[Sci-tech-public] FW: Peter Doshi's Research Gets Major Attention in the International Press

[David Mindell]

  _____  

From: postol at MIT.EDU [mailto:postol at MIT.EDU] 
Sent: Tuesday, December 08, 2009 5:00 PM
To: David Jones; dikaiser at mit.edu; David Mindell
Subject: Peter Doshi's Research Gets Major Attention in the International
Press



Dear Colleagues

Peter Doshi has found, in a collaboration with other researchers, that the
Swiss company Roche, which markets Tamiflu, has been making claims about
Tamiflu while withholding trial data that would allow for an independent
review of the claims.  Attached is breaking news about the lack of
independently verifiable evidence that Tamiflu reduces the risk of
complications of influenza in otherwise healthy adults.  It was the lead
story on the CBS website today.  I have also attached the article that Peter
published today in the British Medical Journal.

Best regards, Ted

 

 

 <http://www.bmj.com/> BMJ - helping doctors make better decisions

  _____  

 <http://www.bmj.com/cgi/content/full/339/dec07_2/b5106> Tamiflu influenza
drug. Tamiflu (oseltamivir) capsules in a blister pack. Tamiflu is an
antiviral drug used to treat influenza (flu). It can be taken to prevent
infection, or to reduce the symptoms and the duration of the infection. It
works by inhibiting the neuraminidase enzyme, which allows the viruses to
exit cells in order to infect other cells.

Pandemic influenza

 <http://www.bmj.com/cgi/content/full/339/dec07_2/b5106> The truth about
Tamiflu?

 <http://www.bmj.com/cgi/content/full/339/dec07_2/b5106> This Cochrane
group's update of a 2005 review of oseltamivir in pandemic influenza
concludes: "Neuraminidase inhibitors have modest effectiveness against the
symptoms of influenza in otherwise healthy adults. The drugs are effective
postexposure against laboratory confirmed influenza, but this is a small
component of influenza-like illness, so for this outcome neuraminidase
inhibitors are not effective. Neuraminidase inhibitors might be regarded as
optional for reducing the symptoms of seasonal influenza. Paucity of good
data has undermined previous findings for oseltamivir's prevention of
complications from influenza. Independent randomised trials to resolve these
uncertainties are needed." 

A cluster of articles on bmj.com seeks to elucidate problems with the data
that have underpinned the use of oseltamivir in healthy adults with pandemic
influenza. Deborah Cohen  <http://www.bmj.com/cgi/doi/10.1136/bmj.b5387>
retraces the steps of the Cochrane reviewers as they tried to obtain all the
relevant data and finds that commitments to transparency are still in doubt.
Peter Doshi  <http://www.bmj.com/cgi/content/full/339/dec07_2/b5164>
explains that the public evidence base for this global public health drug is
fragmented and inconsistent. And Nick Freemantle and Mel Calvert
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5248> find that
observational studies of oseltamivir's efficacy show minimal benefit. In an
accompanying  <http://www.bmj.com/cgi/doi/10.1136/bmj.b5351> editorial,
Fiona Godlee and Mike Clarke say that the full data from drug trials must be
available for scrutiny by the scientific community. 

 

LONDON, Dec. 8, 2009 

Experts Question Effectiveness of Tamiflu

Study of Data on Antiviral Used for Flu Says No Clear Evidence It Prevents
Complications in Otherwise Healthy Adults

http://wwwimage.cbsnews.com/images/2009/05/03/image4988058g.jpg

(CBS/AP)  An updated review of data about the effectiveness of Tamiflu, the
antiviral drug most commonly used against influenza, says there is no clear
evidence that it prevents complications like pneumonia in otherwise healthy
adults. 

According to an article published by the  <http://bmj.com/> British Medical
Journal (part of a joint investigation by BMJ and Britain's Channel 4 News),
the study acknowledges that oseltamivir and other neuraminidase inhibitors
have a modest effect in reducing flu symptoms and infectivity in otherwise
healthy adults by about one day. 

But researchers said there is insufficient published data to know if
oseltamivir reduces complications in otherwise healthy adults. 

The new study updates a 2006 review published in The Cochrane
<http://www.thecochranelibrary.com/> Library. 

