Transcript Responsible Adverse Event (AE) Reporting: Finding

Responsible Adverse Event
(AE) Reporting:
Finding Appropriate AE Terms
Using CTC v2.0 and CTCAE v3.0
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Presentation Outline
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AE Reporting Background/History
AE Terminology
Physician/Investigator Responsibility
AE Grade
AE Attribution
Locating AEs Terms
Use of ‘Other, Specify’
Summary
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Background and History
Why is NCI stressing requirements for accurate,
specific AE documentation and reporting?
• It is the law – Federal Regulations
• Required of all physicians who sign
the FDA1572 investigator registration form
• Ensures human subject safety
• Facilitates accurate analysis of effects from
investigational cancer interventions
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Background and History - continued
NCI requires AE Reporting using
CTC v2.0/CTCAE v3.0 Specific Terms
Within the scope of the CTC/CTCAE:
1. AE definition
2. AE grade (seriousness) assignment
Beyond the scope of CTC/CTCAE:
1. Attribution of AE
2. Interpretation of seriousness of AE
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Background and History - continued
History of the Common Toxicity Criteria (CTC)
Since 1982, NCI CTC has been the standard for
AE reporting in the oncology community.
Historical Timeline
1982
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Adverse Drug Experience Reporting
Study Summaries
IND reports to FDA
Publications
Format:
• 18 CATEGORIES
• 49 AE Terms
• Grades:
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Grade 1 = Mild
Grade 2 = Moderate
Grade 3 = Severe
Grade 4 = Life-threatening
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Background and History - continued
1997 - CTC Review Committee assembled to revise
and expand CTC.
1998 - Introduced CTC v2.0
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24 CATEGORIES
~300 AE Terms (Acute)
Specificity
Radiotherapy
Pediatrics
Appendices
• RTOG/EORTG Late Radiation Morbidity Scoring Scheme
• BMT Complex/Multi-component Event Scheme
NCI CTC v2.0 has become the worldwide standard dictionary for
reporting acute AEs in cancer clinical trials and has been
translated into several languages – NCI and Industry.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Background and History - continued
2002 - CTEP convened a CTC Development Team (CTCDT)
consisting of independent disease and modality-specific
cancer therapy experts and NCI representatives to
oversee the creation of the Common Terminology
Criteria Adverse Event (CTCAE) v3.0.
• Update core criteria.
• Expand to create comprehensive dictionary of AEs and
grades applicable to all oncology clinical trials without
regard to:
• Chronicity
• Modality
• For criteria development, CTEP coordinated:
• Late effects
• Surgical
• Pediatric workshops
• CTCAE v3.0 is the first uniform and comprehensive dictionary
of AE grading criteria available for use by all modalities.
2003 - Introduced CTCAE v3.0.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Adverse Events
Multiple clinical terms are used to convey the occurrence
of an Adverse Event (AE):
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Side effect
Acute effect or late effect
Complication
Toxicity
Morbidity, etc.
All terms essentially point to a change possibly
caused by treatment.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Adverse Events - continued
• An AE is any unfavorable or unintended:
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Sign
Abnormal lab
Symptom
Disease
• An AE is a unique representation of a specific event used
for medical documentation and scientific analyses.
• Each AE term is mapped to a MedDRA v6.0 term and code.
• Same term and code used in Japan and the EU.
• AEs can be:
• Symptomatic or completely asymptomatic.
• Clinically or radiographically detected.
• Noted on laboratory studies or other testing.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Adverse Events - continued
What to report as an AE
• The guideline for clinicians is to capture any effect from
an intervention which may be deleterious.
• Prudent adverse event reporting requires that only AEs
that are mandated in protocols and clinically relevant
positives be documented.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Adverse Events - continued
There are multiple causes of AEs:
• Pre-existing conditions
– Hypertension
– Diabetes
• Concomitant medications
– Anticoagulants
– Steroids
• Other causes
– Transfusion reactions
– Accidental injuries
• Reporting and grading an AE simply reports that an
event occurred and the seriousness of the event.
• The clinician must assign attribution of the event,
either to the intervention or something else.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Adverse Events - continued
Physician Responsibilities in Clinical Research
• Must become familiar with the CTCAE Terms
and Grades.
• Responsible for documenting AEs that can be
verified on audit.
• Must document signs, symptoms, clinical
findings, etc. as they appear.
• Note: Realize documentation of AEs does not
necessarily imply causality to intervention or error in
administration.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Adverse Events - continued
Physician Responsibility Regarding Grade
• Document at least descriptive terms found in definitions of
Grades to enable CRAs easy identification of numeric Grade.
