doi:10.1001/jamainternmed.2016.0050.

In their Cochrane review, Jefferson and Doshi have conducted a thorough and rigorous analysis of the available randomized clinical trial (RCT) data. However, the authors themselves acknowledge the limitations of their conclusions given the quality of the studies reviewed, stating: “Hospitalizations are an important but poorly defined outcome in the oseltamivir protocols, inconsistently reported in the clinical study reports and overlooked in the zanamivir protocols and reports. The oseltamivir trials did not detect any influenza-related deaths, reflecting the relatively benign nature of influenza in the study populations.”Cochrane reviews set rigorous standards for deciding which studies to include, preferentially including RCTs over observational studies, and typically result in conservative recommendations. However, the inability to show benefit under the most rigorous study conditions does not mean that benefit does not exist.3 Given this, it is reasonable to consider the available non-RCT data when evaluating the usefulness of neuraminidase inhibitor drugs (NAI) for influenza.

Academy of Medical Sciences and Wellcome Trust publish report

In October 2015, the Academy and Wellcome Trust published a report exploring the scientific evidence around the treatment of influenza, including the use of existing antivirals, research priorities, methodological improvements and the pipeline of new treatments.

The report laments the uncertainty over the evidence base of NIs and the failure to carry out research during the 2009 influenza pandemic.

Use of neuraminidase inhibitors in influenza, Academy of Medical Sciences and Wellcome Trust, October 2015,  

Download report

Science Media Centre briefing

Pandemic influenza tops the UK’s National Risk Register due to the social and economic disruption that could result from a particularly virulent strain. (Read More)

Experts call for tests on use of flu drugs in pandemic, Guardian newspaper.  Health editor, 8th October 2015

New trials are urgently needed to establish whether the anti-flu drug Tamiflu would help save lives in a pandemic, experts have said.

Flu pandemics are highly dangerous, with the potential to kill millions around the world. Each winter in the UK, hundreds die of flu. Yet the drugs available to treat people, of which the best known and most widely used is Tamiflu, appear to have only a modest effect and have only been tested on seasonal flu, according to a report by the Academy of Medical Sciences and the Wellcome Trust.

The senior doctors on the review panel urge that plans should be put in place to test whether the drugs would work in a pandemic. That could involve people who go to their GP with flu symptoms being randomly assigned either Tamiflu, nothing at all, or an alternative such as paracetamol to deal with the symptoms.

(Read more)

The Conversation publishes on the Tamiflu story

The piece draws several comments. Cochrane reviewer Jefferson points out McVernon’s attempts at blurring the Dobson authors’ conflicts of interest as well as her own. McVernon does not respond, despite two further reminders.

Controversies in medicine: the rise and fall of the challenge to Tamiflu

Associate Professor, Population Health, University of Melbourne

One of the biggest recent controversies in medicine involves the effectiveness – or otherwise – of the antiviral drug Tamiflu. Governments around the world have stockpiled the drug for use in severe influenza pandemics, but many have raised doubts about its effectiveness.

Influenza causes annual “seasonal” epidemics in temperate countries and circulates year-round in the tropics. Pandemics occur when there’s a relatively new flu virus containing components of bird or swine flu viruses, against which the human population has little protection.

Global pandemic preparedness efforts were spurred in the early 2000s by the emergence of SARS, and highly pathogenic H5N1 influenza in birds, which was associated with rare but often fatal infection in humans. The problem is that the severity of pandemics can vary markedly; from the Spanish flu of 1918-19, which is estimated to have killed 20-50 million people worldwide, to the much milder 2009 swine flu, which resulted in between 150,000 and 250,000 deaths (a similar number to the annual mortality of seasonal epidemics).

(Read more)

Letter responses to Dobson et al published in Lancet

Series of responses to Dobson et al  meta-analyses of individual patient published in the Lancet including concerns over the methods.

Oseltamivir for influenza. Lancet 2015; 386: 113336.(9999):11345. Doi: 10.1016/S01406736(15)002020.

