Study type

Study topic

Human medicinal product

Study type

Non-interventional study

Scope of the study

Disease epidemiology
Effectiveness study (incl. comparative)

Data collection methods

Secondary use of data
Non-interventional study

Non-interventional study design

Ecological
Other

Non-interventional study design, other

Population-based nested case-control study
Study drug and medical condition

Name of medicine

GARDASIL
GARDASIL 9

Name of medicine, other

- human papillomavirus vaccine [types 6, 11, 16, 18] (recombinant, adsorbed)
- human papillomavirus vaccine [types 6, 11, 16, 18, 31, 33, 45, 52, 58] (recombinant, adsorbed)

Anatomical Therapeutic Chemical (ATC) code

(J07BM01) papillomavirus (human types 6, 11, 16, 18)
papillomavirus (human types 6, 11, 16, 18)
(J07BM03) papillomavirus (human types 6, 11, 16, 18, 31, 33, 45, 52, 58)
papillomavirus (human types 6, 11, 16, 18, 31, 33, 45, 52, 58)

Additional medical condition(s)

Recurrent respiratory papillomatosis
Population studied

Short description of the study population

Inclusion Criteria:
Primary objective: All females 15-29 years of age after 2006 and eligible for HPV vaccination at <17 years of age, i.e., birth cohorts 1990 and later.
Secondary objective: All individuals (males and females) 0-29 years of age between the following calendar years and birth cohorts:
- Sweden: 2000 – 2021 (birth cohort, 1971 – 2021)
- Denmark: 1997 – 2022 (birth cohort, 1968 – 2022)
- Norway: 2008 – 2022 (birth cohort, 1979 – 2022)

Exclusion Criteria:
- Subjects who receive a first diagnosis of RRP before age 15 will be excluded for primary analysis
- Subjects who immigrated to Sweden or Denmark after 2006, or to Norway after 2008, and age 9 years
- Subjects who receive the bivalent vaccine Cervarix

Age groups

Term newborn infants (0 – 27 days)
Infants and toddlers (28 days – 23 months)
Children (2 to < 12 years)
Adolescents (12 to < 18 years)
Adults (18 to < 46 years)

Estimated number of subjects

15000000
Study design details

Study design

The study design includes population-based nested case control study, and population-based ecological study

Main study objective

The main objective is to assess if the odds of AoRRP among females fully vaccinated with GARDASIL™ or GARDASIL™9 before the age of 17 years versus those unvaccinated.

Setting

Nordic population, patient, and vaccine registries

Comparators

For each case of AoRRP, 10 control subjects free of this diagnosis will be randomly selected from the underlying population at risk in the respective countries, using incidence density sampling procedures. Matching criteria will be age at diagnosis, calendar year, region where case was diagnosed, and length of follow-up.

Outcomes

Primary objective: A subject will be defined as having a first case of AoRRP if she has > or = 1 hospitalization or outpatient record with diagnosis registered as ICD-10 code D14.1 along with appropriate topography/morphology or SNOMED/Norpat codes as deemed necessary by experts, between 15-29 years of age.

Secondary objective:
All subjects will be defined as having a case of JoRRP if he/she has > or = 1 hospitalization or outpatient record with diagnosis registered as D14.1 along with appropriate topography/morphology or SNOMED/Norpat codes as deemed necessary by experts, with a first diagnosis of this condition before 15 years of age.

All subjects will be defined as having a case of AoRRP if he/she has > or = 1 hospitalization or outpatient record with diagnosis registered as D14.1 along with appropriate topography/morphology or SNOMED/Norpat codes as deemed necessary by experts, with a first diagnosis of this condition after 15 years of age and before 30 years of age.

Data analysis plan

Primary objective: Conditional logistic regression will be used for estimation of odds ratios (ORs) and corresponding 95% confidence intervals in the pooled analysis using 1-step approach, with adjustment for clustering and adjustment for relevant covariates; all measured with similar high accuracy in each country. Descriptive statistics will be calculated for the epidemiological measures of interest for cases and controls for age, education level (subject/mother), and income (individual/family) using t-test or chi-2-test for differences in continuous and categorical variables, as appropriate.

Secondary Objective: Annual age-standardized incidence rates (ASIRs) of JoRRP and AoRRP will be calculated, stratified by age group, gender, and calendar period and the p-values from the test for calendar year trends for these rates will be estimated. Confidence intervals will be calculated.