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
• Main study objective:
  Main objectives: ; 1. To assess the effectiveness of HPV vaccination in prevention of invasive cervical cancer, stratified by licenced vaccine brand. ; 2. To assess the effectiveness of HPV vaccination in prevention of CIN2+, stratified by licenced vaccine brand. ; 3. To assess the effectiveness of HPV vaccination in prevention of conisation, stratified by licenced vaccine brand. ; Secondary objectives: ; • To assess the effectiveness of HPV vaccination regardless of the brand or schedule for each of the three outcomes (i.e. invasive cervical cancer, CIN2+ and conisation) ; • To assess the effectiveness of HPV vaccination in prevention of invasive cervical cancer, CIN2+ and conisation separately in subgroups defined by number of doses, within each brand.
• Setting:
  This study was conducted using routinely collected data from 3 databases in 3 European countries.
• 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.
• Summary results:
  CONCLUSION ; We were unable to assess the causal effect of HPV vaccines against cervical cancer using a target trial emulation design due to limited number of outcomes and limited available follow-up to account for the long cancer latency period post-vaccination. For CIN2+ and conisation, vaccine effectiveness seems in the lower range of what is known with the evidence from clinical trials but is potentially underestimated by differences in screening rates between vaccinated and unvaccinated groups.