Torofy Blog

Depression and Heart Disease

Efficacy and safety of the vaccine against the papilloma virus

Hello, ladies and gentlemen. Thank you very much for
asking me to speak to you today. My name is Tom Jefferson I’m a physician I’m an
epidemiologist I am co-author of 17 Cochrane reviews
mainly on vaccines I’m here to talk to you about our work on HPV vaccine human
papillomavirus vaccines I have some questions which we have I have agreed
with Giovanni Guevara and I have some answers I will read the questions and
then discuss the answers questions are numbered one to five and the references
to our work so the people graphical references to our work are in the
document which you should have received please do not quote this document or any
parts of it which are not in the public domain without my authorization thank
you so here we go first of all can you describe your work on HPV vaccines the
human papillomavirus vaccines are global interventions given to healthy
individuals to prevent HPV related diseases such as cervical cancer the
vaccines are considered quote safe and effective unquote by health care
authorities benefits of the major outcomes such as cancer and deaths will
only be verifiable after decades but safety signals raise
concern where the Selective presentation of the evidence had influenced the
authorities considerations of benefits and harms now oh you shouldn’t read as
the first line indicates in the document she read our little introduction called
“Redefining the E in EBM” now this is very important you read this so you will be
given the background to what I’m about to say so if your hand ready yet do so
now as you get to the document the link is on top of the document because of the
white had perceived threat by reporting bias to the bidding trial public journal
publications that’s reporting bias means selective
bias I choose what to report perhaps the most famous form of this is publication
bias and because of the threat posed by reporting bias follows all kinds we
investigated the benefits and harms of the HPV vaccines by going directly to
regulatory submissions made to different regulators and I will list them as we go
along and we did this first of all by building an index of the study programs
so we accessed clinical study reports from the HPV vaccine study programs and
also compared these reports to corresponding study documents like trial
register entries and journal publications and this basic preliminary
part of our work is published and you will have the reference in the document
under one the study programs reconstructed study programs of the HPV
vaccine trials demonstrated deficiencies and variabilities in the availability of
study data in trial register entries and journal publications this is exactly
what we found with Tamiflu a decade ago so that journal publications are a very
dangerous source of data and information and try to trial register entries
sometimes not updated and they contain mistakes for example only half of the
completed studies of HPV vaccines enlisted on clinical had
results posted a third of this of all studies were not published
that’s why constructive index if you like it’s like a database of all studies
and we listed 206 perspective comparative studies sponsored both by
pharmaceutical and non-pharmaceutical agencies within accessed regulatory data
on HPV vaccines from the European regulator European Medicines Agency our
analysis reporting accessing the HPV vaccine trial data from clinical study
reports showed the regulatory policies are in need of change to increase
transparency and fluency and usability and our results are published in the BMJ
were published in the BMJ this summer and again the reference is in the
document to give you an example of the problems that we had he was not possible
to get a complete sent from unredacted clinical study reports on the HPV
vaccines so we have 24 reports but they’re all missing some bits even so
we’re looking at 64,000 pages compare that with 1015 pages on average of a
trial publication the next phase number 3 was minimally biased evidence
synthesis what does that mean our systematic review of 24 clinical study
reports with nearly a hundred thousand participants this is undergoing peer
review at the moment but I can tell you that the review showed that for years
follow-up HPV vaccines decreased HPV related precursors to cancer and they
decreased also treatment procedures for gynecological and mainly cervical reason
but the vaccines increased serious nervous serious nervous system disorders
and general harms the trials used a bias designs and underreported harms which
prevented adequate harm assessment now as I said this is under consideration
for publication this work but you can find the protocol and its amendment on
Prospero and the link is in the document next came the comparisons of published
trials with the clinical study report versions our comparison of corresponding
study documents showed no effect differences of pooled estimates okay
great so we can use publications it doesn’t make any difference but we
demonstrated that the clinical study reports well quantitatively and
qualitatively superior with more outcome data and information than improved risks
and by just the risk of bias judgments you’ve got a mare in mind that one
possible explanation for the finding of no difference within clinical spell
reports and publication is that distortions in the trial designs ensures
that the same results are reached despite the data source used that means
that whether you use publications of 15 pages or clinical study reports of
10,000 pages if the trial has a bias the design and the reporting is biased in
general reporting for instance of harms is fragmented it’s indifferent very many
different categories some of them have got definitions and some of them are not
and the actual surveillance is fragmented and cannot actually be
