CTCAE v4.0 Information Date: March 2010

1. CTCAE v4.0Information Date: March 2010 An overview of the harmonization of the Common Terminology Criteria for Adverse Events (CTCAE) with the Medical Dictionary for Regulatory Activities (MedDRA)

2. Session Details:Training Objectives • Upon successful completion of this session, you will be able to: • Explain the background and purpose of CTCAE. • Discuss what MedDRA is and its relation to CTCAE v4.0. • Describe challenges encountered with the release of CTCAE v4.0. • Identify resources to help further understand CTCAE v4.0.

3. Session Details:Lesson Plan • Introduction to CTCAE • Identify shortcomings of CTCAE v3.0 • Introduction to MedDRA • Introduction to CTCAE v4.0 • Discuss the challenges with the release of CTCAE v4.0 • Identify resources for CTCAE

4. Introduction to CTCAE • In this lesson, we will: • Discuss the background of CTCAE. • Identify the purpose of CTCAE. • Discuss the reasons for the new release of CTCAE.

5. Introduction to CTCAE:Background of CTCAE… • Recognition and reporting of Adverse Events (AEs) of cancer treatment have long been essential activities in the conduct of clinical trials. • AEs are common phenomena affecting patients being treated for cancer. • There have been hundreds of distinct AEs that have been associated with current cancer therapy. • The AEs range in severity from minor, asymptomatic changes noted on physical exam to life-threatening injuries or death.

6. Introduction to CTCAE:Background of CTCAE… • The original terminology criteria was developed by the Cancer Therapy Evaluation Program (CTEP) in 1983 to aid in the recognition and grading severity of adverse effects of chemotherapy. • It is fundamentally intended to be an agreed upon terminology for the designation, reporting and grading of AEs that occur in oncology research. • The NCI CTCAE is a list of AE terms commonly encountered in oncology, and each of the AE terms are accompanied by a grading (severity) scale.

7. Introduction to CTCAE:Background of CTCAE

8. Introduction to CTCAE:Purpose of CTCAE • The CTCAE has several purposes: • Provides a means of standardizing AE reporting within the NCI oncology research community, across groups and modalities • Assists in the evaluation of new cancer therapies, treatment modalities, and supportive measures • Facilitates a common understanding of AE data shared among academic, commercial, and regulatory entities • Aids in the recognition of AEs as well as the severity grading • Helps in monitoring safety data as well as regulatory reporting • Assists in defining oncology research protocol parameters (such as eligibility criteria, dose limiting toxicity, maximum tolerated dose, dose modification, etc.)

9. Shortcomings of CTCAEv3.0:Reasons for the new release • Since publication of CTCAE v3.0 in 2003, a lot of new information has become available in the prevention, diagnosis, and treatment of cancer. • Along with this new information, the rapidly evolving IT systems for biotech research and the Cancer Biomedical Informatics Grid® (caBIG®) initiative have brought forth the necessity for data standardization. • Conformance with caBIG® vocabulary criteria required that the AE terms: • be revised and extended and that severity indicators be machine interpretable • be associated with definitions • Another objective for the new release was to make CTCAE compliant, at the term level, with MedDRA.

10. Introduction to MedDRA • In this lesson, we will: • Identify what MedDRA is. • Explain the organizational hierarchy of MedDRA.

11. Introduction to MedDRA:What is MedDRA • MedDRA is the clinically validated international medical terminology used by regulatory authorities and the regulated biopharmaceutical industry throughout the entire regulatory process, from pre-marketing to post-marketing activities, for data entry, retrieval, evaluation, and presentation. • It is the adverse event classification dictionary endorsed by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). • The MedDRA dictionary includes standardized MedDRA queries (SMQs). These SMQs are groupings of terms that relate to a defined medical condition or area of interest. • Maintenance and Support Services Organization (MSSO) manages MedDRA and reports to International Federation of Pharmaceutical Manufactures and Associations (IFPMA). • MedDRA is currently used by the biopharmaceutical industry and regulatory agencies in the U.S., European Union, and Japan and has been translated into at least 11 languages.