Twenty published trials focusing on prevention, treatment and adverse
reactions were analyzed by researchers led by Professor Chris Del Mar from
Bond University <http://bond.edu.au/>  in Australia. 

Because of a "paucity of good data" from trial authors and Roche
<http://www.roche.com/index.htm> , the drug's manufacturer, and the
inability to independently verify results of eight key trials which were
never fully published (but which were included in the 2006 review) the
researchers concluded they have no confidence in claims that oseltamivir
reduces the risk of complications of influenza in otherwise healthy adults. 

They said they do not believe it should be used in routine control of
seasonal influenza. 

They also called on governments to set up studies monitoring the safety of
neuraminidase inhibitors. 

After reviewing observational studies provided by Roche to the Cochrane
review's authors, Professor Nick Freemantle and Dr. Melanie Calvert of the
University of Birmingham <http://www.bham.ac.uk/>  wrote that "oseltamivir
may reduce the risk of pneumonia in otherwise healthy people who contract
flu. However, the absolute benefit is small, and side effects and safety
should also be considered." 

They said interpretation of data was difficult in part because "It seems
likely that some patients were included in more than one study, which
undermines the ability of these studies to provide independent estimates." 

Freemantle said he sees "very little evidence to support the widespread use
of oseltamivir in the otherwise healthy population who are developing signs
of influenza-like illness." 

The use of neuraminidase inhibitors (especially oseltamivir) has increased
dramatically since the H1N1 pandemic began in April 2009. With no effective
vaccine against the flu available or because of resistance to other drugs'
effectiveness, neuraminidase inhibitors were seen as an answer. 

Governments have stockpiled Tamiflu as part of pandemic preparedness plans,
in part because of claims that the drug prevents complications. 

BMJ's editor in chief, Dr. Fiona Godlee, wrote that the updated review means
important questions about the drug's effectiveness are unresolved. 

"Governments around the world have spent billions of pounds on a drug that
the scientific community now finds itself unable to judge," she said in a
statement. 

But the World Health Organization disagreed. They said data from countries
around the world show that when given early, Tamiflu can reduce the severity
of swine flu symptoms, though the agency recommends the drug be saved for
people at risk of complications, like pregnant women, the elderly, children,
and those with underlying medical problems. 

"This will not change our (Tamiflu) guidelines," said Charles Penn, a WHO
antivirals expert. 

Penn said that while past studies show Tamiflu only has a modest benefit,
when patients with severe illness or at risk of complications are treated
early, there are fewer hospitalizations and deaths. 

Both the British researchers and WHO said there is little evidence to
support the widespread use of Tamiflu in otherwise healthy people -
precisely the policy Britain has adopted to fight swine flu. 

In addition to recommending Tamiflu be saved for at-risk groups, WHO
recommends Tamiflu only be used on a doctor's recommendation. 

In Britain, however, Tamiflu is regularly dispensed to healthy people who
catch the flu. The drug is given out via a national swine flu hotline by
call center workers with no medical training. 

The Switzerland-based Roche recently announced revenues from the sales of
this drug were $2.5 billion this year. 

In an editorial in the BMJ, Dr. Fiona Godlee and Professor Mike Clarke,
Director of the U.K. Cochrane Centre, say the updated review is important
because it calls into question "not only the effectiveness of oseltamivir
but the whole system by which drugs are evaluated, regulated and promoted." 

They call for new global legislation to ensure that "once a trial is
completed, there needs to be ready access to the raw data behind any
analyses used to license and market a drug. 

"When vast quantities of public money, and large amounts of public trust,
are placed in drugs, the full data must be accessible for scrutiny by the
scientific community," they write. "Pending full disclosure and independent
review of the raw data from Roche, the risks and benefits of oseltamivir
remain uncertain." 

In response, Roche said that they "firmly believe in the robustness of the
data," and say that full access to data has been granted to Governments and
regulatory authorities. 

As a result of the BMJ/Channel 4 investigation, Roche announced it will make
all study summaries of oseltamivir (including key data) available on a
password-protected Web site. 



