Common Terminology Criteria
for Adverse Events (CTCAE):
Redesign and
Life Cycle Management
March 8, 2010
Contents
Contents
List of Tables
List of Figures
Introduction to CTCAE
Institutional background
Purpose and scope of CTCAE
Statement of intended use
Impetus for redesign and inception of CTCAE v3.0 redesign project
Criteria to be addressed in the CTCAE 3.0 redesign
The redesign phase
Stakeholders and participants
CTCAE Work Groups
CTCAE Steering Committee
CTCAE Governance Group
Technical support groups
Semantic Media Wiki Team
NCI Enterprise Vocabulary Services (EVS)
caBIG® VCDE Group
Program contractor
Process and standard operating procedures (SOPs)
Life cycle governance
Stakeholders and participants
NCI Core Committee
Community-based Committee
caBIG® Vocabulary Knowledge Center (VKC)
NCI Enterprise Vocabulary System (EVS)
Process and SOPs
Maintenance and extension
CTCAE harmonization with MedDRA
Versioning
Training and education
Documentation and advertisement
Quality assurance and quality control
Structure and content of CTCAE
Summary characteristics of CTCAE v4.0
Two-level hierarchical structure
AE terms as concepts
Structural elements per concept
“Other, specify” concept
Severity grading of each AE
Single-parent is-a hierarchy
Other semantic relationships
Concerns and considerations regarding concepts
Data access
Implementation of CTCAE
Intellectual property
Community acceptance
Reporting requirements
Appendices
Appendix A: Participating Members
Appendix B: Work Group Organization
Appendix C: General Grade Guidelines
Appendix D: Editorial Guidelines
Appendix E: Acronyms
Appendix F: References
Appendix G: Acknowledgements
List of Tables
Table 1: Stakeholder distribution
Table 2: Roles and responsibilities in CTCAE redesign
Table 3: Roles and responsibilities in CTCAE future governance
Table 4: Criteria for inclusion of change request: two examples
Table 5: Comparison of MedDRA v12.0 to CTCAE v4.0
List of Figures
Figure 1: CTCAE redesign process
Figure 2: CTCAE maintenance and extension process
Figure 3: CTCAE training and education process
Figure 4: CTCAE quality assurance and quality control process
Introduction to CTCAE
Institutional background
The National Cancer Institute (NCI), within the National Institutes of Health (NIH), is the principal federal agency for conducting and sponsoring research on cancer, training cancer researchers, and disseminating cancer information to the research community and to the public. The Cancer Therapy Evaluation Program (CTEP), within NCI, sponsors clinical trials to evaluate new anti-cancer agents, and forges broad collaborations within the research community, including pharmaceutical and biotechnology industries, to develop new cancer treatments. The cancer Biomedical Informatics Grid (caBIG®) program guides NCI’s efforts to transform cancer research through an integrated biomedical informatics framework, and the caBIG® Vocabularies and Common Data Element (VCDE) Workspace oversees caBIG® terminology standards and resources.
Purpose and scope of CTCAE
The purpose of the CTCAE (Common Terminology Criteria for Adverse Events) is to provide standards for the description and exchange of safety information in oncology research. It is used to define protocol parameters (such as maximum tolerated dose anddose-limiting toxicity) and provide eligibility assessment and guidelines for dose modification. The CTCAE facilitates the evaluation of new cancer therapies and treatment modalities, and the comparison of safety profiles between interventions.
The precursor to CTCAE was developed by CTEP as CTC (Common Toxicity Criteria) in 1983 to aid in the documentation and analysis of adverse effects of chemotherapy. Subsequently, CTEP maintained and updated the CTC through its third version as CTCAE v3.0, published in 2003. It comprised a list of Adverse Event (AE) terms commonly encountered in oncology therapeutic trials, accompanied by a severity grading scale for each AE.
The adoption of MedDRA® (Medical Dictionary for Regulatory Activities)terminology by the ICH (International Conference on Harmonization), NCI, industry, and regulatory bodies provided the impetus for NCI to undertake a redesign of CTCAE in 2008 to beharmonized with MedDRA. CTEP and CBIIT (Center for Biomedical Informatics and Information Technology) collaborated to make the CTCAE v4.0 structured so that it could be incorporated in the caBIG® (cancer Biomedical Informatics Grid) architecture.
