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© 2022 2023 Clinical Data Interchange Standards Consortium, Inc. All rights reserved. 

1 Introduction

This document describes the CDISC implementation of the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE®) Item Library Version 1.0 (PRO-CTCAE V1.0).

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The CDISC Intellectual Property Policy can be found on the CDISC website at: https://www.cdisc.org/about/bylaws.

1.1 Representations and Warranties, Limitations of Liability, and Disclaimers

This document is a supplement to the SDTMIG for Human Clinical Trials and is covered under Appendix F of that document, which describes representations, warranties, limitations of liability, and disclaimers. Please see Appendix F of the SDTMIG for a complete version of this material.

CDISC specifies how to structure the data that has been collected in a database, not what should be collected or how to conduct clinical assessments or protocols. CDISC disclaims any liability for your use of this material.

Although the United States Food and Drug Administration (US FDA) has provided input with regard to this supplement, this input does not constitute US FDA endorsement of any particular instrument. 

2 Copyright Status

The The PRO-CTCAE® Measurement System is owned exclusively by National Cancer Institute Institute (NCI) is the owner of the PRO-CTCAE V1.0 measurement system

The CDISC documentation of this measurement system consists of: (1) controlled terminology, (2) standard database structure with examples, and (3) CRF(s) annotated with the CDISC SDTMIG variables with submission values.

Note: CDISC Controlled Terminology is maintained by NCI Enterprise Vocabulary Services (EVS). The most recent version should be accessed through the CDISC website at: https://www.cdisc.org/standards/terminology/controlled-terminology.

CDISC has developed this documentation at no cost to copyright holder or any additional cost to users of the measurement system beyond the normal licenses fees charged by the copyright holder.

CDISC acknowledges Sandra Mitchell, PhD, CRNP, Research Scientist and Program Director Scientific Lead, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Outcomes Research Branch; Healthcare Delivery Research Program Division of Cancer Control and Population Sciences, National Cancer Institute, for the approval to include the PRO-CTCAE V1.0 in the CDISC data standards.

Reference for the PRO-CTCAE V1.0:

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• These materials discuss and/or include the PRO-CTCAE® Item Library Version 1.0 (PRO-CTCAE V1.0). The PRO-CTCAE® Measurement System is owned exclusively by the National Cancer Institute. No part of the PRO-CTCAE® Measurement System may be adapted, altered, amended, abridged, modified, condensed, made into derivative works, or translated without prior written permission from the US National Cancer Institute. PRO-CTCAE is a registered trademark of the US Department of Health & Human Services. All rights reserved. For additional terms of use and to access PRO-CTCAE® Measurement System content, visit https://healthcaredelivery.cancer.gov/pro-ctcae/.
• The PRO-CTCAE trademark items and information herein were developed by the Division of Cancer Control and Population Sciences in the National Cancer Institute at the National Institutes of Health, Bethesda, Maryland, USA. Use of the PRO-CTCAE is subject to NCI’s Terms of Use. PRO-CTCAE Measurement System content should be downloaded using the Instruments & Form Builder link (https://healthcaredelivery.cancer.gov/pro-ctcae/).

The CDISC documentation of this measurement system consists of: (1) controlled terminology, (2) standard database structure with examples, and (3) CRF(s) annotated with the CDISC SDTMIG variables with submission values (referred to hereafter as annotated Item Library v1.0 form).

Note: CDISC Controlled Terminology is maintained by NCI Enterprise Vocabulary Services (EVS). The most recent version should be accessed through the CDISC website at: https://www.cdisc.org/standards/terminology/controlled-terminology.

CDISC has developed this documentation at no cost to the owner, trademark holder, or users of the measurement system.

CDISC acknowledges Sandra Mitchell, PhD, CRNP, Research Scientist and Program Director Scientific Lead, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

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 Outcomes Research Branch, Healthcare Delivery Research Program, Division of Cancer Control and Population Sciences

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, National Cancer Institute, for the approval to include the PRO-CTCAE V1.0 in the CDISC data standards.

