DARWIN EU® Effectiveness of Human Papillomavirus Vaccines (HPV) to prevent cervical cancer

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Effectiveness study (incl. comparative)
• If ‘Not applicable’, further details on the study type:
  New user matched cohort study; Complex
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

  Other
• Non-interventional study design, other:
  New user matched cohort study; Complex

Study drug and medical condition

• Medicinal product name:
  CERVARIX

  GARDASIL

  GARDASIL 9

  SILGARD
• Medicinal product name, other:
  - human papillomavirus vaccine [types 16, 18] (recombinant, adjuvanted, adsorbed); - human papillomavirus vaccine [types 6, 11, 16, 18] (recombinant, adsorbed); - human papillomavirus 9-valent vaccine (recombinant, adsorbed); ;
• Anatomical Therapeutic Chemical (ATC) code:
  (J07BM01) papillomavirus (human types 6, 11, 16, 18)

  papillomavirus (human types 6, 11, 16, 18)

  (J07BM02) papillomavirus (human types 16, 18)

  papillomavirus (human types 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):
  Invasive cervical cancer and CIN2+

Population studied

• Short description of the study population:
  All females aged 9 years or older on any date after the launch of the vaccination programme in any of the contributing datasets and with at least 365 days of prior data availability at the beginning of vaccination programme launch date in their country of residence will be eligible. The analysis will be further restricted to matched cohorts of vaccinated and unvaccinated participants with similar baseline characteristics.
• Age groups:
  • Children (2 to < 12 years)
  • Adolescents (12 to < 18 years)
  • Adult and elderly population (≥18 years)

    • Adults (18 to < 65 years)

      • Adults (18 to < 46 years)
      • Adults (46 to < 65 years)
    • Elderly (≥ 65 years)

      • Adults (65 to < 75 years)
      • Adults (75 to < 85 years)
      • Adults (85 years and over)

Study design details

• Study design:
  New-user matched cohort study
• Outcomes:
  The main outcome of interest is invasive cervical cancer. Two secondary outcomes are also considered: CIN2+ and conization. These outcomes will be phenotyped and diagnostics will be carried out.
• Data analysis plan:
  All analyses will be conducted separately for each database, and carried out in a federated manner, with effectiveness estimates meta-analysed and the I2 heterogeneity coefficient reported. ; ; We will conduct a propensity score (PS) matched cohort design, where target and comparator cohort participants will be matched 1:5. ; Matching will be done based on PS, year of birth, year of first dose (for analyses not involving dose number) and geographic region using nearest neighbor matching, with caliper width 0.2 standard deviations as is standard for propensity score matching. ; Large-scale PS will be estimated using lasso regression to estimate the probability of being in the target cohorts, potentially including any of the covariates mentioned above. ; ; The following matched cohorts will be compared: ; Main comparisons: ; Vaccinated vs unvaccinated per brand: ; - Vaccinated with Gardasil/Silgard (target) (1 or more dose) vs unvaccinated (comparator) ; - Vaccinated with Cervarix (target) (1 or more dose) vs unvaccinated (comparator) ; - Vaccinated with Gardasil-9 (target) (1 or more dose) vs unvaccinated (comparator) ; Secondary comparisons: ; - Vaccinated (target) (1 or more dose) (any brand) vs unvaccinated (comparator) overall. ; Dose comparisons: ; - Vaccinated with 2 or more doses (target) vs 1 dose (comparator) of the same brand. ; - Vaccinated with 3 or more doses (target) vs 2 doses (comparator) of the same brand.