Adverse Events:
An Update
Elizabeth Ness, RN, MS
Director, Staff Development
Center for Cancer Research
National Cancer Institute
Objectives
• Describe factors that precipitated CTCAE v3.0 Revision
Project
• Define MedDRA and list major components of MedDRA
• Summarize major AE term issues regarding CTCAE v3.0
and MedDRA
• State sources and purpose of CTCAE v4.0 AE term
definitions
• Describe characteristics of general descriptions of
CTCAE v4.0 Grading Scale
• Differentiate between Instrumental ADLs and Self care
ADLs
• Describe various resources for CTCAE
• Discuss MedDRA versioning related to CTCAE
Background
• 1982/1983: Common Toxicity Criteria (CTC) used to aid in
the recognition and grading severity of adverse events
(AE) of chemotherapy
• List of AE terms commonly encountered in oncology and
each AE is accompanied by a grading (severity) scale
• Fundamentally intended to be an agreed upon terminology
for the designation, reporting and grading of AEs that occur
in oncology research
CTCAE v3.0 Historical Components:
AE Term, Short Name, Grade; Remark; Also Consider;
Navigation Note…
…CTCAE v3.0 Historical Components:
Supra-ordinate & Select Terms, …
…CTCAE v3.0 Historical Components:
Other, specify
Medical Dictionary for
Regulatory Activities (MedDRA)
• Clinically validated international medical
terminology
• Adverse event classification dictionary endorsed by the
International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for
Human Use (ICH)
• Used by regulatory authorities and the regulated
biopharmaceutical industry throughout the entire
regulatory process
• from pre-marketing to post-marketing activities
• data entry, retrieval, evaluation, and presentation
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CTCAE v3.0 Impetus for Revision
• April 2006: MedDRA MSSO (Maintenance and
Support Services Organization) Blue Ribbon Panel
determined that a mechanism to “translate” or
“convert” CTCAE terms to MedDRA terms must be
established in order to facilitate data exchange
within internal databases and between investigators
and regulatory authorities for the purpose of Serious
Adverse Event (SAE) reporting
• CTEP and FDA agreed on a CTCAE redesign to be
harmonized with MedDRA at the AE term level
March 22, 2010
http://evs.nci.nih.gov/ftp1/CTCAE/Documentation/CTCAE_Governance_2010-03-11.doc
MedDRATM Structure and
Content
SOC (26)
HLGT (>300)
HLT (>1,600)
PT (>18,000)
LLT(>86,000)
‘Fatigue’ hierarchy displayed
SOC
HLGT
HLT
PT
LLT
CTCAE Revision Project
June 2008 – June 2009
• Organized and funded by CBIIT, NCI
• CTEP collaboration
• Participants – FDA, Industry, MedDRA MSSO,
Cancer Centers, Others
• Working Groups (~140 members)
• Content expertise based on MedDRA SOCs
• Steering Committee ( 40 members)
• Governance Group (25 members)
• Harmonization with MedDRA
• 100% single concept MedDRA terms
• Isolate critical concepts as unique AE terms
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Comparison
MedDRA to CTCAE
MedDRA
List of terms
>86,000
Content: Comprehensive
--Multiple translations
Hierarchy: 5 levels
Medically validated
---
CTCAE v4.0
List of MedDRA LLTs
790
Content: Oncology
Severity Scale
English; Japanese
Hierarchy: 2 levels
--Includes definitions
CTCAE v4.0
MedDRA SOC Replaces v3.0 CATEGORY…
CTCAE v3.0 CATEGORY (Count 28)
CTCAE v4.0 SOC (Count 26)
AUDITORY / EAR
Ear and labyrinth disorders
DERMATOLOGY / SKIN
Skin and subcutaneous tissue disorders
ENDOCRINE
Endocrine disorders
INFECTION
Infections and infestations
PULMONARY / UPPER
RESPIRATORY
Respiratory and thoracic disorders
VASCULAR
Vascular disorders
…CTCAE v4.0
MedDRA SOC Replaces v3.0 CATEGORY
CTCAE v3.0 CATEGORY
CTCAE v4.0 SOC
CARDIAC ARRHYTHMIA
Cardiac disorders
CARDIAC GENERAL
Nervous system disorders
NEUROLOGY
Psychiatric disorders
v3.0 CATEGORIES Deleted in v4.0…
CTCAE v3.0 CATEGORY
CTCAE v4.0 SOC
General disorders and
administration site conditions
Death NOS
Death neonatal
Sudden death NOS
Pregnancy, puerperium and
perinatal conditions
Fetal death
DEATH
GROWTH AND
DEVELOPMENT
PAIN
CTCAE v4.0 AE Term
Musculoskeletal and connective
tissue disorders
System – specific SOC:
Ear and labyrinth disorders;
Gastrointestinal disorders;
Renal and urinary disorders;
Musculoskeletal and connective
tissue disorders etc.
