Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms

Responsible Adverse Event (AE) Reporting:

Finding Appropriate AE Terms Using CTC v2.0 and CTCAE v3.0

Presentation Outline

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms

• AE Reporting Background/History• AE Terminology• Physician/Investigator Responsibility• AE Grade • AE Attribution• Locating AEs Terms• Use of ‘Other, Specify’• Summary

Background and History

• It is the law – Federal Regulations• Required of all physicians who sign

the FDA1572 investigator registration form• Ensures human subject safety• Facilitates accurate analysis of effects from

investigational cancer interventions

Why is NCI stressing requirements for accurate, specific AE documentation and reporting?


NCI requires AE Reporting using CTC v2.0/CTCAE v3.0 Specific Terms

Within the scope of the CTC/CTCAE:1. AE definition2. AE grade (seriousness) assignment

Beyond the scope of CTC/CTCAE:1. Attribution of AE2. Interpretation of seriousness of AE

Background and History - continued


History of the Common Toxicity Criteria (CTC)


Since 1982, NCI CTC has been the standard for AE reporting in the oncology community.

Historical Timeline

1982 • Adverse Drug Experience Reporting• Study Summaries• IND reports to FDA• Publications• Format:

• 18 CATEGORIES• 49 AE Terms• Grades:

• Grade 1 = Mild• Grade 2 = Moderate• Grade 3 = Severe• Grade 4 = Life-threatening


NCI CTC v2.0 has become the worldwide standard dictionary for reporting acute AEs in cancer clinical trials and has been

translated into several languages – NCI and Industry.

1997 - CTC Review Committee assembled to revise and expand CTC.

1998 - Introduced CTC v2.0• 24 CATEGORIES• ~300 AE Terms (Acute)• Specificity• Radiotherapy• Pediatrics • Appendices

• RTOG/EORTG Late Radiation Morbidity Scoring Scheme• BMT Complex/Multi-component Event Scheme




2002 - CTEP convened a CTC Development Team (CTCDT) consisting of independent disease and modality-specific cancer therapy experts and NCI representatives to oversee the creation of the Common Terminology Criteria Adverse Event (CTCAE) v3.0.

• Update core criteria.• Expand to create comprehensive dictionary of AEs and

grades applicable to all oncology clinical trials without regard to:

• Chronicity• Modality

• For criteria development, CTEP coordinated:• Late effects • Surgical• Pediatric workshops

• CTCAE v3.0 is the first uniform and comprehensive dictionary of AE grading criteria available for use by all modalities.

2003 - Introduced CTCAE v3.0.


Multiple clinical terms are used to convey the occurrence of an Adverse Event (AE):

• Side effect • Acute effect or late effect • Complication • Toxicity • Morbidity, etc.

Adverse Events

All terms essentially point to a change possibly caused by treatment.


• An AE is any unfavorable or unintended:

• Sign• Abnormal lab• Symptom• Disease

• An AE is a unique representation of a specific event used for medical documentation and scientific analyses.

• Each AE term is mapped to a MedDRA v6.0 term and code.• Same term and code used in Japan and the EU.

• AEs can be: • Symptomatic or completely asymptomatic.• Clinically or radiographically detected.• Noted on laboratory studies or other testing.

Adverse Events - continued


• The guideline for clinicians is to capture any effect from an intervention which may be deleterious.

• Prudent adverse event reporting requires that only AEs that are mandated in protocols and clinically relevant positives be documented.

What to report as an AE



• Pre-existing conditions– Hypertension– Diabetes

• Concomitant medications– Anticoagulants– Steroids

• Other causes– Transfusion reactions– Accidental injuries

• Reporting and grading an AE simply reports that an event occurred and the seriousness of the event.

• The clinician must assign attribution of the event, either to the intervention or something else.

There are multiple causes of AEs:



• Must become familiar with the CTCAE Terms and Grades.

• Responsible for documenting AEs that can be verified on audit.

• Must document signs, symptoms, clinical findings, etc. as they appear.

• Note: Realize documentation of AEs does not necessarily imply causality to intervention or error in administration.

