Systematic Review of 58 Publications of Real-World Use of GARDASIL® Presented at EUROGIN Congress


June 16, 2016 7:00 am ET

Studies Published over the Last 10 Years Report Reductions in Cervical Pre-cancers and Other HPV-related Diseases

Merck (NYSE:MRK), known as MSD outside of the United States and Canada,
announced today that in a systematic review conducted of the global
impact and effectiveness of GARDASIL® [Human Papillomavirus
Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant], substantial
reductions were observed in HPV 6/11/16/18-related infection, genital
warts, Pap abnormalities and cervical pre-cancers. This evaluation of 58
effectiveness and impact studies published during the past 10 years
examined the use of GARDASIL in routine vaccination programs in
Australia, Europe, North America and New Zealand, and will be presented
for the first time during an oral session at the European Research
Organization on Genital Infection and Neoplasia (EUROGIN) congress in
Austria. A paper detailing this review was also published online on June
14 in the journal Clinical Infectious Diseases (CID).

Following introduction of vaccination programs with GARDASIL, the
earliest impact of the vaccine was seen in the reduction of genital
warts. Reductions in genital warts were observed in all nine countries
included in this review (based on 28 publications), with declines
occurring as early as one year after vaccine introduction in Australia
and Germany. Reductions in HPV 6/11/16/18 infection, assessed in 14
publications from five countries (Australia, Belgium, Germany, Sweden
and the United States), were also observed shortly after vaccination;
for example, reductions in HPV 6/11/16/18 infection were seen within
four years in several studies from Australia and the United States.
Subsequently, as successive birth cohorts began cervical screening,
reductions in cervical pre-cancers were observed within 3-5 years of
vaccine program implementation in Australia, Canada, Denmark, Sweden and
the United States.

GARDASIL® [Human Papillomavirus Quadrivalent (Types 6, 11, 16
and 18) Vaccine, Recombinant] is indicated for use in females 9 through
26 years of age for the prevention of cervical, vulvar, vaginal and anal
cancers caused by HPV types 16 and 18; genital warts caused by HPV types
6 and 11; and precancerous or dysplastic lesions caused by HPV types 6,
11, 16 and 18. GARDASIL is also approved for use in males 9 through 26
years of age for the prevention of anal cancer caused by HPV types 16
and 18, for the prevention of anal dysplasias and precancerous lesions
caused by HPV types 6, 11, 16 and 18, and for the prevention of genital
warts caused by HPV types 6 and 11. GARDASIL is contraindicated in
individuals with hypersensitivity, including severe allergic reactions
to yeast, or after a previous dose of GARDASIL.

The review identified 58 studies published from January 2007 through
February 2016 that met the pre-specified criteria for assessment of the
real-world impact of vaccination with GARDASIL on HPV-related disease.
These studies were conducted in nine different countries (Australia,
Denmark, Sweden, Belgium, Germany, France, United States, Canada and New
Zealand) with varying degrees of HPV vaccination coverage, among
populations of different ages, and used different study methods and
disease endpoints. Studies reporting only on the bivalent HPV vaccine
were excluded. GARDASIL was predominantly, but not exclusively, used in
all publications reviewed. Short-term endpoints (reduction in HPV
infection and genital warts) and medium-term endpoints (reduction in Pap
abnormalities and cervical pre-cancers) were assessed. Cervical cancer,
however, was not identified because most vaccinated cohorts have not yet
reached ages when cervical cancer is typically diagnosed. Thus the
anticipated benefit of vaccination on certain HPV-related cancer rates
cannot be fully determined yet, because of the long latency periods
following exposure to HPV.

In this review of the studies, decreases in the prevalence of HPV
6/11/16/18 infections, genital warts, Pap abnormalities and cervical
pre-cancers were observed among females in their teens and 20s
subsequent to the introduction of GARDASIL. Decreases were generally
highest in younger populations, reflecting a lower likelihood of
pre-existing HPV infection at time of vaccination, supporting global
recommendations for routine use of HPV vaccine in adolescents.

