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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