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<FONT face=Tahoma size=2><B>From:</B> postol@MIT.EDU [mailto:postol@MIT.EDU]
<BR><B>Sent:</B> Tuesday, December 08, 2009 5:00 PM<BR><B>To:</B> David Jones;
dikaiser@mit.edu; David Mindell<BR><B>Subject:</B> Peter Doshi's Research Gets
Major Attention in the International Press<BR></FONT><BR></DIV>
<DIV></DIV>
<P class=MsoNormal style="MARGIN: 0in 0in 6pt"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial Narrow','sans-serif'; mso-bidi-font-size: 7.5pt; mso-fareast-font-family: 'Times New Roman'; mso-bidi-font-family: Arial">Dear
Colleagues<o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 6pt"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial Narrow','sans-serif'; mso-bidi-font-size: 7.5pt; mso-fareast-font-family: 'Times New Roman'; mso-bidi-font-family: Arial">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.<SPAN style="mso-spacerun: yes"> </SPAN>Attached is breaking news
about the lack of independently verifiable evidence that Tamiflu reduces the
risk of complications of influenza in otherwise healthy adults.<SPAN
style="mso-spacerun: yes"> </SPAN>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.</SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 6pt"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial Narrow','sans-serif'; mso-bidi-font-size: 7.5pt; mso-fareast-font-family: 'Times New Roman'; mso-bidi-font-family: Arial">Best
regards, Ted</SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 6pt"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial Narrow','sans-serif'; mso-bidi-font-size: 7.5pt; mso-fareast-font-family: 'Times New Roman'; mso-bidi-font-family: Arial"><o:p></o:p></SPAN> </P>
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style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial Narrow','sans-serif'; mso-bidi-font-size: 7.5pt; mso-fareast-font-family: 'Times New Roman'; mso-bidi-font-family: Arial"><o:p> </o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><A
href="http://www.bmj.com/"><SPAN
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<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><A name=ContentTop></A><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5106"><SPAN
style="FONT-SIZE: 7.5pt; COLOR: #006990; FONT-FAMILY: 'Arial','sans-serif'; TEXT-DECORATION: none; mso-fareast-font-family: 'Times New Roman'; mso-no-proof: yes; text-underline: none"><SPAN
style="mso-ignore: vglayout"><IMG height=110
alt="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."
src="cid:EB81E7F69C244D459D5E2A0BFA6520AA@LENOVO6ACF2A74" width=160 border=0
v:shapes="Picture_x0020_165"></SPAN></SPAN></A><SPAN
style="FONT-SIZE: 7.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-fareast-font-family: 'Times New Roman'"><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 7.4pt 0in 1.5pt; mso-outline-level: 2"><B><SPAN
style="FONT-SIZE: 20.5pt; COLOR: #009af6; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 13.5pt; mso-fareast-font-family: 'Times New Roman'">Pandemic
influenza<o:p></o:p></SPAN></B></P>
<P class=MsoNormal
style="MARGIN: 7.4pt 0in 1.5pt; mso-outline-level: 3"><B><SPAN
style="FONT-SIZE: 19pt; COLOR: #666666; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'"><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5106"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; mso-bidi-font-size: 11.0pt; text-underline: none">The
truth about Tamiflu?</SPAN></A><o:p></o:p></SPAN></B></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 16pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt; mso-fareast-font-family: 'Times New Roman'"><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5106"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; mso-bidi-font-size: 11.0pt; text-underline: none">This
Cochrane group's update</SPAN></A> 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." <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 16pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt; mso-fareast-font-family: 'Times New Roman'">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 <A
href="http://www.bmj.com/cgi/doi/10.1136/bmj.b5387"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; mso-bidi-font-size: 11.0pt; text-underline: none">retraces</SPAN></A>
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
<A href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; mso-bidi-font-size: 11.0pt; text-underline: none">explains</SPAN></A>
that the public evidence base for this global public health drug is fragmented
and inconsistent. And Nick Freemantle and Mel Calvert <A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5248"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; mso-bidi-font-size: 11.0pt; text-underline: none">find</SPAN></A>
that observational studies of oseltamivir's efficacy show minimal benefit. In an
accompanying <A href="http://www.bmj.com/cgi/doi/10.1136/bmj.b5351"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; mso-bidi-font-size: 11.0pt; text-underline: none">editorial</SPAN></A>,
Fiona Godlee and Mike Clarke say that the full data from drug trials must be
available for scrutiny by the scientific community. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 6pt"><SPAN
style="mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'"><o:p> </o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt"><SPAN
style="mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">LONDON,
Dec. 8, 2009 <o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt; mso-outline-level: 1; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto"><B><SPAN
style="FONT-SIZE: 24pt; mso-fareast-font-family: 'Times New Roman'; mso-font-kerning: 18.0pt">Experts
Question Effectiveness of Tamiflu<o:p></o:p></SPAN></B></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt; mso-outline-level: 2; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto"><B><SPAN
style="FONT-SIZE: 18pt; mso-fareast-font-family: 'Times New Roman'">Study of
Data on Antiviral Used for Flu Says No Clear Evidence It Prevents Complications
in Otherwise Healthy Adults<o:p></o:p></SPAN></B></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto"><SPAN
style="mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'; mso-no-proof: yes"><IMG
height=183 alt=http://wwwimage.cbsnews.com/images/2009/05/03/image4988058g.jpg
src="cid:958CF7400BB4412EA2487C63D97D919B@LENOVO6ACF2A74" width=244 border=0
v:shapes="Picture_x0020_5"></SPAN><SPAN
style="mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'"><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><B><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">(CBS/AP) </SPAN></B><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">
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.
<o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">According
to an article published by the <B><A href="http://bmj.com/" target=new><FONT
color=#006990>British Medical Journal</FONT></A></B> (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.
<o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">But
researchers said there is insufficient published data to know if oseltamivir
reduces complications in otherwise healthy adults. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">The
new study updates a 2006 review published in <B><A
href="http://www.thecochranelibrary.com/" target=new>The Cochrane
Library</A></B>. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">Twenty
published trials focusing on prevention, treatment and adverse reactions were
analyzed by researchers led by Professor Chris Del Mar from <B><A
href="http://bond.edu.au/" target=new>Bond University</A></B> in Australia.
<o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">Because
of a "paucity of good data" from trial authors and <B><A
href="http://www.roche.com/index.htm" target=new>Roche</A></B>, 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. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">They
said they do not believe it should be used in routine control of seasonal
influenza. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">They
also called on governments to set up studies monitoring the safety of
neuraminidase inhibitors. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">After
reviewing observational studies provided by Roche to the Cochrane review's
authors, Professor Nick Freemantle and Dr. Melanie Calvert of the <B><A
href="http://www.bham.ac.uk/" target=new>University of Birmingham</A></B> 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." <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">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." <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">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." <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">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.
<o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">Governments
have stockpiled Tamiflu as part of pandemic preparedness plans, in part because
of claims that the drug prevents complications. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">BMJ's
editor in chief, Dr. Fiona Godlee, wrote that the updated review means important
questions about the drug's effectiveness are unresolved. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">"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.
<o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">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. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">"This
will not change our (Tamiflu) guidelines," said Charles Penn, a WHO antivirals
expert. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">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. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">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. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">In
addition to recommending Tamiflu be saved for at-risk groups, WHO recommends
Tamiflu only be used on a doctor's recommendation. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">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. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">The
Switzerland-based Roche recently announced revenues from the sales of this drug
were $2.5 billion this year. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">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." <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">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. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">"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."
<o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">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. <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'">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. <o:p></o:p></SPAN></P><SPAN
style="FONT-SIZE: 15pt; FONT-FAMILY: 'Times New Roman','serif'; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'; mso-ansi-language: EN-US; mso-fareast-language: EN-US; mso-bidi-language: AR-SA"><BR
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style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">
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<DIV><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Published
8 December 2009, doi:10.1136/bmj.b5164<BR><STRONG><SPAN
style="FONT-FAMILY: 'Arial','sans-serif'">Cite this as:</SPAN></STRONG> BMJ
2009;339:b5164 <o:p></o:p></SPAN></DIV>
<P class=MsoNormal
style="MARGIN: 7.4pt 0in; mso-outline-level: 3; mso-line-height-alt: 16.8pt"><B><SPAN
style="FONT-SIZE: 20pt; COLOR: #37aeee; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 16.0pt">Analysis<o:p></o:p></SPAN></B></P>
<P class=MsoNormal
style="MARGIN: 7.4pt 0in; LINE-HEIGHT: 120%; mso-outline-level: 4"><B><SPAN
style="FONT-SIZE: 18.5pt; COLOR: #3a6d8e; LINE-HEIGHT: 120%; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 14.5pt">Neuraminidase
inhibitors—the story behind the Cochrane review<o:p></o:p></SPAN></B></P>
<P class=MsoNormal
style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><STRONG><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Peter
Doshi</SPAN></STRONG><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">,
<EM><SPAN style="FONT-FAMILY: 'Arial','sans-serif'">doctoral student</SPAN></EM>
<o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SUP><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">1</SPAN></SUP><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">
Program in History, Anthropology, Science, Technology and Society, Massachusetts
Institute of Technology, Cambridge, MA 02139 USA <o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
id=em0><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><A
href="mailto:pnd@mit.edu" jQuery1260308401109="206">pnd@mit.edu</A></SPAN>
<SCRIPT type=text/javascript>
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<o:p></o:p></SPAN></P>
<P class=MsoNormal id=article_remark
style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><I><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Although
billions have been spent on oseltamivir in the face<SUP> </SUP>of pandemic
influenza, the team updating the Cochrane review<SUP> </SUP>of neuraminidase
inhibitors in healthy adults found that the<SUP> </SUP>public evidence base for
this global public health drug was<SUP> </SUP>fragmented and inconsistent.
