1. CTCAE v3.0 Revision Project Draft 2 Tasks – Nov. – Dec. 2008 Working Group Centra/Teleconference Prepared by Ann Setser Nov. 3, 2008

2. Agenda Outcome of Phase 1 Work Objective Priorities for Phase 2 – Grading Scales – New AE Terms – Also Consider; Remarks; Navigation Notes Principles for Development of Grading Scales - Resources – General characteristics of Grade – Remain unchanged for CTCAE v4.0? – Update General Characteristics for current interventions?

3. Agenda (continued) Use of template for consistency across SOCs? Obstruction Perforation Ulcer Hemorrhage Stricture Infection New AE Terms – CTEP Help Desk files; Others – Pre-approval for MedDRA compliance Other components of CTCAE v3.0 – Also consider – Remarks – Navigation Notes – Others

4. Draft 1 818 AE terms 26 ‘Other, specify’

5. Working Group (Tuesday)SOCCount/SOCTotal Count 4 Psychiatric disorders20 78 Nervous system disorders58 8 Musculoskeletal and connective tissue disorders46 84 Skin and subcutaneous tissue disorders38 11 Respiratory, thoracic and mediastinal disorders63 12 Injury, poisoning and procedural complications74

6. Working Group (Wednesday)SOCCount/SOCTotal Count 1 Blood and lymphatic system disorders17 107 Immune system disorders6 Infections and infestations84 2 Cardiac disorders41 60 Vascular disorders19 3 Ear and labyrinth disorders9 36 Eye disorders27 5 Gastrointestinal disorders124 142 Hepatobiliary disorders18 7 General disorders and administration site conditions26 34 Neoplasms benign, malignant and unspecified (incl cysts and polyps)7 Social circumstances1 10 Reproductive system and breast disorders59 60 Pregnancy, puerperium and perinatal conditions1

7. Working Group (Thursday)SOCCount/SOC Total Count 6 Endocrine disorders10 34 Metabolism and nutrition disorders24 9 Congenital, familial and genetic disorders1 70 Investigations33 Renal and urinary disorders36

8. CTCAE v3.0 Grading Scales Background World Health Organization Severity Scale ‘Serious’ vs. ‘Severity’ CTEP Website “CTCAE v3.0 Online Instructions and Guidelines”

9. CTCAE v3.0

10. Explanation of word meaning and punctuation use within descriptions of Grades.

11. Explanation of word meaning and punctuation use within descriptions of Grades: Semicolon = ‘or’ Em dash = Not available

12. 12 Serious vs. Severity Serious AEs are defined by FDA and therefore seriousness (not severity) serves as a guide for defining regulatory reporting obligations for patient/subject safety. ‘Serious’ is based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient’s life or functioning. FDA Federal Regulations require IND sponsors to report serious AEs via expedited reporting. ‘Severity’ is not the same as ‘serious.’ The term ‘severe’ is often used to describe the intensity (severity) of a specific event (as in mild, moderate, severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as severe headache). Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. CTEP, NCI Expedited AE Reporting Requirements: Do not define ‘serious’. Although AEs in CTCAE include some clinical criteria that describe patient/event outcomes or indicated interventions, the CTCAE grading scale is intended to describe severity.

13. Working Group Resources – Information about Grading Scales, etc. CTCAE v3.0 Online Instructions and Guidelines http://ctep.cancer.gov

15. CTCAE v3.0 Instructions and Guidelines Information about Grading

16. Template/Guide used in the development of severity scales for CTCAE v3.0.

17. 0No adverse event or within normal limits 1Mild Adverse Event (minor; no specific medical intervention; asymptomatic laboratory findings only, radiographic findings only; marginal clinical relevance) 2Moderate Adverse Event (minimal intervention; local intervention; noninvasive intervention [packing, cautery]) 3 Severe and undesirable Adverse Event (significant symptoms requiring hospitalization or invasive intervention; transfusion; elective interventional radiological procedure; therapeutic endoscopy or operation) 4Life-threatening or disabling Adverse Event (complicated by acute, life- threatening metabolic or cardiovascular complications such as circulatory failure, hemorrhage, sepsis. Life-threatening physiologic consequences; need for intensive care or emergent invasive procedure; emergent interventional radiological procedure, therapeutic endoscopy or operation) 5Fatal adverse event CTCAE v3.0 General Descriptions of Grade -Severity Scale-

18. CTCAE v3.0 Instructions and Guidelines: Alternate Grading Scales

19. Alternate Grading Scale Based on Anatomic Area Draft 1 Terms: Anal mucositis Esophageal mucositis Gastric mucositis Large intestinal mucositis Laryngeal mucositis Pharyngeal mucositis Rectal mucositis Small intestinal mucositis Stomatitis Tracheal mucositis

20. Alternate Grading Scale Based on Methodology Draft 1 Terms: Hypocalcemia Hypercalcemia

21. Draft 1: Hypercalcemia Hypocalcemia Consider inclusion of MedDRA terms --Ionized calcium decreased --Ionized calcium increased

22. Alternate Grading Scale Based on Patient Population Example #1

23. Alternate Grading Scale Based on Patient Population Example #2 Draft 1 term is MedDRA term: Hearing impaired.

24. CTCAE v3.0 Instructions and Guidelines

28. Grading Scale General Characteristics Remain unchanged for CTCAE v4.0? Update General Characteristics for current interventions? Strive for consistency across SOCs? – Obstruction – Perforation – Ulcer – Hemorrhage – Stricture – Infection

31. Working Group Shared Grading Scales Examples Prepared by: Ann Setser November 4, 2008

32. WG # 4: Psychiatric; Nervous Similar Grading Scales? Agitation Anxiety Depression Euphoria Phantom pain Sinus pain Neuropathy - cranial

33. WG # 8: Skin; Musculoskeletal Similar Grading Scales? Muscle weakness lower limb Muscle weakness right-sided Muscle weakness trunk Muscle weakness upper limb Generalized muscle weakness Etc…….. Abdominal soft tissue necrosis Head soft tissue necrosis Neck soft tissue necrosis Etc…..

