Common Terminology Criteria for Adverse Events
The Common Terminology Criteria for Adverse Events (CTCAE) is a standardized descriptive terminology developed by the National Cancer Institute (NCI) to facilitate the uniform reporting and grading of adverse events (AEs) in cancer clinical trials and other medical research contexts.[1] An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure, regardless of causality.[1] The system incorporates terms from the Medical Dictionary for Regulatory Activities (MedDRA) to ensure consistency in documentation, analysis, and communication across studies, ultimately supporting patient safety and the evaluation of therapeutic interventions.[1] Originating from the NCI's Cancer Therapy Evaluation Program (CTEP), the CTCAE evolved from the earlier Common Toxicity Criteria (CTC) first published in 1982, with subsequent versions refining the terminology to address growing needs in oncology research.[2] Major iterations include CTCAE version 2.0 (1999), version 3.0 (2003), version 4.0 (2009), version 5.0 (2017), and the current version 6.0, released on July 22, 2025, which aligns with MedDRA version 28.0 for enhanced international compatibility.[2][1] This progression reflects ongoing efforts to standardize AE assessment amid advances in cancer therapies, such as immunotherapies and targeted agents, ensuring that novel toxicities can be captured through categories like "Other, Specify."[2] Key features of the CTCAE include a five-grade severity scale that quantifies the impact of AEs on patients: Grade 1 (mild; asymptomatic or mild symptoms, no intervention needed), Grade 2 (moderate; minimal intervention required, limits age-appropriate instrumental activities of daily living), Grade 3 (severe; medically significant but not immediately life-threatening, often requiring hospitalization), Grade 4 (life-threatening; urgent intervention indicated), and Grade 5 (death related to the AE).[1] AEs are organized by MedDRA Primary System Organ Class (SOC) for systematic reporting, with attribution categories ranging from "unrelated" to "definite" to assess causality.[1] Mandated for use in NCI-sponsored trials, where investigators are also required under FDA regulations (via Form FDA 1572) to document and report adverse events, the CTCAE is reported electronically through systems like CTEP-AERS, promoting reliable data for regulatory submissions, protocol amendments, and post-marketing surveillance.[2] Its adoption extends beyond oncology to broader pharmacovigilance, aiding in the comparison of treatment toxicities across global studies.[2]Background
Definition and Purpose
The Common Terminology Criteria for Adverse Events (CTCAE) is a descriptive terminology and grading system developed by the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) to standardize the reporting of adverse events (AEs) in clinical trials.[2] An adverse event is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure, whether or not considered related to the treatment.[1] Each AE term in the CTCAE represents a unique description of a specific event, enabling precise medical documentation and scientific analysis.[1] The primary purpose of the CTCAE is to ensure accurate and specific AE reporting, which facilitates comparability of data across clinical trials, enhances patient safety by identifying risks, allows evaluation of treatment effects, and supports regulatory submissions such as those required for U.S. Food and Drug Administration (FDA) drug approvals.[2] This standardization is mandated for investigators in NCI-sponsored trials under federal regulations, including the FDA Form 1572 statement of investigator commitment.[2] By providing a common language for AEs, the CTCAE helps mitigate variability in how toxicities are described and graded, promoting consistent assessment of intervention safety and efficacy.[3] The CTCAE originated in the early 1980s as the NCI Common Toxicity Criteria (CTC) to address inconsistencies in toxicity reporting observed in oncology clinical trials during that era.[3] These early efforts aimed to create a unified framework for classifying and grading AEs, evolving over time into the comprehensive CTCAE system used today.[3] The grading scale, ranging from mild to life-threatening or fatal, underpins this framework but is applied uniformly to support objective AE evaluation.[2]Scope and Application
The Common Terminology Criteria for Adverse Events (CTCAE) is primarily designed for standardizing the reporting of adverse events (AEs) in oncology clinical trials, encompassing a wide range of toxicities associated with cancer treatments such as chemotherapy, radiation therapy, surgical interventions, and immunotherapy.[1] Its scope extends beyond oncology to other therapeutic areas where consistent AE documentation is needed, facilitating the assessment of treatment-related harms across various medical interventions.[1] The system organizes AEs by system organ classes, providing descriptive terms and a five-grade severity scale to capture clinical observations from mild symptoms to life-threatening events or death.[1] In practice, CTCAE application is mandatory for all National Cancer Institute (NCI)-sponsored clinical trials, including those under the Division of Cancer Treatment and Diagnosis (DCTD), to ensure uniform toxicity evaluation and regulatory compliance.