<B>Peter Doshi </B>tells the story<SUP> </SUP><o:p></o:p></SPAN></I></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Since
August 2009, our Cochrane review team has tried to obtain<SUP> </SUP>the data
needed to verify claims that oseltamivir (Tamiflu)<SUP> </SUP>lowers serious
complications of influenza such as pneumonia.<SUP> </SUP>We failed, but in
failing discovered that the public evidence<SUP> </SUP>base for this global
public health drug is fragmented, inconsistent,<SUP> </SUP>and contradictory. We
are no longer sure that oseltamivir offers<SUP> </SUP>a therapeutic and public
health policy advantage over cheap,<SUP> </SUP>over the counter drugs such as
aspirin. If the public is to<SUP> </SUP>trust in public health policies, the
scientific basis informing<SUP> </SUP>knowledge of the harms and effects of
those interventions must<SUP> </SUP>be public and open to independent
analysis.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 7.4pt 0in; LINE-HEIGHT: 16.8pt; mso-outline-level: 5"><B><SPAN
style="FONT-SIZE: 15pt; COLOR: #37aeee; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">How
a Cochrane review update turned controversial<o:p></o:p></SPAN></B></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Systematic
reviews are designed to synthesise the most reliable<SUP> </SUP>evidence on the
effects of interventions. Following the outbreak<SUP> </SUP>of influenza A/H1N1
in April 2009, the UK NHS National Institute<SUP> </SUP>of Health Research
commissioned an update of the Cochrane systematic<SUP> </SUP>review of
neuraminidase inhibitors in healthy adults. In retrospect,<SUP> </SUP>our review
began on a naive note. Although the review had last<SUP> </SUP>been updated in
2008, our new task was to include a safety assessment<SUP> </SUP>component. Tom
Jefferson, who led the review, wrote to the group<SUP> </SUP>then just being
formed, "Dear Friends...although it is always<SUP> </SUP>dangerous to pre-judge
the issue, I expect no new effectiveness<SUP> </SUP>data but a lot of
pharmacovigilance data." Two days later, a<SUP> </SUP>paediatrician from Japan,
Keiji Hayashi, submitted a comment<SUP> </SUP>to the Cochrane Collaboration that
would ultimately leave us<SUP> </SUP>doubtful about the ability of systematic
reviews to deal with<SUP> </SUP>the challenges of contemporary pharmaceutical
evaluation<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF1"
jQuery1260308401109="207">1</A></SUP> (see<SUP> </SUP>Web Extra of cited paper:
Hayashi’s criticism on previous<SUP> </SUP>review).<SUP>
</SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Hayashi
pointed out that although Jefferson et al’s previous<SUP> </SUP>review<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF2"
jQuery1260308401109="208">2</A></SUP> found oseltamivir effective in reducing
important complications<SUP> </SUP>of influenza such as pneumonia, that
conclusion was drawn from<SUP> </SUP>a single peer-reviewed study by Kaiser et
al.<SUP><A href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF3"
jQuery1260308401109="209">3</A></SUP> The Kaiser study<SUP> </SUP>itself had
meta-analysed 10 manufacturer funded trials from<SUP> </SUP>the late 1990s, of
which only two were published in peer reviewed<SUP> </SUP>journals.<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF4"
jQuery1260308401109="210">4</A></SUP> <SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF5"
jQuery1260308401109="211">5</A></SUP> The remaining eight were apparently either
unpublished<SUP> </SUP>or published only in abstract form. Hayashi suggested
that the<SUP> </SUP>unpublished trials were central to demonstrating
oseltamivir’s<SUP> </SUP>ability to reduce lower respiratory tract complications
of influenza,<SUP> </SUP>and challenged us to "appraise the 8 trials rigidly."
Our team<SUP> </SUP>subsequently attempted to verify the data for ourselves,
but<SUP> </SUP>in doing so found a series of inconsistencies in the
evidence<SUP> </SUP>for oseltamivir’s effectiveness and safety.<SUP>
</SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 7.4pt 0in; LINE-HEIGHT: 16.8pt; mso-outline-level: 5"><B><SPAN
style="FONT-SIZE: 15pt; COLOR: #37aeee; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">A
maze of inconsistencies<o:p></o:p></SPAN></B></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Despite
funding the Kaiser meta-analysis, which concluded that<SUP> </SUP>oseltamivir
reduces complications, oseltamivir’s manufacturer,<SUP> </SUP>Roche, apparently
did not itself make any such claims about<SUP> </SUP>complications. A
Tamiflu.com webpage reads, "Treatment with<SUP> </SUP>TAMIFLU has not been
proven to have a positive impact on these<SUP> </SUP>outcomes," referring to
pneumonia, other respiratory diseases,<SUP> </SUP>and influenza related
death.<SUP><A href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF6"
jQuery1260308401109="212">6</A> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">The
previous Cochrane review had found oseltamivir effective<SUP> </SUP>in reducing
the duration of symptoms in influenza-like illness.<SUP> </SUP>But here, again,
Roche’s position countered Cochrane’s;<SUP> </SUP>Roche stated that oseltamivir
was ineffective against influenza-like<SUP> </SUP>illnesses not caused by
influenza.<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF7"
jQuery1260308401109="213">7</A></SUP> Drug product labelling in<SUP> </SUP>the
United States, European Union, and Japan also states that<SUP> </SUP>oseltamivir
only works for true influenza virus infections (box<SUP> </SUP>1).<SUP>
</SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><BR
style="mso-special-character: line-break" clear=all><o:p></o:p></SPAN></P>
<DIV align=center>
<TABLE class=MsoNormalTable
style="WIDTH: 95%; mso-padding-alt: 0in 0in 0in 0in; mso-cellspacing: 0in; mso-yfti-tbllook: 1184"
cellSpacing=0 cellPadding=0 width="95%" border=1>
<TBODY>
<TR style="mso-yfti-irow: 0; mso-yfti-firstrow: yes; mso-yfti-lastrow: yes">
<TD
style="BORDER-RIGHT: #d4d0c8; PADDING-RIGHT: 0in; BORDER-TOP: #d4d0c8; PADDING-LEFT: 0in; BACKGROUND: #e1e1e1; PADDING-BOTTOM: 0in; BORDER-LEFT: #d4d0c8; PADDING-TOP: 0in; BORDER-BOTTOM: #d4d0c8"><!--style2-->
<TABLE class=MsoNormalTable
style="WIDTH: 100%; mso-padding-alt: 1.5pt 1.5pt 1.5pt 1.5pt; mso-cellspacing: 1.5pt; mso-yfti-tbllook: 1184"
cellPadding=0 width="100%" border=0>
<TBODY>
<TR
style="mso-yfti-irow: 0; mso-yfti-firstrow: yes; mso-yfti-lastrow: yes">
<TD
style="BORDER-RIGHT: #ffffff; PADDING-RIGHT: 1.5pt; BORDER-TOP: #ffffff; PADDING-LEFT: 1.5pt; BACKGROUND: white; PADDING-BOTTOM: 1.5pt; BORDER-LEFT: #ffffff; WIDTH: 300pt; PADDING-TOP: 1.5pt; BORDER-BOTTOM: #ffffff"
vAlign=top width=400>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt; LINE-HEIGHT: 150%"><STRONG><SPAN
style="FONT-SIZE: 12.5pt; COLOR: #333333; LINE-HEIGHT: 150%; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 5.5pt">Box
1—Contradictory statements made about the potential<SUP>
</SUP>benefits of oseltamivir</SPAN></STRONG><SPAN
style="FONT-SIZE: 12.5pt; COLOR: #333333; LINE-HEIGHT: 150%; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 5.5pt"><BR><I>Complications
of influenza</I><BR></SPAN><EM><SPAN
style="FONT-SIZE: 12.5pt; COLOR: #333333; LINE-HEIGHT: 150%; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 10.0pt">For</SPAN></EM><SPAN
style="FONT-SIZE: 12.5pt; COLOR: #333333; LINE-HEIGHT: 150%; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 5.5pt"><o:p></o:p></SPAN></P>
<UL type=disc>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l2 level1 lfo32; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 12.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">Roche<SUP>
</SUP>(roche.com): "Tamiflu delivers ... [a] 67 percent
reduction<SUP> </SUP>in secondary complications such as
bronchitis, pneumonia and<SUP> </SUP>sinusitis in otherwise
healthy individuals."<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF8"
jQuery1260308401109="214"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">8</SPAN></A></SUP><o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l2 level1 lfo32; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 12.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">Kaiser:
"Our<SUP> </SUP>analysis found that early treatment of influenza
illness with<SUP> </SUP>the neuraminidase inhibitor oseltamivir
significantly reduced<SUP> </SUP>influenza-related LRTCs,
associated antibiotic use, and the<SUP> </SUP>risk of
hospitalization. This effect was observed in both at-risk<SUP>
</SUP>subjects and otherwise healthy individuals."<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF3"
jQuery1260308401109="215"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">3</SPAN></A></SUP><o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l2 level1 lfo32; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 12.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">EU
EMEA: "The<SUP> </SUP>proportion of subjects who developed