References for the PRO-CTCAE V1.0:

• at the National Institutes of Health, in Bethesda, Maryland, U.S.A. Use of the PRO-CTCAE is subject to NCI’s "Terms of Use

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  ". PRO-CTCAE Measurement System content should be downloaded using the "Instrument & Form Builder". https://healthcaredelivery.cancer.gov/pro-ctcae/. Basch E, Reeve BB, Mitchell SA, Clauser SB, Minasian LM, Dueck AC, Mendoza TR, Hay J, Atkinson TM, Abernethy AP, Bruner DW, Cleeland CS, Sloan JA, Chilukuri R, Baumgartner P, Denicoff A, St Germain D, O'Mara AM, Chen A, Kelaghan J, Bennett AV, Sit L, Rogak L, Barz A, Paul DB, Schrag D. Development of the National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE).J Natl Cancer Inst 2014 Sep 29;106(9)).
• National Institutes of Health – National Cancer Institute, Division of Cancer Control & Population Sciences. (2017, July 2) https://healthcaredelivery.cancer.gov/pro-ctcae/overview.html

3 The QS Domain Model

3.1 Assumptions for the QS Domain Model

All assumptions and business rules described in the SDTMIG QS domain are applicable to this supplement. Additional assumptions specific to the PRO-CTCAE V1.0 are listed below.

The PRO-CTCAE measurement system is a patient-reported outcome (PRO) developed to capture symptomatic adverse events of patients in cancer clinical trials. The PRO-CTCAE V1.0 was designed to be used in conjunction with the Common Terminology Criteria for Adverse Events (CTCAE). It consists of an item library rather than a static/fixed item type of instrument. This item library concept is different than other CDISC public domain and copyrighted specific QRS instruments. Users are directed to use the form builder as described on the PRO-CTCAE website to build CRFs with instructions provided by NCI to select the items to implement it in a clinical study. The PRO-CTCAE V1.0 includes multiple-choice questions on the frequency, severity, interference, presence/absence, and /or amount of specific adverse events.

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1. As a CDISC QRS standard, the supplement name is PRO-CTCAE V1.0, as provided in this document. As an item library, sponsors sponsors may select items from the overall library as a subset of items with the same CDISC Controlled Terminology as appropriate for the condition being studied. It is the user's responsibility to identify the subset of items used from the overall PRO-CTCAE V1.0 Quick Guide to the Item Library (Version 1.0). The subsetted PRO-CTCAE V1.0 user's measurement system should system should be titled "PRO-CTCAE sponsor-specified symptoms..." based on the sponsor's discretion when they identify the specific items being used. This will distinctly describe the subsetted measurement system from system from the overall PRO-CTCAE V1.0. The form builder does not represent the Quick Guide to the Item Library symptom term when creating forms with selected symptoms. Users need to reference the annotated Item Library v1.0 form to obtain the related symptom term for forms based on selected symptoms. 
2. For the PRO-CTCAE V1.0, QSORRES is represented with the text description; the numeric rating is represented in the standardized character and numeric result variables QSSTRESC and QSSTRESN. Please see the PRO-CTCAE website FAQs for more details on the numeric responses. The responses for the PRO-CTCAE V1.0 are as follows:
   1. Depending on the symptomatic adverse event (AE) being measured, items assessing symptom presence/absence are rated as follows:
      1. Items rated

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         on a binary response scale and rated from 1-0 (e.g., 1 = “Yes” and 0 = “No”);
      2. Items rated on a multiple (more than 2) response scale and rated from 1-0 (e.g., 1 = “Yes” and 0 = “No”, and “Not applicable”);
      rated on a binary response scale (i.e., 0 = “No” and 1 = “Yes”)
   2. Items assessing symptom frequency are Items assessing symptom frequency are rated on a 5-point scale and are rated from 0-4 (i.e.g., 0 = “Never”, 1 = “Rarely”, 2 = “Occasionally”, 3 = “Frequently”, and 4 = “Almost constantly”).
   3. Items assessing symptom severity are rated on a 5-point scale rated from 0-4 (e.g., 0 = “None”, 1 = “Mild”, 2 = “Moderate”, 3 = “Severe”, and 4 = “Very severe”).QSTESTCD=PT01036A assessing symptom severity is rated on a 5-point scale rated from 0-4 (e.g., 0 = “None”, 1 = “Mild”, 2 = “Moderate”, 3 = “Severe”, and 4 = “Very severe”, "Not applicable") JiraserverIssue Tracker (JIRA)serverId85506ce4-3cb3-3d91-85ee-f633aaaf4a45keyQRSSUPP-395
   4. Items assessing symptom interference are rated on a 5-point scale and are rated from 0-4 (e.g., 0 = “Not at all”, 1 = “A little bit”, 2 = “Somewhat”, 3 = “Quite a bit”, and 4 = “Very much”).
   5. Items assessing symptom amount are rated on a 5-point scale and amount are rated from 0-4 (e.g., 0 = “Not at all”, 1 = “A little bit”, 2 = “Somewhat”, 3 = “Quite a bit”, and 4 = “Very much”).
   6. QSTESTCD = "PT01066A " to "PT01071A" sexual symptoms have specific responses.
      1. QSTESTCD=PT01069A and QSTESTCD=PT01070A assessing sexual symptom presence/absence are rated on multiple (more than two2) response scale and rated from 1-0 (e.g., 1 = “Yes” and 0 = “No”, “Not sexually active”, and “Prefer not to answer”).