12. Introduction to MedDRA:Organization of MedDRA • MedDRA aggregates related terms in medically meaningful groupings; the highest level of the MedDRA terminology is the System Organ Class (SOC), of which there are 26. • MedDRA is multi-disciplinary, clinically validated, and is made up of 5 levels of hierarchy. • MedDRA terms are not associated with definitions or severity scales.

13. Introduction to MedDRA:MedDRA hierarchy… Levels of hierarchy* *MedDRA v11.0

14. Introduction to MedDRA:MedDRA hierarchy Example: Fatigue hierarchy SOC HLGT HLT PT LLT

15. Introduction to CTCAE v4.0: • In this lesson, we will: • Discuss the organizational layout of CTCAE v4.0. • Explain replacement of CTCAE v3.0 CATEGORIES with CTCAE v4.0 SOCs. • Identify those CTCAE v3.0 CATEGORIES that were deleted in CTCAE v4.0 and replaced with SOCs. • Review the addition of definitions to AE Terms in CTCAE v4.0. • Identify the general guidelines and changes for Grade descriptions. • Discuss reasons for the elimination of ‘Short Names’ and ‘Supra-ordinate terms.’ • Explain versioning of CTCAE v4.0/MedDRA.

16. Introduction to CTCAE v4.0:Organization of CTCAE v4.0 • Organized by a broad grouping equivalent to MedDRA SOCs Examples: • Immune system disorders • Skin and subcutaneous tissue disorders • Within each of the 26 SOCs, a small subset of MedDRA LLTs common in oncology practice are listed • 764 AE terms (MedDRA LLTs) • 26 SOC names with an ‘Other, specify’ placeholder for the submission of a verbatim term not listed in CTCAE v4.0 • CTCAE Grading (severity) scale includes Grades 1 – 5 although some AEs are not associated with all five Grades

17. Introduction to CTCAE v4.0:CATEGORIES replaced with SOCs… • CTCAE v3.0 was organized at the highest level by 28 CATEGORIES • CTCAE v4.0 is organized at the highest level by MedDRA SOCs • Some v3.0 CATEGORY names correlate with v4.0 SOC names

18. Introduction to CTCAE v4.0:CATEGORIES replaced with SOCs… Some CTCAE v3.0 CATEGORY names either split or merge into CTCAE v4.0 SOC names

19. Introduction to CTCAE v4.0:CATEGORIES replaced with SOCs… While SOC location for most AE terms are obvious, some exceptions are: • SOC Psychiatric disorders • AE term: Restlessness • AE term: Libido increased • SOC Investigations • AE term: Weight loss • AE term: Weight gain

20. Introduction to CTCAE v4.0:CATEGORIES replaced with SOCs • Five CTCAE v3.0 CATEGORIES have been deleted and do not appear in CTCAE v4.0 because the names are broad and non-specific and include AE terms associated within multiple SOCs. Those v3.0 CATEGORIES deleted include: • DEATH • GROWTH & DEVELOPMENT • PAIN • HEMORRHAGE • SYNDROMES

21. Introduction to CTCAE v4.0:Deleted CTCAE v3.0 CATEGORIES

22. Introduction to CTCAE v4.0:AE Changes… • CTCAE v3.0 AE terms did not have definitions. • CTCAE v4.0 AE terms are defined. • Initial definitions for CTCAE terms were provided by the NCI Enterprise Vocabulary Services (EVS) based on NCI Thesaurus (NCIt) definitions already existing or written for this effort. • EVS reviewed definition comments and draft revisions, and made additional changes in conjunction with CTCAE staff to create a final set of CTCAE definitions. • Matching NCIt concepts were identified or created for all CTCAE AE terms, with mapping of codes between the two terminologies. • Matching of concepts provided direct mapping of all CTCAE AE terms to NCI’s core reference terminology. • Mapping also ensures that NCIt synonyms, description logic ontology modeling, and other resources can be leveraged by CTCAE users without having to be recreated in CTCAE itself.