specified lower respiratory<SUP> </SUP>tract complications (mainly
bronchitis) treated with antibiotics<SUP> </SUP>was reduced from
12.7% (135/1063) in the placebo group to 8.6%<SUP>
</SUP>(116/1350) in the oseltamivir treated population (p =
0.0012)."<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF22"
jQuery1260308401109="216"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">22</SPAN></A></SUP><o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l2 level1 lfo32; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 12.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">US
CDC: "In a study that combined data from 10 clinical<SUP>
</SUP>trials, the risk for pneumonia among those participants
with<SUP> </SUP>laboratory-confirmed influenza receiving
oseltamivir was approximately<SUP> </SUP>50% lower than among
those persons receiving a placebo and 34%<SUP> </SUP>lower among
patients at risk for complications (p<0.05 for<SUP> </SUP>both
comparisons) [Kaiser, 2003]."<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF18"
jQuery1260308401109="217"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">18</SPAN></A></SUP><o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l2 level1 lfo32; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 12.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">US
HHS: "Treatment with<SUP> </SUP>a neuraminidase inhibitor
(oseltamivir [Tamiflu] or zanamivir<SUP> </SUP>[Relenza]) will be
effective in decreasing risk of pneumonia,<SUP> </SUP>will
decrease hospitalization by about half (as shown for
interpandemic<SUP> </SUP>influenza), and will also decrease
mortality."<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF19"
jQuery1260308401109="218"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">19</SPAN></A></SUP><o:p></o:p></SPAN></LI></UL>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto"><EM><SPAN
style="FONT-SIZE: 12.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 10.0pt">Against</SPAN></EM><SPAN
style="FONT-SIZE: 12.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><o:p></o:p></SPAN></P>
<UL type=disc>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l9 level1 lfo33; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 12.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">Roche<SUP>
</SUP>(tamiflu.com): "Treatment with TAMIFLU has not been proven
to<SUP> </SUP>have a positive impact on [asthma, emphysema, other
chronic<SUP> </SUP>lower respiratory diseases, pneumonia, other
respiratory diseases,<SUP> </SUP>pneumonitis, and
influenza-related death]."<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF6"
jQuery1260308401109="219"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">6</SPAN></A></SUP><o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l9 level1 lfo33; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 12.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">US
FDA: "Serious<SUP> </SUP>bacterial infections may begin with
influenza-like symptoms<SUP> </SUP>or may coexist with or occur as
complications during the course<SUP> </SUP>of influenza. TAMIFLU
has not been shown to prevent such complications."<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF23"
jQuery1260308401109="220"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">23</SPAN></A></SUP><o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l9 level1 lfo33; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 12.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">Japan
PMDA: no mention of complications on drug product<SUP>
</SUP>information sheet.<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF24"
jQuery1260308401109="221"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">24</SPAN></A></SUP><o:p></o:p></SPAN></LI></UL>
<P class=MsoNormal
style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><I><SPAN
style="FONT-SIZE: 12.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Duration
of symptoms of influenza-like<SUP> </SUP>illness
(ILI)</SPAN></I><SPAN
style="FONT-SIZE: 12.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><BR></SPAN><EM><SPAN
style="FONT-SIZE: 12.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 10.0pt">For</SPAN></EM><SPAN
style="FONT-SIZE: 12.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><o:p></o:p></SPAN></P>
<UL type=disc>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l14 level1 lfo34; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 12.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">Nicholson:
"The duration of illness was<SUP> </SUP>significantly lower in the
intention-to-treat [ILI] population<SUP> </SUP>than in the other
subgroups because of the high proportion of<SUP>
</SUP>influenza-infected patients in this population."<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF5"
jQuery1260308401109="222"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">5</SPAN></A></SUP><o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l14 level1 lfo34; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 12.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">Treanor:<SUP>
</SUP>"As expected, the greatest benefit of therapy was seen in
individuals<SUP> </SUP>with evidence of influenza virus infection.
However, analysis<SUP> </SUP>of the entire population also
demonstrated a significant benefit<SUP> </SUP>of
treatment."<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF4"
jQuery1260308401109="223"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">4</SPAN></A></SUP><o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l14 level1 lfo34; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 12.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">Previous
Cochrane review: "Time to alleviation<SUP> </SUP>of symptoms [for
ILI were] ... in favour of the [neuraminidase<SUP>
</SUP>inhibitor] treated group ... (hazard ratio 1.20, 95% CI
1.06<SUP> </SUP>to 1.35)."<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF2"
jQuery1260308401109="224"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">2</SPAN></A></SUP><o:p></o:p></SPAN></LI></UL>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto"><EM><SPAN
style="FONT-SIZE: 12.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 10.0pt">Against</SPAN></EM><SPAN
style="FONT-SIZE: 12.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><o:p></o:p></SPAN></P>
<UL type=disc>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l25 level1 lfo35; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 12.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">Roche:
"We acknowledge that oseltamivir<SUP> </SUP>is ineffective against
influenza-like illness caused by viruses<SUP> </SUP>other than
influenza."<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF7"
jQuery1260308401109="225"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">7</SPAN></A></SUP><o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l25 level1 lfo35; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 12.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">EU
EMEA: "Oseltamivir is effective<SUP> </SUP>only against illness
caused by influenza viruses. There is no<SUP> </SUP>evidence for
efficacy of oseltamivir in any illness caused by<SUP> </SUP>agents
other than influenza viruses."<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF22"
jQuery1260308401109="226"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">22</SPAN></A></SUP><o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l25 level1 lfo35; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 12.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">US
FDA: "There is no<SUP> </SUP>evidence for efficacy of TAMIFLU in
any illness caused by agents<SUP> </SUP>other than influenza
viruses Types A and B."<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF23"
jQuery1260308401109="227"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">23</SPAN></A></SUP><o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l25 level1 lfo35; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 12.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">Japan
PMDA:<SUP> </SUP>"Tamiflu has no effect against infections except
those caused<SUP> </SUP>by influenza viruses type A and type
B."<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF24"
jQuery1260308401109="228"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">24</SPAN></A></SUP><o:p></o:p></SPAN></LI></UL>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 16.8pt; TEXT-INDENT: 1.2pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto"><SPAN
style="FONT-SIZE: 12.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">CI=confidence<SUP>
</SUP>interval; EU EMEA=European Medicines Agency;
ILI=influenza-like<SUP> </SUP>illness; LRTC=lower respiratory tract
complications; Japan PMDA:<SUP> </SUP>Pharmaceuticals and Medical
Devices Agency, Japan; US FDA=US<SUP> </SUP>Food and Drug
Administration; US HHS=US Department of Health<SUP> </SUP>and Human
Services.