Physician Responsibilities in Clinical Research



Physician Responsibility Regarding Grade

• Document at least descriptive terms found in definitions of Grades to enable CRAs easy identification of numeric Grade.

• Document signs, symptoms, objective measures that characterize severity (Grade).


Refer to CTCAE descriptions of Grade.


• Semi-colon indicates ‘or’ within the description of the Grade.• Em dash (—) indicates a Grade not applicable to the AE.

Documenting Grade


In the development of CTC/CTCAE careful consideration was given to including all descriptions of events that were considered “serious” or “life-threatening” (as defined in the FDA regulations)

in Grade 3 and 4, respectively.


A patient need not exhibit all elements of a Grade description to be designated that Grade.

Example:Induration/fibrosis (skin and subcutaneous tissue)

Grade 3: Dysfunction interfering with ADL; very marked density, retraction or fixation

Read as “Dysfunction ….. OR very marked……”

Interpretation:A patient with very marked density, retraction or fixation, but is able to perform ADLs, is Graded 3.

Documenting Grade

When a patient exhibits elements of multiple Grades, the highest Grade is to be assigned.



Physician Responsibility Regarding Attribution



Physicians are to document the relationship (ATTRIBUTION) of the protocol intervention to each event.

Designating an event as treatment related (or not) is done two ways:

1. By the treating CLINICIAN:Formal “assignment” per adverse event reporting form (“...unlikely, possibly, etc) at the time of clinical evaluation.

2. By Investigators:Later in aggregate data review and reporting by the Investigators.

1. Unrelated:The Adverse Event is clearly not related to the investigational agent(s)

2. Unlikely:The Adverse Event is doubtfully related to the investigational agent(s)

3. Possible: The Adverse Event may be related to the investigational agent(s)

4. Probable: The Adverse Event is likely related to the investigational agent(s)

5. Definite: The Adverse Event is clearly related to the investigational agent(s)

Attribution Standards



The remainder of the presentation provides instruction to locate appropriate AE terms for use in AdEERS, CDUS, and other CTEP data systems.

Each section illustrates the steps used to find an AE using specific Common Toxicity Criteria v2.0 (CTC) and Common Terminology Criteria or Adverse Event v3.0 (CTCAE) examples.


Locating AE Terms - Introduction

The following are the tools available for determining correct AEs. Each correlates to a section within this presentation.

Section 1: CTCAE v3.0 Document Search

Section 2: CTCAE Dictionary and Index

Section 3: CTCAE Online Instructions and Guidelines

All tools are available from the CTEP Home Page at http://ctep.cancer.gov


Available Tools

http://ctep.cancer.gov/

Locating CTC/CTCAE Tools from the CTEP Home Page

1. Access the CTEP Home Page.

2. Scroll halfway down the page.

3. Click on the CTCAE v3.0 link.

The CTCAE v3.0 Web page displays.



Tools available from the CTCAE v3.0 Web page

1. The CTCAE v3.0 Document

2. The CTCAE v3.0 Dictionary and Index

3. The CTCAE v3.0 Online Instructions and Guidelines

The CTCAE v3.0 Web page provides links to the CTCAE v3.0 document and other related tools, including:

Section 1

Searching the CTCAE v3.0 DocumentAccess the CTCAE v3.0 Document PDF file from the Web.

Press CONTROL + F to open the Search Tool. Note: The search tool may appear differently depending on the browser you use.

Enter the term you wish to search and click Search.


Section 1: Searching the CTCAE v3.0 Document - continued

The search returns six instances of the AE term.

Review all to select the most appropriate AE term and Grade.



A search on the term ‘septic’ displays eight instances of the AE term.

See next slide to view the remaining terms.



The term ‘non-septic’ will also match the search criteria and display.


Section 2

Searching the CTCAE DictionaryThe CTCAE Dictionary replaces the CTC Interactive Web Application and provides search capabilities for CTC v2.0 and CTCAE v3.0.

When opened, CTCAE v3.0 is displayed by default with the AE Short Names listed in alphabetical order.