• Document signs, symptoms, objective measures that
characterize severity (Grade).
Refer to CTCAE descriptions of Grade.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Adverse Events - continued
Documenting Grade
• Semi-colon indicates ‘or’ within the description of the Grade.
• Em dash (—) indicates a Grade not applicable to the AE.
In the development of CTC/CTCAE careful consideration was
given to including all descriptions of events that were considered
“serious” or “life-threatening” (as defined in the FDA regulations)
in Grade 3 and 4, respectively.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Adverse Events - continued
Documenting Grade
A patient need not exhibit all elements of a Grade
description to be designated that Grade.
Example:
Induration/fibrosis (skin and subcutaneous tissue)
Grade 3:
Dysfunction interfering with ADL; very marked density,
retraction or fixation
Read as “Dysfunction ….. OR very marked……”
Interpretation:
A patient with very marked density, retraction or fixation,
but is able to perform ADLs, is Graded 3.
When a patient exhibits elements of multiple Grades,
the highest Grade is to be assigned.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Adverse Events - continued
Physician Responsibility Regarding Attribution
Physicians are to document the relationship
(ATTRIBUTION) of the protocol intervention to
each event.
Designating an event as treatment related (or not)
is done two ways:
1. By the treating CLINICIAN:
Formal “assignment” per adverse event reporting form
(“...unlikely, possibly, etc) at the time of clinical evaluation.
2. By Investigators:
Later in aggregate data review and reporting by
the Investigators.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Adverse Events - continued
Attribution Standards
1. Unrelated:
The Adverse Event is clearly not related to the investigational agent(s)
2. Unlikely:
The Adverse Event is doubtfully related to the investigational agent(s)
3. Possible:
The Adverse Event may be related to the investigational agent(s)
4. Probable:
The Adverse Event is likely related to the investigational agent(s)
5. Definite:
The Adverse Event is clearly related to the investigational agent(s)
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Locating AE Terms - Introduction
The remainder of the presentation provides instruction
to locate appropriate AE terms for use in AdEERS, CDUS,
and other CTEP data systems.
Each section illustrates the steps used to find an AE
using specific Common Toxicity Criteria v2.0 (CTC) and
Common Terminology Criteria or Adverse Event v3.0
(CTCAE) examples.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Available Tools
The following are the tools available for determining correct
AEs. Each correlates to a section within this presentation.
Section 1: CTCAE v3.0 Document Search
Section 2: CTCAE Dictionary and Index
Section 3: CTCAE Online Instructions and Guidelines
All tools are available from the CTEP Home Page at
http://ctep.cancer.gov
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Locating CTC/CTCAE Tools from the
CTEP Home Page
1. Access the CTEP Home Page.
2. Scroll halfway down the page.
3. Click on the CTCAE v3.0 link.
The CTCAE v3.0 Web page displays.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Tools available from the
CTCAE v3.0 Web page
The CTCAE v3.0 Web page
provides links to the CTCAE
v3.0 document and other
related tools, including:
1. The CTCAE v3.0 Document
2. The CTCAE v3.0 Dictionary
and Index
3. The CTCAE v3.0 Online
Instructions and
Guidelines
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Section 1
Searching the CTCAE v3.0 Document
Access the
CTCAE v3.0
Document PDF
file from the Web.
Press CONTROL +
F to open the
Search Tool.
Note: The search
tool may appear
differently
depending on the
browser you use.
Enter the term
you wish to
search and click
Search.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Section 1: Searching the CTCAE v3.0 Document - continued
The search
returns six
instances of the
AE term.
Review all to
select the most
appropriate AE
term and Grade.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Section 1: Searching the CTCAE v3.0 Document - continued
A search on the
term ‘septic’
displays eight
instances of the
AE term.
See next slide to
view the remaining
terms.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Section 1: Searching the CTCAE v3.0 Document - continued
The term ‘nonseptic’ will also
match the search
criteria and
display.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Section 2
Searching the CTCAE Dictionary
The CTCAE
Dictionary replaces
the CTC
Interactive Web
Application and
provides search
capabilities for
CTC v2.0 and
CTCAE v3.0.
When opened,
CTCAE v3.0 is
displayed by
default with the AE
Short Names listed
in alphabetical
order.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Section 2: Searching the CTCAE Dictionary - continued
•To access the CTC
v2.0 search page,
click on the CTC v2.0
tab.
•Click one of the
alphabet buttons to
limit the view
alphabetically.
•To view information
related to an AE, click
on the AE term.
The CATEGORY, full
name, grade definitions
and MedDRA codes,
along with any supraordinate terms, remarks,
and also consider
information are displayed
in the right panel.
