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CTCAE and Adverse Event Reporting

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Accurate and specific reporting of adverse events (AE) in clinical trials is critical to protect patients and accurately determine the effects of new cancer treatments.

Federal regulation requires all physicians who sign the FDA1572 Investigator Registration Form to document and report AEs mandated by their clinical trial protocols, including the nature and severity (grade) of the event.

CTEP CTCAE

Since the development of the NCI Common Toxicity Criteria (CTC) in 1982, CTEP has set the standard for assessing and reporting adverse events in clinical trials.1 The current Common Terminology Criteria for Adverse Events (CTCAE) v5.0 was released in 2017.

CTCAE v5.0 Resources

Prior CTCAE Versions

PDF reference guides to versions 2, 3, and 4 are available for download below. Excel files for previous versions are available on the Trial Development Resources page.

Adverse Event Reporting Requirements and CTEP-AERS

AE Reporting Guidelines

NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) INDs and IDEs (PDF)

Reporting Adverse Events 

  • Studies using the Rave-CTEP-AERS Integration: All adverse event reports must be initiated in Rave. If an AE meets the reporting requirements, a report will be generated in CTEP-AERS and the site will be able to access that report to submit additional information.
  • For studies that are not using the Rave-CTEP-AERS Integration, log in to CTEP-AERS to report an AE that requires Expedited Reporting .

Additional Forms and Guidance

CTEP-AERS and AE Reporting Training Resources

AdEERS: CTEP's AE Listserv

To stay informed about CTCAE updates, subscribe to CTEP’s AE Listserv (AdEERS) on https://list.nih.gov/ or by sending an e-mail to LISTSERV@LIST.NIH.GOV with the following text in the message body:

subscribe AdEERS your name

Fill in your name with your name as you would like it shown on the Listserv. The Listserv will get your email address from the "From" address of your e-mail message.

HIPAA and PHI Requests for AE Documentation

Disclosure of PHI for Certain Research Purposes is Permitted Under Section 45 CFR Part 164.512(b) (1)

If an entity qualifies as a public health authority, a covered entity may disclose PHI to the public health authority if the law authorizes the public health authority to collect or receive such information for the purposes set forth in section 45 CFR Part 164.512(b)(1). The HIPAA Privacy Rule permits certain disclosures of PHI for public health activities and research without a patient’s authorization. Disclosures to clinical research facilities/clinical investigators in NCI sponsored clinical studies are permitted, as long as the reason for the requests fit within the Privacy Rule’s relevant exception(s).

Disclosure of PHI of a Deceased Person for Research Purposes

A covered entity may disclose PHI of a deceased person to a clinical investigator, without the authorization of the deceased person’s estate, if the clinical investigator provides the covered entity certain assurances. For this information, the clinical investigator must provide documentation that the person is deceased and must submit a request to the outside med facility stating that: 

  • the use/disclosure of the PHI is for research purposes only
  • the information is necessary for research purposes
  • the person is deceased

Additional Guidance and Assistance

For additional guidance on disclosures of PHI for public health purposes to a government agency that also conducts research, see HIPAA Privacy Rule and Public Health: Guidance from CDC and the U.S. Department of Health and Human Services.

For assistance, contact the AEMD Help Desk:

Suggested Language to Request for Information on Patient Participating in a NCI Clinical Research Study

Dear [insert outside facility or provider],

The following patient is/was a participant in a National Cancer Institute (NCI)/Cancer Therapy Evaluation Program (CTEP) clinical research study. CTEP is required to meet Food and Drug Administration (FDA) established timelines when reporting adverse events from CTEP/DCTD/NCI-sponsored clinical research trials to the FDA and is requesting additional medical documentation/records regarding the adverse event(s)/toxicity(ies) and/or emergency room visit(s)/hospitalization(s) below. Per section 45 CFR Part 164.512(b) (1), the HIPAA Privacy Rule permits certain disclosures of PHI for public health activities and research without a patient’s authorization. Disclosures to clinical research facilities/clinical investigators in NCI sponsored clinical studies are permitted, as long as the reason for the requests fit within the Privacy Rule’s relevant exception(s).

Requestor Information

  • Requestor Name:
  • Requestor Email:
  • Requestor Phone Number:
  • Requestor Fax Number: (if applicable)
  • Due Date:

Patient Information

  • Patient Name/ID:
  • Adverse Event(s)/Toxicity(ies):
  • Emergency Room Visit Date(s): (if applicable)
  • Hospitalization Date(s): (if applicable)

I am requesting the following documentation: 

  • [list requested documentation]

[Insert additional information such as preferred method for transmitting information.]

