Traditionally clinical operations and drug safety / pharmacovigilence departments have elected to independently collect somewhat different sets of safety data from clinical trials. For serious adverse events (SAE), drug safety / pharmacovigilence department will collect the information through the SAE form and the information will be maintainted in a safety database. In clinical operation or data management departments, the adverse events (AE) including SAEs will be collected on case report form (CRFs) or eCRFs if it is an EDC study. For SAEs, the information from safety database and clinical database come from the same source (the investigational sites). During the study or at the end of the study, the key fields regarding the SAEs from two independently maintained databases will need to be reconciled and the key data fields must match in both databases.
A poster by Chamberlain et al “Safety Data Reconciliation for Serious Adverse Events (SAE)” has nicely described the SAE reconciliation process. They stated that for these fields to be reconciled, “some will require a one to one match with no exception, while some may be deemed as acceptable discrepancies based on logical match. “
They also gave examples for fields which require an exact match or logical determination are in the following Table 1
Among these fields, the onset date is the one usually causing problems. It is due to the different interpretation of the regulatory guidelines by the clinical operations and the drug safety/pharmacovigilence departments. The onset date of SAE could be reported as the first date when signs and symptoms appears or as the date when the event meets one of the following SAE criteria (as defined in ICH E2A).
* results in death,
* is life-threatening,
* requires inpatient hospitalisation or prolongation of existing hospitalisation,
* results in persistent or significant disability/incapacity, or
* is a congenital anomaly/birth defect.
Klepper and Dwards did a survery and published their results in their paper “Individual Case Safety Reports – How to Determine the Onset Date of an Adverse Reaction”. The results indicated the variability of determining the onset date of a suspected adverse reaction. They recommend that a criterion for onset time, i.e., beginning of signs or symptoms of the event, or date of diagnosis, be chosen as the standard.
However, many companies and organizations (such as NIH and NCI) indicated in their SAE completion guidelines that event start date should be the date when the event satisfied one of the serious event criteria (for example, if criteria “required hospitalization” was met, the date of admission to the hospital would be the Event Start Date). If the event started prior to becoming serious (was less severe), it should be recorded on the AE page as non-serious AE with a different severity.
In NIDCR Serious Adverse Event Form Completion Instructions, SAE onset date is to “record the date that the event became serious”
In SAE Recording and Reporting Guidelines for Multiple Study Products by Division of Microbiology and Infectious Disease, NIH, the onset date of SAE is instructed to be the date the investigator considers the event to meet one of the serious categories
In the HIV Prevention Trials Network, Adverse Event Reporting and Safety Monitoring section indicated that
“If an AE increases in severity or frequency (worsens) after it has been reported on an Adverse Experience Log case report form, it must be reported as a new AE, at the increased severity or frequency, on a new AE Log. In this case, the status outcome of the first AE will be documented as “severity/frequency increased.” The status of the second AE will be documented as “continuing”. The outcome date of the first AE and the onset date of the new (worsened) AE should be the date upon which the severity or frequency increased.”
In Serious Adverse Event Form Instructions for Completion by National Cancer Institute Division of Cancer Prevention, the event onset date is to be entered as the date the outcome of the event fulfilled one of the serious criteria.
In Good Clinical Practice Q&A: Focus on Safety Reporting in Journal of Clinical Research Best Practice, it contains the following example for reporting SAE onset date.
“What would an SAE’s onset date be if a patient on study develops symptoms of congestive heart failure (CHF) on Monday and is admitted to the hospital the following Friday?
If known, the complete onset date (month-day-year) of the first signs and/or symptoms of
the most recent CHF episode should be recorded. In this case, it would be Monday. If the
onset date of the first signs and/or symptoms is unknown, the date of hospitalization or
diagnosis should be recorded.”
If the SAE onset date is recorded as the date when one of the SAE criteria is met (this seems to be more popular in practice), it may essentially require the splitting of the event. If an event start as non-serious and later on meet one of the serious criteria, the same event will be recorded as two events: one as non-serious event with onset date being the first sign and symptom date and one as serious adverse event with the onset date being the date when one of the SAE criteria is met. Therefore this approach results in a late onset date and a short SAE duration; but double counting perhaps the same event.
If the SAE onset date is recorded as the date when the first sign or symptom appears, it will result in an early onset date and a longer SAE duration. Since SAE reporting to the regulatory authorities / IRBs is based on the SAE onset date, this may be more stringent in meeting the SAE reporting requirement.