 <http://www.bmj.com/> BMJ - helping doctors make better decisions 
 
Published 8 December 2009, doi:10.1136/bmj.b5164
Cite this as: BMJ 2009;339:b5164 

Analysis

Neuraminidase inhibitors-the story behind the Cochrane review

Peter Doshi, doctoral student 

1 Program in History, Anthropology, Science, Technology and Society,
Massachusetts Institute of Technology, Cambridge, MA 02139 USA 

pnd at mit.edu 

Although billions have been spent on oseltamivir in the face of pandemic
influenza, the team updating the Cochrane review of neuraminidase inhibitors
in healthy adults found that the public evidence base for this global public
health drug was fragmented and inconsistent. Peter Doshi tells the story 

Since August 2009, our Cochrane review team has tried to obtain the data
needed to verify claims that oseltamivir (Tamiflu) lowers serious
complications of influenza such as pneumonia. We failed, but in failing
discovered that the public evidence base for this global public health drug
is fragmented, inconsistent, and contradictory. We are no longer sure that
oseltamivir offers a therapeutic and public health policy advantage over
cheap, over the counter drugs such as aspirin. If the public is to trust in
public health policies, the scientific basis informing knowledge of the
harms and effects of those interventions must be public and open to
independent analysis. 

How a Cochrane review update turned controversial

Systematic reviews are designed to synthesise the most reliable evidence on
the effects of interventions. Following the outbreak of influenza A/H1N1 in
April 2009, the UK NHS National Institute of Health Research commissioned an
update of the Cochrane systematic review of neuraminidase inhibitors in
healthy adults. In retrospect, our review began on a naive note. Although
the review had last been updated in 2008, our new task was to include a
safety assessment component. Tom Jefferson, who led the review, wrote to the
group then just being formed, "Dear Friends...although it is always
dangerous to pre-judge the issue, I expect no new effectiveness data but a
lot of pharmacovigilance data." Two days later, a paediatrician from Japan,
Keiji Hayashi, submitted a comment to the Cochrane Collaboration that would
ultimately leave us doubtful about the ability of systematic reviews to deal
with the challenges of contemporary pharmaceutical evaluation1
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF1>  (see Web Extra
of cited paper: Hayashi's criticism on previous review). 

Hayashi pointed out that although Jefferson et al's previous review2
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF2>  found
oseltamivir effective in reducing important complications of influenza such
as pneumonia, that conclusion was drawn from a single peer-reviewed study by
Kaiser et al.3 <http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF3>
The Kaiser study itself had meta-analysed 10 manufacturer funded trials from
the late 1990s, of which only two were published in peer reviewed journals.4
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF4>  5
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF5>  The remaining
eight were apparently either unpublished or published only in abstract form.
Hayashi suggested that the unpublished trials were central to demonstrating
oseltamivir's ability to reduce lower respiratory tract complications of
influenza, and challenged us to "appraise the 8 trials rigidly." Our team
subsequently attempted to verify the data for ourselves, but in doing so
found a series of inconsistencies in the evidence for oseltamivir's
effectiveness and safety. 

A maze of inconsistencies

Despite funding the Kaiser meta-analysis, which concluded that oseltamivir
reduces complications, oseltamivir's manufacturer, Roche, apparently did not
itself make any such claims about complications. A Tamiflu.com webpage
reads, "Treatment with TAMIFLU has not been proven to have a positive impact
on these outcomes," referring to pneumonia, other respiratory diseases, and
influenza related death.6
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF6>  

The previous Cochrane review had found oseltamivir effective in reducing the
duration of symptoms in influenza-like illness. But here, again, Roche's
position countered Cochrane's; Roche stated that oseltamivir was ineffective
against influenza-like illnesses not caused by influenza.7
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF7>  Drug product
labelling in the United States, European Union, and Japan also states that
oseltamivir only works for true influenza virus infections (box 1). 