[2] Physicians participating as investigators in these trials must sign FDA Form 1572, committing to the use of the current CTCAE version for AE identification, grading, and reporting.[2] It is routinely employed in Phase I through III trials to monitor treatment safety, determine dose-limiting toxicities, and inform dose modifications, with protocols requiring explicit CTCAE-based criteria for these assessments.[2] Adverse events from investigational agents, combination therapies, and supportive care under NCI Investigational New Drug applications are systematically tracked using this framework.[2] CTCAE targets both adult and pediatric patient populations, incorporating age-specific considerations in grading, such as impacts on self-care activities of daily living (ADLs) for younger patients to reflect developmental differences in functional impairment.[1] Despite its breadth, CTCAE has notable limitations as a clinician-reported tool that relies on professional judgment and diagnostic data, potentially overlooking subjective patient experiences without supplementary measures.[1] It does not encompass every possible AE, instead using categories like "Other, specify" for novel or unlisted events to allow flexibility in reporting.[1] The system is not intended as a standalone tool for post-marketing surveillance, where additional regulatory frameworks apply.[4] Overall, CTCAE's standardization supports broader impacts, such as enabling meta-analyses of toxicity data and developing safety profiles across multiple studies to inform treatment guidelines and regulatory decisions.[2]History and Development
Origins as Common Toxicity Criteria
The Common Terminology Criteria for Adverse Events (CTCAE) originated as the Common Toxicity Criteria (CTC), developed by the National Cancer Institute's (NCI) Cancer Therapy Evaluation Program (CTEP) between 1982 and 1983 to standardize the reporting of toxicities in phase I oncology clinical trials.[2][5] Prior to this, variability in how investigators described and graded adverse events across trials complicated the comparison of safety profiles and impeded the development of new anticancer agents.[5] The initial version, CTC v1.0, released in 1983, provided a simple framework with 9 broad categories—such as hematologic, gastrointestinal, and neurologic—and 49 specific adverse event (AE) terms, emphasizing common chemotherapy-related toxicities like nausea, vomiting, and myelosuppression.[5] Severity was graded on a scale from 0 (none) to 4 (life-threatening or disabling), allowing for consistent documentation of dose-limiting effects without requiring hospitalization for lower grades.[5] By the late 1990s, the limitations of CTC v1.0, including its narrow scope focused primarily on chemotherapy, prompted further refinement to accommodate emerging multimodal therapies.[5] CTC v2.0, published in 1999, significantly expanded the system to 24 categories and 295 AE terms (334 when including separate radiation-specific terms), incorporating effects from radiation therapy, surgery, and combined regimens.[5][6] This version introduced the impact on activities of daily living (ADL) as a key severity metric and retained the 0-4 grading scale, while adding dedicated radiotherapy grading to better capture acute organ-specific toxicities.[5][6] The term "toxicity" was preserved in CTC v2.0 for historical continuity, even as the criteria began encompassing a broader range of adverse events beyond strict toxicities.[7] These early iterations laid the foundation for uniform AE reporting, addressing inconsistencies that had previously hindered cross-trial analyses and regulatory evaluations in oncology.[5] Subsequent evolutions renamed and further refined the system into the CTCAE, expanding its applicability.Evolution of Versions
The Common Terminology Criteria for Adverse Events (CTCAE) emerged from the earlier Common Toxicity Criteria (CTC) framework, with the renaming occurring alongside the release of version 3.0 in 2003 to better emphasize the broader spectrum of adverse events beyond mere toxicity assessments and to align with evolving international standards for clinical reporting.[3][8] CTCAE v3.0, fully published in 2006, expanded to 28 categories encompassing 373 adverse event terms (expanding to 910 when including sub-options), introducing a grade 5 designation for death related to the event, dedicated criteria for surgical and late effects, and specific pediatric grading scales to address multimodality treatments.[5] In 2009, CTCAE v4.0 refined the structure to 26 categories with 790 terms, establishing direct mappings to the Medical Dictionary for Regulatory Activities (MedDRA) system organ classes to enhance global interoperability and standardization in adverse event coding.[5] CTCAE v5.0, released in 2017, maintained 26 categories but increased to 837 terms, incorporating additional adverse events identified from emerging cancer therapies such as immunotherapies and targeted agents to better capture contemporary treatment-related toxicities.[5][9] The latest iteration, CTCAE v6.0, published on July 22, 2025, organizes terms across 26 MedDRA-based system organ classes aligned with MedDRA version 28.0, adding new terms to reflect advances in oncology, including "Tumor inflammation-associated neurotoxicity" for immune-related adverse events.[1][10] Over its evolution, the CTCAE has seen the number of terms grow from 49 in the original CTC version 1.0 to over 800 in recent editions, shifting from a toxicity-centric tool to a comprehensive system for adverse event documentation, with updates occurring every 3 to 8 years driven by clinical feedback, new therapeutic modalities, and regulatory harmonization.[5]Structure and Organization
