Responsible Adverse Event AE Reporting Finding Appropriate AE

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Using CTC v 2. 0 and CTCAE v 3. 0

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Presentation Outline • • AE Reporting Background/History AE Terminology Physician/Investigator Responsibility AE Grade AE Attribution Locating AEs Terms Use of ‘Other, Specify’ Summary

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Background and History Why is NCI stressing requirements for accurate, specific AE documentation and reporting? • It is the law – Federal Regulations • Required of all physicians who sign the FDA 1572 investigator registration form • Ensures human subject safety • Facilitates accurate analysis of effects from investigational cancer interventions

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Background and History - continued NCI requires AE Reporting using CTC v 2. 0/CTCAE v 3. 0 Specific Terms Within the scope of the CTC/CTCAE: 1. AE definition 2. AE grade (seriousness) assignment Beyond the scope of CTC/CTCAE: 1. Attribution of AE 2. Interpretation of seriousness of AE

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

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Background and History - continued 1997 - CTC Review Committee assembled to revise and expand CTC. 1998 - Introduced CTC v 2. 0 • • • 24 CATEGORIES ~300 AE Terms (Acute) Specificity Radiotherapy Pediatrics Appendices • RTOG/EORTG Late Radiation Morbidity Scoring Scheme • BMT Complex/Multi-component Event Scheme NCI CTC v 2. 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.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Background and History - continued 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) v 3. 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 v 3. 0 is the first uniform and comprehensive dictionary of AE grading criteria available for use by all modalities. 2003 - Introduced CTCAE v 3. 0.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Adverse Events 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. All terms essentially point to a change possibly caused by treatment.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Adverse Events - continued • 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 Med. DRA v 6. 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.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Adverse Events - continued What to report as an AE • 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.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Adverse Events - continued There are multiple causes of AEs: • 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.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Adverse Events - continued Physician Responsibilities in Clinical Research • 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.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Adverse Events - continued 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.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Adverse Events - continued Documenting Grade • Semi-colon indicates ‘or’ within the description of the Grade. • Em dash (—) indicates a Grade not applicable to the AE. 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.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Adverse Events - continued Documenting Grade 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. When a patient exhibits elements of multiple Grades, the highest Grade is to be assigned.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Adverse Events - continued 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.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Adverse Events - continued Attribution Standards 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)

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Locating AE Terms - Introduction The remainder of the presentation provides instruction to locate appropriate AE terms for use in Ad. EERS, CDUS, and other CTEP data systems. Each section illustrates the steps used to find an AE using specific Common Toxicity Criteria v 2. 0 (CTC) and Common Terminology Criteria or Adverse Event v 3. 0 (CTCAE) examples.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Available Tools The following are the tools available for determining correct AEs. Each correlates to a section within this presentation. Section 1: CTCAE v 3. 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

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms 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 v 3. 0 link. The CTCAE v 3. 0 Web page displays.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Tools available from the CTCAE v 3. 0 Web page The CTCAE v 3. 0 Web page provides links to the CTCAE v 3. 0 document and other related tools, including: 1. The CTCAE v 3. 0 Document 2. The CTCAE v 3. 0 Dictionary and Index 3. The CTCAE v 3. 0 Online Instructions and Guidelines

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Section 1 Searching the CTCAE v 3. 0 Document Access the CTCAE v 3. 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.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Section 1: Searching the CTCAE v 3. 0 Document - continued The search returns six instances of the AE term. Review all to select the most appropriate AE term and Grade.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Section 1: Searching the CTCAE v 3. 0 Document - continued A search on the term ‘septic’ displays eight instances of the AE term. See next slide to view the remaining terms.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Section 1: Searching the CTCAE v 3. 0 Document - continued The term ‘nonseptic’ will also match the search criteria and display.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Section 2 Searching the CTCAE Dictionary The CTCAE Dictionary replaces the CTC Interactive Web Application and provides search capabilities for CTC v 2. 0 and CTCAE v 3. 0. When opened, CTCAE v 3. 0 is displayed by default with the AE Short Names listed in alphabetical order.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Section 2: Searching the CTCAE Dictionary - continued • To access the CTC v 2. 0 search page, click on the CTC v 2. 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 Med. DRA codes, along with any supraordinate 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.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Section 2: Searching the CTCAE Dictionary - continued Search by CATEGORY To display the list of AEs 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.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Section 2: Searching the CTCAE Dictionary - continued Search by Keyword To search for a specific AE: 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.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Section 2: Searching the CTCAE Dictionary - continued Search by Index To search for related AEs: 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.

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

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

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Section 3: Searching the CTCAE Instructions and Guidelines - continued 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. Display of related information.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Section 3: Searching the CTCAE Instructions and Guidelines - continued 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. Display of related information.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms Section 3: Searching the CTCAE Instructions and Guidelines - continued 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.

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

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms How and When to use the ‘Other, Specify’ Mechanism for AE Reporting - continued Using the ‘Other, Specify’ Mechanism 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 AE Grade 2 – Moderate AE Grade 3 – Severe AE Grade 4 – Life threatening or disabling AE Grade 5 – Death related to AE For more information, see the Guidelines for CTC/CTCAE ‘Other, Specify’ from the CTC/CTCAE Home Page.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms How and When to use the ‘Other, Specify’ Mechanism for AE Reporting - continued Examples of inappropriate ‘Other, Specify’ (CTC v 2. 0) Inappropriate CATEGORY Appropriate Other, specify CATEGORY AE MUSCULOSKELETAL Joint pain PAIN Arthralgia (Joint pain) AUDITORY/ HEARING Tinnitus AUDITORY/ HEARING Inner ear/hearing CARDIO-VASCULAR (ARRHYTHMIA) Heart Block CARDIOVASCULAR (ARRHYTHMIA) Conduction abnormality/Atrioventricular heart block DERMATOLOGY/SKIN Rash DERMATOLOGY/ SKIN Rash/desquamation Grade 2: tinnitus or hearing loss, not requiring hearing aid or treatment Grade 3: tinnitus or hearing loss, correctable with hearing aid or treatment

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms How and When to use the ‘Other, Specify’ Mechanism for AE Reporting - continued Examples of inappropriate ‘Other, Specify’ (CTC v 2. 0) Unsafe, Meaningless CATEGORY Other, specify CTEP Comments 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.

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms How and When to use the ‘Other, Specify’ Mechanism for AE Reporting - continued Examples of inappropriate ‘Other, Specify’ (CTCAE v 3. 0) Inappropriate CATEGORY Other, specify Appropriate 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

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms How and When to use the ‘Other, Specify’ Mechanism for AE Reporting - continued Examples of inappropriate ‘Other, Specify’ (CTCAE v 3. 0) Unsafe, Meaningless CATEGORY Other, specify CTEP Comments 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/BLE EDING PRBC transfusion Not a CTCAE v 3. 0 AE CARDIOVASCULAR (ARRHYTHMIA) LVEF Refer to CTCAE v 3. 0 for actual AE term and select type of dysrhythmia. Inappropriate use of Other, specify

Responsible Adverse Event (AE) Reporting: Finding Appropriate AE Terms How and When to use the ‘Other, Specify’ Mechanism for AE Reporting - continued Summary: Using CTC v 2. 0/CTCAE v 3. 0 • Use CTC v 2. 0 or CTCAE v 3. 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: ncictephelp@ctep. nci. nih. gov