Box 1-Contradictory statements made about the potential benefits of
oseltamivir
Complications of influenza
For

*	Roche (roche.com): "Tamiflu delivers ... [a] 67 percent reduction in
secondary complications such as bronchitis, pneumonia and sinusitis in
otherwise healthy individuals."
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF8> 8 

*	Kaiser: "Our analysis found that early treatment of influenza
illness with the neuraminidase inhibitor oseltamivir significantly reduced
influenza-related LRTCs, associated antibiotic use, and the risk of
hospitalization. This effect was observed in both at-risk subjects and
otherwise healthy individuals."
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF3> 3 

*	EU EMEA: "The proportion of subjects who developed specified lower
respiratory tract complications (mainly bronchitis) treated with antibiotics
was reduced from 12.7% (135/1063) in the placebo group to 8.6% (116/1350) in
the oseltamivir treated population (p = 0.0012)."
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF22> 22 

*	US CDC: "In a study that combined data from 10 clinical trials, the
risk for pneumonia among those participants with laboratory-confirmed
influenza receiving oseltamivir was approximately 50% lower than among those
persons receiving a placebo and 34% lower among patients at risk for
complications (p<0.05 for both comparisons) [Kaiser, 2003]."
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF18> 18 

*	US HHS: "Treatment with a neuraminidase inhibitor (oseltamivir
[Tamiflu] or zanamivir [Relenza]) will be effective in decreasing risk of
pneumonia, will decrease hospitalization by about half (as shown for
interpandemic influenza), and will also decrease mortality."
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF19> 19

Against

*	Roche (tamiflu.com): "Treatment with TAMIFLU has not been proven to
have a positive impact on [asthma, emphysema, other chronic lower
respiratory diseases, pneumonia, other respiratory diseases, pneumonitis,
and influenza-related death]."
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF6> 6 

*	US FDA: "Serious bacterial infections may begin with influenza-like
symptoms or may coexist with or occur as complications during the course of
influenza. TAMIFLU has not been shown to prevent such complications."
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF23> 23 

*	Japan PMDA: no mention of complications on drug product information
sheet. <http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF24> 24

Duration of symptoms of influenza-like illness (ILI)
For

*	Nicholson: "The duration of illness was significantly lower in the
intention-to-treat [ILI] population than in the other subgroups because of
the high proportion of influenza-infected patients in this population."
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF5> 5 

*	Treanor: "As expected, the greatest benefit of therapy was seen in
individuals with evidence of influenza virus infection. However, analysis of
the entire population also demonstrated a significant benefit of treatment."
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF4> 4 

*	Previous Cochrane review: "Time to alleviation of symptoms [for ILI
were] ... in favour of the [neuraminidase inhibitor] treated group ...
(hazard ratio 1.20, 95% CI 1.06 to 1.35)."
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF2> 2

Against

*	Roche: "We acknowledge that oseltamivir is ineffective against
influenza-like illness caused by viruses other than influenza."
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF7> 7 

*	EU EMEA: "Oseltamivir is effective only against illness caused by
influenza viruses. There is no evidence for efficacy of oseltamivir in any
illness caused by agents other than influenza viruses."
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF22> 22 

*	US FDA: "There is no evidence for efficacy of TAMIFLU in any illness
caused by agents other than influenza viruses Types A and B."
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF23> 23 

*	Japan PMDA: "Tamiflu has no effect against infections except those
caused by influenza viruses type A and type B."
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF24> 24

CI=confidence interval; EU EMEA=European Medicines Agency;
ILI=influenza-like illness; LRTC=lower respiratory tract complications;
Japan PMDA: Pharmaceuticals and Medical Devices Agency, Japan; US FDA=US
Food and Drug Administration; US HHS=US Department of Health and Human
Services. 




These inconsistencies concerning the ability of oseltamivir to work against
all influenza-like illness and reduce the risk of complications pointed to
the uncomfortable conclusion that the Cochrane Collaboration had promoted-by
trusting the validity of other work in the scientific literature-efficacy
claims more optimistic than even the drug manufacturer's. 

Reality, however, proved more complex. The Tamiflu.com website where Roche
declares that oseltamivir is not proven to reduce complications contains a
footnote: "THIS [WEB]SITE IS INTENDED FOR U.S. AUDIENCES ONLY." On
Roche.com, the global website, the manufacturer asserts that "Tamiflu
delivers ... [a] 67 percent reduction in secondary complications such as
bronchitis, pneumonia and sinusitis in otherwise healthy individuals".8
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF8>  Furthermore,
among international products labels we reviewed, only the European Medicines
Agency approved the statement that oseltamivir reduces the complications of
influenza (table), causing us to wonder whether governments had similar
access to trial data. 

