CTCAE v4 - caBIG

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Oct 4, 2013 (3 years and 9 months ago)

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1

Common Terminology
Criteria for Adverse
Events

CTCAE v4.0


Updating a Cancer Research
Standard


Ann Setser, CBIIT, NCI


caBIG Annual Meeting

July 20
-

23, 2009

2

Agenda


CTCAE v3.0 Background


CTCAE v3.0 Revision Project


CTCAE v4.0 Status quo and new


CTCAE v4.0 Documentation & Resources


CTCAE v4.0 Education and Training


Next Steps

3

Acronyms

AE


Adverse Event

caBIG®



cancer Biomedical Informatics Grid

CTCAE


Common Terminology Criteria for Adverse Events

CBIIT


Center for Biomedical Informatics and Information Technology

CTEP


Cancer Therapy Evaluation Program

DLT


Dose Limiting Toxicity

ICH


International Conference on Harmonization

MTD


Maximum Tolerated Dose

MedDRA


Medical Dictionary for Regulatory Activities terminology

SOC


System Organ Class

LLT


Lowest Level Term

SAE


Serious Adverse Event

VCDE


Vocabulary and Common Data Elements (caBIG Workspace)

4

CTCAE Definition, Rationale


The NCI CTCAE is a list of AE terms commonly encountered in
oncology and each AE is accompanied by a grading (severity) scale


AEs are common phenomena affecting patients being treated for
cancer.


Improved survival and the availability of new agents and multimodality
interventions make it critical to monitor systematically AEs linked to
oncology research.


CTCAE is fundamentally intended to be an agreed upon terminology
for the designation, reporting and grading severity of AEs that occur in
oncology research

5

CTCAE Evolution


CTEP, NCI developed CTC to aid in the recognition and grading
severity of AEs of chemotherapy



1983 CTC v1.0



49 AE terms


1998 CTC v 2.0



300 AE Terms*


2003 CTCAE v3.0


1,059 AE Terms*


2009 CTCAE v4.0



790 AE Terms (
MedDRA

LLTs)








*Mapped to
MedDRA

(Medical Dictionary for Regulatory Activities)
terminology


6

CTCAE Purpose


Eligibility criteria


DLT and MTD definitions


Dose modification


AE and SAE reporting


Safety monitoring


Recommended Phase 2 dose


Publications


7

CTCAE v3.0 Example

8

CTCAE Impetus for Revision


2006

MedDRA MSSO Blue Ribbon Panel Meeting


AE Reporting: MedDRA vs. CTCAE


2007

CTEP, FDA discussions


AE data analysis MedDRA vs. CTCAE


2008

caBIG® VCDE evaluation of CTCAE v3.0 as



a standard terminology


Non
-
standard AE terminology


Non
-
machine interpretable


No definitions


Others

9

CTCAE Revision Project

June 2008


June 2009


Funded and organized by CBIIT; CTEP collaboration


Working Groups (~140 members)


Content expertise based on MedDRA SOCs


NCI Cooperative Groups and Academia


PhRMA, FDA, MedDRA MSSO, International Groups, Others


Steering Committee ( 40 members)


Governance Group (25 members)

10


CTCAE Governance Group

FDA,CBIIT,CTEP,Pharma



Steering committee

CBIIT, CTEP,VCDE WG Leads


Semantic

Media Wiki
Team


CTCAE Editing/modeling

Review/Comments

WG

Revision v3 to v4

Readiness
Evaluation

Proposals for long
-
term
governance

Definitions
Group

Policy Decisions

Public Review

CBIIT

Draft version

BOOZ ALLEN HAMILTON


VCDE



CTCAE

v4.0

CTCAE Long Term
Governance

WG

WG

WG

WG

VCDE Review

11

Semantic Media Wiki Team


Biomed GT Wiki


Collaborative terminology development tool for editing CTCAE


Wiki was developed by the NCI Center for Bioinformatics and the Mayo
Clinic Division of Biomedical Informatics with contributions from Apelon,
Inc., Northrup Grumman and Dionne
-
Associates Inc.


Terminology content developed was converted into LexGrid format as a
stand alone source in order to make it available to the caBIG® community
and other interested users


The Wiki team was also responsible for periodic updates and version
releases and for report generation

12

caBIG® VCDE Workspace


Provided expertise to ensure CTCAE compatibility with
caBIG
®
standards and


Developed the initial plan on content representation and CTCAE
maintenance and extension


Performed a readiness evaluation prior to the release of CTCAE v4.0

13

Convert CTCAE to a Standard
Terminology
-

MedDRA


MedDRA is a clinically validated international medical terminology
used by regulatory authorities and the regulated biopharmaceutical
industry throughout the entire regulatory process, from pre
-

to post
-
marketing activities, and for data entry, retrieval, evaluation, and
presentation. ICH
-
endorsed; 11 languages


MedDRA is hierarchical


System Organ Class (SOC)




High Level Group Term (HLGT)


High Level Term (HLT)


Preferred Term (PT)


Lowest Level Term (LLT)





14

CTCAE v4.0 and MedDRA



System Organ Class (SOC) 26


CTCAE v4.0


High Level Group Term (HLGT)


High Level Term (HLT)


Preferred Term (PT)


Lowest Level Term (LLT) >67,000

CTCAE v4.0 (small







subset of total)




15

Comparison:

CTCAE v3.0 CATEGORY to MedDRA SOC

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

16

Comparison:

CTCAE v3.0 CATEGORY to CTCAE v4.0
MedDRA SOC

CTCAE v3.0 CATEGORY

CTCAE v4.0 SOC

CARDIAC ARRHYTHMIA



Cardiac disorders

CARDIAC GENERAL


NEUROLOGY


Nervous system disorders


Psychiatric disorders

17

CTCAE v3.0 CATEGORIES Deleted in
CTCAE v4.0

CTCAE v3.0 CATEGORY

CTCAE v4.0 SOC

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; etc.)