Section 2: Searching the CTCAE Dictionary - continued

•To access the CTC v2.0 search page, click on the CTC v2.0 tab.

•Click one of the alphabet buttons to limit the view alphabetically.

•To view information related to an AE, click on the AE term.

The CATEGORY, full name, grade definitions and MedDRA codes, along with any supra-ordinate terms, remarks, and also consider information are displayed in the right panel.

•To view Navigation Notes, hover the cursor over the icon or click the link.



To display the list of AEs by CATEGORY:

Search by CATEGORY

1. Click the drop down list arrow.

The list of CTCAE CATEGORIES display.

2. Click the CATEGORY.

Note: To revert to the alphabetical list, click ‘All Categories’ from the drop down list.

All AEs associated with the CATEGORY are displayed in alphabetical order.



To search for a specific AE:

Search by Keyword

1. Enter the keyword within the Search for field.

2. Click the Literal button.

The term displays highlighted in blue.

In this example, Rash is also displayed as a consideration. Click Rash.

The term ‘Pruritus’ is listed within the Grade 2 definition.



To search for related AEs:

Search by Index

1. Enter the keyword within the Search for field.

2. Click the Index button.

Possible appropriate AEs are displayed.

Review all to select the most appropriate AE term and Grade.


Section 3

Searching the CTCAE Instructions and Guidelines

The CTCAE Instructions and Guidelines provides a wealth of information regarding the CTCAE and includes four methods to obtain information:

• Contents (displays by default)

• Index (narrow search)

• Search (broad search)

• Glossary


Section 3: Searching the CTCAE Instructions and Guidelines - continued

Search on Contents

To search using the Table of Contents:

1. From the left panel, click the chapter link. The chapter opens and displays all available topics.

2. Click the topic link. The topic displays in the right panel.

3. Topics may directly display information or provide links to information.

Display of related information.



Search on Index

To search using the Index function:

1. Click Index.

2. Either enter the keyword in the search field or scroll to the term.

3. Once the term is located, click the term within the Index list.

4. The topic where the term exists is displayed. It may be necessary to click other links to access the information.




The Search Function

To search using the Search function:

1.Click Search.

2.Enter the keyword in the search field.

3.Click Go.

All topics that include a word(s) that match the keyword will display.

4.Locate and click the topic that best meets your information needs.The topic displays.




The Glossary

To use the Glossary function:

1.Click Glossary.

2.Use the scroll bar to locate the term needed.

3.Click the term.

The term definition displays in the lower left panel.


How and When to use the ‘Other, Specify’ Mechanism for AE Reporting

In recognition that as science and cancer treatments continue to evolve and the potential for novel and unknown untoward affects to occur, the NCI has incorporated a mechanism into the CTC and CTCAE to capture these yet-to-be-defined events.

In the rare event that a suitable CTC or CTCAE term cannot be found, the NCI allows the submitter to report the appropriate verbatim term via the ‘Other, Specify’ mechanism.

The use of the ‘Other, Specify' mechanism is an exception, not the rule.

To minimize overuse, CTEP, NCI will build rules into applications to flag and/or reject reports that take excessive advantage of the ‘Other, Specify’ mechanism. In addition, CTEP, NCI will closely scrutinize all AEs submitted as ‘Other, Specify’. The investigator will be required to correct and resubmit their report if a suitable CTC or CTCAE term is identified by CTEP, NCI staff.


1. If a suitable CTC or CTCAE term is not available, the investigator must make a note to this affect in the source documentation.

2. The investigator must identify the most appropriate CTC or CTCAE CATEGORY to classify the event.

3. Within each CATEGORY is a CTC or CTCAE term ‘Other’ (i.e., ‘Cardiac Arrhythmia – Other’). The submitter must describe or ‘specify’ what the adverse event was. Descriptions must be explicit and provide sufficient detail to describe the event and should be as brief as possible (for example, two to four words).