System Organ Classes
The adverse events (AEs) in the Common Terminology Criteria for Adverse Events (CTCAE) are systematically organized into System Organ Classes (SOCs), which form the highest level of the MedDRA-derived hierarchy used for classification. In CTCAE v6.0, AEs are grouped under 26 primary SOCs, categorized by anatomical or physiological systems, etiology, or purpose, ensuring alignment with the Medical Dictionary for Regulatory Activities (MedDRA) v28.0. Examples of these SOCs include Blood and lymphatic system disorders, Cardiac disorders, and Gastrointestinal disorders, each encompassing related AEs for standardized grouping.[1][11] This organizational framework has evolved across CTCAE versions to enhance precision and international compatibility. The precursor Common Toxicity Criteria (CTC) v1.0 utilized 9 broad categories for AE classification, which expanded to 28 categories in CTCAE v3.0 to accommodate a wider range of toxicities observed in clinical trials. Subsequent versions consolidated these into 26 SOCs starting with v4.0, a structure retained through v5.0 and v6.0 to better integrate MedDRA terminology and reduce redundancy while maintaining comprehensive coverage.[5][12] The primary purpose of SOCs is to enable systematic classification of AEs, supporting efficient analysis, regulatory reporting, and cross-study comparisons in oncology clinical trials. By grouping AEs thematically, SOCs allow researchers to identify patterns in treatment-related toxicities, such as organ-specific effects, without overlap in categorization. Each SOC contains multiple AE terms—ranging from dozens to over 100 depending on the class—facilitating detailed documentation while promoting consistency in adverse event assessment.[1] Notable among the SOCs are specialized classes that address unique AE types beyond standard organ systems. The Infections and infestations SOC captures pathogen-related events across the body, the Injury, poisoning and procedural complications SOC addresses iatrogenic or external harms, and the Investigations SOC focuses on laboratory or diagnostic findings, such as abnormal test results. These classes ensure inclusive coverage for non-symptomatic or procedure-linked AEs.[1] While most SOCs support the application of severity grading (1-5 scale) to individual AE terms within them, not all do so uniformly; for example, the Investigations SOC often relies on descriptive thresholds based on objective measurements rather than graded symptoms, prioritizing quantitative lab deviations for reporting. This variability accommodates the diverse nature of AEs while maintaining overall standardization.[1]Adverse Event Terms and Grading
The adverse event (AE) terms in the Common Terminology Criteria for Adverse Events (CTCAE) serve as unique, standardized descriptors for specific occurrences in oncology clinical trials and patient care. These terms include examples such as "Nausea" for gastrointestinal symptoms and "Febrile neutropenia" for hematologic complications, encompassing signs, symptoms, laboratory abnormalities, diseases, and other clinical findings. In version 6.0, the CTCAE comprises over 800 such terms, each mapped to a Lowest Level Term from MedDRA version 28.0 to ensure consistency in reporting. For AEs not covered by predefined terms, the option "Other, specify" enables detailed documentation of unlisted events.[1] Severity for each AE term is evaluated using a 5-point grading scale, which was introduced in CTCAE version 3.0 to provide a comprehensive framework for assessing clinical impact. This scale categorizes events based on symptom intensity, required interventions, and effects on daily functioning, with grades ranging from mild to fatal outcomes. The following table outlines the general criteria for each grade:| Grade | Severity Description | Required Intervention | Impact on Activities of Daily Living (ADL) |
|---|---|---|---|
| 1 | Mild; asymptomatic or mild symptoms | None or minimal | No limitation; no impact on age-appropriate pediatric activity |
| 2 | Moderate; minimal, local, or noninvasive | Minimal, local, or noninvasive | Limits instrumental ADL (e.g., preparing meals); mild/moderate impact on age-appropriate pediatric activity |
| 3 | Severe or medically significant | Significant or invasive; hospitalization may be indicated | Limits self-care ADL (e.g., bathing); severe impact on age-appropriate pediatric activity |
| 4 | Life-threatening; urgent intervention needed | Urgent; life-sustaining measures (e.g., pressors, mechanical support) | Severe functional impairment |
| 5 | Death related to the AE | N/A | N/A |