Download Adverse Event Assessing, Recording, and Reporting

PREP Course #10:
Adverse Event Assessing,
Recording, and Reporting
Presented by:
Sharon Hochman
CME Disclosure Statement
•
•
•
The North Shore LIJ Health System adheres to the ACCME’s new Standards for
Commercial Support. Any individuals in a position to control the content of a CME
activity, including faculty, planners, and managers, are required to disclose all financial
relationships with commercial interests. All identified potential conflicts of interest
are thoroughly vetted by the North Shore-LIJ for fair balance and scientific objectivity
and to ensure appropriateness of patient care recommendations.
Course Director and Course Planner, Kevin Tracey, MD and Tina Chuck, MPH have
nothing to disclose.
Sharon Hochman has nothing to disclose
Objectives
• Definitions and terminologies
• How to identify and access the safety
events
• How to record the safety events
• How to report the safety events
• Case study
FDA Safety Reporting:
AE & SAE Definitions
Adverse
Event
Serious
Adverse
Event
• An adverse event is any undesirable experience
associated with the use of a medical product in a
patient
• Reported on the source documents, CRFs.
• Defined as death; or a life threatening experience;
• hospitalization (for a person not already hospitalized);
prolongation of hospitalization (for a patient already
hospitalized);
• persistent or significant disability or incapacity; congenital
anomaly and/or birth defects;
• or an event that jeopardizes the subject and may require
medical or surgical treatment to prevent one of the
preceding outcomes.
• Reported on the source documents, SAE report
What is an adverse event
• Any change in the subject health, a new symptom,
an accident or new diagnosis after the subject has
received a drug or device or during a medical
procedure
• These are documented for all device or drug trials
while subjects on study
• They are classified by grade 1-5, or mild, moderate
or severe and death. Relationship to the
experimental drug or device must be included
FDA definitions
• FDA regulations use different terms when
referring to an adverse event. For example,
adverse effect is used in 21 CFR 312.64;
adverse experience is used in § 312.32;
and unanticipated problems is used in §
312.66. For the purposes of this guidance,
the term adverse event is used, except
when quoting specific regulations. For
device studies, part 812 uses the term
unanticipated adverse device effect, which
is defined in 21 CFR 812.3(s).
FDA Inspection
• “Failure to prepare and submit complete and
accurate and timely reports of unanticipated
adverse device effects”
Expected Vs. Unexpected
• Expected
– Known to Occur and
is Listed in the
Investigational
Brochure, Informed
Consent, or General
Investigational Plan
• Unexpected
– Not listed in
Investigational
Brochure, Informed
Consent, or General
Investigational Plan
– Also not listed in a
drug package insert
Unanticipated problems
• Report as an unexpected problem
• Related to participation in research
• Placed subject at a greater risk of
physical harm than was previously
known
Examples would be:
• A single occurrence of a serious, unexpected event that
is uncommon and strongly associated with drug
exposure
• A single occurrence, or a small number of occurrences,
of a serious, unexpected event that is not commonly
associated with drug exposure, but uncommon in the
study population
• An AE that is described or addressed in the
investigator’s brochure, protocol, or informed consent
documents, but occurs at a specificity or severity that
is inconsistent with prior observations.
Identifying and assessing safety events
• AEs can be directly observed by research staff or
reported by research subjects.
• If a subject experiences a change in condition
during the course of participation, the change
may constitute an AE. Changes can take two
forms:
1) The appearance of a new symptom or sign
or
2) The increased severity or frequency of an existing
symptom or sign
Examples :
Examples of observed AEs include
• A rash noted during a physical examination
• An abnormal laboratory result
• A headache that the subject mentions during a study visit
Examples of Adverse Events which are not related
to [or caused by] the study drug but if they occur
while the subject is on study, would have to be
collected, reviewed by PI and tracked:
• Transfusion reactions
• Accidental injuries
• Surgery
Attribution
• What should the investigator consider prior to
assigning attribution?
