E-DRUG: German scientists call for a reassessment of HPV vaccination
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13 well known medical scientists from Germany have asked for a reassessment
of the information and policies on the HPV vaccination. This statement is
now available in English (full text below). Among the signatories are two
members of the German State Advisory Council on the Assessment of
Developments in the Health Care System.
The basis for this call is the ill-informed perception of the efficacy of
the HPV-vaccines. The experts question the scientific basis for the
recommendation of the German Standing Vaccination Committee (STIKO) to
vaccinate all girls aged 12-17 years against HPV. As a result of STIKOs
decision the public German health insurance system spends on HPV
vaccinations an estimated amount of 500 million Euro per year.
The statement of the 13 scientists was published at the end of November 2008 and led to considerable discussions in Germany. Most notably the German Federal Joint Committee, which decides about the reimbursement of drugs and services in the public health system (Krankenkassen), on 19 December requested STIKO to do a scientific re-assessment of the HPV vaccination.
The statement of these 13 scientists has implications beyond Germany. There
is an urgent need to discuss the efficacy of the HPV vaccination globally.
The vaccination is discussed as a quick fix for developing countries.
Countries need to discuss where to spend their resources for health best.
Cervical cancer is not a common disease in poor countries either. In Africa
it is responsible for 0.46% of deaths. HIV/AIDS kills 18 times as many
women. Death due to maternal causes is five times as often.
If the efficacy of the vaccines is low they may not be the best option for
cervical cancer prevention, especially in countries where screening
programmes for cervical lesions are limited.
Jörg Schaaber
Pharma-Brief
BUKO Pharma-Kampagne
August-Bebel-Str. 62
D 33602 Bielefeld
Germany
www.bukopharma.de
jschaaber[AT]bukopharma.de
The statement as PDF:
www.uni-bielefeld.de/gesundhw/ag3/downloads/Statement_HPV-vaccine.pdf
[repair link]
SCIENTISTS IN GERMANY CALL FOR A REASSESSMENT OF THE HPV VACCINATION AND AN
END TO MISLEADING INFORMATION
As of autumn 2006, adolescent girls and women in Germany can be vaccinated
against human papilloma virus (HPV). Ever since then there have been intense discussions about possible side effects and the costs of the vaccines, as well as the partly misleading promotional information which is given out to the public. The question of how effective the vaccines really are is hardly ever asked. Yet this crucial issue of efficacy i.e., to what degree the vaccine actually lowers the rate of new cervical cancer cases has not been sufficiently evaluated, and is the object of misleading information.
STIKO made its recommendations before the relevant studies were published
In March 2007 the Ständige Impfkommission (STIKO) [Standing Vaccination
Committee] of the Robert Koch-Institute recommended the HPV vaccine for all
girls aged 12-17 years to decrease the burden of disease due to cervical
cancer. However, at the time the recommendation was made, the results of the decisive studies had not yet been published.
It was not until May 2007 that the most important studies on the Gardasil®
vaccine, FUTURE I and FUTURE II, were published in The New England Journal
of Medicine (NEJM). The central message of an editorial published in this
journal more than one year later was: The bad news is that the overall
effect of the vaccines on cervical cancer remains unknown (Haug 2008) (1).
The most important study on the second vaccine, Cervarix®, was published in
June 2007. Cervarix® has not yet been approved in the USA.
What do studies and other documents say about the efficacy of the HPV
vaccines?
Cervical cancer is closely associated with HPV infection. Of the
approximately 100 known strains of HPV, at least 13 can trigger cervical
cancer. Strains 16 and 18, which are the target of these two vaccines, are
assumed to be responsible for 70% of all cervical cancer cases.
However, rather than assessing the effect of the vaccine against cervical
cancer, the studies examined the incidence of high-grade cervical lesions (a potential precursor of cervical cancer) in 15-26 year-old women.
The vaccine did achieve a 98% (2) decrease in the precancerous stages
associated with HPV 16 or 18 in women who had not yet been infected with
these two strains. This gave rise to much optimism, and it was widely
proclaimed that the 70% of cervical cancer cases associated with HPV strains 16 and 18 could be almost completely prevented (thus achieving a decline in all cervical cancer cases of almost 70%). This assumption, however, has so far not been confirmed by studies.
In analyses which included all women enrolled, FUTURE I found a decline of
7.8% (3) in the incidence of all high-grade cervical lesions (number
extracted from EMEA [European Medicines Agency] 2008), and FUTURE II a
decrease of 17%.(4) These evaluations have not yet been considered by STIKO.
Regarding the second vaccine, Cervarix®, STIKO based its recommendations
exclusively on data on the prevention of persistent infections. Data
regarding the efficacy of Cervarix® against precancerous stages or cancer
were not yet available.
The efficacy of Gardasil®, which has been described as modest, was
partially explained by the fact that some of the women examined had already
been infected with HPV 16 or 18. It is well known that the vaccine does not
work once women have been infected. Hence it was recommended that women
should be vaccinated before they could be infected with HPV, i.e., before
they become sexually active. STIKO, in its recommendation, set this age at
12-17 years. Data on the efficacy against early stages of cervical cancer,
however, are only available for females aged 15-17 years, not for 12-14
year-olds.
To make up for this lack of data, the FUTURE studies conducted statistical
analyses including only girls and women who tested negative for HPV 16 or 18 at the beginning of the study. This group was expected to approximate
12-year old girls. However, it remains unclear how Gardasil® affects the
total number of high-grade cervical lesions in this group. Here, the only
available data comes from a two-year follow-up of the FUTURE studies
published by the FDA in 2006 which found an efficacy of 16.9%.(5) The FUTURE II study gives an efficacy estimate of 27%.(6) EMEA provides estimates of 37.9% (7) for 2006 and 46.1% (8) for 2008 for varying populations. However, in order to derive the figure of 46.1%, about half of the women enrolled were excluded post hoc.
