For all adverse events including serious adverse events in
clinical trials, severity (or intensity) should be assessed and recorded. AE
severity used to be called AE intensity. Nowadays, severity is more commonly
used. The assessment of severity is based on the investigator’s clinical
judgement, therefore, there are lot of subjective judgement in the AE severity
assessment/reporting.
There seems to be three different grading scale in assessing/recording the severity:
Mild, Moderate, and Severe
This is commonly used in non-oncology studies. The
definition of the mild, moderate, and severe may be different from one study protocol
to another. The severity (intensity) of each AE including SAE recorded
in the CRF should be assigned to one of the following categories:
- Mild: An event that is easily tolerated by the subject,
causing minimal discomfort and not interfering with everyday activities.
- Moderate: An event that is sufficiently discomforting to
interfere with normal everyday activities.
- Severe: An event that prevents normal everyday activities.
or
- Mild: awareness of sign or symptom, but easily tolerated
- Moderate: discomfort sufficient to cause interference
with normal activities
- Severe: incapacitating, with inability to perform normal
activities
CTCAE
In oncology clinical trials, the AE severity is usually graded
according to NCI’s AE Severity Grading Scale -
Common Terminology
Criteria for Adverse Events (CTCAE). CTCAE can also be used to grade the AE
for non-oncology studies, but generally not appropriate for studies using
healthy volunteers.
- Grade 1 Mild; asymptomatic or mild symptoms; clinical or
diagnostic observations only; no intervention indicated
- Grade 2 Moderate; minimal, local or noninvasive intervention
indicated; limiting age-appropriate instrumental ADL
- Grade 3 Severe or medically significant but not immediately
lifethreatening; hospitalization or prolongation of hospitalization indicated;
disabling; limiting self care ADL
- Grade 4 Life-threatening consequences; urgent intervention
indicated.
- Grade 5 Death related to AE.
Vaccine's Trials
- Mild (grade 1)
- Moderate (Grade 2)
- Severe (Grade 3)
- Potentially Life Threatening (Grade 4)
In statistical summaries, the grade 1 is counted as ‘mild’,
the grade 2 as ‘moderate’, >= grade 3 will be counted as ‘severe’.
During the course of an adverse event, the severity may change
– which may have impact on how we report the adverse event.
In one of the previous posts ‘
SAE
Reconciliation and Determining / recording
the SAE Onset Date’, we discussed that an AE with the change in seriousness
might need to be split into two events for recording: one non-serious AE with
onset date of the first sign/symptom and one serious AE with onset date of the
event meeting one of the SAE criteria. The similar issue arises when we try to
record the AE with severity change.
The most common instruction for AE recording is that when
there is severity change, a new AE should be recorded. Here are some example instructions:
Start Date
Record the date the adverse event started. The date should
be recorded to the level of granularity known (e.g., year, year and month,
complete date) and in the specified format. If a previously recorded AE
worsens, a new record should be created with a new start date. There should be
no AE start date prior to the date of the informed consent. Any AE that started
prior to the informed consent date belongs instead in the medical history. If
an item recorded on the medical history worsens during the study, the date of
the worsening is entered as an AE with the start date as the date the condition
worsened.
End Date
Record the date the adverse event stopped or worsened. The date should be recorded to the level of
granularity known (e.g., year, year and month, complete date) and in the
specified format. If an AE worsens,
record an end date and create a new AE record with a new start date and
severity.
If the AE increases in severity per the DAIDS Grading Table,
a new AE Log CRF should be completed to document this change in severity.
the eCRF Completion Guidelines for adverse events: Enter a new event if action taken,
seriousness, causality, severity (intensity), etc. changes over the course of
an adverse event. A timestamp for any changes in events can be seen in
the data via event start/stop dates.
However, this way of recording the adverse events may result
in splitting the single event into multiple adverse events and may result in over
reporting in the number of adverse events.
Suppose the subject experienced a headache adverse
event, the event started with mild intensity, then progressed to moderate, and
then went back to the mild intensity. Should this headache be reported
as three separate adverse events (two with mild severity and one with moderate
severity)? or Should it be reported as single event with moderate severity?
This question was submitted to FDA and the FDA response (see the link below) suggested
that this should be reported as one event (with the maximum severity)
The second question and answer explicitly stated:
Question 2:
[Redacted] is the sponsor of the study. We have been advised by our data coordinating center to record an AE that changes in severity as two AEs instead of 1 AE - starting a new AE each time the severity changes. This convention is different than that of our previous coordinating center and has caused us great concern.
Answer 2:
We have concerns that an approach to adverse event reporting as you described below (i.e., a change in severity of an adverse event necessitates a new adverse event report) may inaccurately reflect the adverse event profile for the product. Therefore, we strongly recommend that you contact the FDA review division regulating this clinical investigation for additional input on the most scientifically and medically sound approach to the adverse event reporting specifically for this trial.
Question:
We constantly run into the issue how to record the
adverse event in the database in the situation there is a severity change or
seriousness change during the course of the adverse event.
A subject in clinical trial reported a mild headache. Two
days later, the headache became moderate in severity. Then headache became mild
in severity again.
In this case, shall we record this as one headache event
with moderate severity or record as three headache events (a new event is
record whenever there is a severity change)?
Similarly, a subject in clinical trial reported a
non-serious adverse event. Several days later, subject needs to be hospitalized
for this adverse event – now the event meets the seriousness criteria.
In a situation of a non-serious adverse event becoming
serious, shall we record it as a single AE with seriousness or shall we record
as two separate AEs (one non-serious AE and one serious AE)?
OC-GCP Response:
Given your brief description that the subject's headache is ongoing,
it would seem that this adverse event would best be reported as a single event
with variable severity. However, the clinical judgment of the principal
investigator (or, if the principal investigator is not a clinician, then a
physician consultant to the research) would be helpful in clarifying the
symptoms and hence the reporting of the adverse event(s). There are several
cogent clinical scenarios the understanding of which would require more
information than you have supplied. For example, the subject's symptomatology
could represent an unremitting headache of several days duration or episodic
headaches of finite duration with varying intensities or a symptom of another
event altogether such as a change in blood pressure, etc. The same would apply for
the hospitalization event.
To best sort out the adverse event(s) itself and therefore
the appropriate reporting, I would recommend a clinical assessment of the
headache. In addition, the protocol may have detailed how adverse events should
be reported. As well, the sponsor (I'm not sure of [Redacted] status in this
trial, i.e., is/is not the sponsor) may have specifications for adverse event
reporting that could guide you. If you still feel uncertain, I would strongly
recommend contacting the FDA review division regulating this trial.
Lastly, if it becomes apparent that this same "fact
pattern" recurs, it may be advisable for the sponsor to clearly articulate
standards for adverse event reporting such that there can be consistency in reporting
of headaches.
From the statistical analysis standpoint, whether or not it is
recorded as one event with maximum severity or multiple events with various
seventies do not have impact on our calculation of the incidence of AEs.
However, it will have great impact on the calculation of the number of AEs.
It is the common understanding that if an event recorded on the
medical history worsens during the study or after the initiation of the study
drug, a new AE should be recorded and the date of the worsening is entered as the
new AE onset date