Oseltamivir for influenza. Peter Doshi, Carl Heneghan, Tom Jefferson.

Meta-analyses of individual patient data hold the potential of offering new insights into old data, but the Article by Joanna Dobson and colleagues fails to do this, presenting no new data on the potential treatment effect of oseltamivir in reducing the risk of influenza complications or admittance to hospital. Instead, the authors provide only new interpretations of already public data.2 We are concerned, however, that Dobson and colleagues’ interpretation of their results1 seems to be driven by a methodology not described in the methods section of their Article. Dobson and colleagues list nine data sources: four journal articles, three conference abstracts, secure web-access to participant-level data, and data clarifications from the drug’s manufacturer. These sources do not contain enough detail to support the authors’ comment that “specific diagnostic tests were not necessary” for respiratory complications. For example, one conference abstract that is cited (for a trial of more than 1400 participants) is just a paragraph long. (Read More)

Oseltamivir for influenza. Mark Jones, Rokuro Hama, Chris Del Mar.

In their Article (May 2, p 1729)1 on oseltamivir treatment for influenza, Joanna Dobson and colleagues reported both fewer admittances to hospital for those treated with oseltamivir in the subgroup of patients classified as infected and fewer lower respiratory tract complications in patients treated with antibiotics as a surrogate for severity than in placebo recipients. However, our Cochrane review2 found insufficient evidence of a difference between groups for complications classified as serious or leading to patient withdrawal, or for rate of admittance to hospital. (Read More)

Oseltamivir for influenza. Kubo et al.

In their article, Joanna Dobson and colleagues presented the value of oseltamivir for influenza treatment. But does this end the debate about the efficacy of oseltamivir?

The authors selected a secondary outcome of lower respiratory tract infection more than 48 h after randomisation requiring antibiotics and thus included 143 cases of bronchitis, 30 cases of pneumonia, and five cases of lower respiratory tract infection. However, in general, most cases of bronchitis do not need treatment with antibiotics. It is commendable that the authors are the first to present results from pooled individual patient data without significant heterogeneity, but they seem to be limited and non-specific, as Dobson and colleagues themselves noted in their Article. (Read More)

Oseltamivir for influenza. Radecki.

Joanna Dobson and colleagues1 present an individual patient meta-analysis assessing the efficacy of oseltamivir for the treatment of influenza infection. The authors report that the data for their analysis were acquired from Roche Pharmaceuticals via a secure web portal. Interestingly, the data presented differ substantially from the data reported by the Cochrane Collaboration in their review of clinical study reports.2 Five trials had populations common to both analyses for comparison, and differences in admittance to hospital reported are presented in the table. (Read More)

Oseltamivir for influenza. Arnold S Monto, Joanna Dobson, Stuart Pocock, Richard J Whitley.
We thank the correspondents for their interest in our study.1 We did our meta-analysis of oseltamivir treatment studies in view of the controversy that has arisen about oseltamivir’s rational use. To us, an analysis with the most robust design, namely an individual patient data analysis, would help clarify issues of importance not only to clinicians but also to public health decision makers. (Read More)


Imbalance of baseline renal function between oseltamivir and placebo group reported

Participants in five prophylaxis randomized controlled trials with high baseline creatinine level (154μmol/L or more) were significantly less reported in the oseltamivir group than in the placebo group: pooled odds ratio was 0.29 (P = 0.005).

Hama R, Jones M and Jefferson T. Concerns about the randomization in the prophylaxis trials of oseltamivir.  Rapid response to Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments.  BMJ 2014;348:g2545

In our Cochrane review [1], we reported a non-significant increase in renal events in oseltamivir prophylaxis trials on-treatment (RR 3.17, 95% CI 0.96 to 10.49) by random effect model. However there was a statistically significant increase (P=0.02) in sensitivity analysis using Peto’s method. We also noticed two patients in oseltamivir groups who experienced renal failure prior to death [1]: one in trial WV15825 and on in trial WV15708. While assessing the evidence in individual patient data in prophylaxis trials, we found imbalance of baseline renal disorders between the oseltamivir and placebo groups. 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) [2].

