GARDASIL™ Vaccine Impact in Population Study (V501-033) (VIP)

GARDASIL™ Vaccine Impact in Population Study

This study will assess the impact of GARDASIL™ human papillomavirus (HPV) vaccine in the general female population by utilizing nationwide registry databases in the participating Nordic countries.

Study Overview

• Status: Completed
• Conditions: Human Papillomavirus Infections

Detailed Description

Time perspective: The study will be conducted using data collected both retrospectively/concurrently from registries and prospectively by questionnaire survey.

Baseline survey data were collected during a prior study from 2004-2005.

Safety Monitoring: An expert panel on teratology consisting of one teratologist from each of the participating countries will review all available medical records related to any congenital anomalies to search for any emerging patterns that may be indicative of an association between GARDASIL™ exposure in the mother and the subsequent congenital anomalies in the babies.

• Study Type: Observational
• Enrollment (Actual): 54516

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

• Sampling Method: Probability Sample

Study Population

Registry data from the Population, Cervical Cancer Screening, Pathology, Cancer, and Death registries; Survey: Questionnaire sent to random sampling of women from the Central Population Registry Database; HPV Data: liquid-based cytology and histology samples from hospitals in participating countries

Description

Inclusion Criteria: - Registry Data: * Female residents of participating Nordic countries who were alive on January 1st in the year the data will be used for analysis - Survey Data: --Female residents alive in the participating countries on July 1, 2011 --Women must provide consent to use questionnaire data and to link data to other registry databases - Cervical Sample Collection: --For HPV data in the general population: cervical samples from residents of the participating countries who are 45 years and under collected between 2006 and 2007, or in 2011-2012 --For HPV data in lesional samples: cervical samples from women with a diagnosis of CIN or cervical cancer between 2004-2006 and 2011-2012 Exclusion Criteria: - Registry Data: * Women who participated in Protocol V501-015 (NCT00092534) and are included in the Long-Term Follow-Up study - Survey Data: --Women under 18 or above age 45 on July 1, 2011 --Women who participated in Protocol V501-015 and are included in the Long-Term Follow-Up study - Cervical Sample Collection: --Samples from women who participated in Protocol V501-015 and are included in the Long-Term Follow-Up study --Samples with inadequate integrity for HPV testing

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Pre-Vaccine; Registry, survey, and HPV status data from 2004-2006
Post-Vaccine; Registry, survey, and HPV status data from 2011-2012

