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OPEN DATA

What does oseltamivir do, and how will we know?Two different groups are now working on meta-analyses of the unpublished patient level data onthe effects of oseltamivir in flu. Will they come to the same conclusions?

Trish Groves deputy editor, BMJ

Jonathan Nguyen-Van-Tam, a virologist and researcher from

the University of Nottingham, told a group of triallists and

virologists last month, We must remember why were here:

because of the controversies. The clinical world doesnt believe

that Tamiflu [oseltamivir] works. We should assess whether the

regulatory approval/product insert for Tamiflu is valid.

That group, the Multiparty Group for Advice on Science

(MUGAS), was at a workshop in Brussels on 18 June organised

by the European Scientific Working Group on Influenza and

supported by an unrestricted grant from Roche, manufacturer

of oseltamivir. Led by several of the original oseltamivir

regulatory triallists, the workshop heard plenty of evidence to

challenge current claims about the drugs effects. MUGAS

decided to plan and conduct individual participant data (IPD)

meta-analyses of the randomised trial dataand observational

data. Thats quite a remarkable turnaround, given the strength

of claims made by some ofthe same people over the past decade.

BMJreaders will already be familiar with growing concerns

about oseltamivirs effectiveness. Earlier this year Harlan

Krumholz and coauthors concluded in an editorial in the BMJ

that, despite government claims, we should acknowledge the

uncertainty surrounding oseltamivirs effectiveness and the gaps

in publicly available evidence.1 They continued, On the basis

of the available data, at best the drug shortens symptoms byabout a day when used within the first two days of symptoms,

but it has no effect on hospital admissions. In addition, trial data

from which to draw conclusions about complications and

transmission of flu are lacking.

The World Health Organization made particularly firm claims

about oseltamivir in August 2009 during the swine flu (H1N1)

pandemic. WHO then stated, The guidelines represent the

consensus reached by an international panel of experts who

reviewed all available studies on the safety and effectiveness

of these drugs . . . Evidence reviewed by the panel indicates that

oseltamivir, when properly prescribed, can significantly reduce

the risk of pneumonia (a leading cause of death for both

pandemic and seasonal influenza) and the need forhospitalization.

That expert panel advising WHO was anonymous: all its

members had signed a confidentiality agreement. But at least

one member was identified later as Arnold Monto of the

University of Michigan, who coauthored several trials of

neuraminidase inhibitors back in the 1990s. Monto is one of the

four convenors of MUGAS, along with Ab Osterhaus (of

Erasmus MC University in Rotterdam, a scientific adviser to

Roche and another oseltamivir triallist), Menno de Jong (of

Academic Medical Center Amsterdam, a virologist and

researcher), and Rich Whitley (of University of Alabama at

Birmingham, professor of paediatric infectious diseases and anadviser on flu to the Obama administration).

Barry Clinch, principal clinical scientist at F Hoffmann-La

Roche, presented at the MUGAS workshop an overview of all

the studies in the companys oseltamivir research programme.

His slides showed that, in all, 18 928 patients had taken part in

trials, observational studies of treatment, and studies of

prophylaxis; around 11 500 of them were treated with oral

oseltamivir. Randomised controlled trials had included 4799

adults and 1368 children; along with some open label studies,

a total of 8078 patients had taken part. All but one of the 12

randomised controlled trials took place in the late 1990s.

Roches lab researchers had also done experimental flu studies

and clinical pharmacology studies.Clinch confirmed that the investigators were told to always

report admissions to hospital during the Roche trials but warned

that caution should be exercised in interpreting results on

hospitalisation. This is because there were such low event rates:

for example, in trial WV15671 just one of 201 participants was

hospitalised. The main intentionto treatanalyses in the 12 Roche

randomised controlled trials (for all patients enrolled with

flu-like illness and who had at least one dose of the trial drug)

failed to find statistically significant evidence that hospitalisation

rates were any lower in the oseltamivir group than in the placebo

group. For the ITTI population (intention to treat infectedthe

subset with flu confirmed by culture or a greater than fourfold

rise in antibody titre) the overall P value was 0.06, but this wasgrossly underpowered.

tgroves@bmj.com

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8/22/2019 What Does Oseltamivir Do, And How Will We Know

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Presenting the key oseltamivir trials that yielded data on

complications of flu, Clinch explained that a standard case report

form was used to collect data on secondary illness. We didnt

ask physicians to actively look for complications, he said.