HEMORRHAGE

SYNDROMES

Blood and lymphatic system disorders; Cardiac
disorders; Immune system disorders; Metabolism and
nutrition disorders; Neoplasms benign, malignant and
unspecified (incl cysts and polyps); Nervous system
disorders; Respiratory, thoracic and mediastinal
disorders; Skin and subcutaneous tissue disorders;
Vascular disorders

18

CTCAE v4.0

Changes at AE Term Level

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

19

Changes at AE Term Level


v3.0 Supra
-
ordinate and
Select

Terms Deleted in v4.0


Infection (documented clinically or microbiologically) with Grade 3 or 4
neutrophils (ANC <1.0 x 10e9/L)
-

Select



77 sites


Infection with normal ANC or Gr 1 or 2 neutrophils


Select


77 sites


Infection with unknown ANC


Select


77 sites



CTCAE v4.0 AE terms:


Neutrophil count decreased


Single sites of infection

20

Changes at Grade Level

General Characteristics of Severity


Example Grade 3


CTCAE v3.0

CTCAE v4.0

Severe and undesirable AE

-
significant symptoms;

-
requiring hospitalization;

-
invasive intervention;

transfusion;

-
elective interventional radiological
procedure;

-
therapeutic endoscopy or operation

-
interfering with ADL

Severe AE

-
medically significant but not life
-
threatening;

-
inpatient or prolongation of hospitalization
indicated;

-
important medical event 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;

-
results in persistent or significant disability or
incapacity;

1
Exception: SOC Psychiatric disorders Gr 4 = hospitalization

21

CTCAE v4.0 Changes at Grade Level

General Guidelines: Summary


Gr 1

Nonprescription intervention

Gr 2

Limiting instrumental ADL

Gr 3

Limiting self care ADL; disabling

Gr 4

Not disabling

Gr 5

No change

22

CTCAE v4.0 Changes at Grade Level

Grade 5

Laboratory / diagnostic tests & values are listed within
several SOCs


SOC Investigations


Grading scales for lab test AEs are quantitative range values or
descriptions of variation from normal


Grade 5 Death is
not

an option for these AEs because an
abnormal value/ test result alone is unlikely to result in death

23

CTCAE v4.0 Changes at Grade Level

Grade 5
(continued)

Laboratory / diagnostic tests & values are listed within
several SOCs


SOC Metabolism and nutrition disorders


AE terms are diagnoses and
are associated

with Grade 5
Death


Examples:


Hypocalcemia


Hyperkalemia


Exception: SOC Blood and lymphatic disorders


Anemia includes quantitative ranges for Hemoglobin and
is
associated

with Grade 5 Death

24

Summary of Changes in CTCAE v4.0

CTCAE v3.0

CTCAE v4.0

CATEGORY

SOC

Combination AE terms

Single concept MedDRA LLTs

Short Names

None

Supra
-
ordinate terms
-

Select

None

1,059 AE terms (28 = Other,
specify)

790 AE terms (26 = Other,
specify)

No AE term definitions

AE term definitions

No long
-
term governance

Long
-
term governance: NCI
Core Committee & Community
based Committee

25

CTCAE v4.0 Documentation

Mayo Vocabulary Knowledge Center


https://cabig
-
kc.nci.nih.gov/Vocab/KC/index.php/Main_Page



CTCAE v3.0 to v4.0 mapping (CTEP pending):


What’s new in CTCAE v4.0?


FAQ


Governance Document


Governance Structure and Revision Process


Technical documentation


Plans for future maintenance of CTCAE


Extension, Curation, Advertisement, Education, QA/QC

26

27

28

29

30

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CTCAE v4.0 Education & Training


caBIG Training Portal


PP Presentations


Self
-
paced training modules


caBIG Mayo
-

Vocabulary Knowledge Center


BiomedGT Wiki


F2F


CTEP Cooperative Groups


National and International Meetings


Publications


32

33

CTCAE Revision Project

Lessons Learned


Technology challenges


gForge; BiomedGT Wiki; Centra


SOC Working Groups


Narrow focus


Insufficient background educational material


Documentation of decisions made


Version control


Omission of mapping discussions from WG


34

Acknowledgements

CBIIT, NCI


Frank
Hartel
, Ph.D.





George
Komatsoulis
, Ph.D.





John
Speakman





Larry Wright M.A.





Sherri
DeCoronado
, MS, MBA

CTEP



Alice Chen, M.D.





Shanda

Finnigan
, RN

BAH



Ranjana

Srivastava
, Ph.D.





Mike Keller, Ph.D.

caBIG

VCDE


Brian Davis, Ph.D.

3rd Millennium, Inc.






Stuart Turner, DVM, MS

UC Davis





Lewis Frey, Ph.D.

University of Utah





Sal
Mungal


Duke University





Mike
Riben
, M.D.


MD Anderson

MedDRA

MSSO


Anna Zhao
-
Wong, M.D.





Judy Harrison, M.D.

Volunteers


100+

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Discussion

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