Adverse Event and Reporting

Requirements
Module 4

Ana Doris Gómez Granados, MSc

Research Quality Specialist

All Rights Reserved by PRCCI, 2022

 Objectives

• Define and classify an adverse event

• Examples of adverse event
• Distinguish “routine” adverse events from serious adverse events.
• Serious Adverse Event (SAE) Definition
• Unexpected Adverse Event Definition
• Adverse drug reaction definition
• Discuss the process for soliciting and capturing adverse events including
determination of causal links with a drug/device
• Specify differences between the drug and device regulatory definitions
and reporting requirements.

All Rights Reserved by PRCCI, 2022

Adverse Event - Definition

ICH Definition (ICH E6 1.2)

“Any untoward medical occurrence in a patient or clinical

investigational subject administered a pharmacological
product and which does not necessarily have a causal
relationship with this treatment.”

FDA Definition (21 CFR 312.32)

“Any untoward medical occurrence associated with the use of

a drug in humans, whether or not considered drug related.”

All Rights Reserved by PRCCI, 2022

Adverse Event - Definition

An AE

May be a worsening of a condition

that was present at the beginning of
the study.

May also be any “Unwanted effects”:

Symptoms (e.g., headache, nausea, dizziness)
Physical findings (e.g., increased blood pressure, hair loss)
Syndromes or diseases (e.g., flu syndrome, development of
diabetes, etc.)

All Rights Reserved by PRCCI, 2022

The Data Triangle

AEs

Baseline
Medical
Conditions
Concomitant
Medications
All Rights Reserved by PRCCI, 2022
 Examples

• Concurrent illness.
• Worsening of pre-existing • Increase in frequency or intensity
illness of a pre-existing condition
• Events related to concomitant • A condition first detected after
medications - Drug interaction administration of the study drug
• Signs and symptoms • Hypersensitivity
• Physical findings • Medical effects of an overdose
• Syndromes or new diseases
• Laboratory abnormalities

All Rights Reserved by PRCCI, 2022

Adverse Drug Reaction - Definition

Both definitions imply there is a causal relationship

between the IP and the adverse event

ICH - Adverse Drug Reaction (ADR)

All noxious and unintended responses to a medicinal product related to any
dose

FDA – Suspected Adverse Reaction

Any adverse event for which there is a reasonable possibility that the drug
caused the adverse event

All Rights Reserved by PRCCI, 2022

Unexpected Adverse Event - Definition

Unexpected Adverse Event:

The nature or severity of the
experience or event is not
consistent with the applicable
product information.
(such as the Investigator Brochure-IB)

All Rights Reserved by PRCCI, 2022

Unexpected Adverse Event

Unexpected Adverse Event or Experience:

Also refers to an AE or suspected adverse reaction that may
be mentioned in the IB as occurring in a class of drug but
are not specifically mentioned as occurring with the drug
under investigation

All Rights Reserved by PRCCI, 2022

Unexpected Adverse Event

Sponsor is required to
submit safety report to
FDA and participating
investigators within 15
calendar days.
• Form 3500A (MedWatch)
• CIOMS

All Rights Reserved by PRCCI, 2022

Serious Adverse Event (SAE) - Definition

Is considered “serious” if, in the view of the investigator or

sponsor, it results in:

• Death
• A life-threatening event
• Disability/incapacity
• Requires or prolongs hospitalization
• Congenital anomaly/birth defect

All Rights Reserved by PRCCI, 2022

Serious Adverse Event (SAE) Categories

Life Threatening
Hospitalization
The subject was, in the view of the
Usually doesn’t apply to pre-planned
investigator or sponsor, its occurrence places
hospitalizations or emergency room visits
the subject at immediate risk of death

Death
Fatality itself isn’t the SAE
but the cause/condition
that led to death

Significant Disability / Incapacity Congenital Anomaly/Birth Defect

Substantial disruption of a person’s ability to Usually, pregnancy in a study subject is not
conduct normal life functions reported as an AE/SAE (may be captured
separately) but a birth defect in the subject’s
child is an SAE

All Rights Reserved by PRCCI, 2022

Identifying AEs and SAEs

Adverse Events can be found in…

• Patient Questionnaires
• Patient Diaries
• Progress notes in patient medical file
• New concomitant medications
• Checklists of symptoms
• Other study specific source documents

All Rights Reserved by PRCCI, 2022

SUSAR: FDA Definition
Drug Regulations: Serious and
Unexpected Suspected Adverse Reaction
- 21 CFR 312.32(c)(1)(i)
• Meets SAE definition
• Reasonable possibility that the drug caused the
adverse event
• Is unexpected
• Requires Safety Report – a special notice to
Investigators and the FDA of new safety
information about the drug

All Rights Reserved by PRCCI, 2022

 Common AE Issues
• Sites not documenting all AEs

• Site doesn’t supply full medical record for monitoring

• Site fails to capture detailed baseline health

• A patient experiences a bleeding stomach ulcer which requires hospitalization; the

event recorded on the AE CRF page should be “bleeding stomach ulcer”, not
“hospitalization”.