The new CTCAE v4.0 standards include:
- AE terms that correspond to MedDRA Lowest Level Terms (LLTs), are organized in MedDRA System Organ Class (SOC) groupings, and that:
▫Promote consistency in AE term reporting across groups and modalities.
▫Are commonly used in oncology studies to define parameters such as eligibility criteria, dose modification, dose limiting toxicity, and maximum tolerated dose.
▫Are signs, symptoms, laboratory values, and diagnoses of AEs commonly monitored in oncology research studies.
- A severity grading scale that:
▫Provides a scale to measure severity of clinical findings and the impact on the study participant.
▫Promotes consistency within a given grade across all AEs.
▫Provides guidance in the evaluation and documentation of severity of the AE.
▫Facilitates a common understanding of AE data shared among academic, commercial, and regulatory entities.
▫Provide framework to compare AEs across different studies.
Statement of intended use
CTCAE is intended for use by a wide range of health care, scientific, and administrative personnel:
- Clinical investigators and physicians
- Nurses and Clinical Research Associates (CRAs)
- Data managers and Study coordinators
- Statisticians
- Medical and technical writers
- Information technology personnel
- Regulatory personnel
- Pharmaceutical companies
- Other oncology research-associated personnel
Users will be better able to systematically monitor AEs linked to oncology research and to evaluate safety outcome data of clinical trials.
Impetus for redesign and inception of CTCAE v3.0 redesign project
MedDRA MSSO (Maintenance and Support Services Organization) Blue Ribbon Panel in April 2006 determined that a mechanism to “translate” or “convert” CTCAE terms to MedDRA terms must be established in order to facilitate data exchange within internal databases and between investigators and regulatory authorities for the purpose of Serious Adverse Event (SAE) reporting. In resulting discussions, CTEP and FDA (Food and Drug Administration) agreed on a CTCAE redesign to be harmonized with MedDRA at the AE term level.
The caBIG® VCDE Workspace performed a review of CTCAE v3.0 terminology. Jim Cimino of the VCDE Workspace conducted the review and presented the results to the Workspace in 2007. Based on the VCDE vocabulary criteria, Cimino concluded that:
- CTCAE v3.0 does not meet most VCDE vocabulary criteria and is not a true controlled terminology.
- Lack of harmonization with MedDRA is an issue.
- Codes should be used as pointers.
- Lack of standard governance and content maintenance is an issue.
- Lack of formal evaluations of content is an issue.
NCI Center for Biomedical Informatics and Information Technology (CBIIT), via the caBIG® initiative, and CTEP collaborated to redesign CTCAE v3.0.
The goals of the CTCAE redesign project were to:
- Harmonization of CTCAE with MedDRA at the AE term level.
- Revise and update adverse events and severity indicators in the CTCAE terminology.
- Make the terminology machine interpretable conforming to caBIG® vocabulary criteria.
- Establish a formal life-cycle governance for future maintenance of CTCAE.
Criteria to be addressed in the CTCAE 3.0 redesign
The VCDE Group identified several areas for improvement. These included:
- Harmonization with MedDRA:
CTEP mandates CTCAE for AE reporting in trials it sponsors, while industry adheres to MedDRA, the ICH standard for regulatory reporting. Industry, regulators, and the NCI are best served by harmonizing CTCAE with MedDRA in the spirit of international collaboration and standardized data exchange.
- Establishment of a stable governance structure:
▫Establish on-going maintenance and extension policies and procedures.
▫Establish an editorial process with documentation, explicit rules for content versioning, community participation, and decision making.
▫Establish policies and processes for archival storage of versions and version management.
▫Provide training and conduct outreach activities.
- Inclusion of text definitions for both AE terms and updating descriptions of severity grades.
- Development of formats that are machine-readable (OWL and RDF), file serialized (XLS and XML), and human-readable (PDF).
The redesign phase
During the period June 2008 to May 2009, CTCAE v3.0 was redesigned to address the recommendations provided by Jim Cimino’s review.