      2. QSTESTCD=PT01066A, PT01068A, and PT01071A assessing sexual symptom severity are rated on a 5-point scale rated from 0-4 (e.g., 0 = “None”, 1 = “Mild”, 2 = “Moderate”, 3 = “Severe”, and 4 = “Very severe”, "Not sexually active", and “Prefer not to answer”).

      3. QSTESTCD = "PT01067A" assessing sexual symptom frequency is rated on a 5-point scale rated from 0-4 (e.g., 0 = “Never”, 1 = “Rarely”, 2 = “Occasionally”, 3 = “Frequently”, 4 = “Almost constantly”, "Not sexually active", and “Prefer not to answer”).
   7. Selected items include additional response options such as "Not applicable", "Not sexually active", and "Prefer not to answer". Users will need to apply a customized value to each of these (e.g., -99 = "Not applicable", 999 = "Not sexually active", and 9999 = "Prefer not to answer"). For example,
      1. QSTESTCD=PT01036A assessing symptom severity is rated from 0-4 (e.g., 4 = “Almost constantly”, "Not sexually active", and “Prefer not to answer”).0 = “None”, 1 = “Mild”, 2 = “Moderate”, 3 = “Severe”, and 4 = “Very severe”. The response "Not applicable" is also given and could be provided a value of -99.)
3. The CRF represents up to 5 "other symptoms" to be recorded. In discussions with NIH, it was agreed to provide up to 10 "other symptoms" to be recorded if they existed. QSTESTCDs (QSTESTCDs "PT01082A" through

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   "PT01091A") and severity of the symptom at its worst (QSTESTCDs "PT01082B" through "PT01091B").
4. PRO-CTCAE V1.0 total scoring instructions have not yet been developed. Item-level scores are not combined (i.e., No no total score nor symptom-specific scores are calculated.).
5. The time period of evaluation for the PRO-CTCAE V1.0 is populated in the QSEVLINT field in ISO 8601 format when the evaluation interval can be precisely described as duration. The evaluation interval for the PRO-CTCAE V1.0 is the past 7 days (QSEVLINT = "-P7D"). Please see the PRO-CTCAE website for more details on the evaluation interval.
6. Items are divided into 15 subcategories represented in the QSSCAT variable. These categorizations represent how the symptom terms are categorized in the PRO-CTCAE V1.0 Item Library (Version 1.0). See Section 4, SDTM Mapping Strategy, for a list of these subcategory values. 
   1. The symptomatic AE being measured by a given item (e.g., the Symptom Term represented on the CRF corresponding to a given item) is stored in the SUPPQS dataset with the QNAM = "QSSYMPTM". This matches the symptom term identified in the PRO-CTCAE V1.0 Quick guide to the Item Library (Version 1. 0). The exception to this is the solicited verbatim symptom terms QSTESTCD = "PT01081 to PT01091B"with QNAM = "OTHER SYMPTOMS".
7. Conditional branching is recommended by NCI/NIH in the conduct of the electronic version of the PRO-CTCAE V1.0 for symptom terms that have 2 or more items. The logic branches from frequency, then to severity, then to interference. For example, if frequency is > (greater than) never, next pose the severity question, and if severity > none, pose the interference question. Please see the PRO-CTCAE website for more details on the electronic conditional branching approach.
   1. When a paper version is administered, conditional branching does not apply.
8. Some items on the PRO-CTCAE may be not done due to conditional branching per the electronic instrument instructions as described in assumption 7. A derived record is created with the assigned responses based on the PRO-CTCAE V1.0 website FAQ and a QS supplemental qualifier variable is used to indicate an item was conditionally branched. Per NIH, these items are assigned values as follows: severity items are assigned responses of "None" and 0; interference items are assigned "Not at all" and 0. When an item is not done due to conditional branching, it is represented as follows:

   1. QSDRVFL = "Y"

   2. QNAM = “QSCBRFL”, QLABEL = “Conditional “Conditionally Branched Item Indicator Flag “, QVAL = “Y” (This this is a QS supplemental qualifier variable.)     

   3. QSORRES

      1. For severity items, QSORRES = "None"

      2. For interference items, QSORRES = "Not at all"
   4. QSSTRESC = 0 and QSSTRESN = 0
9. Records are created in qs.xpt for every item on the sponsor's version of the instrument. In the conduct of the PRO-CTCAE V1.0 NIH expects responses for each item and there should be no missing responses. 
   1. For items not done due to conditional branching, refer to assumption 8.
   2. In the unexpected situation where the reason is unknown, then QSORRES, QSSTRESC, and QSSTRESN are all missing, ; QSSTAT = "NOT DONE", ; and QSREASND is missing.
10. The language in which the PRO-CTCAE V1.0 was administered (e.g., English, Spanish, Japanese) is collected with the Form Builder application and may be represented as a supplemental qualifier with QNAM = "QSLANGDC". See the PRO-CTCAE V1.0 website for a list of available language translations.
11. Terminology

    1. QSCAT, QSTESTCD, and QSTEST values are included in CDISC Controlled Terminology.

    2. A full list of value sets for the qualifier, and result fields is provided in Section 4, SDTM Mapping Strategy.

3.2 Example for the PRO-CTCAE V1.0 QS Domain Model

The PRO-CTCAE V1.0 example below shows the terminology used to implement the measurement system in the QS domain. This example shows the data for 1 subject collected at the baseline visit for a PRO-CTCAE V1.0. The example uses CDISC Controlled Terminology for QSTESTCD, QSTEST, and QSCAT. All original results, matching the CRF item response text, are represented in QSORRES.This result is then represented as a standard numeric score in QSSTRESN and as a standard character representation in QSSTRESC.

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The SUPPQS dataset shows the items in the QS dataset which have assigned responses (QSDRVFL QSCBRFL = "Y") due to electronic conditional branching and also relates the symptom terms from the PRO-CTCAE ITEM LIBRARY (Version 1annotated Item Library v1.0 ) form to each symptom item represented in the QS dataset.

Example 2: PRO-CTCAE V1.0 measuring the subset of symptoms from the following subcategories as represented in the PRO-CTCAE ITEM LIBRARY (Version 1.0)Quick Guide to the Item Library:

• RESPIRATORY
• CARDIO/CIRCULATORY
• NEUROLOGICAL
• ATTENTION/MEMORY

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The SUPPQS dataset relates the symptom terms from the PRO-CTCAE ITEM LIBRARY (Version 1annotated Item Library v1.0 ) form to each symptom item represented in the subset of symptoms in the QS dataset.

4 SDTM Mapping Strategy

This section is used for reference regarding the CRF data capture and to understand the alignment of the measurement system to the SDTM QS domain. It also provides guidance on how the result variables (QSORRES, QSSTRESC, and QSSTRESN) should be populated.

QSSCAT alignment with QSTESTCD

As stated in Section 3.1 assumptions, Assumptions, the PRO-CTCAE V1.0 symptom terms are grouped into subcategories as represented in the PRO-CTCAE ITEM LIBRARY (Version 1.0). Quick Guide to the Item Library. The table below includes the subcategory names along with the applicable question numbers for each category. The values of the subcategories are used to populate QSSCAT and are annotated on the CRF.

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5 Supplemental Qualifier Name Codes

The following table contains additional standard name codes for use in the Supplement Qualifiers for Questionnaires (SUPPQS) special purpose dataset.

PRO-CTCAE V1.0 conditional branching items

PRO-CTCAE V1.0 supported languages

PRO-CTCAE ITEM LIBRARY (Version 1V1.0 ) symptom terms

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