– Individual medical history
– Known effects of concomitant medications
– Trends in adverse events for their study.
Attribution
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Definite – Clearly related to study agent
Probable – Likely related to study agent
Possible – May be related to study agent
Unlikely – Doubtfully related to study agent
Unrelated – Clearly not related to study agent
• Classifying AE’s
•On the Common Terminology Criteria
for Adverse Events (CTCAE ) scale, AE’s are
assigned a grade based on their severity.
•Grade 1- Mild
•Grade 2-Moderate
•Grade 3-Severe
•Grade 4-life threatening or disabling
Monitoring studies
• Monitoring is done to ensure safety of the
subjects in the clinical studies. Separate safety
and clinical study conduct monitoring is done.
Data Safety Monitoring board (DSMB)
• A DSMB is an independent group of people
that reviews on a regular basis accumulating
data from a clinical study.
• They must have no involvement with the
conduct of the study
DSMB
• The DSMB should review each protocol for any
major concern prior to implementation. During
the trial, the DSMB should review cumulative
study data to evaluate safety, study conduct, and
scientific validity and integrity of the trial.
• There are 3-7 members and one must be a
biostatistician. None of them should have direct
involvement with the conduct of the study.
Most common monitoring findings
• not recording ALL AEs regardless of causality or severity to look for
trends over time
• ignoring reports of minor seemingly unrelated events like stomach
aches or dizziness
• not having appropriate CRFs to document AE assessments - we
always try to suggest using the Common Terminology Criteria
for Adverse Events (CTCAE):
• not having delegation or appropriate clinician to assess AEs - AE
CRFs signed off by coordinators lacking source documentation for
assessment of severity or significance
• Lab results outside of normal range are often not assessed by
clinician
• inadequate documentation in the protocol to define AE severity
and SAE reporting criteria
When do you start communicating about the AE?
• AE’s should be captured starting at the baseline visit
• PI should always be notified as soon as an AE is identified
regardless of the casuality or type.
• Discussions should occur with the sponsor and study team .
• PI determines need to Update informed consent, or protocol
if multiple similar events happen
• Patients can be educated to be aware of symptoms that may
be associated with an adverse reaction.
Subject diary
Monitoring tips
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•
•
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Reviewing AEs is a priority for monitors
All AEs must have source documentation (e.g. clinic note, medical record)
It is essential to have the patient’s medical record available for review by the
monitor (to make sure none are missed)
The monitor can provide advice on completing the AE case report form properly
When in doubt, ask your monitor or the sponsor about how to complete the AE
Case Report Form
The monitor can also connect you with the sponsor’s medical director if requested.
Serious & Life-Threat
Case Report Forms Completion
Participating Sites
• Case Report Forms will be completed by the local PI and/or
his/her designee at each subject visit. For Multi center
studies, Case Report forms will be sent to the Coordinating
Center, where they will perform data integrity monitoring
through cross-checking and source documentation.
GCP CRF Tips
• The investigator should ensure the accuracy, completeness,
legibility, and timeliness of the data reported to the sponsor
in the CRFs and in all required reports (GCP E6 4.9.1).
• Data reported on the CRF, that are derived from source
documents, should be consistent with the source documents
or the discrepancies should be explained (GCP E6 4.9.2).
• Any change or correction to a CRF should be dated, initialed,
and explained (if necessary) and should not obscure the
original entry; this applies to both written and electronic
changes or corrections. The investigator should retain records
of the changes and corrections (GCP E6 4.9.3).
• Ink should be used when completing paper CRFs. Pencil and
correction fluid should not be used.
Source Documentation
• Source Documentation of adverse events include
documentation in the medical records of:
– Event
– Date it occurred
– Grade as determined by CTCAE
– Expected or Unexpected
– Attribution as assigned by PI
– Date resolved
– Treatment patient received specifically related to
event
Source Documents
The foundation of study data:
• Where information was first recorded - Original documents, data, and
records to supports subject eligibility, enrollment, and protocol required
data
• Monitors will need to view Source and compare to completed CRFS and
Eligibility determinations
Medical
records
Clinical &
office
charts
X-rays,
ECGs,
scans
Progress
notes
Labs
Rx
Notes to file
27
Fundamental Elements of Data Quality
A
• Attributable – Does the documentation clearly
demonstrate who created the record and when,,
what happened, and when it occurred?