Stakeholders and participants
CTCAE redesign was carried out with very broad participation from the oncology community, directly involving about 170 members from various organizations (see Table 1).
Table 1: Stakeholder distribution
Stakeholder Organization / Number of participantsNIH / 42
FDA / 3
PhRMA (Pharmaceutical Research and Manufacturers of America) / 23
Cooperative Groups; Academic Institutions / 40
Cancer Centers / 29
International / 12
Other / 5
Oversight and coordination of the CTCAE redesign effort was provided by NCI (CBIIT and CTEP) in collaboration with the project contractor (Booz Allen Hamilton). The program staff refined the overall project management plan, detailed schedules, resource allocation, and risk mitigation strategies. A governance structure to coordinate the redesign activities was developed and implemented.The governance structure included 12 Work Groups (WG), a Steering Committee (SC), and a Governance Group (GG) with support provided from additional groups. Participants were recruited from various government agencies (FDA, NCI) private industry (PhRMA), academia, and the MedDRA MSSO (Maintenance and Support Services Organization). Participating members are listed in Appendix A: Participating Members. The final draft version of CTCAE v4.0 was posted for public comment.
The project team leveraged Web 2.0 technology (Semantic Media Wiki) to engage subject matter experts in a collaborative work environment. Consequently, a diverse group of people with different backgrounds and needs contributed to the project. Involving a diverse group of stakeholders helped ground the CTCAE redesign in practical reality, incorporating the latest in oncological care, and ensured that information gained from the redesign effort benefited all participants as well as the extended community.
CTCAE Work Groups
Twelve Work Groups (WGs) were organized by MedDRA SOCs based on member expertise (seeAppendix B: Work Group Organization), and each WG was assigned CTCAE v3.0 AE terms and candidate v4.0 terms. WG members consisted of revision core members, CTEP physicians, Cooperative Group investigators, RNs, pharmaceutical representatives, and VCDE members. Weekly teleconference calls were held, and BiomedGT Wiki was used for ongoing editing and documentation.
The responsibility of the WGs was to revise the CTCAE content to meet the goals of the redesign project. Each WG was represented by a WG lead that was responsible for coordinating and finalizing work in conjunction with NCI, other project members, and also served as the WG representative to the Steering Committee.
CTCAE Steering Committee
The Steering Committee (SC) served as a strategic and guiding body to provide project oversight and coordination across the CTCAE WGs. The goal of the SC was to maintain an overall balance of perspective in the CTCAE, provide oversight of day-to-day activities of the WGs, and to address cross-WG issues. In addition, the SC reviewed proposed content and provided feedback to the WGs. The SC was comprised of members from NCI, VCDE, MedDRA MSSO, WG leads, and members from the research community. NCI staff from CBIIT and CTEP acted as Chairs of the SC and participated in bimonthly virtual meetings to provide recommendations and guidance. The voting structure for the SC was by majority. The committee chairs made the deciding vote when a majority was not reached.Work Group leads abstained from voting on issues pertaining to their own WG.
CTCAE Governance Group
The Governance Group (GG) developed the strategic vision for CTCAE and contributed toward the development of CTCAE by providing objectives and direction for the project. It provided recommendations for the long-term governance of CTCAE including maintenance, extension, training, education, outreach, advertisement, and quality control. The GG was comprised of members from NCI (CBIIT and CTEP), the FDA, Cooperative Groups,MedDRA MSSO, and pharmaceutical companies. All members remained on the GG until the release of CTCAE v4.0 with the option to participate in long-term governance of CTCAE.
Technical support groups
Semantic Media Wiki Team
The Semantic Media Wiki Team provided a collaborative terminology development tool (BiomedGT) for editing the CTCAE. This Wiki was developed by the NCI Center for Bioinformatics and the Mayo Clinic (Rochester, MN) Clinic Division of Biomedical Informatics with contributions from Apelon, Inc., Northrop Grumman, and Dionne-Associates Inc. Terminology content 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.