“Based on this comprehensive review of studies published during the past
10 years since the licensure of GARDASIL, reductions in HPV infections
as well as reductions in the prevalence of HPV 6/11/16/18-related
diseases, as noted by decreases in Pap abnormalities, cervical
pre-cancers, and genital warts, were detected within four years after
vaccine introduction,” said Professor Suzanne Garland, M.D., director of
microbiological research and head of clinical microbiology and
infectious diseases, The Royal Women’s Hospital, Victoria, Australia,
who will present these data at EUROGIN and is lead author on the CID
publication. “Despite the progress we have made with Pap screening and
vaccination, cervical cancer and other HPV-related diseases are still a
public health issue in both developed and developing nations, which
underscores the need for comprehensive HPV vaccination programs in
adolescents before they’re at risk of contracting the virus,” added

Results varied depending on the vaccine coverage (percent of the
population who had been vaccinated), breadth of the immunization program
(the age range of those vaccinated and whether catch-up vaccination was
included), the number of doses received, the study design, and the
disease outcome assessed. The overall impact on the population was
greatest in countries that achieved high vaccination rates soon after
the introduction of GARDASIL [Human Papillomavirus Quadrivalent (Types
6, 11, 16 and 18) Vaccine, Recombinant] and in the youngest cohorts. For
example, in Australia, a country with 3-dose vaccination coverage of 73
percent among adolescent females, prevalent HPV 6/11/16/18-related
infection decreased by 86 percent in females 18-24 years of age after
three doses within six years of vaccine introduction, compared to
unvaccinated women during the same timeframe. Furthermore, a 92.6
percent reduction in genital warts diagnosed among females <21 years of
age was observed four years after the vaccine program was initiated.
Within four years of vaccine introduction in Australia, reductions in
cervical pre-cancers were seen in females 11-27 years old at the start
of the vaccination program in 2007 and who received all three vaccine
doses, with declines ranging from 57 percent in females 15-18 years old
to 5 percent in females 23-27 years old. Reductions in disease endpoints
were generally lower in older individuals and in countries with lower
vaccine coverage. For example, in the same Australian study where a 92.6
percent reduction in genital warts was observed in females <21 years of
age, the reduction in genital warts in females 21-30 years of age was
72.6 percent. Reductions in genital warts were <50 percent in teens
15-19 years old in France and Germany where vaccine coverage was much
lower than Australia.

“These data reinforce that GARDASIL is important in the fight against
cervical cancer and certain other HPV-related cancers and diseases,
however the full public health potential of HPV vaccination of males and
females is not yet realized even after a decade of use,” said Jacques
Cholat, M.D., president of Merck Vaccines. “Increasing HPV vaccination
rates and access to the vaccine has the potential to make an even
greater impact globally.”

Systematic review of 58 peer-reviewed publications

This review synthesized available data assessed through a systematic
search of PubMed and Embase for peer-reviewed manuscripts from January
2007 through February 2016. The search identified observational studies
that reported on the impact or effectiveness of GARDASIL on HPV
infection, genital warts, cervical abnormalities and pre-cancers. Both
vaccine effectiveness and impact aim at evaluating ‘real-life benefit’
and are typically measured through observational studies. Vaccine impact
denotes the population-prevented fraction of infection or disease and is
assessed by comparing prevalence or incidence in the vaccine era to a
comparable population from the prevaccine era or by measuring
population-level trends over time. Vaccine effectiveness corresponds to
the proportion of infection or disease prevented among vaccinated
individuals, and is estimated by comparing the incidence in vaccinated
versus unvaccinated individuals within similar populations. After
screening 903 papers, 58 publications from nine countries met the
pre-specified inclusion criteria.

Important information about GARDASIL


Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine,

GARDASIL does not eliminate the necessity for women to continue to
undergo recommended cervical cancer screening. Recipients of GARDASIL
should not discontinue anal cancer screening if it has been recommended
by a health care provider.

GARDASIL has not been demonstrated to provide protection against
diseases from vaccine and non-vaccine HPV types to which a person has
previously been exposed through sexual activity.