L
• Legible – Can the information be easily read
and understood?
C
• Contemporaneous - Was the information documented
with timeliness?
• Complete – Does the documentation include all of the
necessary information?
O
• Original – Did you maintain the “source” of the
information (see GCP Glossary, Sections 1.51 and 1.52)?
A
• Accurate – Does the information
represent what actually happened?
Adapted from - FDA - GUIDANCE FOR INDUSTRY - COMPUTERIZED SYSTEMS USED IN CLINICAL TRIALS - ALCOA
http//www.fda.gov/downloads/ICECI/EnforcementActions/BioresearchMonitoring/UCM133749.pdf
Sample Adverse Event Recording Form
The following are required when completing an AE
form
• Date of onset
• Description
• Grading
• Relatedness
• Expected/unexpected
• Treatment
• Resolution date/outcome
Reporting
Reporting Serious Events
• An investigator must promptly report to the
sponsor any adverse effect that may
reasonably be regarded as caused by or
probably caused by the drug. If the adverse
effect is alarming, the investigator shall report
the adverse effect immediately.
– 21CFR312.64
Reporting Criteria
• Routine Reporting
– Know which events can be reported at interim analysis or
annual reviews
• Expedited Reporting
– Know which events require immediate reporting
Safety Reporting Requirements
.
This is the responsibility
of the sponsor not each
investigator
• Investigator must immediately report all
unanticipated problems and deviations
involving risk to subjects or others, serious
adverse events related to participation in
the study and subject deaths related to
participation in the study
• Major protocol/consent modifications
related to change of safety information
Reporting timelines example
What Event is Reported
When is Event Reported
Fatal or life-threatening unexpected,
suspected serious adverse reactions
Within 7 calendar days of initial
receipt of information
Non-fatal, non-life-threatening
unexpected, suspected serious
adverse reactions
Within 15 calendar days of initial
receipt of information
Unanticipated adverse device effects
Within 10 working days of
investigator first learning of effect
Unanticipated Problem that is not an
SAE
Within 14 days of the investigator
becoming aware of the problem
All Unanticipated Problems2
Within 30 days of the IRB’s receipt of
the report of the UP from the
investigator.
Reporting Criteria
• Know which type of expedited reports each
regulatory body requires
– FDA
– Sponsor
– Co-Sponsor
– IRB
FDA IND Safety Report Criteria
Three Criteria:
1. Suspected adverse reaction
2. Serious
3. Unexpected
Issues in reporting
• Often times, patients are admitted with one
diagnosis such as this one. Following
admission, secondary events are found.
• All of these can be reported using one form
Consequences of Improper Reporting
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Protocol Violations
IRB may suspend protocol
FDA Hold
Sponsor Hold
Research Privileges Revoked
Patient Safety
Multi center trial rules
• Sponsors are specifically required to notify all
participating investigators (and FDA) in a written IND
safety report of “any adverse experience associated
with the use of the drug or device that is both serious
and unexpected” and “any finding from tests in
laboratory animals that suggests a significant risk for
human subjects” (§ 312.32(c)(1)(i)(A),(B)). And, more
generally, sponsors are required to “keep each
participating investigator informed of new
observations discovered by or reported to the sponsor
on the drug, particularly with respect to adverse effects
and safe use” (§ 312.55(b)).
Possible Adverse event???
• Phase 2 study of an antihypertensive
agent
•3/10 subjects develop GERD within a
week of starting the drug
Take home points…
• Record all AEs and report as appropriate and
according to guidelines
• Report to FDA annual safety reports when
applicable
• Protocol should include appropriate safety
language and reporting criteria and
timeframes and safety monitoring process