Data pertaining to oseltamivir's safety were equally confusing. We
discovered the US Food and Drug Administration (FDA) postmarketing Adverse
Event Reporting System, which collects reports of adverse events worldwide
relating to FDA approved drugs, had fewer entries in total than Roche's own
postmarketing database held for neuropsychiatric classified adverse events
alone.1 <http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF1>  Of
2466 such neuropsychiatric events in the Roche global safety database
between 1999 and 15 September 2007, Roche researchers classed 562 as
"serious".9 <http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF9>
Over this period, the FDA Adverse Event Reporting System database only holds
1805 adverse event reports of any kind. 

In publications-or secrecy-we trust?

Analyses of and reliance on publications in the scientific literature are
the key elements of practising evidence based medicine. Essential to this
practice is a trust that trials are carried out properly and that published
reports accurately reflect the original study protocol (including
pre-specified primary outcome measures) and the study data. Hayashi's
comment questioning the wisdom of trusting unpublished, industry-sponsored
trial data revealed the degree to which Cochrane reviews are fundamentally
based on the premise that the published literature about a drug's efficacy
and safety is backed by hard, verifiable data. 

Obtaining raw data from properly carried out trials on complications is the
only way to resolve the inconsistencies surrounding oseltamivir's effect on
reducing complications. On behalf of the review team, Jefferson wrote in
August to the authors of the Kaiser paper, but was told that they no longer
had the files and to contact Roche. Jefferson also wrote to authors of the
two peer reviewed published trials used in Kaiser's meta-analysis. One
responded, but once again Jefferson was directed to the manufacturer. 

Jefferson first requested data from Roche in early September. On 2 October,
Roche indicated a willingness to share data, but not openly. It furnished
Jefferson with a "confidentiality agreement," containing a clause saying
that the signee (Jefferson) agrees "not to disclose ... the existence and
terms of this Agreement" (see Web Extra: Roche confidentiality agreement).
Roche apparently intended not only to keep its data concealed, but also to
conceal the fact that it was quieting people through a secrecy clause. 

Jefferson did not sign the confidentiality agreement, but wrote the next day
asking for clarification, which he never received. On 7 October the company
asked Jefferson to restate which data he was seeking. After Jefferson's
answer, Roche said it was unable to provide data because it had already
provided it for a similar meta-analysis being started by an independent
expert influenza group. The Cochrane request, Roche said, might conflict
with that review. In return, Jefferson challenged Roche to outline its
concerns and explain why sending data to multiple groups of independent
researchers should pose a problem. Roche did not answer these questions, but
eight days later (21 October), it unexpectedly emailed Jefferson seven 10-17
page excerpts of company reports from all clinical trials used in the Kaiser
meta-analysis. 

Our team analysed the data, and Jefferson wrote to Roche explaining that the
files were insufficient to verify the effects on complications claims in
Kaiser and the methods used in the trials1
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF1>  (see Web Extra
of cited paper: Comments on Kaiser et al's paper). Roche responded on 28
October, saying it would send more information the following week. Jefferson
informed them that our deadline was now past, but that we would accept any
additional information for future updates. As of 1 December we have heard
nothing. 

The previous Cochrane review placed its trust in publications and included
Kaiser's unpublished data, but to do so once again, despite our inability to
obtain data sufficient to perform an independent analysis, would have
shifted our position from that of trust in publication to that of trust in
secrecy. We dropped Kaiser's paper from our analysis. 

Implications

After four months of seeking the data used to support the findings of Kaiser
and colleagues, we have come up empty-handed. This raises the troubling
question of whether Cochrane reviewers should have ever included the study
in their review in the first place. The previous reviewers endorsed the
conclusion that oseltamivir reduces complications such as pneumonia and
bronchitis by implicitly trusting that the unpublished data were verifiable.
This trust now seems naive. The fact that a trust in unpublished data
extends to many systematic reviews of neuraminidase inhibitors by other
researchers10 <http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF10>
11 <http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF11>  12
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF12>  and was not
questioned until the Hayashi comment is even more troubling, raising
questions about the ability of high quality reviews to be performed by
volunteer organisations. 