•To view Navigation
Notes, hover the
cursor over the
icon or click the link.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Section 2: Searching the CTCAE Dictionary - continued
Search by CATEGORY
To display the list
of AEs by
CATEGORY:
1. Click the drop
down list arrow.
The list of CTCAE
CATEGORIES
display.
2. Click the
CATEGORY.
Note: To revert to
the alphabetical
list, click ‘All
Categories’ from
the drop down list.
All AEs
associated with
the CATEGORY
are displayed in
alphabetical
order.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Section 2: Searching the CTCAE Dictionary - continued
Search by Keyword
To search for a
specific AE:
1. Enter the keyword
within the Search
for field.
2. Click the Literal
button.
The term displays
highlighted in
blue.
In this example,
Rash is also
displayed as a
consideration.
Click Rash.
The term ‘Pruritus’ is listed within
the Grade 2 definition.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Section 2: Searching the CTCAE Dictionary - continued
Search by Index
To search for
related AEs:
1. Enter the keyword
within the Search
for field.
2. Click the Index
button.
Possible
appropriate AEs
are displayed.
Review all to
select the most
appropriate AE
term and Grade.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Section 3
Searching the CTCAE Instructions and Guidelines
The CTCAE
Instructions and
Guidelines
provides a wealth
of information
regarding the
CTCAE and
includes four
methods to obtain
information:
• Contents
(displays by
default)
• Index
(narrow search)
• Search
(broad search)
• Glossary
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Section 3: Searching the CTCAE Instructions and Guidelines - continued
Search on Contents
To search using
the Table of
Contents:
1. From the left panel,
click the chapter link.
The chapter opens
and displays all
available topics.
2. Click the topic link.
The topic displays in
the right panel.
3. Topics may directly
display information or
provide links to
information.
Display of related information.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Section 3: Searching the CTCAE Instructions and Guidelines - continued
Search on Index
To search using
the Index
function:
1. Click Index.
2. Either enter the
keyword in the
search field or scroll
to the term.
3. Once the term is
located, click the term
within the Index list.
4. The topic where the
term exists is
displayed. It may be
necessary to click
other links to access
the information.
Display of related information.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Section 3: Searching the CTCAE Instructions and Guidelines - continued
The Search Function
To search using
the Search
function:
1. Click Search.
2. Enter the keyword in
the search field.
3. Click Go.
All topics that include
a word(s) that match
the keyword will
display.
4. Locate and click the
topic that best meets
your information
needs.
The topic displays.
Display of related information.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
Section 3: Searching the CTCAE Instructions and Guidelines - continued
The Glossary
To use the
Glossary function:
1. Click Glossary.
2. Use the scroll bar to
locate the term
needed.
3. Click the term.
The term definition
displays in the lower
left panel.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
How and When to use the ‘Other, Specify’
Mechanism for AE Reporting
In recognition that as science and cancer treatments continue to evolve and
the potential for novel and unknown untoward affects to occur, the NCI has
incorporated a mechanism into the CTC and CTCAE to capture these
yet-to-be-defined events.
In the rare event that a suitable CTC or CTCAE term cannot be found, the NCI
allows the submitter to report the appropriate verbatim term via the
‘Other, Specify’ mechanism.
The use of the ‘Other, Specify' mechanism is an exception, not the rule.
To minimize overuse, CTEP, NCI will build rules into applications to flag and/or
reject reports that take excessive advantage of the ‘Other, Specify’ mechanism.
In addition, CTEP, NCI will closely scrutinize all AEs submitted as ‘Other, Specify’.
The investigator will be required to correct and resubmit their report if a suitable
CTC or CTCAE term is identified by CTEP, NCI staff.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
How and When to use the ‘Other, Specify’ Mechanism for AE Reporting - continued
Using the ‘Other, Specify’ Mechanism
1. If a suitable CTC or CTCAE term is not available, the investigator must make a note to this
affect in the source documentation.
2. The investigator must identify the most appropriate CTC or CTCAE CATEGORY to classify
the event.
3. Within each CATEGORY is a CTC or CTCAE term ‘Other’ (i.e., ‘Cardiac Arrhythmia – Other’).
The submitter must describe or ‘specify’ what the adverse event was. Descriptions must be
explicit and provide sufficient detail to describe the event and should be as brief as possible
(for example, two to four words).