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia (CIN) for Participants of All Ages in Denmark	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Denmark was recorded. Incidence rates are for all age groups and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.	Three years before Gardasil licensure (2004 to 2006 combined) and annually after Gardasil licensure (2007, 2008, 2009, 2010, and 2011)
Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants <=26 Years of Age in Denmark	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Denmark was recorded. Incidence rates are for women <=26 years of age and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.	Three years before Gardasil licensure (2004 to 2006 combined) and annually after Gardasil licensure (2007, 2008, 2009, 2010, and 2011)
Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants >26 Years of Age in Denmark	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Denmark was recorded. Incidence rates are for women >26 years of age and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.	Three years before Gardasil licensure (2004 to 2006 combined) and annually after Gardasil licensure (2007, 2008, 2009, 2010, and 2011)
Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants of All Ages in Norway	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Norway was recorded. Incidence rates are for all age groups and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.	Three years before Gardasil licensure (2004 to 2006 combined) and annually after Gardasil licensure (2007, 2008, 2009, 2010, and 2011)
Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants <=26 Years of Age in Norway	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Norway was recorded. Incidence rates are for women <=26 years of age and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.	Three years before Gardasil licensure (2004 to 2006 combined) and annually after Gardasil licensure (2007, 2008, 2009, 2010, and 2011)
Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants >26 Years of Age in Norway	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Norway was recorded. Incidence rates are for women >26 years of age were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.	Three years before Gardasil licensure (2004 to 2006 combined) and annually after Gardasil licensure (2007, 2008, 2009, 2010, and 2011)
Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants of All Ages in Sweden	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Sweden was recorded. Incidence rates are for all age groups and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.	Three years before Gardasil licensure (2004 to 2006 combined) and annually after Gardasil licensure (2007, 2008, 2009, 2010, and 2011)
Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants <=26 Years of Age in Sweden	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Sweden was recorded. Incidence rates are for women <=26 years of age and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.	Three years before Gardasil licensure (2004 to 2006 combined) and annually after Gardasil licensure (2007, 2008, 2009, 2010, and 2011)
Incidence of Histologically-confirmed Cervical Intraepithelial Neoplasia for Participants >26 Years of Age in Sweden	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. The collection of such data in these registries is mandated by law and compliance is generally very high. The number of new cases of high-grade (2/3) CIN registered during the assessment periods in Sweden was recorded. Incidence rates are for women >26 years of age and were age-adjusted using the European Standard Population. The incidence before Gardasil licensure is an average over the 3-year period.	Three years before Gardasil licensure (2004 to 2006 combined) and annually after Gardasil licensure (2007, 2008, 2009, 2010, and 2011)
Incidence of Human Papillomavirus (HPV) 6/11/16/18-related Cervical Intraepithelial Neoplasia for Participants of All Ages	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The number of new cases of HPV 6/11/16/18-related high-grade (2/3) CIN was estimated based on the proportion of HPV 6/11/16/18 in all CIN in a representative sample. Incidence was age-adjusted according to Nordic Standard Population.	Three years before Gardasil licensure (2004 to 2006) and two years after Gardasil licensure (2011 to 2012)
Incidence of HPV 6/11/16/18-related Cervical Intraepithelial Neoplasia for Participants <=26 Years of Age	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The number of new cases of HPV 6/11/16/18-related high-grade (2/3) CIN was estimated based on the proportion of HPV 6/11/16/18 in all CIN in a representative sample. Incidence was age-adjusted according to Nordic Standard Population.	Three years before Gardasil licensure (2004 to 2006) and two years after Gardasil licensure (2011 to 2012)
Incidence of HPV 6/11/16/18-related Cervical Intraepithelial Neoplasia for Participants >26 Years of Age	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The number of new cases of HPV 6/11/16/18-related high-grade (2/3) CIN was estimated based on the proportion of HPV 6/11/16/18 in all CIN in a representative sample. Incidence was age-adjusted according to Nordic Standard Population.	Three years before Gardasil licensure (2004 to 2006) and two years after Gardasil licensure (2011 to 2012)
Incidence of Cervical Intraepithelial Neoplasia Associated With High-risk HPV Types Other Than 16/18 in Participants <=26 Years of Age	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The percentage of new cases of high-grade (2/3) CIN related to high-risk HPV types other than 16 and 18 was analyzed. High-risk HPV types include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. Incidence was age-adjusted according to Nordic Standard Population.	Three years before Gardasil licensure (2004 to 2006) and two years after Gardasil licensure (2011 to 2012)
Incidence of Cervical Intraepithelial Neoplasia Associated With High-risk HPV Types Other Than 16/18 in Participants >26 Years of Age	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The percentage of new cases of high-grade (2/3) CIN related to high-risk HPV types other than 16 and 18 was analyzed. High-risk HPV types include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. Incidence was age-adjusted according to Nordic Standard Population.	Three years before Gardasil licensure (2004 to 2006) and two years after Gardasil licensure (2011 to 2012)
Incidence of HPV 6/11/16/18-related Cervical Cancer in Participants of All Ages	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The number of new cases of HPV 6/11/16/18-related cervical cancer was estimated based on the proportion of HPV 6/11/16/18 in all cervical cancers in a representative sample. Incidence was age-adjusted according to Nordic Standard Population.	Three years before Gardasil licensure (2004 to 2006) and two years after Gardasil licensure (2011 to 2012)
Incidence of HPV 6/11/16/18-related Cervical Cancer in Participants <=26 Years of Age	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The number of new cases of HPV 6/11/16/18-related cervical cancer was estimated based on the proportion of HPV 6/11/16/18 in all cervical cancers in a representative sample. Incidence was age-adjusted according to Nordic Standard Population.	Three years before Gardasil licensure (2004 to 2006) and two years after Gardasil licensure (2011 to 2012)
Incidence of HPV 6/11/16/18-related Cervical Cancer in Participants >26 Years of Age	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The number of new cases of HPV 6/11/16/18-related cervical cancer was estimated based on the proportion of HPV 6/11/16/18 in all cervical cancers in a representative sample. Incidence was age-adjusted according to Nordic Standard Population.	Three years before Gardasil licensure (2004 to 2006) and two years after Gardasil licensure (2011 to 2012)
Incidence of Cervical Cancer Associated With High-risk HPV Types Other Than 16/18 in Participants <=26 Years of Age	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The percentage of new cases of cervical cancer associated with high-risk HPV types other than 16 and 18 was estimated based on the proportion of HPV 16/18 in all cervical cancer in a representative sample. Incidence was age-adjusted according to Nordic Standard Population.	Three years before Gardasil licensure (2004 to 2006) and two years after Gardasil licensure (2011 to 2012)
Incidence of Cervical Cancer Associated With High-risk HPV Types Other Than 16/18 in Participants >26 Years of Age	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The percentage of new cases of cervical cancer associated with high-risk HPV types other than 16 and 18 was estimated based on the proportion of HPV 16/18 in all cervical cancer in a representative sample. Incidence was age-adjusted according to Nordic Standard Population.	Three years before Gardasil licensure (2004 to 2006) and two years after Gardasil licensure (2011 to 2012)
Incidence of HPV-related Histologically Confirmed Female Genital Diseases, Including Vulvar and Vaginal Cancer and Their High-grade Precursors	The incidence of HPV-related histologically confirmed female genital diseases, including vulvar and vaginal cancer and their high-grade precursors was to be assessed.	Three years before Gardasil licensure (2004 to 2006) and two years after Gardasil licensure (2011 to 2012)
Prevalence of HPV 6/11/16/18 Infection in Participants <=26 Years of Age	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The percentage of liquid-based cervical cytology samples positive for HPV 6, 11, 16, or 18 was analyzed.	Three years before Gardasil licensure (2004 to 2006) and two years after Gardasil licensure (2011 to 2012)
Prevalence of HPV 6/11/16/18 Infection in Participants >26 Years of Age	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The percentage of liquid-based cervical cytology samples positive for HPV 6, 11, 16, or 18 was analyzed.	Three years before Gardasil licensure (2004 to 2006) and two years after Gardasil licensure (2011 to 2012)
Prevalence of HPV Infection for High-risk Types Other Than 16/18 for Participants <=26 Years of Age	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The percentage of liquid-based cervical cytology samples positive for high-risk HPV Types other than 16 or 18, and not co-infected with Types 16 or 18, was analyzed.	Three years before Gardasil licensure (2004 to 2006) and two years after Gardasil licensure (2011 to 2012)
Prevalence of HPV Infection for High-risk Types Other Than 16/18 for Participants >26 Years of Age	All Nordic countries participating in this study have national cervical cancer screening programs and registry systems that routinely collect information on cervical cytology, histology, and/or definitive therapy results. In addition, lesional tissue samples were routinely collected and stored; the 2004 to 2006 period was chosen because it was sufficiently recent to reflect HPV type status immediately before licensure of Gardasil. The percentage of liquid-based cervical cytology samples positive for high-risk HPV Types other than 16 or 18, and not co-infected with Types 16 or 18, was analyzed.	Three years before Gardasil licensure (2004 to 2006) and two years after Gardasil licensure (2011 to 2012)
Percentage of Live Born Babies With a Major Congenital Anomaly	The percentage of live born babies with major congenital anomalies (MCA) born to women vaccinated with Gardasil during pregnancy and to women in the general population was assessed. For Denmark and Sweden diagnoses of congenital anomaly within 1 year of birth are included; for Norway diagnoses at birth are included.	Up to 5 years after Gardasil licensure (2007 to 2011)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Cervical Intraepithelial Neoplasia by Gardasil Vaccination Status	The incidence of CIN by Gardasil vaccination status was to be assessed.	Four years to 5 years after Gardasil licensure (2011 to 2012)
Incidence of Cervical Cancer by Gardasil Vaccination Status	The incidence of other cervical cancers by Gardasil vaccination status was to be assessed.	Four years to 5 years after Gardasil licensure (2011 to 2012)
Incidence of Other HPV-related Genital Diseases by Gardasil Vaccination Status	The incidence of other HPV-related genital diseases, including vulvar and vaginal cancers, by Gardasil vaccination status was to be assessed.	Four years to 5 years after Gardasil licensure (2011 to 2012)
Prevalence of HPV 6, 11, 16, and 18 Infection by Gardasil Vaccination Status	The percentage of participants with liquid-based cervical cytology samples positive for HPV 6, 11, 16, and 18 was to be analyzed by Gardasil vaccination status.	Four years to 5 years after Gardasil licensure (2011 to 2012)

