Adverse event (AE) is any untoward medical occurrence including:
- undesirable signs & symptoms
- disease or accidents
- abnormal lab finding (leading to dose reduction/discontinuation/intervention)
Adverse events is typically collected after signing the informed consent form and could be related or unrelated to the study drug.
Adverse drug reaction (ADR) is defined as:
- For approved pharmaceutical product: a noxious and unintended response at doses normally used or tested in humans;
- for a new unregistered pharmaceutical product: a noxious and unintended response at any dose.
The difference between AE and ADR is that AE event does not imply causality, but for ADR, a causal rule is suspected.
Another confusion is about the term 'treatment-emergent adverse event (TEAE)'. A treatment-emergent adverse event is defined as any event not present prior to the initiation of the treatments or any event already present that worsens in either intensity or frequency following exposure to the treatments. Since the starting point for AE collection is the signing of the informed consent, not the start of the study treatment, there are some adverse events occurred prior to the initiation of the study treatment. These AEs may be called "baseline-emergent adverse event" which defined as any event which occurs or worsens during the staged screening process (after informed consent) including the randomization visit. It is common to have separate summaries for AEs occurred piror to the initiation of the treatment and AEs occurred after the initiation of the treatment (ie, summary of treatment emergent adverse events).
I was asked about a programming practice to define the TEAE used in some companies. For any AE with onset date/time after the first study drug administration date/time,they compare if there is a same AE with the same severity. If yes, AE is not counted as TEAE (even though the onset date/time is after the study drug administration). For example, a subject has a mild headache 30 days after using the study medication and subjects also has a mild headache event before using the study medication,the programming will identify this event as non treatment emergent. However I think this is wrong these are two distinct events and the second one should be counted as treatment emergent AE.
The TEAE is different from the drug-related adverse events. While the treatment emergent AEs refers to adverse events temporally related to the study treatment, the drug-related AEs refers to the causality assessment by the investigator.
28 comments:
very helpful, thx
Thank You so much, it was very helpfull.
Extremely helpful!
"However I think this is wrong these are two distinct events and the second one should be counted as treatment emergent AE. "
Please explain why you think second headache is counted as TEAE. I have one more question: If an AE is resolved prior to start of first dose and occurs after first dose with same AETOXGR, do we flag this as TEAE?
Because the second headache is considered as new event, not a continuation of the previous headache. Since the second headache occurred after the study drug, it should be considered as 'treatment-emergent'.
"If an AE is resolved prior to start of first dose and occurs after first dose with same AETOXGR" is self-contradicting. If an AE is resolved, any new event should be considered as a new AE. If you considered the new event as the continuation of the previous AE, you should not say 'an AE is resolved...'.
Thanks for this! It also might help to distinguish TEAE and ADR using placebo. Patients in the placebo group can experience TEAEs, but not ADRs
Hi All -
the last comment is interesting! Do you know when a sponsor reports blinded SUSAR reports (control group is either Placebo or other Medication) - do they break the code (unblind) when writing the SUSAR report in order to classify the event as Suspected Adverse Reaction?
J.
Hi All -
the last comment is interesting! Do you know when a sponsor reports blinded SUSAR reports (control group is either Placebo or other Medication) - do they break the code (unblind) when writing the SUSAR report in order to classify the event as Suspected Adverse Reaction?
for SUSAR reporting, the guidance below contains instructions about the unblinding.
http://ec.europa.eu/health/files/clinicaltrials/pc_final_06-2010_en.pdf
clinical trial if this is relevant to the safety of the clinical trial participant.
94. As regards the sponsor, when an event may be a SUSAR the blind should be broken
by the sponsor only for that specific patient. The blind should be maintained for
persons responsible for the ongoing conduct of the study (such as the study
management, monitors, investigators) and those responsible for data-analysis and
interpretation of results at the conclusion of the study, such as biometrics personnel.
Unblinded information should only be accessible to those who need to be involved
in the safety reporting to EVCTM, national competent authorities, investigators,
ethics committees and Data Safety Monitoring Boards29, or persons performing
ongoing safety evaluations during the trial.
95. However, for trials in high morbidity or high mortality disease, where efficacy endpoints
could also be SUSARs or when mortality or another ‘serious’ outcome (that
may potentially be reported as a SUSAR) is the efficacy endpoint in a clinical trial,
the integrity of the clinical trial may be compromised if the blind is systematicallybroken. Under these and similar circumstances, it may be appropriate to reach
agreement in the authorisation process which serious events that would be treated as
disease-related and not subject to systematic unblinding and expedited reporting.
96. For such trials, sponsors are strongly encouraged to appoint an independent Data
Monitoring Committee in order to review safety data on the ongoing trial on a
regular basis and when necessary to recommend to the sponsor whether to continue,
modify or terminate the trial. The composition and operation of a Data Monitoring
Committee must be described in the protocol. Following unblinding, if the event turns out to be a SUSAR, the reporting rules for
SUSARs apply (see sections above). For cases where the SUSAR becomes apparent only after the trial has ended, reference is made to section 4.2.4.
Why should we call all untoward medical (abnormalities) occurances before the treatment has started as Adverse event .
According to ICH GCP, all abnormalities (untoward medial occurances) after the pharmaceutical administration are defined as adverse events.
Therefore all abnormalities only after study drug is given should be considered as adverse events.
The abornomalities occured before the study drug treament should not be called as Adverse Events.
It is not written in any guidelines (ICH GCP or any regulatory guielines) that all the abnormalities after the inform consent is signed should be treated as adverse events.
