Presentation on theme: "An overview of the harmonization of the Common Terminology Criteria for Adverse Events (CTCAE) with the Medical Dictionary for Regulatory Activities (MedDRA)"— Presentation transcript:
An overview of the harmonization of the Common Terminology Criteria for Adverse Events (CTCAE) with the Medical Dictionary for Regulatory Activities (MedDRA) CTCAE v4.0 Information Date: March 2010
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 CTCCTC v2.0CTCAE v3.0CTCAE v AE Terms~300 AE Terms1,059 AE Terms790 AE Terms _Appendix: Late Radiation Morbidity Scoring Scheme Acute & Late_ _Appendix: BMT Complex/Multi-component Events All Modalities _Pediatric-specificFew 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… System Organ Class SOCHighest level of the terminology, and distinguished by anatomical and physiological system, etiology, or purpose 26 High Level Group Term HLGTSubordinate to the SOC, supraordinate descriptor for one or more High Level Terms 332 High Level Term HLTSubordinate to the HLGT, supraordinate descriptor for one or more Preferred Terms 1,688 Preferred Terms PTRepresents a single medical concept18,075 Lowest Level Terms LLTLowest 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 Levels of hierarchy* *MedDRA v11.0
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 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 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
Introduction to CTCAE v4.0: CATEGORIES replaced with SOCs… CTCAE v3.0 CATEGORYCTCAE v4.0 SOC CARDIAC ARRHYTHMIA Cardiac disorders CARDIAC GENERAL NEUROLOGY Nervous system disorders Psychiatric disorders Some CTCAE v3.0 CATEGORY names either split or merge into CTCAE v4.0 SOC names
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
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 SOCCTCAE v4.0 AE Term DEATH General disorders and administration site conditions Death NOS Death neonatal Sudden death NOS Pregnancy, puerperium and perinatal conditionsFetal 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. SYNDROMES9 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.
Introduction to CTCAE v4.0: AE Changes… CTCAE v3.0CTCAE v4.0 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 AE terms are single concept MedDRA LLTs 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 definedEach AE term is defined
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. *Fatigue, Asthenia, Lethargy, Malaise are unique concepts in MedDRA and are not: –related to a single Preferred Term –synonyms, lexical variants, or quasi-synonyms Mapped to MedDRA: Fatigue
Introduction to CTCAE v4.0: AE Changes… SOC MedDRA PT 3 LLTs MedDRA Example: Lethargy Lethargy is associated with 3 SOCs. In CTCAE v4.0 Lethargy is listed in the Primary SOC Nervous system disorders Lethargy is associated with three SOCs in v4.0
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.
Introduction to CTCAE v4.0: AE Changes… CTCAE v3.0 CATEGORY CTCAE v3.0 AE Term CTCAE v4.0 SOCCTCAE 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 v3.0 AE term split into 6 single concept v4.0 AE terms – Example:
Introduction to CTCAE v4.0: AE Changes… CTCAE v3.0 CATEGORY CTCAE v3.0 AE Term CTCAE v4.0 SOCCTCAE v4.0 AE Term CARDIAC GENERAL Valvular heart disease Aortic valve disease Cardiac disordersMitral valve disease Pulmonary valve disease Tricuspid valve disease CTCAE v4.0 More specific AE term – Example:
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.
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.
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. ‘Site name’ infection‘itis’‘itis infective’Other Abdominal infectionAppendicitisArteritis infectivePapulopustular rash Anorectal infection Appendicitis perforated Conjunctivitis infectiveParonychia Biliary tract infectionEndophthalmitis Endocarditis infectiveRash pustular Bladder infectionHepatitis viralPhlebitis infectiveSepsis Bone infectionInfective myositisRhinitis infective Breast infectionLaryngitis Bronchial infectionMeningitis Catheter related infectionOtitis externa + 45 additional + 5 additional
‘Pain’ ~80% of AE TermsDiagnosis ~20% of AE Terms Abdominal painArthralgia Stomach painToothache Gastrointestinal painNeuralgia Pharyngolaryngeal painSore throat Ear pain External ear pain Etc. 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.
Electronic search of CTCAE v4.0 PDF may assist in the identification of AE terms. Access to the PDF can be found at: Introduction to CTCAE v4.0: AE Changes… Click on the QuickReference link to access CTCAE v4.0 PDF
Introduction to CTCAE v4.0: AE Changes… Click Search icon to open Search PDF window Within the CTCAE v4.0 PDF, you can search for the required AE. Example 1: Sweat
Introduction to CTCAE v4.0: AE Changes… Type in word to search for with optional search parameters, and click Search.
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.
Introduction to CTCAE v4.0: AE Changes… 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
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
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) Introduction to CTCAE v4.0: Grading Scale v4.0…
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 Grade 4 = hospitalization 2 Exception: Blindness Grade 4 & Hearing impaired Grade 4 = disabling Introduction to CTCAE v4.0: Grading Scale v4.0…
Grade 1Nonprescription intervention Grade 2Limiting instrumental ADL Grade 3Limiting self care ADL; disabling Grade 4Not disabling Grade 5No 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: Grading Scale v4.0 Summary of changes to CTCAE v4.0:
Introduction to CTCAE v4.0: AEs not associated with Grade 5 SOCCount of AE TermsNo Grade 5Percentage Eye disorders25 100% Investigations383797% Musculoskeletal and connective tissue disorders413073% Skin and subcutaneous tissue disorders342368% Ear and labyrinth disorders9667% Reproductive system and breast disorders513263% Pregnancy, puerperium and perinatal conditions5360% Nervous system disorders633759% General disorders and administration site conditions241458% Endocrine disorders11655% Social circumstances2150% Renal and urinary disorders20945% Psychiatric disorders20840% Vascular disorders17635% Gastrointestinal disorders % Respiratory, thoracic and mediastinal disorders591220% Neoplasm's benign, malignant and unspecified (including cysts and polyps)6117% Hepatobiliary disorders16213% Injury, poisoning and procedural complications7679% Cardiac disorders3638% Infections and infestations7668%
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.
Introduction to CTCAE v4.0: Grading Scale and Activities of Daily Living… 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 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; , (1969)
Introduction to CTCAE v4.0: Grading Scale and Activities of Daily Living 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 Examples of Self Care ADLs:
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: 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