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 3

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

10. ‘Fatigue’ hierarchy displayed
SOC
HLGT
HLT PT
LLT

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 11 11

12. Comparison MedDRA to CTCAE
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 12 12

13. 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

14. …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

15. v3.0 CATEGORIES Deleted in v4.0…
CTCAE v3.0 CATEGORY
CTCAE v4.0 SOC
CTCAE 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.

16. …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

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) 17 17

18. CTCAE v3.0 Multiple Concepts in one AE Term
Mapped to MedDRA: Fatigue
Fatigue, Asthenia, Lethargy, Malaise
Are unique concepts in MedDRA (PTs)
Are not
related to a single Preferred Term
synonyms, lexical variants, or quasi-synonyms 18 18 18

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

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

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

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

23. CTCAE v3.0 Critical concept listed in Grade only – not as AE Term23 23

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

25. CTCAE v3.0 Issue Non-MedDRA Terms + CTEP-Only Codes INFECTION CATEGORY25 25

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

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 27 27

28. CTCAE v4.0 Hemorrhage AE Terms
CTCAE v4.0 SOC
AE Count
Comments
Eye disorders 1
Gastrointestinal disorders 17
Hepatobiliary disorders
Injury, poisoning and procedural complications 6
The word ‘bleeding’ is used instead of hemorrhage for 3 AE Terms:
Nervous system disorders
Renal and urinary disorders
Reproductive system and breast disorders
Respiratory, thoracic and mediastinal disorders 5
Total 38

29. CTCAE v4.0 Pain AE Terms Blood and lymphatic system disorders 1
CTCAE v4.0 SOC
AE Count
Blood and lymphatic system disorders 1
Cardiac disorders
Ear and labyrinth disorders 2
Eye disorders
Gastrointestinal disorders 9
General disorders and administration site conditions 3
Hepatobiliary disorders
Musculoskeletal and connective tissue disorders 7
Neoplasms benign, malignant and unspecified (incl cysts and polyps)

30. CTCAE v4.0 Pain AE Terms (continued) Nervous system disorders 2
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
Skin and subcutaneous tissue disorders
Total 44

31. 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)
White blood cell decreased
Neutrophils/granulocytes (ANC/AGC)
Neutrophil count decreased
Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis)
Hemolysis
CD4 count
CD4 lymphocytes decreased
Bone marrow cellularity
Bone marrow hypocellular
Myelodysplasia
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myelodysplastic syndrome
Splenic function
Spleen 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. CTCAE v4.0 General Guidelines for Grade Descriptions…
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)
General Guidelines for Grades are Foundation for AE-Specific Severity Scales

34. …CTCAE v4.0 General Guidelines for Grade Descriptions
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 = hospitalization
2Exception: Blindness Gr 4 & Hearing impaired Gr 4 = disabling

35. CTCAE v4.0 Resources http://evs.nci.nih.gov/ftp1/CTCAE35

36. CTCAE v4.0 Resources BioMedGT Wiki 36

37. 37

38. 38

39. 39

40. 40

41. 41

42. 42

43. 43

44. 44

45. 45

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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

48. Questions
Liz Ness