23. Introduction to CTCAE v4.0:AE Changes…

24. Introduction to CTCAE v4.0:AE Changes… • Multiple Concept Example: CTCAE v3.0 Fatigue: • In v3.0 Fatigue shared the same grading scale as Asthenia, Lethargy, and Malaise. In v4.0 these concepts are now listed separately, therefore they each have their own separate grading scale. Mapped to MedDRA: Fatigue • *Fatigue, Asthenia, Lethargy, Malaise are unique concepts in MedDRA and are not: • related to a single Preferred Term • synonyms, lexical variants, or quasi-synonyms

25. Introduction to CTCAE v4.0:AE Changes… MedDRA Example: Fatigue SOC MedDRA PT 21 LLTs

26. Introduction to CTCAE v4.0:AE Changes… MedDRA Example: Malaise SOC MedDRA PT 21 LLTs

27. Introduction to CTCAE v4.0:AE Changes… MedDRA Example: Lethargy SOC MedDRA PT Lethargy is associated with three SOCs in v4.0 Lethargy is associated with 3 SOCs. In CTCAE v4.0 Lethargy is listed in the Primary SOC Nervous system disorders 3 LLTs

28. Introduction to CTCAE v4.0:AE Changes… CTCAE v4.0 Single Concept MedDRA LLT Examples: Unlike CTCAE v3.0 multiple concept terms, CTCAE v4.0 single concept AE terms are associated with Grading Scales specific for each term.

29. Introduction to CTCAE v4.0:AE Changes… CTCAE v3.0 AE term split into 6 single concept v4.0 AE terms – Example:

30. Introduction to CTCAE v4.0:AE Changes… CTCAE v4.0 More specific AE term – Example:

31. Introduction to CTCAE v4.0:AE Changes… Anaphylaxis is now recognized as a critical concept AE in v4.0, but was reported as a Grade of the AE, Allergic Reaction, in v3.0. Grade of AE in v3.0; now recognized as critical enough for its own AE concept in v4.0.

32. Introduction to CTCAE v4.0:AE Changes… CTCAE v4.0 critical concept listed as unique AE term – Example: Anaphylaxis is now its own AE in v4.0 and no longer part of the AE Allergic reaction.

33. Introduction to CTCAE v4.0:AE Changes… In v3.0 all AE ‘infection’ terms were on one page, shared the same grading scale, and included the word infection in all terms. In v4.0 ‘infection’ terms are located throughout various SOCs and the wording format has changed.

34. Introduction to CTCAE v4.0:AE Changes… In v3.0 all AE ‘pain’ terms were on one page, shared the same grading scale, and included the word pain in all terms. In v4.0 ‘pain’ terms are located throughout various SOCs and the wording format has changed.

35. Introduction to CTCAE v4.0:AE Changes… Electronic search of CTCAE v4.0 PDF may assist in the identification of AE terms. Access to the PDF can be found at: http://evs.nci.nih.gov/ftp1/CTCAE Click on the QuickReference link to access CTCAE v4.0 PDF

36. Introduction to CTCAE v4.0:AE Changes… Within the CTCAE v4.0 PDF, you can search for the required AE. Example 1: Sweat Click Search icon to open Search PDF window

37. Introduction to CTCAE v4.0:AE Changes… Type in word to search for with optional search parameters, and click Search.

38. Introduction to CTCAE v4.0:AE Changes… The search will provide you with the total results for the particular inquiry. You can choose which result you want by clicking on the result.  You will then be taken directly to that part of CTCAE v4.0. Click on the appropriate result to see that section of CTCAE v4.0.

39. Introduction to CTCAE v4.0:AE Changes… Example 2: Perspiration Type in word to search for with optional search parameters, and click Search.