Defining Adverse Events

An Adverse Event is any untoward medical occurrence associated with the use of a drug or intervention in humans, whether or not considered related to the drug or intervention. An AE can be ANY unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use the drug or intervention, whether or not considered related to the drug or intervention. AEs can be symptomatic or completely asymptomatic. They may be detected clinically or radiographically or noted on labs or other testing results.

Clinical terms such as side effect, complication, toxicity, morbidity, acute effect, or late effect can all be used to convey the occurrence of an AE.

The documentation of AEs does not necessarily imply causality to intervention or error in administration. Reporting and grading an AE simply reports that an event occurred and the severity of the event. The Clinical Team must assign attribution of the event, either to the drug or intervention or something else.

Clinical Team Responsibilities:

  • Capture any effects from the drug or intervention which may be deleterious.
  • Document only AEs that are mandated in the protocol and clinically relevant.
  • Become familiar with the CTCAE Terms and Grades.
  • Document signs, symptoms, clinical findings, etc. as they appear, and in a manner that can be verified by audit.
  • The Principal Investigator is ultimately responsible for all elements of an AE report.

AE Grading (Severity)

Clinical Team Responsibilities with regard to AE Grading:

  1. Document signs, symptoms, and objective measures that characterize severity of an AE.
  2. Attempt to utilize descriptive terms found in the CTCAE Definitions and Grades where possible to assist with grading.

Grade Nomenclature:

Semi-colon indicates ‘or’ within the description of the Grade. In the example below, grade 2 fatigue is defined as fatigue either "not relieved by rest" OR "limiting instrumental ADL."

Em dash (—) indicates a Grade not applicable to the AE. In the example below, Grades 4 and 5 (typically indicating an AE that is life-threatening or results in death) are not applicable.

A participant need not exhibit all elements of a Grade description to be designated that Grade. When a participant exhibits elements of multiple Grades, the highest Grade is to be assigned.

In the example below, a patient who experiences fatigue that is not relived by rest has a Grade 3 AE, even if they are able to perform self-care ADLs.

CTCAE TermGrade 1Grade 2Grade 3Grade 4Grade 5Definition
FatigueFatigue relieved by restFatigue not relieved by rest; limiting instrumental ADLFatigue not relieved by rest; limiting self-care ADL--A disorder characterized by a state of generalized weakness with a pronounced inability to summon sufficient energy to accomplish daily activities.

Attribution

The documentation of AEs does not necessarily imply causality to the drug or intervention nor does it imply an error in administration. The clinical team must assign attribution of the event, either to the drug or intervention or something else.

Causes of AEs can include:

  • Protocol treatment (investigational agent, radiation)
  • Pre-existing conditions (such as diabetes or hypertension)
  • Concomitant medications (such as anticoagulants or steroids)
  • Other causes (such as a transfusion reaction or accidental injury)

Attribution Standards Include:

  • Unrelated: The Adverse Event is clearly not related to the investigational agent(s)
  • Unlikely: The Adverse Event is doubtfully related to the investigational agent(s)
  • Possible: The Adverse Event may be related to the investigational agent(s)
  • Probable: The Adverse Event is likely related to the investigational agent(s)
  • Definite: The Adverse Event is clearly related to the investigational agent(s)

Designating an event as treatment-related (or not) can be done by the treating clinician at the time of clinical evaluation (by formally assigning an attribution on the AE reporting form). Investigators may also make these designations later, during aggregate data review and reporting.

Novel AEs not described in the CTCAE

The CTCAE is regularly updated to reflect the continuing evolution of cancer treatment and to describe any deleterious event a patient may experience. In recognition that as science and cancer treatments continue to evolve and the potential for novel and unknown untoward affects to occur, the NCI allows the submitter to report the appropriate verbatim term via the ‘Other, Specify’ mechanism.

This mechanism should only be used in the rare event that a suitable CTCAE term cannot be found for a novel, yet-to-be-defined adverse event. Overuse of the "other, specify" mechanism may lead a report to be flagged or rejected; investigators will be required to correct and resubmit reports if NCI staff identify a suitable CTCAE term.

In order to use the "Other, Specify" mechanism, the Clinical Team must:

  1. Identify the most appropriate CTCAE System Organ Class (SOC) to classify the event. Within each SOC is a CTCAE term ‘Other’ (e.g., ‘Cardiac disorders - Other, specify’).
  2. Name ("specify") the adverse event. The name must be explicit, brief (2-4 words) and provide sufficient detail to name the event.
  3. Grade the event from Grade 1 to Grade 5 according to the descriptions below:
    • Grade 1 – Mild
    • Grade 2 – Moderate
    • Grade 3 – Severe
    • Grade 4 – Life threatening or disabling
    • Grade 5 – Death related to AE

Selected Reference

  1. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, Cumberlin R, Coleman CN, Rubin P. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol. 2003 Jul;13(3):176-81. 

    [PubMed Abstract]
  • Updated:

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