<o:p></o:p></SPAN></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></DIV>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><BR
style="mso-special-character: line-break" clear=all><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">These
inconsistencies concerning the ability of oseltamivir<SUP> </SUP>to work against
all influenza-like illness and reduce the risk<SUP> </SUP>of complications
pointed to the uncomfortable conclusion that<SUP> </SUP>the Cochrane
Collaboration had promoted—by trusting the<SUP> </SUP>validity of other work in
the scientific literature—efficacy<SUP> </SUP>claims more optimistic than even
the drug manufacturer’s.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Reality,
however, proved more complex. The Tamiflu.com website<SUP> </SUP>where Roche
declares that oseltamivir is not proven to reduce<SUP> </SUP>complications
contains a footnote: "THIS [WEB]SITE IS INTENDED<SUP> </SUP>FOR U.S. AUDIENCES
ONLY." On Roche.com, the global website,<SUP> </SUP>the manufacturer asserts
that "Tamiflu delivers ... [a] 67 percent<SUP> </SUP>reduction in secondary
complications such as bronchitis, pneumonia<SUP> </SUP>and sinusitis in
otherwise healthy individuals".<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF8"
jQuery1260308401109="229">8</A></SUP> Furthermore,<SUP> </SUP>among
international products labels we reviewed, only the European<SUP>
</SUP>Medicines Agency approved the statement that oseltamivir reduces<SUP>
</SUP>the complications of influenza (table), causing us to wonder<SUP>
</SUP>whether governments had similar access to trial data.<SUP>
</SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Data
pertaining to oseltamivir’s safety were equally confusing.<SUP> </SUP>We
discovered the US Food and Drug Administration (FDA) postmarketing<SUP>
</SUP>Adverse Event Reporting System, which collects reports of adverse<SUP>
</SUP>events worldwide relating to FDA approved drugs, had fewer entries<SUP>
</SUP>in total than Roche’s own postmarketing database held<SUP> </SUP>for
neuropsychiatric classified adverse events alone.<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF1"
jQuery1260308401109="230">1</A></SUP> Of 2466<SUP> </SUP>such neuropsychiatric
events in the Roche global safety database<SUP> </SUP>between 1999 and 15
September 2007, Roche researchers classed<SUP> </SUP>562 as "serious".<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF9"
jQuery1260308401109="231">9</A></SUP> Over this period, the FDA Adverse Event
Reporting<SUP> </SUP>System database only holds 1805 adverse event reports of
any<SUP> </SUP>kind.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 7.4pt 0in; LINE-HEIGHT: 16.8pt; mso-outline-level: 5"><B><SPAN
style="FONT-SIZE: 15pt; COLOR: #37aeee; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">In
publications—or secrecy—we trust?<o:p></o:p></SPAN></B></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Analyses
of and reliance on publications in the scientific literature<SUP> </SUP>are the
key elements of practising evidence based medicine.<SUP> </SUP>Essential to this
practice is a trust that trials are carried<SUP> </SUP>out properly and that
published reports accurately reflect the<SUP> </SUP>original study protocol
(including pre-specified primary outcome<SUP> </SUP>measures) and the study
data. Hayashi’s comment questioning<SUP> </SUP>the wisdom of trusting
unpublished, industry-sponsored trial<SUP> </SUP>data revealed the degree to
which Cochrane reviews are fundamentally<SUP> </SUP>based on the premise that
the published literature about a drug’s<SUP> </SUP>efficacy and safety is backed
by hard, verifiable data.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Obtaining
raw data from properly carried out trials on complications<SUP> </SUP>is the
only way to resolve the inconsistencies surrounding oseltamivir’s<SUP>
</SUP>effect on reducing complications. On behalf of the review team,<SUP>
</SUP>Jefferson wrote in August to the authors of the Kaiser paper,<SUP>
</SUP>but was told that they no longer had the files and to contact<SUP>
</SUP>Roche. Jefferson also wrote to authors of the two peer reviewed<SUP>
</SUP>published trials used in Kaiser’s meta-analysis. One responded,<SUP>
</SUP>but once again Jefferson was directed to the manufacturer.<SUP>
</SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Jefferson
first requested data from Roche in early September.<SUP> </SUP>On 2 October,
Roche indicated a willingness to share data, but<SUP> </SUP>not openly. It
furnished Jefferson with a "confidentiality agreement,"<SUP> </SUP>containing a
clause saying that the signee (Jefferson) agrees<SUP> </SUP>"not to disclose ...
the existence and terms of this Agreement"<SUP> </SUP>(see Web Extra: Roche
confidentiality agreement). Roche apparently<SUP> </SUP>intended not only to
keep its data concealed, but also to conceal<SUP> </SUP>the fact that it was
quieting people through a secrecy clause.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Jefferson
did not sign the confidentiality agreement, but wrote<SUP> </SUP>the next day
asking for clarification, which he never received.<SUP> </SUP>On 7 October the
company asked Jefferson to restate which data<SUP> </SUP>he was seeking. After
Jefferson’s answer, Roche said it<SUP> </SUP>was unable to provide data because
it had already provided it<SUP> </SUP>for a similar meta-analysis being started
by an independent<SUP> </SUP>expert influenza group. The Cochrane request, Roche
said, might<SUP> </SUP>conflict with that review. In return, Jefferson
challenged Roche<SUP> </SUP>to outline its concerns and explain why sending data
to multiple<SUP> </SUP>groups of independent researchers should pose a problem.
Roche<SUP> </SUP>did not answer these questions, but eight days later (21
October),<SUP> </SUP>it unexpectedly emailed Jefferson seven 10-17 page
excerpts<SUP> </SUP>of company reports from all clinical trials used in the
Kaiser<SUP> </SUP>meta-analysis.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Our
team analysed the data, and Jefferson wrote to Roche explaining<SUP> </SUP>that
the files were insufficient to verify the effects on complications<SUP>
</SUP>claims in Kaiser and the methods used in the trials<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF1"
jQuery1260308401109="232">1</A></SUP> (see Web<SUP> </SUP>Extra of cited paper:
Comments on Kaiser et al’s paper).<SUP> </SUP>Roche responded on 28 October,
saying it would send more information<SUP> </SUP>the following week. Jefferson
informed them that our deadline<SUP> </SUP>was now past, but that we would
accept any additional information<SUP> </SUP>for future updates. As of 1
December we have heard nothing.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">The
previous Cochrane review placed its trust in publications<SUP> </SUP>and
included Kaiser’s unpublished data, but to do so once<SUP> </SUP>again, despite
our inability to obtain data sufficient to perform<SUP> </SUP>an independent
analysis, would have shifted our position from<SUP> </SUP>that of trust in
publication to that of trust in secrecy. We<SUP> </SUP>dropped Kaiser’s paper
from our analysis.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 7.4pt 0in; LINE-HEIGHT: 16.8pt; mso-outline-level: 5"><B><SPAN
style="FONT-SIZE: 15pt; COLOR: #37aeee; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Implications<o:p></o:p></SPAN></B></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">After
four months of seeking the data used to support the findings<SUP> </SUP>of
Kaiser and colleagues, we have come up empty-handed. This<SUP> </SUP>raises the
troubling question of whether Cochrane reviewers<SUP> </SUP>should have ever
included the study in their review in the first<SUP> </SUP>place. The previous
reviewers endorsed the conclusion that oseltamivir<SUP> </SUP>reduces
complications such as pneumonia and bronchitis by implicitly<SUP> </SUP>trusting
that the unpublished data were verifiable. This trust<SUP> </SUP>now seems
naive. The fact that a trust in unpublished data extends<SUP> </SUP>to many
systematic reviews of neuraminidase inhibitors by other<SUP>
</SUP>researchers<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF10"
jQuery1260308401109="233">10</A></SUP> <SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF11"
jQuery1260308401109="234">11</A></SUP> <SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF12"
jQuery1260308401109="235">12</A></SUP> and was not questioned until the
Hayashi<SUP> </SUP>comment is even more troubling, raising questions about
the<SUP> </SUP>ability of high quality reviews to be performed by volunteer<SUP>
</SUP>organisations.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Although
the excerpted reports Roche provided us were insufficient<SUP> </SUP>to verify
claims about the complications of influenza, they<SUP> </SUP>did clarify an
outstanding anomaly of the published trial reports.<SUP> </SUP>According to the
published studies, patients randomised into<SUP> </SUP>trials had febrile
influenza-like illness with at least one<SUP> </SUP>respiratory symptom (such as
cough or sore throat) and at least<SUP> </SUP>one constitutional symptom (such
as fatigue)—in other<SUP> </SUP>words, the clinical syndrome usually called "the
flu" that presents<SUP> </SUP>in routine clinical care. Without laboratory
testing, one cannot<SUP> </SUP>know whether influenza virus or some other agent
is causing<SUP> </SUP>these patients’ discomfort.<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF13"
jQuery1260308401109="236">13</A></SUP> In past influenza seasons,<SUP> </SUP>US
virological surveillance data indicate that at peak "flu<SUP> </SUP>season" the
proportion of respiratory specimens testing positive<SUP> </SUP>for influenza
typically reached between 25-35%, but over the<SUP> </SUP>entire season,
influenza viruses were found in only a minority<SUP> </SUP>(14%) of tested
patients. By contrast, in the ten Roche trials<SUP> </SUP>analysed by Kaiser, an
average 68% of randomised patients tested<SUP> </SUP>positive for influenza
(figure<A href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#FIG1"
jQuery1260308401109="237"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none"><SPAN
style="mso-ignore: vglayout"><IMG height=7 alt=Go
src="cid:BD5C7AAFD350454E8BAC90ED3E0AFD11@LENOVO6ACF2A74" width=8 border=0
v:shapes="_x0000_i1030"></SPAN></SPAN></A>). The discrepancy seems the
likely<SUP> </SUP>outcome of a special patient inclusion methodology
mentioned<SUP> </SUP>in company reports but absent in the corresponding
published<SUP> </SUP>papers.<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF4"
jQuery1260308401109="238">4</A></SUP> <SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF5"
jQuery1260308401109="239">5</A></SUP> Company reports state: "Centers were
activated to<SUP> </SUP>recruit subjects during an influenza outbreak in the
locality,<SUP> </SUP>detected using standardized surveillance techniques."
