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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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GARDASIL™ Vaccine Impact in Population Study

Conditions
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Human Papillomavirus Infections

Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Pre-Vaccine<br>Registry, survey, and HPV status data from 2004-2006 | |
| Post-Vaccine<br>Registry, survey, and HPV status data from 2011-2012 | |

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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congenital anomaly, pregnancy, GARDASIL®, Nordic, population-based