GARDASIL is not intended to be used for treatment of active external
genital lesions; cervical, vulvar, vaginal and anal cancers; cervical
intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN),
vaginal intraepithelial neoplasia (VaIN), or anal intraepithelial
neoplasia (AIN).

GARDASIL has not been demonstrated to protect against diseases due to
HPV types not contained in the vaccine.

Not all vulvar, vaginal and anal cancers are caused by HPV, and GARDASIL
protects only against those vulvar, vaginal and anal cancers caused by
HPV Types 16 and 18.

GARDASIL does not protect against diseases not caused by HPV.
Vaccination with GARDASIL may not result in protection in all vaccine

Select safety information for GARDASIL


[Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine,

GARDASIL is contraindicated in individuals with hypersensitivity,
including severe allergic reactions to yeast, or after a previous dose

Because vaccinees may develop syncope, sometimes resulting in falling
with injury, observation for 15 minutes after administration is
recommended. Syncope, sometimes associated with tonic-clonic movements
and other seizure-like activity, has been reported following vaccination
with GARDASIL. When syncope is associated with tonic-clonic movements,
the activity is usually transient and typically responds to restoring
cerebral perfusion.

GARDASIL is not recommended for use in pregnant women.

The most common adverse reaction was headache. Common adverse reactions
that were observed among recipients of GARDASIL at a frequency of at
least 1.0 percent and greater than placebo were fever, nausea,
dizziness; and injection-site pain, swelling, erythema, pruritus and

Dosage and administration for GARDASIL

GARDASIL should be administered in 3 separate intramuscular injections
in the deltoid region of the upper arm or in the higher anterolateral
area of the thigh over a 6-month period with the first dose at an
elected date, the second dose 2 months after the first dose, and the
third dose 6 months after the first dose.


GARDASIL is approved for use in 132 countries. To date, more than 208
million doses have been distributed worldwide.

About HPV and related cancers and diseases

In the United States, human papillomavirus (HPV) will infect most
sexually active males and females in their lifetime. According to the
CDC, there are approximately 14 million new genital HPV infections in
the United States each year, half of which occur in people 15 through 24
years of age. For most people, HPV clears on its own, but for others who
don’t clear the virus, it could lead to cancers and other diseases in
males as well as females, and there is no way to predict who will clear
the virus.

In women, HPV causes virtually all cervical cancer cases of which an
estimated 70 percent are caused by HPV types 16 and 18. Each day another
35 women are diagnosed with cervical cancer in the United States — about
12,900 women per year. HPV also causes approximately 70-75 percent of
vaginal cancer cases and approximately 30 percent of vulvar cancer
cases. HPV types 16 and 18 cause an estimated 65% of hpv-related vaginal
cancer cases and 75% of hpv-related vulvar cancer cases. Additionally,
there are an estimated 3 million abnormal Pap results, many of which are
caused by HPV, that require follow-up each year in the United States.

HPV causes approximately 85-90 percent of anal cancers in both males and
females, and HPV types 16 and 18 cause an estimated 85% of those cases.
According to the American Cancer Society, an estimated 2,600 men and
4,600 women in the United States will be diagnosed with anal cancer in
2015, and overall rates have been increasing. There is no routine
screening recommended for the general population to screen for anal

HPV causes approximately 90 percent of genital warts in both males and
females. There are approximately 360,000 cases of genital warts each
year in the United States. Treatment of genital warts can be painful,
and they may recur after treatment, especially in the first three
months. Approximately 3 out of 4 people get them after having genital
contact with someone who has genital warts.

About Merck

For 125 years, Merck has been a global health care leader working to
help the world be well. Merck is known as MSD outside the United States
and Canada. Through our prescription medicines, vaccines, biologic
therapies, and animal health products, we work with customers and
operate in more than 140 countries to deliver innovative health
solutions. We also demonstrate our commitment to increasing access to
health care through far-reaching policies, programs and partnerships.
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Please see Prescribing Information for GARDASIL


[Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine,
Recombinant] at

and Patient Information for GARDASIL at

Pamela Eisele, 267-305-3558
Deb Wambold, 215-652-2913
Teri Loxam, 908-740-1986
Justin Holko, 908-740-1879

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