compared from one trial to the next well when they use a clinical study report or
a journal publication as a source of data doesn’t actually make much
difference it does make a difference is that you can see
distortions and the clinical study reports and rarely in the publication a second question is what are the main
problems with the evidence of efficacy and safety of the HPV vaccines it is not
clear to what extent the HPV vaccines benefits outweigh their harms as the
study programs and clinical study reports were influenced by reporting
biased and bias trial designs the clinical study reports where superior
study documents that contain better information for risk of biased judgments
the reports should therefore be used for systematic reviews of important
interventions such as HPV vaccines the next question number three that I was
asked was what are the main problems of the Cochran HPV vaccine review published
in May 2000 18 by Arbonne at AU well I’ve given you a I have put a link to
main christens which are published on BMJ
evidence-based medicine BM j e BM they listed there and you can read them but
just briefly the reviewers the Cochrane reviews ignored evidence of bias
despite being sent our HPV study index four months before publication the
cochrane office based their review on journal articles had made some very
fundamental mistakes such as referring to active comparators as possible and
misclassifying for deaths they attribute to them the deaths to a control arm when
in fact it was the intervention arm what do we mean by active comparators
described as percy bows all of the trials except for two
murk trials Gardasil and the goddess Illinois named trials have comparators
which there are either their adyuvants the elements of the vaccine or another
vaccine like hepatitis A and hepatitis B and these comparators are active there’s
nothing more active in Maxine ology than an argument there’s nothing more active
in vaccinology than another vaccine despite this the authors describe them
as placebos and as Percy bows they are described in the majority publications
which brings me back to my original point about accessing clinical study
reports we know exactly what we’re in those procedures we know each dose of
those missing probes so called acebos and I can assure you that were not
persons with two exceptions one is a Gardasil trial which had a which was
requested in fact specifically by FDA so somebody at FDA must have been pretty
nervous about these safety of these vaccines but essentially the so-called
percy ball was normal saline they described it but in fact it wasn’t he
had a carrot solution was the Karason transonic sippie’s things like between
80 and pobeda and we don’t know what these substances where the effects of
these substances are the other smaller trial Galison line was carried out was a
placebo control trial but the problem was that the participants have been pre
exposed to Gardasil for so he’ll all been exposed to at least four different
virus-like particles and the adjuvant so the placebo was actually given to people
who had already had one or more doses of god stuff next question is what are the
current challenges in the paradigm of evidence-based medicine and these are
described as we can see them they’re described in the
“Redefining the E in EBM” publication summary which I mentioned and which is linked
again at the beginning and that question for of this document briefly as you will
gathered by now the main challenge facing us is the use of more reliable
and detailed sources of evidence than journal publications and probably also
more detailed than register entries remember register entries are not
updated and they do not contain methods but also unstructured in imrad
introduction methods results and discussion forum so they’re not easy to
consult goggle stereo reports are expensive documents which run into
thousands of pages but they are structured along similar lines to imrad
so they’re familiar and if you don’t want to read the whole clinical study
report you can read a synopsis which is usually anything between 5 and 15 pages
which packs a lot more information and any publication the bias is also minimal
because although these are still commercial publications clinical stare
reports are written to get vaccines registered the same as publications are
written to have vaccines sold vaccines or pharmaceuticals sold despite the fact
that they’re still commercial publications they have a considerable
amount of detail that allows you to go in and do those kind of research work
that you need to do to understand what the evidence and what the intervention
are ok the last question that dr. Guevara posed to me was how are you
following up your HPV vaccines work well some of you may be aware that one of us,
my colleague Peter Doshi, he won a court case in the summer
against Health Canada in the federal court in the Canadian federal court
Health Canada is the Canadian regulator the judge ordered that thousands of
files regulatory files to be released to Peter Doshi and the two other named
claimants that’s myself and a statistician that means that we will
received what Peter Doshi are really receive awaiting for IRB clearance we
received thousands more regulatory files from Health Canada as a consequence of
this decision essentially we have as much as Health Canada had so probably
everything that a regulator should know not necessarily use so further analysis
and integration of what I have just said to you of the available reviews an
update of available reviews and integrational available reviews is
possible with an unprecedented level of detail down to individual participant
data and down to individual case report forms that’s the notes that are kept on
each participant of each trial and that ladies and gentlemen concludes well I
have to say to you again thank you very much for giving me the chance of
speaking. Finito!

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