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Adverse Events: An Update
Elizabeth Ness, RN, MSDirector, Staff DevelopmentCenter 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…
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
7
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, 2010http://evs.nci.nih.gov/ftp1/CTCAE/Documentation/CTCAE_Governance_2010-03-11.doc
CTCAE Revision ProjectJune 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
11
ComparisonMedDRA to CTCAE
MedDRAList of terms >86,000Content: Comprehensive---Multiple translationsHierarchy: 5 levelsMedically validated---
CTCAE v4.0List of MedDRA LLTs
790Content: OncologySeverity ScaleEnglish; JapaneseHierarchy: 2 levels---Includes definitions
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 v4.0 MedDRA SOC Replaces v3.0 CATEGORY
CTCAE v3.0 CATEGORY CTCAE v4.0 SOC
CARDIAC ARRHYTHMIA Cardiac disorders
CARDIAC GENERAL
NEUROLOGY Nervous system disorders
Psychiatric disorders
CTCAE v3.0 CATEGORY CTCAE v4.0 SOC CTCAE v4.0 AE Term
DEATH
General disorders and administration site conditions
Death NOSDeath neonatalSudden death NOS
Pregnancy, puerperium and perinatal conditions
Fetal death
GROWTH AND DEVELOPMENT
Musculoskeletal and connective tissue disorders
PAIN
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
…v3.0 CATEGORIES Deleted in v4.0
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
18
Fatigue, Asthenia, Lethargy, Malaise
•Are unique concepts in MedDRA (PTs)
•Are not
–related to a single Preferred Term
–synonyms, lexical variants, or quasi-synonyms
Mapped to MedDRA: Fatigue 10016256
MedDRA Preferred TermFatigue + 20 LLTs
LLTs
Primary SOCGeneral disorders and administration
site conditions
MedDRA Preferred TermMalaise + 12 LLTs
LLTs
Primary SOCGeneral disorders and administration
site conditions
MedDRA Preferred TermAsthenia + 20 LLTs
LLTsPrimary SOC
General disorders and administration site conditions
CTCAE v4.0 RevisionAllergic reaction/hypersensitivity
• SOC: Immune system disorders• Allergic reaction • Anaphylaxis
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
• Infection with normal ANC or Grade 1 or 2 neutrophils - Conjunctiva
9 codes
CTCAE v4.0 SOC AE Count Comments
Eye disorders 1
Gastrointestinal disorders 17
Hepatobiliary disorders 1
Injury, poisoning and procedural complications 6
The word ‘bleeding’ is used instead of hemorrhage for 3 AE Terms:
Nervous system disorders 1
Renal and urinary disorders 1
Reproductive system and breast disorders 6
Respiratory, thoracic and mediastinal disorders 5
Total 38
CTCAE v4.0 Hemorrhage AE Terms
CTCAE v4.0 SOC AE Count
Blood and lymphatic system disorders 1Cardiac disorders 1Ear and labyrinth disorders 2Eye disorders 1Gastrointestinal disorders 9General disorders and administration site conditions 3Hepatobiliary disorders 2Musculoskeletal and connective tissue disorders 7Neoplasms benign, malignant and unspecified (incl cysts and polyps)
1
CTCAE v4.0 Pain AE Terms
CTCAE v4.0 SOC AE Count
Nervous system disorders 2
Renal and urinary disorders 1
Reproductive system and breast disorders 10Respiratory, thoracic and mediastinal disorders 2Skin and subcutaneous tissue disorders 2
Total 44
CTCAE v4.0 Pain AE Terms(continued)
Location of AE Terms: Comparison
CTCAE v3.0 AE TermBLOOD/BONE MARROW
CATEGORY
CTCAE v4.0 SOC CTCAE v4.0 AE Term
HemoglobinBlood and lymphatic system disorders Anemia
Platelets Investigations Platelet count decreased
Leukocytes (total WBC) Investigations White blood cell decreased Neutrophils/granulocytes (ANC/AGC) Investigations Neutrophil count decreasedHemolysis (e.g., immune hemolytic anemia, drug-related hemolysis)
Blood and lymphatic system disorders Hemolysis
CD4 count Investigations CD4 lymphocytes decreased
Bone marrow cellularityBlood and lymphatic system disorders Bone marrow hypocellular
MyelodysplasiaNeoplasms benign, malignant and unspecified (incl cysts and polyps) Myelodysplastic syndrome
Splenic functionBlood 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
Grade 1 Grade 2
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
Moderate AE- intervention indicated;- minimal, local, noninvasive intervention (e.g. packing, cautery);
- limiting instrumental ADL (e.g., shopping; laundry; transportation; ability to conduct finances)
CTCAE v4.0 General Guidelines for Grade Descriptions…
General Guidelines for Grades are Foundation for AE-Specific Severity Scales
Grade 3 Grade 4 Grade 5
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
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
Death
1Exception: SOC Psychiatric disorders Gr 4 = hospitalization2Exception: Blindness Gr 4 & Hearing impaired Gr 4 = disabling
…CTCAE v4.0 General Guidelines for Grade Descriptions
CTCAE v4.0 ResourcesBioMedGT Wiki http://biomedgt.nci.nih.gov/wiki/index.php/CTCAE4
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
47
http://ctep.info.nih.gov/protocolDevelopment/electronic_applications/ctc.htm