CTCAE v4.0 Information Date: March 2010

CTCAE v4.0 Information 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)

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.

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

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.

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.

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.

Introduction to CTCAE: Background of CTCAE
CTC v2.0 CTCAE v3.0 CTCAE v4.0 1983 1998 2003 2009 49 AE Terms ~300 AE Terms 1,059 AE Terms 790 AE Terms _ Appendix: Late Radiation Morbidity Scoring Scheme Acute & Late Appendix: BMT Complex/Multi-component Events All Modalities Pediatric-specific Few Pediatric-specific Mapped to MedDRA MedDRA LLTs AE Term Definitions

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.)

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.

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

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.

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.

Introduction to MedDRA: MedDRA hierarchy…
Levels of hierarchy* System Organ Class SOC Highest level of the terminology, and distinguished by anatomical and physiological system, etiology, or purpose 26 High Level Group Term HLGT Subordinate to the SOC, supraordinate descriptor for one or more High Level Terms 332 High Level Term HLT Subordinate to the HLGT, supraordinate descriptor for one or more Preferred Terms 1,688 Preferred Terms PT Represents a single medical concept 18,075 Lowest Level Terms LLT Lowest level of the terminology, related to a single PT as a synonym, lexical variant, or quasi-synonym (Note: All PTs have an identical LLT). >66,000 *MedDRA v11.0

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

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.

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

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 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

Some CTCAE v3.0 CATEGORY names either split or merge into CTCAE v4.0 SOC names CTCAE v3.0 CATEGORY CTCAE v4.0 SOC CARDIAC ARRHYTHMIA Cardiac disorders CARDIAC GENERAL NEUROLOGY Nervous system disorders Psychiatric disorders

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

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

Introduction to CTCAE v4.0: Deleted CTCAE v3.0 CATEGORIES
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. SYNDROMES 9 SOCs

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.

AE terms were listed in CATEGORIES, a non-validated hierarchical association Each AE term is listed within its MedDRA Primary SOC AE terms were ‘mapped’ to MedDRA but mapping was imprecise AE terms are single concept MedDRA LLTs Some AE terms were multiple concept terms Some important medical concepts were buried within the description of Grade Some critical concepts were removed from description of Grade and listed as unique AE terms Consistent use of similar concepts: Pain, Infection, Hemorrhage Variable word format and word order AE terms were not defined Each AE term is defined

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

MedDRA Example: Fatigue SOC MedDRA PT 21 LLTs

MedDRA Example: Malaise SOC MedDRA PT 21 LLTs

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

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.

CTCAE v3.0 AE term split into 6 single concept v4.0 AE terms – Example: CTCAE v3.0 CATEGORY CTCAE v3.0 AE Term CTCAE v4.0 SOC CTCAE v4.0 AE Term PULMONARY / UPPER RESPIRATORY Voice changes/ dysarthria (e.g., hoarseness, loss or alteration in voice, laryngitis) Respiratory, thoracic and mediastinal disorders Voice alteration Hoarseness Laryngeal inflammation Nervous system disorders Aphonia Dysarthria Infections and infestations Laryngitis

CTCAE v4.0 More specific AE term – Example: CTCAE v3.0 CATEGORY CTCAE v3.0 AE Term CTCAE v4.0 SOC CTCAE v4.0 AE Term CARDIAC GENERAL Valvular heart disease Aortic valve disease Cardiac disorders Mitral valve disease Pulmonary valve disease Tricuspid valve disease

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.

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.

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. ‘Site name’ infection ‘itis’ ‘itis infective’ Other Abdominal infection Appendicitis Arteritis infective Papulopustular rash Anorectal infection Appendicitis perforated Conjunctivitis infective Paronychia Biliary tract infection Endophthalmitis Endocarditis infective Rash pustular Bladder infection Hepatitis viral Phlebitis infective Sepsis Bone infection Infective myositis Rhinitis infective Breast infection Laryngitis Bronchial infection Meningitis Catheter related infection Otitis externa + 45 additional + 5 additional

Diagnosis ~20% of AE Terms
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. ‘Pain’ ~80% of AE Terms Diagnosis ~20% of AE Terms Abdominal pain Arthralgia Stomach pain Toothache Gastrointestinal pain Neuralgia Pharyngolaryngeal pain Sore throat Ear pain External ear pain Etc.

Click on the QuickReference link to access CTCAE v4.0 PDF
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: Click on the QuickReference link to access CTCAE v4.0 PDF

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

Type in word to search for with optional search parameters, and click Search.

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.

Example 2: Perspiration Type in word to search for with optional search parameters, and click Search.

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

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

‘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.