4. Once the CTC or CTCAE CATEGORY ‘Other’ term has been selected and specified, the submitter must ‘Grade’ the event. The grade refers to the severity of the event. The general description of grades to be used for the ‘Other; Specify’ mechanism are as follows:

Grade 1 – Mild AEGrade 2 – Moderate AEGrade 3 – Severe AEGrade 4 – Life threatening or disabling AEGrade 5 – Death related to AE

How and When to use the ‘Other, Specify’ Mechanism for AE Reporting - continued


Using the ‘Other, Specify’ Mechanism

For more information, see the Guidelines for CTC/CTCAE ‘Other, Specify’ from the CTC/CTCAE Home Page.

Inappropriate Appropriate

CATEGORY Other, specify

CATEGORY AE Grade

MUSCULOSKELETAL Joint pain PAIN Arthralgia (Joint pain)

AUDITORY/

HEARING

Tinnitus AUDITORY/

HEARING

Inner ear/hearing Grade 2: tinnitus or hearing loss, not requiring hearing aid or treatment

Grade 3: tinnitus or hearing loss, correctable with hearing aid or treatment

CARDIO-VASCULAR (ARRHYTHMIA)

Heart Block CARDIOVASCULAR (ARRHYTHMIA)

Conduction abnormality/Atrio-ventricular heart block

DERMATOLOGY/SKIN Rash DERMATOLOGY/ SKIN

Rash/desquamation

Examples of inappropriate ‘Other, Specify’(CTC v2.0)



Unsafe, Meaningless CTEP CommentsCATEGORY Other, specify

CARDIOVASCULAR (ARRHYTHMIA)

Arrhythmia Consult PI. Inappropriate, meaningless AE reporting. When an arrhythmia is witnessed, report the specific arrhythmia and Grade.

PULMONARY Other Consult PI. Inappropriate, unsafe, meaningless AE reporting.

NEUROLOGY Not specified Consult PI. Inappropriate, unsafe, meaningless AE reporting.

OCULAR/VISUAL Name#? Consult PI. Inappropriate, unsafe, meaningless AE reporting.

Examples of inappropriate ‘Other, Specify’(CTC v2.0)



Inappropriate Appropriate

CATEGORY Other, specify CATEGORY AE

HEMORRHAGE/ BLEEDING

Hematuria HEMORRHAGE/ BLEEDING

GU - Bladder

DERMATOLOGY/ SKIN

Leg edema LYMPHATICS Edema - limb

BLOOD/BONE MARROW

Thrombocytopenia BLOOD/BONE MARROW

Platelets

CONSTITUTIONAL SYMPTOMS

Jitteriness and being easily excitable

NEUROLOGY Mood alteration - Agitation

Examples of inappropriate ‘Other, Specify’(CTCAE v3.0)



Unsafe, Meaningless CTEP Comments

CATEGORY Other, specify CATEGORY

CONSTITUTIONAL SYMPTOMS

Fall Consult PI. Inappropriate, meaningless AE reporting. Is this a NEUROLOGY AE (e.g., Ataxia); MUSCULOSKELETAL (e.g., Bruising; Fracture, etc); PAIN?

INFECTION E-coli Consult PI. Where is the infection? Sepsis? Report one of 3 available ‘Infection’ AEs and specify site.

HEMORRHAGE/BLEEDING

PRBC transfusion Not a CTCAE v3.0 AE

CARDIOVASCULAR (ARRHYTHMIA)

LVEF Refer to CTCAE v3.0 for actual AE term and select type of dysrhythmia. Inappropriate use of Other, specify

Examples of inappropriate ‘Other, Specify’(CTCAE v3.0)



Summary: Using CTC v2.0/CTCAE v3.0

• Use CTC v2.0 or CTCAE v3.0 to locate appropriate AE term.

• Document the grade of the AE.• If a patient exhibits elements of multiple grades,

assign the highest grade.

• Assign attribution of the AE.

• If a CTC or CTCAE term cannot be found using the different tools available, the ‘Other, Specify’ option should be used.

• Grade and attribution must be assigned.



Contact the NCI CTEP Help Desk if further assistance is needed.

Phone: 888-CTEPHLP (1-888-283-7457)Fax: 301.948.2242

E-mail: [email protected]

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Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms

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