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Collaborators: Karolinska Institutet; Danish Cancer Society; Cancer Registry of Norway; Union for International Cancer Control

Publications and helpful links

General Publications

• Bonanni P, Cohet C, Kjaer SK, Latham NB, Lambert PH, Reisinger K, Haupt RM. A summary of the post-licensure surveillance initiatives for GARDASIL/SILGARD. Vaccine. 2010 Jul 5;28(30):4719-30. doi: 10.1016/j.vaccine.2010.04.070. Epub 2010 May 6.
• Baldur-Felskov B, Dehlendorff C, Munk C, Kjaer SK. Early impact of human papillomavirus vaccination on cervical neoplasia--nationwide follow-up of young Danish women. J Natl Cancer Inst. 2014 Mar;106(3):djt460. doi: 10.1093/jnci/djt460. Epub 2014 Feb 19.
• Nygard M, Hansen BT, Kjaer SK, Hortlund M, Tryggvadottir L, Munk C, Lagheden C, Sigurdardottir LG, Campbell S, Liaw KL, Dillner J. Human papillomavirus genotype-specific risks for cervical intraepithelial lesions. Hum Vaccin Immunother. 2021 Apr 3;17(4):972-981. doi: 10.1080/21645515.2020.1814097. Epub 2020 Sep 29.

Helpful Links

• EUPAS Register (EUPAS17505)

Study record dates

Study Major Dates

• Study Start (Actual): May 29, 2007
• Primary Completion (Actual): December 2, 2014
• Study Completion (Actual): December 2, 2014

Study Registration Dates

• First Submitted: February 26, 2010
• First Submitted That Met QC Criteria: February 26, 2010
• First Posted (Estimate): March 1, 2010

Study Record Updates

• Last Update Posted (Actual): September 13, 2022
• Last Update Submitted That Met QC Criteria: August 24, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: pregnancy; GARDASIL®; population-based; Nordic; congenital anomaly
• Additional Relevant MeSH Terms: Virus Diseases; Infections; DNA Virus Infections; Tumor Virus Infections; Papillomavirus Infections
• Other Study ID Numbers: V501-033; 2010_018 (Other Identifier: Merck Registration Number); EP08014.033 (Other Identifier: Merck Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Study Data/Documents

1. CSR Synopsis