Why should we call all untoward medical (abnormalities) occurances before the treatment has started as Adverse event .
According to ICH GCP, all abnormalities (untoward medial occurances) after the pharmaceutical administration are defined as adverse events.
Therefore all abnormalities only after study drug is given should be considered as adverse events.
The abornomalities occured before the study drug treament should not be called as Adverse Events.
It is not written in any guidelines (ICH GCP or any regulatory guielines) that all the abnormalities after the inform consent is signed should be treated as adverse events.
Why should we call all untoward medical (abnormalities) occurances before the treatment has started as Adverse event .
According to ICH GCP, all abnormalities (untoward medial occurances) after the pharmaceutical administration are defined as adverse events.
Therefore all abnormalities only after study drug is given should be considered as adverse events.
The abornomalities occured before the study drug treament should not be called as Adverse Events.
It is not written in any guidelines (ICH GCP or any regulatory guielines) that all the abnormalities after the inform consent is signed should be treated as adverse events.
It is true that the definition of adverse event from ICH suggest only the events occurred after the drug administration - similar to our definition of treatment emergent adverse events. However, in practice, the term 'adverse event' also refers to the side effects occurred during the screening period (after the signing of the informed consent and prior to the administration of the study treatment). Any untoward medical (abnormalities) occurances due to the screening procedures will be collected as adverse events - eventually will be categorized as non-treatment-emergent adverse events.
Thanks for all for your thoughts on adverse event.
After going through your discussion, I can summarise that, any abrnormalities occured between informed consent and before first dose could be related to past medical history/ongoing medical history /clinical event related to disease under study/base line values for efficacy and saftey parameters. Since the variables(data) collected about these event (which happened before first dose of study drug) are same as adverse event,we use the same form (adverse event form)though technically these event are not adverse event Since adverse event forms are used to collect these data, industry is treating these events as adverse events which actually is not as per regulatory guidelines.
Thefore these abnormailities can be called as medical history/clinical event/baseline values for efficacy or saftey/Non treatment emergent adverse event. But should not be called as adverse event.
Note: I apologise as my English is not good.
Thanks for all for your thoughts on adverse event.
After going through your discussion, I can summarise that, any abrnormalities occured between informed consent and before first dose could be related to past medical history/ongoing medical history /clinical event related to disease under study/base line values for efficacy and saftey parameters. Since the variables(data) collected about these event (which happened before first dose of study drug) are same as adverse event,we use the same form (adverse event form)though technically these event are not adverse event Since adverse event forms are used to collect these data, industry is treating these events as adverse events which actually is not as per regulatory guidelines.
Thefore these abnormailities can be called as medical history/clinical event/baseline values for efficacy or saftey/Non treatment emergent adverse event. But should not be called as adverse event.
I had a similar discussion on whether the same event reported before study drug administration and after study drug administration should be counted as treatment-emergent AE some time ago and fully agree with your recommendation.
I'm currently also interested to know your opinion on another topic. If a patient with a treatment-emergent event that ocurred during the follow up period (i.e. 30 days after last study drug administration)dies due to this event after the follow up period (i.e. more than 30 days after last study drug administration), should this death be considered treatment-emergent / on-therapy death?
Thanks,
"If a patient with a treatment-emergent event that ocurred during the follow up period (i.e. 30 days after last study drug administration)dies due to this event after the follow up period (i.e. more than 30 days after last study drug administration), should this death be considered treatment-emergent / on-therapy death?"
if the protocol specified the AE collection period will include 30 day follow-up period after the last study drug administration, if the reported AE that occurred within the reporting period causes the death, a SAE should be reported.
The reporting period post study drug (one week, 30 days or longer) varies depending on the drug and the study design.
Do you consider con medications and treatment medications the same?
if 'treatment medications' means the study medication, con medications are the medications other than the study medication used during the study. Therefore, the "con medications" and "treatment medications" are not the same.
Your information about events is really interesting. Thanks for posting this informative article.
Event organizers in Chennai
In sdtm till now i did nt heard about baseline emergency adverse events
Ajay is correct. There is no such thing as a TEAE in any regulatory guidance or practice. Adverse events only occur in subjects taking investigational products, not at the time of screening. Any event that occurs before a subject begins study treatment is considered a medical history finding. Companies that collect AEs at the point of signing an ICF are incorrect, which led to the creation of TEAE as a way to distinguish pre-treatment events from post-treatment.
The best and most accurate way to classify adverse events is to follow ICH definitions and regulatory practice (i.e. After subjects take IP). This way your statisticians will not need to program separate tables for AE vs TEAE. All AEs by classic definition are indeed TEAE because they occur after dosing. Anything that occurs before is a medical history finding.
Hope this clarifies the confusion that has plagued our industry!
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Very informative articlWe are an educational consultancy agency based in UAE. We help students those are seeking to get admission in top institutes. specially for Study Medicine in Europe in English.e i am not finished this yet will continue reading
Please comment if this is correct use of TEAE? This is three year trial but study drug stopped at year 2. NO study drug given throughout year three. Are the AEs observed in Year 2 to YEAR 3 AEs or TEAEs? Does it depend on how TEAEs were defined? For both placebo and PREVIOUSLY TREATED groups? thank you
Thank you very much!! Very helpful!
In reply to "anonymous" at 12.07 above.. While conceptually the statement is true, practically ICH also requires sponsors to protect subjects from the procedures associated with the trial.
This is why companies collect all events from the time of consent.
It is a matter of ethical compliance and not an "incorrect" interpretation of the guidance.
Clive.
Very helpful, thank you.
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