4. Once the CTC or CTCAE CATEGORY ‘Other’ term has been selected and specified, the
submitter must ‘Grade’ the event. The grade refers to the severity of the event. The general
description of grades to be used for the ‘Other; Specify’ mechanism are as follows:
Grade 1 – Mild AE
Grade 2 – Moderate AE
Grade 3 – Severe AE
Grade 4 – Life threatening or disabling AE
Grade 5 – Death related to AE
For more information, see the Guidelines for CTC/CTCAE ‘Other, Specify’ from the CTC/CTCAE Home Page.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
How and When to use the ‘Other, Specify’ Mechanism for AE Reporting - continued
Examples of inappropriate ‘Other, Specify’
(CTC v2.0)
Inappropriate
CATEGORY
Appropriate
Other,
specify
CATEGORY
AE
MUSCULOSKELETAL
Joint pain
PAIN
Arthralgia (Joint pain)
AUDITORY/
HEARING
Tinnitus
AUDITORY/
HEARING
Inner ear/hearing
CARDIO-VASCULAR
(ARRHYTHMIA)
Heart Block
CARDIOVASCULAR
(ARRHYTHMIA)
Conduction
abnormality/Atrioventricular heart block
DERMATOLOGY/SKIN
Rash
DERMATOLOGY/
SKIN
Rash/desquamation
Grade
Grade 2: tinnitus or
hearing loss, not
requiring hearing aid or
treatment
Grade 3: tinnitus or
hearing loss, correctable
with hearing aid or
treatment
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
How and When to use the ‘Other, Specify’ Mechanism for AE Reporting - continued
Examples of inappropriate ‘Other, Specify’
(CTC v2.0)
Unsafe, Meaningless
CATEGORY
CTEP Comments
Other, specify
CARDIOVASCULAR
(ARRHYTHMIA)
Arrhythmia
Consult PI. Inappropriate, meaningless AE reporting.
When an arrhythmia is witnessed, report the specific
arrhythmia and Grade.
PULMONARY
Other
Consult PI. Inappropriate, unsafe, meaningless AE
reporting.
NEUROLOGY
Not specified
Consult PI. Inappropriate, unsafe, meaningless AE
reporting.
OCULAR/VISUAL
Name#?
Consult PI. Inappropriate, unsafe, meaningless AE
reporting.
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
How and When to use the ‘Other, Specify’ Mechanism for AE Reporting - continued
Examples of inappropriate ‘Other, Specify’
(CTCAE v3.0)
Inappropriate
CATEGORY
Other, specify
Appropriate
CATEGORY
AE
HEMORRHAGE/
BLEEDING
Hematuria
HEMORRHAGE/
BLEEDING
GU - Bladder
DERMATOLOGY/
SKIN
Leg edema
LYMPHATICS
Edema - limb
BLOOD/BONE
MARROW
Thrombocytopenia
BLOOD/BONE
MARROW
Platelets
CONSTITUTIONAL
SYMPTOMS
Jitteriness and being easily
excitable
NEUROLOGY
Mood alteration - Agitation
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
How and When to use the ‘Other, Specify’ Mechanism for AE Reporting - continued
Examples of inappropriate ‘Other, Specify’
(CTCAE v3.0)
Unsafe, Meaningless
CATEGORY
CTEP Comments
Other, specify
CATEGORY
CONSTITUTIONAL
SYMPTOMS
Fall
Consult PI. Inappropriate, meaningless AE reporting. Is
this a NEUROLOGY AE (e.g., Ataxia);
MUSCULOSKELETAL (e.g., Bruising; Fracture, etc);
PAIN?
INFECTION
E-coli
Consult PI. Where is the infection? Sepsis? Report one
of 3 available ‘Infection’ AEs and specify site.
HEMORRHAGE/BLE
EDING
PRBC transfusion
Not a CTCAE v3.0 AE
CARDIOVASCULAR
(ARRHYTHMIA)
LVEF
Refer to CTCAE v3.0 for actual AE term and select type
of dysrhythmia. Inappropriate use of Other, specify
Responsible Adverse Event (AE) Reporting:
Finding Appropriate AE Terms
How and When to use the ‘Other, Specify’ Mechanism for AE Reporting - continued
Summary: Using CTC v2.0/CTCAE v3.0
• Use CTC v2.0 or CTCAE v3.0 to locate appropriate
AE term.
• Document the grade of the AE.
• If a patient exhibits elements of multiple grades,
assign the highest grade.
• Assign attribution of the AE.
• If a CTC or CTCAE term cannot be found using
the different tools available, the ‘Other, Specify’ option
should be used.
• Grade and attribution must be assigned.
Contact the NCI CTEP Help Desk
if further assistance is needed.
Phone: 888-CTEPHLP (1-888-283-7457)
Fax: 301.948.2242
E-mail: [email protected]