CTCAE v6.0: The New Standard in Adverse Event Grading

Common Terminology Criteria for Adverse Events (CTCAE) has become the backbone of how oncology trials describe and grade treatment side effects. CTCAE v6.0, released in 2025, is now the latest standard and is quietly reshaping how adverse events are captured, interpreted, and acted upon across cancer research. For anyone involved in clinical trials—industry, academia, or site-level teams—understanding what CTCAE is and why v6.0 matters is now essential.

What CTCAE Actually Does

CTCAE is a controlled vocabulary that assigns standardized terms and severity grades to adverse events (AEs) that occur in clinical trials, primarily in oncology. Every AE term comes with a definition and five potential grades (1–5), which map to increasing levels of severity, from mild symptoms to life-threatening consequences or death.

This shared language is what allows:

• Investigators in different countries to describe toxicities consistently

• Sponsors and regulators to interpret trial safety profiles in a comparable way

• Biostatisticians to analyze safety data across studies and programs

Because CTCAE terms are aligned with MedDRA, they also plug cleanly into regulatory reporting systems and standardized data models. Without CTCAE, safety data would be fragmented, narrative-heavy, and far harder to interpret at scale.

From v5.0 to v6.0: Why an Update Was Needed

CTCAE v5.0 was released in 2017 and quickly became the default for oncologic clinical trials worldwide. However, oncology changed dramatically over the past decade: immune checkpoint inhibitors became routine, cellular therapies entered practice, and targeted agents multiplied. These shifts exposed limitations in older toxicity definitions and thresholds that were originally tuned for cytotoxic chemotherapy.

Key drivers for CTCAE v6.0 included:

• The need to better capture immune-related toxicities and complex syndromes

• Modernization of lab-based criteria and cytopenia grading

• Closer alignment with updated MedDRA versions and regulatory expectations

In response, NCI released CTCAE v6.0 in 2025, making it available as structured PDF and spreadsheet resources for broad implementation across new and ongoing trials.

What's New in CTCAE v6.0

CTCAE v6.0 introduces several types of changes compared with v5.0, some subtle and some with significant operational impact.

Major categories of updates include:

• New and revised AE terms – Some outdated terms were retired, new ones added, and a variety of definitions updated to better reflect current clinical practice.

• Recalibrated grading thresholds – Lab abnormalities and hematologic toxicities in particular have been re-analyzed, leading to more clinically meaningful grade cutoffs for parameters such as neutrophils and other cytopenias.

• Stronger MedDRA alignment – CTCAE v6.0 is tightly mapped to MedDRA, facilitating cleaner integration with safety databases, E2B reporting, and analytic pipelines.

Importantly, v6.0 is designated as a "final" version, with no incremental revisions planned; the next major changes are reserved for a future v7.0, targeted in the later 2020s.

How CTCAE v6.0 Affects Clinical Trials

At the protocol and operations level, CTCAE v6.0 touches multiple layers of a trial:

• Protocol design – Dose-limiting toxicity definitions, stopping rules, and dose-modification criteria all depend on CTCAE terms and grades. Updated thresholds can alter how conservative or permissive a trial appears.

• Data capture – CRFs and EDC systems must be updated to reflect the new terms and grading definitions, including revised lab ranges and nuanced symptom criteria.

• Safety analysis – Sponsors that pool data across programs must deal with both v5.0 and v6.0. Mapping tools supplied by NCI are specifically designed to help bridge these gaps.

For NCI-sponsored trials, there is a clear implementation boundary: existing studies generally remain on v5.0, while new trials coming online after the relevant system updates (such as Rave ALS 7.2) are expected to adopt v6.0 prospectively.

CTCAE and Patient-Reported Outcomes

One of the most important parallel developments has been PRO-CTCAE, NCI's patient-reported outcome measurement system that captures symptomatic toxicities directly from patients rather than solely from clinician grading. Studies consistently show partial discordance between clinician-assigned CTCAE grades and what patients themselves report for symptoms like fatigue, neuropathy, and gastrointestinal issues.

CTCAE v6.0 does not replace PRO-CTCAE, but it sits beside it as the clinician-facing standard, and ongoing research is defining best practices for combining these two perspectives.

Practical Takeaways for Stakeholders

Different stakeholders will experience CTCAE v6.0 in different ways:

• Oncologists and investigators must update their mental models of what qualifies as Grade 2 vs Grade 3 for key toxicities, especially hematologic and lab-based events.

• CROs and data teams need to reconfigure databases, edit checks, and mapping strategies to handle mixed-version datasets.

• Sponsors and regulators gain more precise, aligned safety data that is easier to interpret and defend in aggregate analyses.

• Site nurses and coordinators require clear, example-driven training to ensure consistency in how symptoms and labs are graded at the point of care.

CTCAE v6.0 is not just another version; it is the new baseline for how toxicity is described in cancer research. For any organization running oncology trials, treating it as a strategic transition—not just a document update—will pay dividends in cleaner data, more interpretable results, and safer patient care.