Thus,<SUP> </SUP>the trial population seems likely to have been
unrepresentative<SUP> </SUP>of the general population of people with
influenza-like illness,<SUP> </SUP>the majority of whom do not have influenza
(seemingly even during<SUP> </SUP>the current pandemic<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF14"
jQuery1260308401109="240">14</A></SUP>) and will not benefit from
neuraminidase<SUP> </SUP>inhibitors.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 24pt; LINE-HEIGHT: 16.8pt"><A
name=FIG1 jQuery1260308401109="241"><!-- null --></A><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><BR
clear=all></SPAN><SPAN
style="FONT-SIZE: 9pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'"><A
href="http://www.bmj.com/content/vol339/issuedec07_2/images/large/dosp731166.f1_default.jpeg"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none"><SPAN
style="mso-ignore: vglayout"><IMG height=253 alt="Figure 1" hspace=10
src="cid:117199F35D0E44918214FEA454D91ED9@LENOVO6ACF2A74" width=630 vspace=5
border=0 v:shapes="_x0000_i1033"></SPAN></SPAN></A></SPAN><SPAN
style="FONT-SIZE: 13pt; COLOR: #c0504d; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt; mso-themecolor: accent2">Proportion
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<o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">If
oseltamivir is no better than placebo in its ability to reduce<SUP> </SUP>the
complications of influenza, and if it is also ineffective<SUP> </SUP>against
influenza-like illness not caused by influenza, then<SUP> </SUP>the drug’s
ability to treat the symptoms of influenza<SUP> </SUP>may be similar to that of
an NSAID such as aspirin. Although<SUP> </SUP>aspirin is clearly not indicated
for children because of its<SUP> </SUP>association with Reye’s syndrome, head to
head trials<SUP> </SUP>of oseltamivir versus an NSAID or paracetamol (for
children)<SUP> </SUP>may be the only way to establish the relative benefits of
these<SUP> </SUP>drugs.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">With
respect to safety concerns, FDA reporting rules turn out<SUP> </SUP>to have
important limitations. Although manufacturers are under<SUP> </SUP>mandatory
reporting requirements, adverse events occurring outside<SUP> </SUP>the United
States judged to not meet the "both serious and unexpected"<SUP> </SUP>criteria
are under no requirement to be reported. Thus the public<SUP> </SUP>Adverse
Event Reporting System database relies on manufacturers<SUP> </SUP>to honestly
and accurately judge whether adverse events reported<SUP> </SUP>in conjunction
with their products are "serious" and therefore<SUP> </SUP>must be reported—or
not. In the case of oseltamivir, considering<SUP> </SUP>that 75% of global
consumption has occurred in Japan, this has<SUP> </SUP>important implications
for our knowledge of its safety.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 7.4pt 0in; LINE-HEIGHT: 16.8pt; mso-outline-level: 5"><B><SPAN
style="FONT-SIZE: 15pt; COLOR: #37aeee; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Public
health drugs<o:p></o:p></SPAN></B></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Since
oseltamivir’s approval in 1999, neither American<SUP> </SUP>nor Japanese
regulators have ever approved statements that the<SUP> </SUP>drug lowers rates
of influenza related complications. The FDA<SUP> </SUP>reportedly even required
Roche to declare: "Tamiflu has not<SUP> </SUP>been proven to have a positive
impact on the potential consequences<SUP> </SUP>(such as hospitalizations,
mortality, or economic impact) of<SUP> </SUP>seasonal, avian, or pandemic
influenza."<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF15"
jQuery1260308401109="249">15</A></SUP> Despite the work<SUP> </SUP>of these
regulators, public health officials trusted the conclusions<SUP> </SUP>of the
published literature at face value. Citing the Kaiser<SUP> </SUP>paper, several
recommendations from the Centers for Disease<SUP> </SUP>Control and Prevention
stated that oseltamivir reduces the risk<SUP> </SUP>of hospitalisation and
pneumonia.<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF16"
jQuery1260308401109="250">16</A></SUP> <SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF17"
jQuery1260308401109="251">17</A></SUP> <SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF18"
jQuery1260308401109="252">18</A></SUP> The US even partly<SUP> </SUP>based its
national pandemic preparedness strategy on similar<SUP> </SUP>assumptions
(table).<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF19"
jQuery1260308401109="253">19</A></SUP> Billions of dollars were spent
building<SUP> </SUP>drug stockpiles, and oseltamivir was elevated to the
status<SUP> </SUP>of a public health drug.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Like
vaccines, public health drugs get deployed on a population<SUP> </SUP>basis,
directed by national or international level policy decisions.<SUP> </SUP>As
witnessed in the UK, when the government declared that oseltamivir<SUP>
</SUP>may be used to treat all symptomatic cases even without consultation<SUP>
</SUP>with a physician or laboratory diagnosis, hundreds of thousands<SUP>
</SUP>of courses of the drug were used in a fortnight.<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF20"
jQuery1260308401109="254">20</A></SUP> Mass prescription<SUP> </SUP>carries
serious responsibilities. While the evidence base for<SUP> </SUP>all approved
drugs should be sound, the evidence base for public<SUP> </SUP>health drugs must
be of the highest quality, publicly available,<SUP> </SUP>and open to
independent scrutiny.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Evidence
based medicine should not hinge on a singular trust<SUP> </SUP>in any one
institution, particularly in for-profit companies<SUP> </SUP>whose primary
responsibility is to shareholders and investors<SUP> </SUP>rather than the
public’s health. As John Abraham observed,<SUP> </SUP>there seems a tragic irony
in the situation: when pharmaceutical<SUP> </SUP>companies do not trust each
other, why should the public or<SUP> </SUP>government be asked to trust
them?<SUP><A href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF21"
jQuery1260308401109="255">21</A></SUP> If governments have the<SUP>
</SUP>authority to purchase and govern the use of multi-billion dollar<SUP>
</SUP>drug stockpiles, they should require access to primary research<SUP>
</SUP>data and commit the resources to independently evaluate the<SUP>
</SUP>efficacy and safety of that drug. Box 2 contains ideas on where<SUP>
</SUP>to start.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><BR
style="mso-special-character: line-break" clear=all><o:p></o:p></SPAN></P>
<DIV align=center>
<TABLE class=MsoNormalTable
style="WIDTH: 95%; mso-padding-alt: 0in 0in 0in 0in; mso-cellspacing: 0in; mso-yfti-tbllook: 1184"
cellSpacing=0 cellPadding=0 width="95%" border=1>
<TBODY>
<TR style="mso-yfti-irow: 0; mso-yfti-firstrow: yes; mso-yfti-lastrow: yes">
<TD
style="BORDER-RIGHT: #d4d0c8; PADDING-RIGHT: 0in; BORDER-TOP: #d4d0c8; PADDING-LEFT: 0in; BACKGROUND: #e1e1e1; PADDING-BOTTOM: 0in; BORDER-LEFT: #d4d0c8; PADDING-TOP: 0in; BORDER-BOTTOM: #d4d0c8"><!--style2-->
<TABLE class=MsoNormalTable
style="WIDTH: 100%; mso-padding-alt: 1.5pt 1.5pt 1.5pt 1.5pt; mso-cellspacing: 1.5pt; mso-yfti-tbllook: 1184"
cellPadding=0 width="100%" border=0>
<TBODY>
<TR
style="mso-yfti-irow: 0; mso-yfti-firstrow: yes; mso-yfti-lastrow: yes">
<TD
style="BORDER-RIGHT: #ffffff; PADDING-RIGHT: 1.5pt; BORDER-TOP: #ffffff; PADDING-LEFT: 1.5pt; BACKGROUND: white; PADDING-BOTTOM: 1.5pt; BORDER-LEFT: #ffffff; WIDTH: 300pt; PADDING-TOP: 1.5pt; BORDER-BOTTOM: #ffffff"
vAlign=top width=400>
<P class=MsoNormal style="MARGIN: 0in 0in 6pt"><STRONG><SPAN
style="FONT-SIZE: 15.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 5.5pt">Box
2—A short (and incomplete) list of higher standards<SUP> </SUP>for
evidence based public health decision making</SPAN></STRONG><SPAN
style="FONT-SIZE: 15.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 5.5pt"><BR><I>Clarify
expectations<SUP> </SUP>and provide evidence</I><BR>Public health
policies aiming to implement<SUP> </SUP>mass interventions should
clearly state and identify (before<SUP> </SUP>approving the policy)
the expected harms and benefits of that<SUP> </SUP>intervention.
Clarity about the expectations of a drug can help<SUP>
</SUP>reviewers assess whether a drug meets predefined
performance<SUP> </SUP>targets and reveal important inconsistencies
or shortcomings,<SUP> </SUP>flagging them as areas of uncertainty
for which better evidence<SUP> </SUP>is needed.
<o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 6pt"><SPAN
style="FONT-SIZE: 15.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 5.5pt"><o:p> </o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><I><SPAN
style="FONT-SIZE: 14.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Strengthen
trial registration processes</SPAN></I><SPAN
style="FONT-SIZE: 14.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><BR>All
trials<SUP> </SUP>should be centrally registered (perhaps with the
government<SUP> </SUP>in initiatives similar to ClinicalTrials.gov).