• An Alzheimer’s patient is transferred to a nursing home. If this is due to death of a

caretaker, this is not an AE. If this is due to worsening or deterioration of patient’s
baseline condition, then this would be considered an AE.

All Rights Reserved by PRCCI, 2022

Recording AEs in Source Documents

• Document the AE in the words of the

subject.
• Advantages
• Challenges

• These terms may then need to be clarified

in the CRF to comply with the “coding
dictionary”.

All Rights Reserved by PRCCI, 2022

All Rights Reserved by PRCCI, 2022
Adverse Event CRF
Evaluation: Adverse Event
Severity

Causality

Treatment of adverse event

Action taken with

investigational product

Outcome

All Rights Reserved by PRCCI, 2022

 Adverse Event – Severity
“Severe” is an intensity classification.
✓“Severe” events are not necessarily “serious”. Severity (Oncology Study)
✓A subject could experience severe itching,
but this is not life threatening, doesn’t result Grading Severity
in hospitalization, etc.; Grade 1 Mild
✓Therefore, the event does not meet the Grade 2 Moderate
definition of “serious” and doesn’t have to be Grade 3 Severe
reported in an expedited fashion.
Grade 4 Life-threatening or
Disabling
Severity
Grade 5 Death
Mild
Moderate
Severe
All Rights Reserved by PRCCI, 2022
Adverse Event – Causality

Suspected of being related to IP Not suspected of being related to IP

Makes a causal relationship Makes a causal relationship
possible unlikely

No standard nomenclature
✓ Definite The CRC can not assess causality
✓ Probable
✓ Possible
✓ Not Related

All Rights Reserved by PRCCI, 2022

21
 Adverse Event -Treatment of AE

❖ None
❖ Medication – ensure collected
❖ Procedure – ensure collection
❖ Hospitalization – ensure SAE
reporting
 Adverse Event – Action taken with IP

• IP withdrawn
• IP interrupted
• IP dose reduced
• IP dose increased
• IP dose unchanged or none
• Unknown

All Rights Reserved by PRCCI, 2022

Adverse Event – Outcome

Resolved

Resolved with Sequela

Resolving

Ongoing

Fatal

All Rights Reserved by PRCCI, 2022

Adverse Event CRF
Evaluation: Adverse Event
Severity

Causality

Treatment of adverse event

Action taken with

investigational product

Outcome

All Rights Reserved by PRCCI, 2022

 BREAK

All Rights Reserved by PRCCI, 2022

All Rights Reserved by PRCCI, 2022
REPORT

All Rights Reserved by PRCCI, 2022

AE Follow-up Requirements

How long post-study termination must AEs be followed and/or

reported?

• SAEs typically followed until resolution or have become chronic

• “Routine” AEs are usually no longer captured except for those

collected during protocol-required follow-up visit.

• 30 days after the last dose of IP and depends on the known

half-life of the product.

All Rights Reserved by PRCCI, 2022

Drug Reporting Requirements
Investigator to the IRB
• Individual IRBs have their own procedures for what is an
unanticipated problem and in what timeframe reporting is
required.
Investigator to Sponsor
• The investigator is required to report all SAEs to the
sponsor, upon becoming aware of the event
regardless of whether the investigator believes that they are
drug related, including those events listed in the IB.

Promptly report all adverse drug reactions that are

both serious and unexpected – 24 hour.
All Rights Reserved by PRCCI, 2022
SAE – Reporting and Follow Up
Promptly report all adverse drug reactions that are both
serious and unexpected – 24 hour.

• If there is additional or updated information to be reported

regarding an event, the CRC will send the information per the
requirements of the sponsor
The original form might be updated, or a separate update
form may be required

• CRA should communicate with the CRC to ensure any protocol

or other guidance is followed for the timeliness of follow-up
reports
All Rights Reserved by PRCCI, 2022
Consequences of Inadequate Safety Reporting

• Patient safety may be compromised

• Safety profile may be adversely affected
• IRB/IEC may request an Investigator audit
• Regulatory authority may conduct an inspection of the
site and/or the sponsor
• Site may be cited for regulatory non-compliance
• Site data may be dropped from study analysis
• May lead to non-approval of product

All Rights Reserved by PRCCI, 2022

Reference documents

• https://www.fda.gov/drugs/surveillance/questions-and-answers-fdas-
adverse-event-reporting-system-faers

• file:///C:/Users/Ana%20Gomez/Downloads/Participant%20Safety%20&a
mp%3B%20Adverse%20Events.pdf

• https://www.tga.gov.au/publication/note-guidance-good-clinical-practice

• ICH Guideline for Good Clinical Practice | Therapeutic Goods

Administration (TGA)

All Rights Reserved by PRCCI, 2022

All Rights Reserved by PRCCI, 2022
Thanks

All Rights Reserved by PRCCI, 2022