Although the excerpted reports Roche provided us were insufficient to verify
claims about the complications of influenza, they did clarify an outstanding
anomaly of the published trial reports. According to the published studies,
patients randomised into trials had febrile influenza-like illness with at
least one respiratory symptom (such as cough or sore throat) and at least
one constitutional symptom (such as fatigue)-in other words, the clinical
syndrome usually called "the flu" that presents in routine clinical care.
Without laboratory testing, one cannot know whether influenza virus or some
other agent is causing these patients' discomfort.13
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF13>  In past
influenza seasons, US virological surveillance data indicate that at peak
"flu season" the proportion of respiratory specimens testing positive for
influenza typically reached between 25-35%, but over the entire season,
influenza viruses were found in only a minority (14%) of tested patients. By
contrast, in the ten Roche trials analysed by Kaiser, an average 68% of
randomised patients tested positive for influenza (figure
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#FIG1> Go). The
discrepancy seems the likely outcome of a special patient inclusion
methodology mentioned in company reports but absent in the corresponding
published papers.4
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF4>  5
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF5>  Company
reports state: "Centers were activated to recruit subjects during an
influenza outbreak in the locality, detected using standardized surveillance
techniques." Thus, the trial population seems likely to have been
unrepresentative of the general population of people with influenza-like
illness, the majority of whom do not have influenza (seemingly even during
the current pandemic14
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF14> ) and will not
benefit from neuraminidase inhibitors. 


 
<http://www.bmj.com/content/vol339/issuedec07_2/images/large/dosp731166.f1_d
efault.jpeg> Figure 1Proportion of respiratory specimens testing positive
for influenza during influenza seasons (commencing on week 40), 1997-98 to
2008-9, USA, and comparison with proportion of intention-to-treat population
with influenza enrolled in ten Roche clinical trials reported by Nicholson,5
Treanor,4 and Kaiser.3 Peak weekly rate of influenza positivity also shown.
Seasonal data from US Centers for Disease Control and Prevention

If oseltamivir is no better than placebo in its ability to reduce the
complications of influenza, and if it is also ineffective against
influenza-like illness not caused by influenza, then the drug's ability to
treat the symptoms of influenza may be similar to that of an NSAID such as
aspirin. Although aspirin is clearly not indicated for children because of
its association with Reye's syndrome, head to head trials of oseltamivir
versus an NSAID or paracetamol (for children) may be the only way to
establish the relative benefits of these drugs. 

With respect to safety concerns, FDA reporting rules turn out to have
important limitations. Although manufacturers are under mandatory reporting
requirements, adverse events occurring outside the United States judged to
not meet the "both serious and unexpected" criteria are under no requirement
to be reported. Thus the public Adverse Event Reporting System database
relies on manufacturers to honestly and accurately judge whether adverse
events reported in conjunction with their products are "serious" and
therefore must be reported-or not. In the case of oseltamivir, considering
that 75% of global consumption has occurred in Japan, this has important
implications for our knowledge of its safety. 

Public health drugs

Since oseltamivir's approval in 1999, neither American nor Japanese
regulators have ever approved statements that the drug lowers rates of
influenza related complications. The FDA reportedly even required Roche to
declare: "Tamiflu has not been proven to have a positive impact on the
potential consequences (such as hospitalizations, mortality, or economic
impact) of seasonal, avian, or pandemic influenza."15
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF15>  Despite the
work of these regulators, public health officials trusted the conclusions of
the published literature at face value. Citing the Kaiser paper, several
recommendations from the Centers for Disease Control and Prevention stated
that oseltamivir reduces the risk of hospitalisation and pneumonia.16
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF16>  17
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF17>  18
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF18>  The US even
partly based its national pandemic preparedness strategy on similar
assumptions (table).19
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF19>  Billions of
dollars were spent building drug stockpiles, and oseltamivir was elevated to
the status of a public health drug. 

Like vaccines, public health drugs get deployed on a population basis,
directed by national or international level policy decisions. As witnessed
in the UK, when the government declared that oseltamivir may be used to
treat all symptomatic cases even without consultation with a physician or
laboratory diagnosis, hundreds of thousands of courses of the drug were used
in a fortnight.20
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF20>  Mass
prescription carries serious responsibilities. While the evidence base for
all approved drugs should be sound, the evidence base for public health
drugs must be of the highest quality, publicly available, and open to
independent scrutiny. 