A field for recoding<SUP> </SUP>the citation to any publications
resulting from a given trial,<SUP> </SUP>and a field to explain why
a study has not been published within<SUP> </SUP>a year of
completion, would help third party investigators match<SUP>
</SUP>clinical trial to publication, and bring more awareness of
the<SUP> </SUP>importance of publishing "negative" results.
<o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><I><SPAN
style="FONT-SIZE: 14.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Make
patient level<SUP> </SUP>data available</SPAN></I><SPAN
style="FONT-SIZE: 14.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><BR>Individual
patient data are often the only way<SUP> </SUP>to resolve questions
about the effects of a drug. Publicly available<SUP>
</SUP>anonymised patient level datasets on regulator websites
would<SUP> </SUP>increase transparency and enable independent
re-analyses of<SUP> </SUP>trial results. <o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><I><SPAN
style="FONT-SIZE: 14.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Reduce
the reliance on trust</SPAN></I><SPAN
style="FONT-SIZE: 14.5pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><BR>Methods
of data<SUP> </SUP>collection (such as adverse events reporting
systems) that rely<SUP> </SUP>on companies to self-evaluate
potential harms may lead to bias.<SUP> </SUP>Where mandatory
reporting requirements already exist (for example,<SUP> </SUP>in the
US FDA Adverse Events Reporting System<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF25"
jQuery1260308401109="256"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">25</SPAN></A></SUP>)
reduce potential<SUP> </SUP>bias by making them apply to all known
adverse events, and make<SUP> </SUP>these data publicly accessible,
enabling independent researchers<SUP> </SUP>to investigate the
possible significance of reports. For manufacturers,<SUP>
</SUP>internet-only based reporting of adverse events would
lessen<SUP> </SUP>the workload of regulators and facilitate entry of
all known<SUP> </SUP>adverse events into public
databases.</SPAN><SPAN
style="FONT-SIZE: 17pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">
</SPAN><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><o:p></o:p></SPAN></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></DIV>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><BR
style="mso-special-character: line-break" clear=all><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><BR
style="mso-special-character: line-break" clear=all><o:p></o:p></SPAN></P>
<DIV align=center>
<TABLE class=MsoNormalTable
style="WIDTH: 95%; mso-padding-alt: 0in 0in 0in 0in; mso-cellspacing: 0in; mso-yfti-tbllook: 1184"
cellSpacing=0 cellPadding=0 width="95%" border=1>
<TBODY>
<TR style="mso-yfti-irow: 0; mso-yfti-firstrow: yes; mso-yfti-lastrow: yes">
<TD
style="BORDER-RIGHT: #d4d0c8; PADDING-RIGHT: 0in; BORDER-TOP: #d4d0c8; PADDING-LEFT: 0in; BACKGROUND: #e1e1e1; PADDING-BOTTOM: 0in; BORDER-LEFT: #d4d0c8; PADDING-TOP: 0in; BORDER-BOTTOM: #d4d0c8"><!--style2-->
<TABLE class=MsoNormalTable
style="WIDTH: 100%; mso-padding-alt: 1.5pt 1.5pt 1.5pt 1.5pt; mso-cellspacing: 1.5pt; mso-yfti-tbllook: 1184"
cellPadding=0 width="100%" border=0>
<TBODY>
<TR
style="mso-yfti-irow: 0; mso-yfti-firstrow: yes; mso-yfti-lastrow: yes">
<TD
style="BORDER-RIGHT: #ffffff; PADDING-RIGHT: 1.5pt; BORDER-TOP: #ffffff; PADDING-LEFT: 1.5pt; BACKGROUND: white; PADDING-BOTTOM: 1.5pt; BORDER-LEFT: #ffffff; WIDTH: 300pt; PADDING-TOP: 1.5pt; BORDER-BOTTOM: #ffffff"
vAlign=top width=400>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt; LINE-HEIGHT: 150%"><STRONG><SPAN
style="FONT-SIZE: 16.5pt; COLOR: #333333; LINE-HEIGHT: 150%; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 5.5pt">Box
3—Timeline</SPAN></STRONG><SPAN
style="FONT-SIZE: 16.5pt; COLOR: #333333; LINE-HEIGHT: 150%; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 5.5pt"><o:p></o:p></SPAN></P>
<UL type=disc>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; LINE-HEIGHT: 19.2pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l5 level1 lfo36; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">April
2009—CDC reports two cases<SUP> </SUP>of novel swine-origin A/H1N1
influenza<o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; LINE-HEIGHT: 19.2pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l5 level1 lfo36; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">June—WHO
declares<SUP> </SUP>A/H1N1 influenza a pandemic<o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; LINE-HEIGHT: 19.2pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l5 level1 lfo36; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">July—UK
NHS National Institute<SUP> </SUP>of Health Research commissions
update of Cochrane review of<SUP> </SUP>neuraminidase inhibitors
in healthy adults; lead researcher<SUP> </SUP>Tom Jefferson forms
review team<o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; LINE-HEIGHT: 19.2pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l5 level1 lfo36; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">14
July—Keiji Hayashi<SUP> </SUP>submits comment to Cochrane
Collaboration stating that unpublished,<SUP> </SUP>manufacturer
funded trial data are central to the claim that<SUP>
</SUP>oseltamivir reduces complications<o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; LINE-HEIGHT: 19.2pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l5 level1 lfo36; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">August—Jefferson
attempts<SUP> </SUP>to obtain data necessary from authors of
meta-analysis<SUP><A
href="http://www.bmj.com/cgi/content/full/339/dec07_2/b5164#REF3"
jQuery1260308401109="257"><SPAN
style="COLOR: #006990; TEXT-DECORATION: none; text-underline: none">3</SPAN></A></SUP>
that<SUP> </SUP>used the unpublished data; he is directed to speak
with the<SUP> </SUP>manufacturer (Roche)<o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; LINE-HEIGHT: 19.2pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l5 level1 lfo36; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">September—Jefferson
requests data<SUP> </SUP>directly from Roche<o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; LINE-HEIGHT: 19.2pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l5 level1 lfo36; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">October—Roche
sends Jefferson confidentiality<SUP> </SUP>contract. Contract is
not signed, but Roche later sends Jefferson<SUP> </SUP>excerpts of
trial reports, which are insufficient to verify<SUP> </SUP>the
claims questioned by Hayashi<o:p></o:p></SPAN>
<LI class=MsoNormal
style="MARGIN: 0in 0in 6pt; COLOR: #333333; LINE-HEIGHT: 19.2pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l5 level1 lfo36; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt">December—Cochrane
review<SUP> </SUP>update goes to press unable to verify claims
that oseltamivir<SUP> </SUP>reduces complications of
influenza</SPAN><SPAN
style="FONT-SIZE: 16.5pt; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 6.5pt"><o:p></o:p></SPAN></LI></UL></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></DIV>
<P class=MsoNormal style="MARGIN: 0in 0in 0pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><BR
style="mso-special-character: line-break" clear=all><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><B><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Cite
this as:</SPAN></B><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">
<I>BMJ</I> 2009;339:b5164<SUP> </SUP><o:p></o:p></SPAN></P>
<DIV class=MsoNormal style="MARGIN: 0in 0in 0pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">
<HR style="COLOR: gray" align=left width="30%" noShade SIZE=1>
</SPAN></DIV>
<P class=MsoNormal style="MARGIN: 0in 0in 6pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><!-- null -->Acknowledgments:
I would like to acknowledge the support of<SUP> </SUP>my Cochrane co-authors,
and in particular thank Yuko Hara, Tom<SUP> </SUP>Jefferson, two external
referees, and the <I>BMJ</I> editors for their<SUP> </SUP>helpful comments on
the draft manuscript as well as Ted Postol<SUP> </SUP>for his advice.<SUP>
</SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><!-- null -->Contributors
and sources: PD has studied and published on public<SUP> </SUP>health policy
responses to epidemic disease and has a strong<SUP> </SUP>research interest in
the intersection of science and society,<SUP> </SUP>particularly under
situations of high uncertainty. This article<SUP> </SUP>arose out of a sense
that the story behind the review needed<SUP> </SUP>to be told. PD is sole author
and guarantor.<SUP> </SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><!-- null -->PD
has completed the Unified Competing Interest form at <A
href="http://www.icmje.org/coi_disclosure.pdf"
jQuery1260308401109="261">www.icmje.org/coi_disclosure.pdf</A><SUP>
</SUP>(available on request from author) and declares that (1) PD<SUP> </SUP>has
no financial support from Roche for the submitted work;<SUP> </SUP>(2) PD has no
relationship with commercial entities that might<SUP> </SUP>have an interest in
the submitted work in the previous three<SUP> </SUP>years; (3) their spouses,
partners, or children have no financial<SUP> </SUP>relationships that may be
relevant to the submitted work; and<SUP> </SUP>(4) PD is a co-author of the
Cochrane review about which this<SUP> </SUP>article is written, which may be a
relevant competing interest<SUP> </SUP>to the submitted work.<SUP>
</SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 1.5pt 0in 7.4pt; LINE-HEIGHT: 16.8pt"><A
name="" jQuery1260308401109="262"><!-- null --></A><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt">Provenance
and peer review: Commissioned, externally peer reviewed.<SUP>
</SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 7.4pt 0in; LINE-HEIGHT: 16.8pt; mso-outline-level: 5"><B><SPAN
style="FONT-SIZE: 15pt; COLOR: #37aeee; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">References<o:p></o:p></SPAN></B></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo37; tab-stops: list .5in"><A
name=REF1 jQuery1260308401109="263"><!-- null --></A><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">1.<SPAN
style="FONT: 7pt 'Times New Roman'"> </SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Jefferson
T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors for preventing and
treating influenza in healthy adults: systematic review and meta-analysis.