40. Introduction to CTCAE v4.0:AE Changes Click on the appropriate result to see that section of CTCAE v4.0.

41. Introduction to CTCAE v4.0:Grading Scale v4.0… • Grade refers to the severity of the AE. • A 5-point scale generally corresponding to mild, moderate, severe, life-threatening and death. • Unique clinical descriptions of severity for each AE are based on general characteristics/guidelines. • This grading system inherently places a value on the importance of an event, although there is not necessarily “proportionality” among grades (a Grade 2 is not necessarily twice as bad as a Grade 1). • Some AEs are difficult to ‘fit’ into this 5-point schema, but altering the general guidelines of severity scaling would render the system useless of comparing results between trials; an important purpose of the system. • All grades are not appropriate for all AEs. • Most Grade 4 AEs have a Grade 5 AE, with exceptions • Exception: Blindness Grade 4 is not associated with Grade 5

42. Introduction to CTCAE v4.0:Grading Scale v4.0… • ‘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. • Most AEs in CTCAE include clinical criteria that describe clinical findings or impact on activities of daily living (ADLs) to more clearly substantiate severity. • Some AE terms are associated with <five grades.

43. Introduction to CTCAE v4.0:Grading Scale v4.0…

44. Introduction to CTCAE v4.0:Grading Scale v4.0… 1Exception: SOC Psychiatric disorders Grade 4 = hospitalization 2Exception: Blindness Grade 4 & Hearing impaired Grade 4 = disabling

45. Introduction to CTCAE v4.0: Grading Scale v4.0 Summary of changes to CTCAE v4.0: • General Guidelines for Grades are the foundation for AE-specific severity scales • Documentation of Grade is unique for each CTCAE v4.0 AE term • Assignment of Grade is not to be arbitrary because all five Grades are not appropriate for all AE terms

46. Introduction to CTCAE v4.0:AEs not associated with Grade 5

47. Introduction to CTCAE v4.0:Grading Scale and Activities of Daily Living… • Activities of Daily Living (ADLs) is a term used in medicine and nursing referring to the things we normally do in daily living, including any daily activity we perform for self-care (such as feeding ourselves, bathing, dressing, grooming), work, homemaking, and leisure. • Health professionals routinely refer to the ability or inability to perform ADLs as a measurement of the functional status of a person. • This measurement is useful for assessing the elderly, the mentally ill, those with chronic diseases or being treated for disease, and others, in order to evaluate what type of health care services an individual may need.

48. Introduction to CTCAE v4.0:Grading Scale and Activities of Daily Living… Examples of Instrumental ADLs: Mode of Transportation • Travels independently on public transportation or drives own car • Arranges own travel via taxi, but does not otherwise use public transportation • Travels on public transportation when accompanied by another • Travel limited to taxi or automobile with assistance of another • Does not travel at all • Source: Lawton, M.P. and Brody, E.M. “Assessment of older people: Self-maintaining and instrumental activities of daily living.” Gerontologist 9;179-186, (1969) Doing light housework • Maintains house alone or with occasional assistance (e.g., ‘heavy work domestic help’) • Performs light daily tasks such as dishwashing, bed making • Performs light daily tasks but cannot maintain acceptable level of cleanliness • Does not participate in any housekeeping tasks

49. Introduction to CTCAE v4.0:Grading Scale and Activities of Daily Living Examples of Self Care ADLs: The basic activities of daily living consist of these self-care tasks • Personal hygiene • Dressing and undressing • Eating • Transferring from bed to chair, and back • Voluntarily controlling urinary and fecal discharge • Elimination • Moving around (as opposed to being bedridden) Attention to self-care and daily living skills (e.g., brushing one’s own teeth, shaving, combing hair, getting dressed, etc.), serves three purposes: • Increases your ability to perform these activities • Provides overall muscle toning • Increases your range of motion

50. Introduction to CTCAE v4.0:Elimination of ‘Short Names’ • Because AE documentation has been largely on paper, and many CTCAE v3.0 AE terms were made up of multiple concepts and/or phrases, ‘Short Names’ were listed to facilitate hand entry of AE term on paper Case Report Forms (CRFs). • CTCAE v4.0 lists MedDRA LLTs, single concept terms which are easier to record on paper, thus eliminating the need for ‘Short Names.’