Evidence based medicine should not hinge on a singular trust in any one
institution, particularly in for-profit companies whose primary
responsibility is to shareholders and investors rather than the public's
health. As John Abraham observed, there seems a tragic irony in the
situation: when pharmaceutical companies do not trust each other, why should
the public or government be asked to trust them?21
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF21>  If
governments have the authority to purchase and govern the use of
multi-billion dollar drug stockpiles, they should require access to primary
research data and commit the resources to independently evaluate the
efficacy and safety of that drug. Box 2 contains ideas on where to start. 






Box 2-A short (and incomplete) list of higher standards for evidence based
public health decision making
Clarify expectations and provide evidence
Public health policies aiming to implement mass interventions should clearly
state and identify (before approving the policy) the expected harms and
benefits of that intervention. Clarity about the expectations of a drug can
help reviewers assess whether a drug meets predefined performance targets
and reveal important inconsistencies or shortcomings, flagging them as areas
of uncertainty for which better evidence is needed. 

 

Strengthen trial registration processes
All trials should be centrally registered (perhaps with the government in
initiatives similar to ClinicalTrials.gov). A field for recoding the
citation to any publications resulting from a given trial, and a field to
explain why a study has not been published within a year of completion,
would help third party investigators match clinical trial to publication,
and bring more awareness of the importance of publishing "negative" results.


Make patient level data available
Individual patient data are often the only way to resolve questions about
the effects of a drug. Publicly available anonymised patient level datasets
on regulator websites would increase transparency and enable independent
re-analyses of trial results. 

Reduce the reliance on trust
Methods of data collection (such as adverse events reporting systems) that
rely on companies to self-evaluate potential harms may lead to bias. Where
mandatory reporting requirements already exist (for example, in the US FDA
Adverse Events Reporting System
<http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF25> 25) reduce
potential bias by making them apply to all known adverse events, and make
these data publicly accessible, enabling independent researchers to
investigate the possible significance of reports. For manufacturers,
internet-only based reporting of adverse events would lessen the workload of
regulators and facilitate entry of all known adverse events into public
databases. 









Box 3-Timeline

*	April 2009-CDC reports two cases of novel swine-origin A/H1N1
influenza 

*	June-WHO declares A/H1N1 influenza a pandemic 

*	July-UK NHS National Institute of Health Research commissions update
of Cochrane review of neuraminidase inhibitors in healthy adults; lead
researcher Tom Jefferson forms review team 

*	14 July-Keiji Hayashi submits comment to Cochrane Collaboration
stating that unpublished, manufacturer funded trial data are central to the
claim that oseltamivir reduces complications 

*	August-Jefferson attempts to obtain data necessary from authors of
meta-analysis <http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF3> 3
that used the unpublished data; he is directed to speak with the
manufacturer (Roche) 

*	September-Jefferson requests data directly from Roche 

*	October-Roche sends Jefferson confidentiality contract. Contract is
not signed, but Roche later sends Jefferson excerpts of trial reports, which
are insufficient to verify the claims questioned by Hayashi 

*	December-Cochrane review update goes to press unable to verify
claims that oseltamivir reduces complications of influenza




Cite this as: BMJ 2009;339:b5164 

  _____  

Acknowledgments: I would like to acknowledge the support of my Cochrane
co-authors, and in particular thank Yuko Hara, Tom Jefferson, two external
referees, and the BMJ editors for their helpful comments on the draft
manuscript as well as Ted Postol for his advice. 

Contributors and sources: PD has studied and published on public health
policy responses to epidemic disease and has a strong research interest in
the intersection of science and society, particularly under situations of
high uncertainty. This article arose out of a sense that the story behind
the review needed to be told. PD is sole author and guarantor. 

PD has completed the Unified Competing Interest form at
www.icmje.org/coi_disclosure.pdf (available on request from author) and
declares that (1) PD has no financial support from Roche for the submitted
work; (2) PD has no relationship with commercial entities that might have an
interest in the submitted work in the previous three years; (3) their
spouses, partners, or children have no financial relationships that may be
relevant to the submitted work; and (4) PD is a co-author of the Cochrane
review about which this article is written, which may be a relevant
competing interest to the submitted work. 

Provenance and peer review: Commissioned, externally peer reviewed. 

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