Saturday, January 28, 2012

Recording the outcome for AE/SAE when multiple events contribute to Death

In clinical trials, death event may occur. According to CDISC CDASH standards, death should not be recorded as an adverse event (AE) or serious AE, but should be recorded as the outcome of the event. The condition that resulted in the death should be recorded as the AE/SAE.

In the case of multiple AE/SAEs contributing to the fatal (death) outcome, there seem to be two different ways in recording the AE outcome. There is no clear regulatory guideline in detail about this situation. The most closely related guideline may be from the ICH E2B where it states:

B.2.i.8 Outcome of reaction/event at the time of last observation
  •  recovered/resolved
  •  recovering/resolving
  •  not recovered/not resolved
  •  recovered/resolved with sequelae
  •  fatal
  •  unknown

User Guidance:
In case of irreversible congenital anomalies the choice, not recovered/not resolved should be used.
Fatal should be used when death is possibly related to the reaction/event. Considering the difficulty of deciding between "reaction/event caused death" and "reaction/event contributed significantly to death", both were grouped in a single category. Where the death is unrelated, according to both the reporter and the sender, to the reaction/event, death should not be selected here, but should be reported only under section B.1.9.
In practice, one way is to record multiple SAEs and record 'fatal' for each of these SAEs. The drawback of this approach is to have multiple SAEs with 'fatal' outcome for the same subject while subject can only die once.

Another way is to identify one SAE as the principal cause of the death. In this case, only will one SAE have the outcome recorded as Fatal. The subject can only die once so it makes sense to record ‘fatal’ as the outcome for the principal event  The question is that what the appropriate outcome should be for other SAEs that may also contribute to the death event. If there is an 'Ongoing' option in the list of AE outcomes, the appropriate choice may be 'ongoing' indicating that the SAE is ongoing during the time of death. If there is no choice of 'ongoing' in the AE outcome list (as specified in E2B above), the most appropriate choice seems to be "not recovered/not resolved" indicating that the SAE is still not resolved during the time of death. For AE stop time, the principal SAE with fatal outcome should be the time of death. For other SAEs contributing to death, the stop time may be appropriately recorded as 'ongoing' instead of recording the death time as the SAE stop time.

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