They simply reported them if they thought patients had, for

example, sinusitis, otitis media, bronchitis, pneumonia, or otherchest infections. Clinicians could also say whether patients

needed antibiotics or radiographythereby implying there

might be some secondary illnessbut there was no requirement

to confirm diagnoses without anything more than a clinical

diagnosis. Tobe honest, we werent that stringent at the time,

acknowledged Clinch. (And, of course, at that time Roche was

testing oseltamivir primarily as another antiviral for seasonal

flu, not as a lifesaver in a pandemic.) Only two trial protocols

required reporting of clinically diagnosed complications (coded

as bronchitis, pneumonia, lower respiratory tract complication,

or antibiotic prescription occurring at least 48 hours after start

of treatment with oseltamivir) as a formal secondary endpoint:

those among older and at-risk participants. Statistical analyses

of these outcomes were exploratory, said Clinch.

The ensuing questions and discussion among the MUGAS

review board members (some of whom coauthored some of the

trials in question) confirmed that secondary illness was indeed

only a clinical diagnosis, that in most of the trials its reporting

was ad hoc, and that Roche did not know the extent of any

missing data. Decisions to give antibiotics were made for

unspecified clinical reasons, and, as someone pointed out,

antibiotic usage rates will have varied a lot from site to site

because of geographical variations in prescribing behaviour.

However, some of the MUGAS virologists said that we know

from Roches original observational studies and from subsequent

case series from the H1N1 pandemic that oseltamivir does

reduce the incidence of complications. Do we? Not yet, although

Van-Tams group has conducted a systematic review and

individual patient data meta-analysis of published and

unpublished observational study data during the H1N1 pandemic

that will be submitted soon for publication. This study was

sponsored by Roche, but Van-Tam said that the data agreement

gave Roche no access to the data. The authors plan, however,

to share the data with other investigators on request.

When asked what proportion of the original Roche oseltamivir

research programme had results in the public domain, Clinch

said, About 90% in one form or another. The virologist Fred

Hayden, coauthor of several Roche trials, asked, The

contentious area is the 8-10 unpublished trials done some time

ago. Are there any plans to publish those? Clinch replied, Itsa good question . . . Wed like MUGAS to discuss that. Roche

has no objection to that. Osterhaus said that MUGAS wanted

to analyse the individual patient data from those trials and to

publish the resulting papers in peer reviewed journals.

So, of course, does the Cochrane Acute Respiratory Infections

Group, which has been struggling for years to get the

unpublished trial data from Roche (bmj.com/tamiflu). That data

release has now begun, and the Cochrane group is poring over

the partly redacted clinical study reports right now.

So, its from famine to feast, with two different groups working

towards meta-analyses of the unpublished patient-level data on

the effects of oseltamivir in flu. Will they come to the same

conclusions?

Competing interests: The MUGAS meeting was funded by an

unrestricted grant from Roche which covered expenses for travel and

accommodation. The BMJpaid my expenses,though I dideat thebuffet

lunch and hitched a taxi ride back to the station with a MUGAS review

board member. I was there as a reporter for the BMJ, present for all the

discussions and presentations, able to report them freely, free to talk

with all participants in the meeting breaks, and able to ask questions in

the final session.

bmj.com Data sharingmaking it real [blog]. 26 Jun2013. http://blogs.

bmj.com/bmj/2013/06/26/trish-groves-data-sharing-making-it-real/.

Letter: Adverse effects of oseltamivir: Neuropsychiatric adverse effects

in FDA reporting system (BMJ2013;347:f4656)For more on the BMJs open data campaign go to bmj.com/open-data.

Trish Groves is on Twitter @trished.

1 Krumholz HM, Hines HH Jr, Jackevicius CA, Ross JS. Tamiflu: 14 flu seasons and still

questions. BMJ2013;346:f547.

Cite this as: BMJ 2013;347:f4687

BMJ Publishi ng Group Ltd 2013

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