<I>BMJ</I> 2009;339:b5106.<A
href="http://www.bmj.com/cgi/ijlink?linkType=ABST&journalCode=bmj&resid=339/dec07_2/b5106"
jQuery1260308401109="264"><!-- HIGHWIRE ID="339:dec07_2:b5164:1" --><NOBR>[Abstract/<SPAN
style="COLOR: #cc0000">Free</SPAN> Full Text]</NOBR></A><SUP><!-- /HIGHWIRE -->
</SUP><A name=REF2
jQuery1260308401109="265"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo38; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">2.<SPAN
style="FONT: 7pt 'Times New Roman'"> </SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Jefferson
TO, Demicheli V, Di Pietrantonj C, Jones M, Rivetti D. Neuraminidase inhibitors
for preventing and treating influenza in healthy adults. <I>Cochrane Database
Syst Rev</I> 2006;3:CD001265.<A
href="http://www.bmj.com/cgi/external_ref?access_num=16855962&link_type=MED"
jQuery1260308401109="266"><!-- HIGHWIRE ID="339:dec07_2:b5164:2" -->[Medline]</A><SUP><!-- /HIGHWIRE -->
</SUP><A name=REF3
jQuery1260308401109="267"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo39; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">3.<SPAN
style="FONT: 7pt 'Times New Roman'"> </SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Kaiser
L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oseltamivir treatment
on influenza-related lower respiratory tract complications and hospitalizations.
<I>Arch Intern Med</I> 2003;163:1667-72.<A
href="http://www.bmj.com/cgi/ijlink?linkType=ABST&journalCode=archinte&resid=163/14/1667"
jQuery1260308401109="268"><!-- HIGHWIRE ID="339:dec07_2:b5164:3" --><NOBR>[Abstract/<SPAN
style="COLOR: #cc0000">Free</SPAN> Full Text]</NOBR></A><SUP><!-- /HIGHWIRE -->
</SUP><A name=REF4
jQuery1260308401109="269"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo40; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">4.<SPAN
style="FONT: 7pt 'Times New Roman'"> </SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Treanor
JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, et al. Efficacy and
safety of the oral neuraminidase inhibitor oseltamivir in treating acute
influenza: a randomized controlled trial. US Oral Neuraminidase Study Group.
<I>JAMA</I> 2000;283:1016-24.<A
href="http://www.bmj.com/cgi/ijlink?linkType=ABST&journalCode=jama&resid=283/8/1016"
jQuery1260308401109="270"><!-- HIGHWIRE ID="339:dec07_2:b5164:4" --><NOBR>[Abstract/<SPAN
style="COLOR: #cc0000">Free</SPAN> Full Text]</NOBR></A><SUP><!-- /HIGHWIRE -->
</SUP><A name=REF5
jQuery1260308401109="271"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo41; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">5.<SPAN
style="FONT: 7pt 'Times New Roman'"> </SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Nicholson
KG, Aoki FY, Osterhaus AD, Trottier S, Carewicz O, Mercier CH, et al. Efficacy
and safety of oseltamivir in treatment of acute influenza: a randomised
controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group.
<I>Lancet</I> 2000;355:1845-50.<A
href="http://www.bmj.com/cgi/external_ref?access_num=10.1016%2FS0140-6736%2800%2902288-1&link_type=DOI"
jQuery1260308401109="272"><!-- HIGHWIRE ID="339:dec07_2:b5164:5" -->[CrossRef]</A><A
href="http://www.bmj.com/cgi/external_ref?access_num=000087306500010&link_type=ISI"
jQuery1260308401109="273">[Web of Science]</A><A
href="http://www.bmj.com/cgi/external_ref?access_num=10866439&link_type=MED"
jQuery1260308401109="274">[Medline]</A><SUP><!-- /HIGHWIRE --> </SUP><A
name=REF6 jQuery1260308401109="275"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo42; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">6.<SPAN
style="FONT: 7pt 'Times New Roman'"> </SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Roche
Laboratories. Impact of influenza. <A
href="http://www.tamiflu.com/hcp/influenza/impact.aspx"
jQuery1260308401109="276">www.tamiflu.com/hcp/influenza/impact.aspx</A>.<SUP><!-- HIGHWIRE ID="339:dec07_2:b5164:6" --><!-- /HIGHWIRE -->
</SUP><A name=REF7
jQuery1260308401109="277"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo43; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">7.<SPAN
style="FONT: 7pt 'Times New Roman'"> </SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Smith
J, Dutkowski R, Ward P. Antivirals for influenza in healthy adults.
<I>Lancet</I> 2006;367:1571.<A
href="http://www.bmj.com/cgi/external_ref?access_num=000237598000018&link_type=ISI"
jQuery1260308401109="278"><!-- HIGHWIRE ID="339:dec07_2:b5164:7" -->[Web of
Science]</A><A
href="http://www.bmj.com/cgi/external_ref?access_num=16698402&link_type=MED"
jQuery1260308401109="279">[Medline]</A><SUP><!-- /HIGHWIRE --> </SUP><A
name=REF8 jQuery1260308401109="280"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo44; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">8.<SPAN
style="FONT: 7pt 'Times New Roman'"> </SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Hoffman-La
Roche. Investor update: tamiflu shown to reduce risk of death in patients with
influenza. 13 September 2005. <A
href="http://www.roche.com/investors/ir_update/inv-update-2005-09-13b.htm"
jQuery1260308401109="281">www.roche.com/investors/ir_update/inv-update-2005-09-13b.htm</A>.<SUP><!-- HIGHWIRE ID="339:dec07_2:b5164:8" --><!-- /HIGHWIRE -->
</SUP><A name=REF9
jQuery1260308401109="282"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo45; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">9.<SPAN
style="FONT: 7pt 'Times New Roman'"> </SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Toovey
S, Rayner C, Prinssen E, Chu T, Donner B, Thakrar B, et al. Assessment of
neuropsychiatric adverse events in influenza patients treated with oseltamivir:
a comprehensive review. <I>Drug Saf</I> 2008;31:1097-114.<A
href="http://www.bmj.com/cgi/external_ref?access_num=000262344000005&link_type=ISI"
jQuery1260308401109="283"><!-- HIGHWIRE ID="339:dec07_2:b5164:9" -->[Web of
Science]</A><A
href="http://www.bmj.com/cgi/external_ref?access_num=19026027&link_type=MED"
jQuery1260308401109="284">[Medline]</A><SUP><!-- /HIGHWIRE --> </SUP><A
name=REF10 jQuery1260308401109="285"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo46; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">10.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Turner
D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K. Systematic review and
economic decision modelling for the prevention and treatment of influenza A and
B. <I>Health Technol Assess</I> 2003;7:1-170.<A
href="http://www.bmj.com/cgi/external_ref?access_num=12583822&link_type=MED"
jQuery1260308401109="286"><!-- HIGHWIRE ID="339:dec07_2:b5164:10" -->[Medline]</A><SUP><!-- /HIGHWIRE -->
</SUP><A name=REF11
jQuery1260308401109="287"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo47; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">11.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Tappenden
P, Jackson R, Cooper K, Rees A, Simpson E, Read R, et al. Amantadine,
oseltamivir and zanamivir for the prophylaxis of influenza (including a review
of existing guidance no. 67): a systematic review and economic evaluation.
<I>Health Technol Assess</I> 2009;13:1-246.<A
href="http://www.bmj.com/cgi/external_ref?access_num=000265139300001&link_type=ISI"
jQuery1260308401109="288"><!-- HIGHWIRE ID="339:dec07_2:b5164:11" -->[Web of
Science]</A><A
href="http://www.bmj.com/cgi/external_ref?access_num=19958718&link_type=MED"
jQuery1260308401109="289">[Medline]</A><SUP><!-- /HIGHWIRE --> </SUP><A
name=REF12 jQuery1260308401109="290"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo48; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">12.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Burch
J, Corbett M, Stock C, Nicholson K, Elliot AJ, Duffy S, et al. Prescription of
anti-influenza drugs for healthy adults: a systematic review and meta-analysis.
