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.
- 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
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.
In FDA’s guidance on vaccine trials “Toxicity GradingScale for Healthy Adult and Adolescent Volunteers Enrolled in PreventiveVaccine Clinical Trials”, the AE severity based on clinical abnormalities and laboratory abnormalities was graded as
- 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:
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.
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:
[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.
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.
I recently submitted this same question to FDA’s OC GCPQuestions and Answers and got the following response:
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)?
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