…v3.0 CATEGORIES Deleted in v4.0
CTCAE v3.0
CATEGORY
CTCAE v4.0 SOC
Blood and lymphatic system disorders
Cardiac disorders
Immune system disorders
Metabolism and nutrition disorders
SYNDROMES
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Nervous system disorders
Respiratory, thoracic and mediastinal disorders
Skin and subcutaneous tissue disorders
Vascular disorders
CTCAE v3.0 AE Term Issues
Related to MedDRA
• CTCAE v3.0 AE Terms
• Multiple concepts
• One/many element of Grade description is
critical AE concept
• Not all MedDRA terms
• 72% CTCAE = ‘mapped’ to a single MedDRA
term/code
• 28% CTCAE = CTEP-only code (leading 9’s with
meaning to no one outside CTEP)
CTCAE v3.0
Multiple Concepts in one AE Term
Mapped to MedDRA: Fatigue 10016256
Fatigue, Asthenia, Lethargy, Malaise
•Are unique concepts in MedDRA (PTs)
•Are not
–related to a single Preferred Term
–synonyms, lexical variants, or quasi-synonyms
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MedDRA Preferred Term
Fatigue + 20 LLTs
Primary SOC
General disorders and administration
site conditions
LLTs
MedDRA Preferred Term
Malaise + 12 LLTs
Primary SOC
General disorders and administration
site conditions
LLTs
MedDRA Preferred Term
Lethargy + 3 LLTs
Primary SOC
Nervous system disorders
LLTs
MedDRA Preferred Term
Asthenia + 20 LLTs
LLTs
Primary SOC
General disorders and administration
site conditions
CTCAE v3.0
Critical concept listed in Grade only –
not as AE Term
CTCAE v4.0 Revision
Allergic reaction/hypersensitivity
• SOC: Immune system disorders
• Allergic reaction
• Anaphylaxis
CTCAE v3.0 Issue
Non-MedDRA Terms + CTEP-Only Codes
INFECTION CATEGORY
CTCAE v3.0 Count of 77 INFECTION terms
99% map to MedDRA
CTCAE v3.0 INFECTION CATEGORY
• Infection with unknown ANC – Conjunctiva
• MedDRA: Conjunctivitis infective -10010742
• Infection (documented clinically or
microbiologically) with Grade 3 or 4 neutrophils
(ANC <1.0 x 10e9/L) – Conjunctiva
9
codes
• Infection with normal ANC or Grade 1 or 2
neutrophils - Conjunctiva
CTCAE v4.0 Hemorrhage AE Terms
CTCAE v4.0 SOC
AE Count
Eye disorders
1
Gastrointestinal disorders
17
Hepatobiliary disorders
1
Injury, poisoning and procedural
complications
6
Nervous system disorders
1
Renal and urinary disorders
1
Reproductive system and breast
disorders
6
Respiratory, thoracic and mediastinal
disorders
Total
5
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Comments
The word ‘bleeding’ is used instead of
hemorrhage for 3 AE Terms:
CTCAE v4.0 Pain AE Terms
CTCAE v4.0 SOC
AE Count
Blood and lymphatic system disorders
1
Cardiac disorders
1
Ear and labyrinth disorders
2
Eye disorders
1
Gastrointestinal disorders
9
General disorders and administration site
conditions
3
Hepatobiliary disorders
2
Musculoskeletal and connective tissue disorders
7
Neoplasms benign, malignant and unspecified
(incl cysts and polyps)
1
CTCAE v4.0 Pain AE Terms
(continued)
CTCAE v4.0 SOC
AE Count
Nervous system disorders
2
Renal and urinary disorders
1
Reproductive system and breast disorders
10
Respiratory, thoracic and mediastinal
disorders
2
Skin and subcutaneous tissue disorders
2
Total
44
Location of AE Terms: Comparison
CTCAE v3.0 AE Term
BLOOD/BONE MARROW
CATEGORY
CTCAE v4.0 SOC
CTCAE v4.0 AE Term
Hemoglobin
Blood and lymphatic system
disorders
Anemia
Platelets
Investigations