When asked for additional data, Sanofi-Pasteur MSD Germany replied:
Unpublished figures and tables are only available to the colleagues who
were immediately involved in evaluating the results, that is to say, at the
headquarters in the USA. We do not have this data, and we will not get it,
either.
The STIKO recommendations for the HPV vaccine must be reassessed now
The STIKO recommendations made in March 2007 were not based on explicit data on efficacy. Instead, STIKO mentions that lifelong immunity was 92.5% (9), apparently based on its own extrapolations. No explanation was given for how this number was arrived at, nor was or is there any data on lifelong immunity. No study indicated an efficacy of this magnitude.
The STIKO recommendations must be reassessed immediately. STIKO should
consider more recent study results and ask manufacturers for the missing
data, which must then be included in a new evaluation. This evaluation
should indicate clearly and precisely what efficacy STIKO expects of the
vaccine, and what assumptions and data these expectations rest on.
Adolescent girls and women must be informed adequately
The results of the studies clearly contradict many overly optimistic
pronouncements. Adolescent girls and women are entitled to be adequately
informed. We strongly object to stirring up fear regarding the risk of
cervical cancer and feelings of guilt by disseminating incorrrect
information. We demand that gaps in the data be discussed openly. Assertions that a vaccine reduces the risk of cervical cancer by 70% or even 98% should simply not be made at this point in time. Instead, data should be used which is supported by sound research and which gives all those involved an opportunity to make an informed choice.
Prof. Martina Dören Charité, Berlin
Dr. Ansgar Gerhardus University of Bielefeld
Prof. Ferdinand M. Gerlach, University of Frankfurt
Prof. Claudia Hornberg, University of Bielefeld
Prof. Michael M. Kochen, University of Göttingen
Prof. Petra Kolip, University of Bremen
Prof. Wolf-Dieter Ludwig, Charité, Berlin
Prof. Ingrid Mühlhauser, University of Hamburg
Prof. Oliver Razum, University of Bielefeld
Prof. Rolf Rosenbrock, Social Science Research Center Berlin (WZB),
Berlin
Corinna Schach, University of Bremen
Prof. Norbert Schmacke, University of Bremen
Prof. Jürgen Windeler, Medical Advisory Service of the German
Social Health Insurance (MDS), Essen
German version: 25.11. 2008, translated: 23.12. 2008
Contact: Dr. Ansgar Gerhardus, University of Bielefeld,
ansgar.gerhardus@uni-bielefeld.de
References with exact positions of quotations and numbers
1 Haug, CJ (2008) Human Papillomavirus Vaccination Reasons for Caution. N Engl J Med 2008;359:861-62.
http://content.nejm.org/cgi/reprint/359/8/861.pdf
Quotation from p. 861, first paragraph
2 Number: 98%
The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915-1927. http://content.nejm.org/cgi/reprint/356/19/1915.pdf?ijkey=24cc07867ea2faad48
e9e69c3463c8905ab010bf
Abstract and page 1920. Table 3. Last Column
3 Number: 7.8% (for FUTURE I study = Protocol 013)
EMEA (2008): Gardasil: European Public Assessment Report. Scientific
Discussion (May 2008):
http://www.emea.europa.eu/humandocs/PDFs/EPAR/gardasil/EMEA-H-703-II-13-AR.pdf
Page 11. Table 6. 6th column, 4th row from below.
4 Number: 17%
The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915-1927. http://content.nejm.org/cgi/reprint/356/19/1915.pdf?ijkey=24cc07867ea2faad48
e9e69c3463c8905ab010bf
Abstract and page 1921. Table 3. Last Column
5 Number: 16.9%
FDA (2006): Vaccines and Related Biological Products Advisory Committee.
(VRBPAC). Background Document, May 2006
http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4222B3.pdf
Page 17. Table 25. 10th column
6 Number: 27%
The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915-1927. http://content.nejm.org/cgi/reprint/356/19/1915.pdf?ijkey=24cc07867ea2faad48
e9e69c3463c8905ab010bf
Page 1922. 2nd paragraph, 6th line
7 Number: 37.9%
EMEA (2006): Gardasil: European Public Assessment Report. Scientific
Discussion (October 2006):
http://www.emea.europa.eu/humandocs/PDFs/EPAR/gardasil/070306en6.pdf
Page 28, 2nd paragraf following the heading Population benefit integrated
summary of efficacy. Number refers to R-MITT-2-Population
8 Number: 46.1%
EMEA (2008): Gardasil: European Public Assessment Report. Scientific
Discussion (May 2008):
http://www.emea.europa.eu/humandocs/PDFs/EPAR/gardasil/EMEA-H-703-II-13-AR.pdf
Page 22. Table 15. R-MITT-2-population, 6th column.
9 Number: 92.5%
Ständige Impfkommission (STIKO) am Robert Koch-Institut (2007): Impfung
gegen humane Papillomaviren (HPV) für Mädchen von 12 bis 17 Jahren
Empfehlung und Begründung. Epidemiologisches Bulletin 12/2007: 97-103.
http://www.rki.de/cln_091/nn_195848/DE/Content/Infekt/EpidBull/Archiv/2007/Ausschnitte/HPV__STIKO__12__07,templateId=raw,property=publicationFile.pdf/HPV_STIKO_12_07.pdf
Page 101. 2nd paragraph following the heading Mögliche Auswirkungen einer
Impfung gegen HPV