NCI Enterprise Vocabulary Services (EVS)
Initial definitions for the CTCAE terms were provided by the NCI 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 so that all CTCAE AE terms would have direct mappings to NCI’s core reference terminology, and so that NCIt synonyms, description logic ontology modeling, and other resources can be leveraged by CTCAE users without having to be recreated in CTCAE itself.
caBIG® VCDE Group
The caBIG® VCDE Group provided expertise to ensure CTCAE compatibility with caBIG® standards, and developed the initial plan for content representation and for CTCAE maintenance and extension. The VCDE Group also carried out a readiness evaluation prior to the release of CTCAE v4.0.
Program contractor
Booz Allen Hamilton was the program contractor and was responsible for managing the operations of the CTCAE redesign process, establishing initial governance process, and ensuring coordination across all CTCAE entities. The program contractor also organized two face-to-face meetings with the GG to discuss the strategic vision and the long-term governance of CTCAE. The program contractor organized and facilitated all WG, SC, and GG meetings.
The program contractor successfully coordinated over 170 participants from government, academia, and PhRMA to participate in the CTCAE redesign project. The program contractor facilitated 12 WGs, the SC, and the GG to revise the adverse event terms, the grades and the structure of CTCAE. The program contractor also provided project management to ensure the CTCAE groups, the Semantic Media Wiki Team, the caBIG® Vocabulary Knowledge Center, and the caBIG® VCDE Group were coordinated. Finally, the program contractor provided detailed analysis of the updated CTCAE to ensure consistency across the AE terms and grades.
Table 2 summarizes roles and responsibilities of each group, which the program contractor coordinated, during the CTCAE redesign phase.
Table 2: Roles and responsibilities in CTCAE redesign
Area of responsibility / Responsible group / Responsibilities / ParticipantsOversight / CBIIT & CTEP / Set priorities and direction
Defined the structure and processes to be used during the CTCAE redesign
Prioritized and scheduled content submitted to the WGs
Ensured coordination with other NCI initiatives and activities / CBIIT & CTEP staff
Strategic Vision & Future Governance / Governance Group / Set the strategic vision for CTCAE
Reviewed each draft of CTCAE v4.0
Assessed impact on data systems, FDA policies
Provided guidance on future governance of CTCAE / CBIIT, CTEP, DCP, FDA, MedDRA MSSO, PhRMA
Interface between strategic vision and the redesign process / Steering Committee / Provided domain expertise and leadership
Interfaced between WGs and GG
Addressed cross-WG issues and ensured uniformity across WGs
Reviewed user community feedback and its implementation
Reviewed each draft during the redesign process / Chairs – staff of CBIIT and CTEP
CBIIT, CTEP, VCDE, MedDRA MSSO, WG Leads
Redesign / Work groups / Evaluated content quality
Added new toxicities
Edited the terminology and grading, using the BiomedGT Wiki tool
Provided expert comments and discussion on the terminology and grading
Was responsible for timely completion of the assigned work / CTEP staff, CBIIT staff, Cooperative Group investigators, academic investigators, pharmaceutical representatives, VCDE members, CRAs, coding experts
Technical support for development versions / Semantic Media Wiki Team / Provided the collaborative terminology development tool (BiomedGT) for editing the terminology
Performed periodic updates to the terminology and generated reports of the updated terminology when necessary
Provided periodic version releases
Made the terminology available in various formats / CBIIT, Division of Biomedical Statistics and Informatics, Mayo Clinic (Rochester, MN)
Technical compatibility with caBIG® / VCDE Review Group / Ensured the terminology is caBIG® compatible using several compatibility and review criteria
Performed a readiness evaluation of the terminology / caBIG®
Project management / Program contractor / Ensured coordination across the CTCAE entities
Developed standard operating procedures for review and updates of CTCAE terminology post version 4.0
Established and communicated initial governance and priorities
Was responsible for oversight of initiative activities
Conducted WG sessions
Reported progress to CBIIT and CTEP staff / Booz Allen Hamilton
Process and standard operating procedures (SOPs)
See Figure 1 for an illustration of this process.
1.Potential WG participants were recruited based on suggestions from CBIIT, CTEP, and an open call to the general cancer research community.
2.An invitation letter was sent to potential participants.
3.Those expressing interest in the project were sent orientation packages with information regarding the project. Feedback regarding why individuals did not participate was solicited to more efficiently recruit participants in future.