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…

…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, 2010http://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

HLGT

HLT

SOC

LLT

PT

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

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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

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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 TermLethargy + 3 LLTs

LLTs

Primary SOCNervous system disorders

MedDRA Preferred TermAsthenia + 20 LLTs

LLTsPrimary SOC

General disorders and administration site conditions

CTCAE v3.0 Critical concept listed in Grade only –

not as AE Term

CTCAE v4.0 RevisionAllergic reaction/hypersensitivity

• SOC: Immune system disorders• Allergic reaction • Anaphylaxis

CTCAE v3.0 IssueNon-MedDRA Terms + CTEP-Only Codes

INFECTION CATEGORY

CTCAE v3.0 Count of 77 INFECTION terms99% 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

• 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 Resources http://evs.nci.nih.gov/ftp1/CTCAE

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CTCAE v4.0 ResourcesBioMedGT 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

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http://ctep.info.nih.gov/protocolDevelopment/electronic_applications/ctc.htm

Questions

Liz Nessnesse@mail.nih.gov

301-451-2179