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Adverse Events: An Update Elizabeth Ness, RN, MS Director, Staff Development Center for Cancer Research National Cancer Institute.

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Presentation on theme: "Adverse Events: An Update Elizabeth Ness, RN, MS Director, Staff Development Center for Cancer Research National Cancer Institute."— Presentation transcript:

1 Adverse Events: An Update Elizabeth Ness, RN, MS Director, Staff Development Center for Cancer Research National Cancer Institute

2 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

3 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

4 CTCAE v3.0 Historical Components: AE Term, Short Name, Grade; Remark; Also Consider; Navigation Note…

5 …CTCAE v3.0 Historical Components: Supra-ordinate & Select Terms, …

6 …CTCAE v3.0 Historical Components: Other, specify

7 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

8 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

9 MedDRA TM Structure and Content SOC (26) HLGT (>300) HLT (>1,600) PT (>18,000) LLT(>86,000)

10 ‘Fatigue’ hierarchy displayed HLGT HLT SOC LLT PT

11 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 11

12 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

13 CTCAE v3.0 CATEGORY (Count 28)CTCAE v4.0 SOC (Count 26) AUDITORY / EAREar and labyrinth disorders DERMATOLOGY / SKINSkin and subcutaneous tissue disorders ENDOCRINEEndocrine disorders INFECTIONInfections and infestations PULMONARY / UPPER RESPIRATORY Respiratory and thoracic disorders VASCULARVascular disorders CTCAE v4.0 MedDRA SOC Replaces v3.0 CATEGORY…

14 …CTCAE v4.0 MedDRA SOC Replaces v3.0 CATEGORY CTCAE v3.0 CATEGORYCTCAE v4.0 SOC CARDIAC ARRHYTHMIA Cardiac disorders CARDIAC GENERAL NEUROLOGY Nervous system disorders Psychiatric disorders

15 CTCAE v3.0 CATEGORYCTCAE v4.0 SOCCTCAE v4.0 AE Term DEATH General disorders and administration site conditions Death NOS Death neonatal Sudden 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…

16 CTCAE v3.0 CATEGORY CTCAE v4.0 SOC Blood and lymphatic system disorders Cardiac disorders Immune system disorders Metabolism and nutrition disorders SYNDROMESNeoplasms 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

17 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)

18 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

19 MedDRA Preferred Term Fatigue + 20 LLTs LLTs Primary SOC General disorders and administration site conditions

20 MedDRA Preferred Term Malaise + 12 LLTs LLTs Primary SOC General disorders and administration site conditions

21 MedDRA Preferred Term Lethargy + 3 LLTs LLTs Primary SOC Nervous system disorders

22 MedDRA Preferred Term Asthenia + 20 LLTs LLTs Primary SOC General disorders and administration site conditions

23 CTCAE v3.0 Critical concept listed in Grade only – not as AE Term

24 CTCAE v4.0 Revision Allergic reaction/hypersensitivity SOC: Immune system disorders Allergic reaction Anaphylaxis

25 CTCAE v3.0 Issue Non-MedDRA Terms + CTEP-Only Codes INFECTION CATEGORY

26 CTCAE v3.0 Count of 77 INFECTION terms 99% map to MedDRA

27 CTCAE v3.0 INFECTION CATEGORY Infection with unknown ANC – Conjunctiva MedDRA: Conjunctivitis infective 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

28 CTCAE v4.0 SOCAE CountComments 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

29 CTCAE v4.0 SOCAE 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

30 CTCAE v4.0 SOCAE 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 CTCAE v4.0 Pain AE Terms (continued)

31 Location of AE Terms: Comparison CTCAE v3.0 AE Term BLOOD/BONE MARROW CATEGORY CTCAE v4.0 SOCCTCAE v4.0 AE Term Hemoglobin Blood and lymphatic system disordersAnemia PlateletsInvestigationsPlatelet count decreased Leukocytes (total WBC) Investigations White blood cell decreased Neutrophils/granulocytes (ANC/AGC) Investigations Neutrophil count decreased Hemolysis (e.g., immune hemolytic anemia, drug- related hemolysis) Blood and lymphatic system disordersHemolysis CD4 countInvestigationsCD4 lymphocytes decreased Bone marrow cellularity Blood and lymphatic system disordersBone marrow hypocellular Myelodysplasia Neoplasms benign, malignant and unspecified (incl cysts and polyps)Myelodysplastic syndrome Splenic function Blood and lymphatic system disordersSpleen disorder

32 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

33 Grade 1Grade 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

34 Grade 3Grade 4Grade 5 Severe AE - medically significant but not life-threatening; - inpatient or prolongation of hospitalization indicated; - important medical events that do not result in hospitalization 1 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) - disabling 2 ; - 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 1 Exception: SOC Psychiatric disorders Gr 4 = hospitalization 2 Exception: Blindness Gr 4 & Hearing impaired Gr 4 = disabling …CTCAE v4.0 General Guidelines for Grade Descriptions

35 CTCAE v4.0 Resources 35

36 36 CTCAE v4.0 Resources BioMedGT Wiki

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47 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 nt/electronic_applications/ctc.htm

48 Questions Liz Ness


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