34. WG # 12: Injury….. Similar Grading Scales? All of the CTCAE v3.0 terms in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY utilized a single Grading Scale Terms from 9 CTCAE v3.0 CATEGORIES – DERMATOLOGY/SKIN proposed terms = 7 CTCAE v3.0 Burn is now split into 2 terms: Thermal burn; Chemical burn – HEMORRHAGE/BLEEDING proposed terms = 4 – MUSCULOSKELETAL/SOFT TISSUE proposed terms = 3 – VASCULAR Proposed terms = 9 – SURGERY/INTRA-OPERATIVE INJURY 18

35. WG # 12: Injury….. Proposed terms that might require harmonization with Grading Scales in other SOCs: – GASTROINTESTINAL: Proposed terms = 15 Anastomotic leak Necrosis Obstruction Stricture Ulcer – RENAL/GENITOURINARY Proposed terms = 14 Anastomotic leak Obstruction Perforation Stricture – PULMONARY/UPPER RESPIRATORY Proposed terms = 3 Obstruction Stenosis

36. WG # 11: Respiratory… Similar Grading Scales? Bronchial fistula Laryngeal fistula Pharyngeal fistula Pleural fistula Pulmonary fistula Tracheal fistula Etc….. Bronchial obstruction Laryngeal obstruction Etc…..

37. WG # 8: Skin; Musculoskeletal Similar Grading Scales? Muscle weakness lower limb Muscle weakness right-sided Muscle weakness trunk Muscle weakness upper limb Generalized muscle weakness Etc…….. Abdominal soft tissue necrosis Head soft tissue necrosis Neck soft tissue necrosis Etc…..

38. CTCAE v4.0 Grading Scale Guidance Explanation of word meaning and punctuation Definitions of words within Grades – Existing CTCAE v3.0 definitions -ADLs, etc. – New words within new Grades Special instructions for GVHD, VOD, others?

39. ‘Function’

40. New AE Terms - CTEP Help Desk

41. CTCAE v3.0 Also Consider; Navigation Notes; Remarks Statistics (Ranjana Srivastava) Total number of terms in v 3.1 for grades818 Number of new terms in v 3.1 for grades71 New terms from split in v 3.1 for grades89 Total Number of terms in V3.0 With “ ALSO CONSIDER ” 194 Total Number of terms in V3.1 With “ ALSO CONSIDER ” ** >600 Deleted terms in V3.1 With “ ALSO CONSIDER ” 6 Total Number of terms in V3.0 With “ NAVIGATION NOTES ” 57 Total Number of terms in V3.1 With “ NAVIGATION NOTES ” ** Deleted terms in V3.1 With “ NAVIGATION NOTES ” Total Number of terms in V3.0 With “ REMARK ” 81 Total Number of terms in V3.1 With “ REMARK ” ** 195 Deleted terms in V3.1 With “ REMARK ” 13 ** If the split terms also have the same annotation

42. CTCAE v3.0 Online Instructions and Guidelines http://ctep.cancer.gov

43. CTCAE v3.0 Online Instructions and Guidelines http://ctep.cancer.gov

44. CTCAE v3.0 Also Consider Example

45. CTCAE v3.0 Also Consider Examples

47. Encephalopathy NEUROLOGY Cognitive disturbance; Confusion; Dizziness; Memory impairment; Mental status; Mood alteration – Select; Psychosis (hallucinations/delusions); Somnolence/depressed level of consciousness. Delirium Encephalopathy Hepatic Encephalopathy Cognitive disturbance Dizziness Vertigo Dizziness & Cognitive disturbance Confusion Memory impairment Delirium ALSO CONSIDER Confusion & Mood alteration: Psychosis (hallucinations/de lusions) Delusions & Hallucinations & Psychosis V3.0 V3.1 CTCAE v3.0 Also Consider (Ranjana Srivastava)

48. CTCAE v4.0 – Draft Maintain ‘Also Consider’or Another Directive? Infection terms – Are dissociated from neutrophil count – Are all associated with SOC Infections…. Abdominal infection Biliary tract infection Urinary tract infection – Require reporting Neutropenia whenever an Infection term is reported? (Grade >1?) Electronic – Abdominal infection is reported + automatically, Neutropenia returns to be reported (or NA) – When Neutropenia is reported before Infection, should reverse apply? Neutropenia reported + automatically, general Infection question?

49. CTCAE v3.0 Navigation Note Example

51. CTCAE v3.0 ‘Remark’ Example

53. Wiki Work for Draft 2 Organized by SOC

54. When a SOC is selected, all AEs listed within that SOC appear. Grading scales will appear if the term is an ‘Edited’ or a ‘Split’ CTCAE v3.0 term. Grading scale will not appear if the term is ‘New’ (not previously listed in CTCAE v3.0)

55. New AE Terms New terms must be entered into the correct SOC. Two ways to enter new terms: 1.Pre-approval required when a term is entered within a SOC. 2.If SOC is unknown and if pre-approval is not available, Wiki provides pathway for entering general new term (for MedDRA approval and SOC assignment later)

56. How to Add New Terms to Draft

60. CTCAE v4.0 AE Term Definitions NCI Enterprise Vocabulary Services CTCAE v3.0 ‘Remarks’ Others Working Group review of definitions ~ December

61. Draft 2 Timeline WG:Nov. 4, 2008 – Jan. 1, 2009 SC:Nov. 17, Dec. 1, Dec. 15, Dec. 29

62. Discussion