The European Medicines Agency (EMA) and the European Medicines Regulatory Network established a coordination centre to provide timely and reliable evidence on the use, safety and effectiveness of medicines for human use, including vaccines, from real world healthcare databases across the European Union (EU). This capability is called the Data Analysis and Real World Interrogation Network (DARWIN EU®).

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Self-controlled case risk interval

Study Type/s

Self-controlled case risk interval studies are classified as ‘complex’ analyses.

Study Design

Self-controlled case risk interval (SCRI).

Participant/s

Just like SCCS, SCRI studies include one or more cohort/s of people who suffer a specified safety event/group of event/s at least once in their record/s. Additional eligibility criteria could apply based on socio-demographics or clinical characteristics.

Follow-up

The SCRI design uses a pre-specified control interval relative to the exposure (typically vaccination) date as the control time. These control intervals can be before or after exposure, but must be defined a priori. We will therefore pre-define study-specific follow-up pre- and/or post-exposure control interval periods, and participants will be followed/observed for the pre-specified control interval, and immediately after/during exposure to a medicinal product. Similar to SCCS, the specified control interval (either pre- and/or post-exposure) periods will be considered as “baseline” or “unexposed”, whilst treatment episode/s are “exposed”.

Outcome/s

One or more study outcomes will be pre-specified, based on previous DARWIN EU algorithms or newly developed and validated ones. Ideally, outcomes should be acute in presentation and with a clear and accurate diagnosis date.

In addition, a long list of negative control outcomes will be assessed, which are not known to have a causal association with the drug/s or medicinal product/s under study.

Analyses

Details will be discussed during programming of pipelines, but SCRI will include:

  • Large-scale characterisation of SCRI participants at the time of diagnosis, including all recorded features available in the data before or on index date, based on SNOMED code/s
  • Pre-specified patient-level characteristics on and/or before diagnosis, based on pre-existing cohorts or definitions (e.g., history of type 2 diabetes, or Charlson comorbidity index).
  • Pre-specified patient-level characteristics on and/or before diagnosis, based on concepts and descendants where no previously validated algorithms are available
  • Incidence rate/s during pre-specified control interval and exposed time
  • Diagnostic/s:
    • Event-exposure independence: a histogram of the time between the event date and the end of observation for individuals censored and uncensored will be plotted to assess for potentially event-dependent observation time
    • Analyses will not be conducted where there is insufficient data, based on a pre-specified minimum detectable rate ratio (e.g., MDRR>5)
    • Optional: In addition to the two above, residual confounding/systematic error will be available for estimation, as based on the number of negative control outcomes significantly associated with the exposure of interest
  • Incidence rate ratios and 95% confidence intervals will be estimated using conditional Poisson regression models, comparing the exposed vs the control interval period.
  • Adjusted incidence rate ratios and 95% confidence intervals will be calculated after adjustment for age and seasonality
  • Optionally, calibrated incidence rate ratios will be estimated after empirical calibration of the adjusted incidence rate ratio based on the observed systematic error
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