Participants with high baseline creatinine level (154μmol/L or more) were significantly less reported in the oseltamivir group than in the placebo group: pooled odds ratio was 0.29 (95% CI = 0.12 to 0.69, P = 0.005, I2= 0%: Figure). In trial WV15708 which was never published, participants with high baseline creatinine level (154μmol/L or more) 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 high baseline creatinine level and/or concomitant renal/UTD were 5.8% (11/190) and 16.5% (30/182) for oseltamivir group and placebo group respectively: odds ratio 0.31 (95%CI = 0.14 to 0.67, P = 0.0014).

In an experiment using beagle dogs to test the effects on cardiac functions such as especially QT time [3], mean baseline 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). Difference was significant (p=0.0372) by the summary data t-test. There was also evidence that the variation was higher in the control group (P=0.005; Bartlett’s test).
We don’t know the reason why such large and systemic imbalances occurred, but they are unlikely to have occurred by chance.

1. Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, et al. Neuraminidase inhibitors for preventing and treating influenza in adults and children. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD008965. DOI: 10.1002/14651858.CD008965.pub4
2. The Dryad Digital Repository.
3. 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)

Competing interests: All authors were co-recipients of a UK National Institute for Health Research grant (HTA–10/80/01, Update and amalgamation of two Cochrane reviews: neuraminidase inhibitors for preventing and treating influenza in healthy adults and children— RH wrote two books on the harm of Tamiflu and/or antipyretics and provided scientific opinions and expert testimony on 14 adverse reaction cases related to oseltamivir in the law suits. MJ has no additional conflict of interest to be declared. TJ receives royalties from his books published by Blackwells and Il Pensiero Scientifico Editore, Rome. TJ is occasionally interviewed by market research companies for anonymous interviews about phase I or II pharmaceutical products. In 2011-13, TJ acted as an expert witness in a litigation case related to oseltamivir and in a labour case on influenza vaccines in healthcare workers in Canada. TJ was a consultant for IMS Health in 2013, and in 2014 was retained as a scientific adviser to a legal team acting on oseltamivir. In the next 12 months, TJ anticipates reimbursement for travel and accommodation in a potential lawsuit related to oseltamivir, and expert witness fees for cases involving alleged harm from vaccination. TJ is a recipient of a travel grant from the Cochrane Collaboration to attend the bi-annnual editors’ meeting in 2015.

Cochrane reviewers summarise results of review

The authors subsequently published the underlying documents simultaneously with the Cochrane review, endorsing the concept of open science” Roche and Van Tam et al also publish articles in the same issue.

Mark Jones, Tom Jefferson, Peter Doshi, Chris Del Mar, Carl Heneghan, Igho Onakpoya. Commentary on Cochrane review of Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Clinical Microbiology and Infection 2015, 21, 217–221.


In recent years there has been much debate and controversy surrounding the efficacy and safety of neuraminidase inhibitors for influenza, in part because the data underlying certain efficacy claims were not available for independent scrutiny. In 2014, a Cochrane review was published, based exclusively on an almost complete set of clinical study reports and other regulatory documents. Clinical study reports can run to thousands of pages, providing an extensive amount of information on the planning, conduct and results of each trial. After a protracted campaign to obtain the reports, the manufacturers of the medications provided them unconditionally. The review authors subsequently published the underlying documents simultaneously with the Cochrane review, endorsing the concept of open science. In the following commentary, the background to and results of this review are summarized and put into clinical context.

Clinch, B., Smith, J. Roche perspectives on Tamiflu. Clinical Microbiology and Infection 2015, 21, 226–229.

J.S. Nguyen-Van-Tam, S. Venkatesan, S.G. Muthuri, P.R. Myles. Neuraminidase inhibitors: who, when, where? Clinical Microbiology and Infection 2015, 21, 222-225


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