Adverse event / serious adverse event data entry when death event occurs

If the death event is an efficacy endpoint in the study, should the death event still be reported as AE/SAE? 

If the death (or mortality) is an efficacy endpoint, the death event will ordinarily not be reported as AE/SAE. Only in some special situation, for example, a death due to anaphylactic reaction, car accident,... that are not related to the underlying disease, will the death be reported as AE/SAE. 

FDA's guidance Safety Reporting Requirements for INDs and BA/BE Studies clearly stated this: 

Generally, study endpoints refer to outcomes that sponsors are measuring to evaluate efficacy. For trials designed to evaluate the effect of a drug on disease-related mortality or major morbidity, endpoint information should be collected, tracked, and monitored, usually by a Data Monitoring Committee (DMC), during the course of the study. The protocol would prespecify a monitoring plan for determining whether subjects receiving the drug treatment are at higher risk for the outcome (e.g., all-cause mortality), and such results would be reported according to the protocol. The study endpoints must be reported to FDA by the sponsor according to the protocol, and ordinarily would not be reported as IND safety reports, except when there is evidence suggesting a causal relationship between the drug and the event (21 CFR 312.32(c)(5)). For example, a death ordinarily would not be reported as an individual case in an expedited report from a trial designed to compare all-cause mortality in subjects receiving either drug treatment or a placebo. On the other hand, in the same trial with an all-cause mortality endpoint, if the death occurred as a result of an anaphylactic reaction that coincided with initial exposure to the drug, or as a result of fatal hepatic necrosis, the death must be reported as an individual case in an IND safety report because there would then be evidence suggesting a causal relationship between the drug and the event (21 CFR 312.32(c)(5)).  

In our clinical trial "Dinutuximab and Irinotecan Versus Irinotecan to Treat Subjects With Relapsed or Refractory Small Cell Lung Cancer", the overall survival (time to death) was the primary efficacy endpoint. The death event would not be reported as AE/SAE and not recorded on AE/SAE case report form. It would be odd and inappropriate to record the AEs like "Death due to disease progression', 'death due to small cell lung cancer', 'death due to the underlying disease'. With Death being an efficacy endpoint, the death information should be recorded on separate case report form - Death Details form according to CDASH. 

Should death be reported as an event or an outcome of an AE/SAE?

Usually, when death event occurred, there were the adverse events leading to the death. The adverse event leading to the death will need to be reported as series adverse event with fatal outcome. The death is the outcome of a SAE and is not entered as an adverse event on its own. 

There are situations that the death is instantaneous or within very short period (for example one hour) of onset of symptoms or an unobserved cessation of life that cannot be attributed to a specific AE term. The death in this situation will be reported as Sudden Death or Sudden Death NOS on the AE case report form. 

If there are multiple ongoing AEs at the time of trial participant's death, should all these ongoing AEs be considered as SAEs with fatal outcome? 

This issue was discussed in a previous post "Recording the outcome for AE/SAE when multiple events contribute to Death". It is preferred in my opinion that a single AE/SAE should be identified as the primary cause for the death. This AE/SAE will have the fatal outcome recorded on the AE case report form. Other ongoing AEs at the time of death will have the AE outcome recorded as 'not recovered/not resolved"

How to fill out other fields on AE forms when death event occurs? 

As discussed above, for AE outcome, 'Fatal' should be selected for the AE/SAE that directly or primarily contribute to the study participant's death. 

For other ongoing AEs at the time of death, the AE outcome 'Not recovered or Not Resolved' should be selected.  

'Action Taken with Study Treatment' is another field on AE form and it is difficult to decide which choice should be selected when a death event occurs. 

At the time of death, there are two appropriate choices for 'Action Taken with Study Treatment": Dose Not Changed or Drug Withdrawn. Which choice to select depends on the sequence of the events: the last dose date/time in relevance to the death date/time. Assuming a study treatment with QD dose frequency, if the last dose date is the same as the death date or if the last dose date is one day prior to the death date, it is reasonable to assume that there is no dose withdrawn. Therefore, it is appropriate to select 'Dose Not Changed' for 'Action Taken with Study Treatment' field. On the other hand, if the last dose date is two days or earlier than the death date, it is appropriate to select 'Dose Withdrawn' for 'Action Taken with Study Treatment' field.