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)

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 Grade 4 = hospitalization 2Exception: Blindness Grade 4 & Hearing impaired Grade 4 = disabling

Grading Scale v4.0 Grade 1 Nonprescription intervention Grade 2
Introduction to CTCAE v4.0: Grading Scale v4.0 Summary of changes to CTCAE v4.0: Grade 1 Nonprescription intervention Grade 2 Limiting instrumental ADL Grade 3 Limiting self care ADL; disabling Grade 4 Not disabling Grade 5 No change 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

Introduction to CTCAE v4.0: AEs not associated with Grade 5
Count of AE Terms No Grade 5 Percentage Eye disorders 25 100% Investigations 38 37 97% Musculoskeletal and connective tissue disorders 41 30 73% Skin and subcutaneous tissue disorders 34 23 68% Ear and labyrinth disorders 9 6 67% Reproductive system and breast disorders 51 32 63% Pregnancy, puerperium and perinatal conditions 5 3 60% Nervous system disorders 63 59% General disorders and administration site conditions 24 14 58% Endocrine disorders 11 55% Social circumstances 2 1 50% Renal and urinary disorders 20 45% Psychiatric disorders 8 40% Vascular disorders 17 35% Gastrointestinal disorders 117 21% Respiratory, thoracic and mediastinal disorders 59 12 20% Neoplasm's benign, malignant and unspecified (including cysts and polyps) 17% Hepatobiliary disorders 16 13% Injury, poisoning and procedural complications 76 7 9% Cardiac disorders 36 8% Infections and infestations

Introduction to CTCAE v4
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.

Examples of Instrumental ADLs:
Introduction to CTCAE v4.0: Grading Scale and Activities of Daily Living… Examples of Instrumental ADLs: 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 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; , (1969)

Examples of Self Care ADLs:
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

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.’

Introduction to CTCAE v4.0: Elimination of ‘Supra-ordinate Terms’
In CTCAE v3.0 a Supra-ordinate term served as a grouping term based on disease process, signs, symptoms, or diagnosis. A Supra-ordinate term was followed by the word ‘Select’ and was accompanied by specific AEs that were all related to the Supra-ordinate term Example: CTCAE v3.0 PAIN CATEGORY included one Supra-ordinate term followed by a list of may specific sites of pain. All sites use the same grading scale. CTCAE v4.0 includes 52 pain AE terms located across 14 MedDRA SOCs. Example 1: Ear and labyrinth disorders SOC in CTCAE v4.0 includes two separate AE terms: Ear pain & External Ear Pain Example 2: Musculoskeletal and connective tissues disorders SOC in CTCAE v4.0 includes eleven separate AE terms including: Arthralgia, Back pain, Myalgia, Neck pain, etc.

Introduction to CTCAE v4.0: CTCAE v4.0/MedDRA Versioning
CTCAE will be harmonized with MedDRA annually to coincide with the MedDRA complex release in March. With each MedDRA complex release, although unlikely, there may be very limited modifications to a CTCAE (MedDRA LLT) term or code which will not impact the medical/clinical content or interpretation of CTCAE. It is estimated that a new version of CTCAE will occur no more often than every two years in March to coincide with alternating complex releases of MedDRA. CTCAE terms are largely stable MedDRA LLTs, and although a rare term may become “non-current,” CTCAE MedDRA LLTs will not be deleted.

CTCAE v4.0 Assistance In this lesson, we will:
Locate resources for CTCAE Describe utilization of CTCAE KC and Wiki for ongoing CTCAE community correspondences Summarize the CTCAE Governance process Discuss MedDRA versioning related to CTCAE Explain chronology for CTCAE revision

CTCAE v4.0 Assistance: Resources
NCIt EVS BiomedGT Wiki NCI CTCAE Help Desk NCI caBIG® Knowledge Center NCI Publications To check availability of CTCAE v4.0 Booklets, visit: When available, 20 copies may be ordered without charge.

CTCAE v4.0 Assistance: BioMedGT Wiki…
Choose CTCAE4

CTCAE v4.0 Assistance: BioMedGT Wiki…
Click here for frequently asked questions (FAQs)

CTCAE v4.0 Assistance: BioMedGT Wiki
This will redirect you to the caBIG® Knowledge Center for the CTCAE FAQs

CTCAE v4.0 Assistance: CTCAE Help Desk…
To send an click Contact us

CTCAE v4.0 Assistance: CTCAE Help Desk
will be sent to the CTCAE help

CTCAE v4.0 Assistance: Knowledge Center…
URL: Choose Vocabulary from the drop-down menu

CTCAE v4.0 Assistance: Knowledge Center…
Choose CTCAE

CTCAE v4.0 Assistance: Knowledge Center

CTCAE v4.0 Assistance: Resources: NCI Publications
URL: Click your Topic to view and order Fact Sheets

Session Review: Objectives
Now that you have completed this session, you should be able to: Explain the background and purpose of CTCAE Discuss what MedDRA is and its relation to CTCAE v3.0 and v4.0 Describe challenges encountered with the release of CTCAE v4.0 Identify resources to help further understand CTCAE v4.0

CTCAE v4.0 Information Date: March 2010

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CTCAE v4.0 Information Date: March 2010

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