Platelet count decreased
Leukocytes (total WBC)
Neutrophils/granulocytes
(ANC/AGC)
Hemolysis (e.g., immune
hemolytic anemia, drugrelated hemolysis)
CD4 count
Investigations
White blood cell decreased
Investigations
Neutrophil count decreased
Bone marrow cellularity
Myelodysplasia
Splenic function
Blood and lymphatic system
disorders
Investigations
Blood and lymphatic system
disorders
Hemolysis
CD4 lymphocytes decreased
Bone marrow hypocellular
Neoplasms benign, malignant and
unspecified (incl cysts and polyps) Myelodysplastic syndrome
Blood and lymphatic system
disorders
Spleen disorder
CTCAE v4.0:
Highlights of What Else is New
• AE term definitions
• Initial definitions for the CTCAE terms were provided
by the NCI’s Enterprise Vocabulary Services (EVS)
• ADLs
• Grade 2: limiting instrumental ADL
• e.g., shopping; laundry; transportation; ability to conduct
finances
• Grade 3: limiting self care ADL
• e.g., getting in and out of bed; dressing; eating; getting
around inside; bathing; using the toilet
• General Guidelines for grade descriptions
CTCAE v4.0 General Guidelines
for Grade Descriptions…
Grade 1
Mild AE
- minor;
- no specific medical intervention
- asymptomatic laboratory finding only;
- radiographic finding only;
- marginal clinical relevance;
- mild symptoms and intervention not
indicated;
- non-prescription intervention indicated
Grade 2
Moderate AE
- intervention indicated;
- minimal, local, noninvasive
intervention (e.g. packing, cautery);
- limiting instrumental ADL (e.g.,
shopping; laundry; transportation;
ability to conduct finances)
General Guidelines for Grades are
Foundation for AE-Specific Severity Scales
…CTCAE v4.0 General Guidelines
for Grade Descriptions
Grade 3
Severe AE
- medically significant but not life-threatening;
- inpatient or prolongation of hospitalization
indicated;
- important medical events that do not result in
hospitalization1 but may jeopardize the
patient or may require intervention either to
prevent hospitalization or to prevent the AE
from becoming life-threatening or potentially
resulting in death;
- limiting self care ADL (e.g., getting in and out
of bed; dressing; eating; getting around
inside; bathing; using the toilet)
- disabling2;
- results in persistent or significant disability or
incapacity
1Exception:
Grade 4
Grade 5
Life-threatening AE
- life-threatening consequences
- urgent intervention indicated
- urgent operative intervention
indicated
- patient is at risk of death at the
time of the event if immediate
intervention is not undertaken
SOC Psychiatric disorders Gr 4 = hospitalization
2Exception: Blindness Gr 4 & Hearing impaired Gr 4 = disabling
Death
CTCAE v4.0 Resources
http://evs.nci.nih.gov/ftp1/CTCAE
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CTCAE v4.0 Resources
BioMedGT Wiki http://biomedgt.nci.nih.gov/wiki/index.php/CTCAE4
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MedDRA Versioning
• CTCAE will continue to be harmonized
with MedDRA
• MedDRA versions:
• March: major release
• September: minor release
• Estimated that a new version of CTCAE
will occur every 2 years in March
• CTCAE/MedDRA LLTs will not be deleted
• Governance/oversight
http://ctep.info.nih.gov/protocolDevelopme
nt/electronic_applications/ctc.htm
47
Questions
Liz Ness
nesse@mail.nih.gov
301-451-2179