<I>Lancet Infect Dis</I> 2009;9:537-45.<A
href="http://www.bmj.com/cgi/external_ref?access_num=10.1016%2FS1473-3099%2809%2970199-9&link_type=DOI"
jQuery1260308401109="291"><!-- HIGHWIRE ID="339:dec07_2:b5164:12" -->[CrossRef]</A><A
href="http://www.bmj.com/cgi/external_ref?access_num=000269431700017&link_type=ISI"
jQuery1260308401109="292">[Web of Science]</A><A
href="http://www.bmj.com/cgi/external_ref?access_num=19665930&link_type=MED"
jQuery1260308401109="293">[Medline]</A><SUP><!-- /HIGHWIRE --> </SUP><A
name=REF13 jQuery1260308401109="294"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo49; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">13.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Call
SA, Vollenweider MA, Hornung CA, Simel DL, McKinney WP. Does this patient have
influenza? <I>JAMA</I> 2005;293:987-97.<A
href="http://www.bmj.com/cgi/ijlink?linkType=ABST&journalCode=jama&resid=293/8/987"
jQuery1260308401109="295"><!-- HIGHWIRE ID="339:dec07_2:b5164:13" --><NOBR>[Abstract/<SPAN
style="COLOR: #cc0000">Free</SPAN> Full Text]</NOBR></A><SUP><!-- /HIGHWIRE -->
</SUP><A name=REF14
jQuery1260308401109="296"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo50; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">14.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Kelly
HA. A pandemic response to a disease of predominantly seasonal intensity. <I>Med
J Aust</I> 2010;192:1-3.<SUP><!-- HIGHWIRE ID="339:dec07_2:b5164:14" --><!-- /HIGHWIRE -->
</SUP><A name=REF15
jQuery1260308401109="297"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo51; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">15.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Brownlee
S, Lenzer J. Does the vaccine matter? The Atlantic November 2009. <A
href="http://www.theatlantic.com/doc/200911/brownlee-h1n1"
jQuery1260308401109="298">www.theatlantic.com/doc/200911/brownlee-h1n1</A>.<SUP><!-- HIGHWIRE ID="339:dec07_2:b5164:15" --><!-- /HIGHWIRE -->
</SUP><A name=REF16
jQuery1260308401109="299"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo52; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">16.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Smith
NM, Bresee JS, Shay DK, Uyeki TM, Cox NJ, Strikas RA. Prevention and control of
influenza: recommendations of the Advisory Committee on Immunization Practices
(ACIP). <I>MMWR Recomm Rep</I> 2006;55(RR-10):1-42.<A
href="http://www.bmj.com/cgi/external_ref?access_num=16498385&link_type=MED"
jQuery1260308401109="300"><!-- HIGHWIRE ID="339:dec07_2:b5164:16" -->[Medline]</A><SUP><!-- /HIGHWIRE -->
</SUP><A name=REF17
jQuery1260308401109="301"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo53; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">17.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Fiore
AE, Shay DK, Haber P, Iskander JK, Uyeki TM, Mootrey G, et al. Prevention and
control of influenza. Recommendations of the Advisory Committee on Immunization
Practices (ACIP), 2007. MMWR Recomm Rep 2007 Jul 13;56(RR-6):1-54.<SUP><!-- HIGHWIRE ID="339:dec07_2:b5164:17" --><!-- /HIGHWIRE -->
</SUP><A name=REF18
jQuery1260308401109="302"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo54; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">18.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Fiore
AE, Shay DK, Broder K, Iskander JK, Uyeki TM, Mootrey G, et al. Prevention and
control of influenza: recommendations of the Advisory Committee on Immunization
Practices (ACIP), 2008. MMWR Recomm Rep 2008 Aug 8;57(RR-7):1-60.<SUP><!-- HIGHWIRE ID="339:dec07_2:b5164:18" --><!-- /HIGHWIRE -->
</SUP><A name=REF19
jQuery1260308401109="303"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo55; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">19.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">US
Department of Health and Human Services. HHS pandemic influenza plan.November
2005. <A
href="http://www.hhs.gov/pandemicflu/plan/pdf/HHSPandemicInfluenzaPlan.pdf"
jQuery1260308401109="304">www.hhs.gov/pandemicflu/plan/pdf/HHSPandemicInfluenzaPlan.pdf</A>.<SUP><!-- HIGHWIRE ID="339:dec07_2:b5164:19" --><!-- /HIGHWIRE -->
</SUP><A name=REF20
jQuery1260308401109="305"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo56; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">20.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Sturcke
J. Experts warned dispersal of Tamiflu would do more harm than good. The
Guardian 16 August 2009. <A
href="http://www.guardian.co.uk/world/2009/aug/16/swine-flu-tamiflu-helpline-paracetamol"
jQuery1260308401109="306">www.guardian.co.uk/world/2009/aug/16/swine-flu-tamiflu-helpline-paracetamol</A>.<SUP><!-- HIGHWIRE ID="339:dec07_2:b5164:20" --><!-- /HIGHWIRE -->
</SUP><A name=REF21
jQuery1260308401109="307"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo57; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">21.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Abraham
J. Science, politics and the pharmaceutical industry: controversy and bias in
drug regulation. 1st ed. Routledge, 1995.<SUP><!-- HIGHWIRE ID="339:dec07_2:b5164:21" --><!-- /HIGHWIRE --> </SUP><A
name=REF22 jQuery1260308401109="308"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo58; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">22.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Roche
Registration. Product information. Tamiflu-H-C-402-II-68. 9 September 2009. <A
href="http://www.emea.europa.eu/humandocs/PDFs/EPAR/tamiflu/emea-combined-h402en.pdf"
jQuery1260308401109="309">www.emea.europa.eu/humandocs/PDFs/EPAR/tamiflu/emea-combined-h402en.pdf</A>.<SUP><!-- HIGHWIRE ID="339:dec07_2:b5164:22" --><!-- /HIGHWIRE -->
</SUP><A name=REF23
jQuery1260308401109="310"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo59; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">23.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Hoffman-La
Roche. Product label. Tamiflu (oseltamivir phosphate) capsules and for oral
suspension. 25 September 2008. <A
href="http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021087s047,%20021246s033lbl.pdf"
jQuery1260308401109="311">www.accessdata.fda.gov/drugsatfda_docs/label/2008/021087s047,%20021246s033lbl.pdf</A>.<SUP><!-- HIGHWIRE ID="339:dec07_2:b5164:23" --><!-- /HIGHWIRE -->
</SUP><A name=REF24
jQuery1260308401109="312"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo60; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">24.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">Chugai
Pharmaceutical Co. Product information. Tamiflu 75mg capsule. September 2009. <A
href="http://www.info.pmda.go.jp/downfiles/ph/PDF/450045_6250021M1027_1_21.pdf"
jQuery1260308401109="313">www.info.pmda.go.jp/downfiles/ph/PDF/450045_6250021M1027_1_21.pdf</A>.<SUP><!-- HIGHWIRE ID="339:dec07_2:b5164:24" --><!-- /HIGHWIRE -->
</SUP><A name=REF25
jQuery1260308401109="314"><!-- null --></A><o:p></o:p></SPAN></P>
<P class=MsoNormal
style="MARGIN: 0in 0in 6pt 0.5in; TEXT-INDENT: -0.25in; LINE-HEIGHT: 16.8pt; mso-margin-top-alt: auto; mso-margin-bottom-alt: auto; mso-list: l20 level1 lfo61; tab-stops: list .5in"><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt; mso-fareast-font-family: Arial"><SPAN
style="mso-list: Ignore">25.<SPAN
style="FONT: 7pt 'Times New Roman'">
</SPAN></SPAN></SPAN><SPAN
style="FONT-SIZE: 14pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 11.0pt">US
Food and Drug Administration. CFR—code of federal regulations title 21. Sec.
314.80. Postmarketing reporting of adverse drug experiences. 1 April 2009. <A
href="http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.80"
jQuery1260308401109="315">www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.80</A>.<SUP><!-- HIGHWIRE ID="339:dec07_2:b5164:25" --><!-- /HIGHWIRE -->
</SUP><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 6pt"><SPAN
style="FONT-SIZE: 13pt; COLOR: #333333; FONT-FAMILY: 'Arial','sans-serif'; mso-bidi-font-size: 9.0pt"><IMG
height=30 alt=" " src="cid:A3DAC03EA956487E9183BDC1F5BEEDAB@LENOVO6ACF2A74"
width=30 border=0 v:shapes="_x0000_i1032"></SPAN><SPAN
style="FONT-SIZE: 19pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'"><o:p></o:p></SPAN></P>
<P class=MsoNormal style="MARGIN: 0in 0in 10pt"><SPAN
style="FONT-SIZE: 15pt; mso-bidi-font-size: 12.0pt; mso-fareast-font-family: 'Times New Roman'"><o:p> </o:p></SPAN></P></BODY></HTML>