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GCP Workshop: Ethics Committee Members
Serious Adverse
Events
C.Adithan
Objectives
To make the EC members understand the
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importance of adverse event (AE)
differences between AE and ADR
importance of serious adverse event (SAE)
regulatory requirements in reporting SAE
Investigator’s responsibility in SAE
sponsor’s responsibility in SAE
timelines for SAE reporting
responsibilities of IEC in case of SAE
Adverse Event (AE)
Any untoward medical occurrence including
• undesirable signs & symptoms
• disease or accidents
• abnormal lab. finding ( leading to dose
reduction / discontinuation / intervention
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during treatment with a pharmaceutical product in
a patient or a human volunteer that does not
necessarily have a relationship with the treatment
given.
• After signing the Informed Consent Form
• Related / unrelated to the study drug
Adverse Events: Sources
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Hospital / physician / nurses notes
Patient’s diaries
Assessment forms
Concomitant medications (indications)
Abnormal lab. results
Reasons for withdrawal and drop outs
Missed visits
Adverse Events: Why to report ?
• Ethical requirements
• Regulatory requirements
• Legal requirements
A joint responsibility of the
sponsor & the investigator
Adverse Drug Reaction (ADR)
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
A response to a drug which is noxious & unintended
and which occurs at doses normally used for prophylaxis,
diagnosis or therapy of a disease or for modification of a
physiological function.
--- WHO
What is the difference between AE and ADR?
AE event: does NOT imply Causality
ADR: A causal role is suspected
Serious Adverse Event (SAE)
An AE or ADR that is associated with
• Death
• Inpatient hospitalization
• Prolonged hospitalization
• Persistent or significant disability or incapacity
• Congenital anomaly or birth defect
• Otherwise life threatening
---- GCP guidelines
What is a life threatening event?
Places the patient , in the view of the
investigator, at immediate risk of
death from the event as it occurred
Does not include an event that,
had it occurred in a more severe form,
might have caused death
AE is reported: What next?
• Evaluate AE based on protocol &
seriousness of the event
• Medical care for the subject
• Document appropriately
• Notify sponsor & others
• Verify and maintain all data contained in
CRF & supporting source documents
Adverse Event Recording
• Duration (Date of onset & resolution)
• Severity (Mild, Moderate, Severe)
• Assessment (Serious / Non serious)
• Relationship to study medication
(Suspected / Not suspected)
• Action taken (discontinued/dose )
• Outcome (Recovered, Improving, Unchanged,
Deteriorated, Permanent Disability,
Death, Unknown)
When to record AE?
Do complete an SAE form if:
 an adverse event caused the patient
to be hospitalized
 the hospitalization is related to a
deterioration of the disease state
under investigation or a pre-existing
condition
When not to record AE?
Do not complete an SAE form if the hospitalization:
• was planned prior to the patient entering the study
• is part of the regular treatment for the disease
under study and there is no deterioration e.g.
seizure monitoring
• occurs for a situation that is elective in nature
• involved only treatment in the emergency room
and no admission as an in-patient, unless other
criteria of seriousness are met
SAEs – What to report ?
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Minimal information for “regulatory” reporting
 an identifiable patient
 an investigational drug
 an identifiable reporter
 a serious adverse event
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Initial SAE form to be sent as soon as the above
minimum information is available
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Recurrent episodes or complication of a previous
reported SAE occurring at different time intervals should
be always reported as a follow-up (= regulatory
requirement)
Data Elements for reporting SAE
Patient details: Pt. identifier, initials, sex, age, Wt. etc
Suspected drug: generic name, indication, dates of
admin., dose, starting & stopping date and time
Other treatments
Details of suspected ADR
Outcome
Details about the investigator
Date reporting to Licensing authority
Date reporting to Ethics Committee
Signature of the Investigator
Schedule Y, 20, January 2005
WHO causality algorithm
• Certain
 Temporal relationship
• Probable
• Possible
 Concomitant Medication
• Unlikely
 +Ve De-Challenge
• Unclassifiable
 +Ve Re-Challenge
 Concurrent Illness
Investigator Notification / Alert
If an SAE is:
‘serious’
‘unlabelled’ (i.e. not noted in the Investigator’s Brochure)
and ‘suspected’ of being related to trial drug
An Investigator Notification may be issued to:
• keep the investigator aware of potential safety issues
• enable sponsor to meet it’s global regulatory requirements
(An IN does not necessarily mean that the
SAE was caused by the trial drug)
Investigator’s responsibilities
Record all AEs in the CRF
Report all SAEs immediately to sponsor
Ensure adequate follow-up and
inform sponsor
Report the event to IEC
Report any Investigator Notifications to IEC
Sponsor’s responsibilities
Adequate training of investigator and team
Expeditious reporting of all SAEs to HA
verification of the SAE Form data against
source documents
Consistency of SAE Form data with the CRF data
Generate “Investigator Notifications”
when required
Generate periodic safety updates
Timelines for Reporting SAE
IEC
Sponsors
24 h
Investigator
7 days
notices SAE
14 calendar days
DCGI
What Ethics Committee can do?
• Modification
of Protocol
• Updating the clinical IB
• Obtaining additional consent from
ongoing Patients
• Stopping the study
Group Exercises
Thank you...