1. Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events
Sandra A. Mitchell, PhD, CRNP
Outcomes Research Branch, DCCPS
Ethan Basch, MD, MSc
University of North Carolina
September 9, 2013

2. TAXOTERE 75 mg/m2 every 3 weeks
Taxotere Drug Label
TAXOTERE 75 mg/m2 every 3 weeks
ADVERSE REACTION
ANY (%)
GRADE 3/4 (%)
Anemia 67 5
Neutropenia 41 32
Thrombocytopenia 3 1
Infection 6
Epistaxis
Allergic Reactions 8
Neuropathy Sensory 30 2
Neuropathy Motor 7
Rash/Desquamation
Alopecia 65
N/A
Nail Changes
Nausea
Diarrhea
Stomatitis/Pharyngitis 20
Taste Disturbance 18
Vomiting 17
Anorexia
Cough 12
Dyspnea 15
Cardiac function 10
Fatigue 53
Myalgia
Tearing
Arthralgia

3. Clinician vs. Patient AE Reporting
Clinicians systematically miss adverse symptoms
Including at baseline in trials

4. Reliability of Clinician CTCAE Symptom Reports

5. Patient vs. Clinician Gr3 Diarrhea
NCCTG 9741: Phase 3 trial in metastatic colon cancer
IFL Arm

6. Patient-Reported Gr3 Diarrhea
Between study arms

7. Patients Don’t Over-Report Non-Relevant Symptoms
Symptom (Gr3)
Reporter
Arm 2
Arm 1 P
Cough
Clinician 1% 2%
0.4
PRO 3% 4%
0.2
Dyspnea 5%
0.1
Concentration problems
n/a
0.9

8. Worsening from Baseline
Better Detection of Baseline Symptoms Leads to Better Delineation of Cumulative AEs Between Arms
Symptom
Arm
Treatment
Worsening from Baseline P
Nausea
Arm 1
43%
35%
0.004
Arm 2
38%
24%
Fatigue
90%
47%
0.3
89%
50%
Diarrhea
72%
45%
<0.001
64%
31%

9. Worsening from Baseline
Better Detection of Baseline Symptoms Leads to Better Delineation of Cumulative AEs Between Arms
Symptom
Arm
Treatment
Worsening from Baseline P
Nausea
Arm 1
43%
35% 67%
0.004
Arm 2
38%
24% 71%
Fatigue
90%
47% 58%
0.3
89%
50% 70%
Diarrhea
72%
45% 65%
<0.001
64%
31% 56%
In label

10. Investigator Agreement with Patient CTCAE in Phase 2 Trial

11. PRO-CTCAE Measurement System
1. Symptom Library
2. System for Survey Administration
78 symptomatic adverse events drawn from CTCAE
PRO-CTCAE questions (items) evaluate symptom occurrence, frequency, severity, and interference
Web-based system to customize surveys and manage survey administration
Patients respond to surveys using web, tablet or interactive voice response (IVRS) telephone system
Conditional branching (skip patterns)
Write-ins with automatic mapping to standardized terminology
Electronic architecture for survey administration and data capture

12. 4/26/2017
NCI PRO-CTCAE Study Group Supported through NCI contracts HHSN C and HHSN C
Ethan Basch
Sandra Mitchell
Amy Abernethy
Jeff Abrams
Suneel Allareddy
Benjamin Arnold
Pamela Atherton
Thomas Atkinson
Natalie Barragan
Paul Baumgartner
Lauren Becker
Antonia Bennett
Nancy Breen
Deborah Bruner
Laurie Burke
Kate Castro
David Cella
Alice Chen
Ram Chilukuri
Steven Clauser
Charles Cleeland
Catherine Coleman
Stephanie Consoli
Cori Couture
Andrea Denicoff
Amylou Dueck
Jana Eisenstein
Maria Fawzy
Shanda Finnigan
Steve Friedman
Joshua Gagne
Vinay Gangoli
Marcha Gatewood
Araceli Garcia-Gonzalez
Cindy Geoghegan
Maria Gonzalez
Mehul Gulati
Gaurav Gupta
Jennifer Hay
Madeline Hernandez-Krause
Jessica Hess
Lori Hudson
Norval Johnson
Joseph Kelaghan
Reshma Koganti
Edward Korn
George Komatsoulis
Virginia Kwitkowski
Suzanne Lechner
Lauren Lent
Yuelin Li
Carol Lowenstein
Donna Malveaux
Michael Mejia
Tito Mendoza
Lori Minasian
Michael Montello
Hannah O'Gorman
Ann O'Mara
Diane Paul
John Payne
Frank Penedo
Barbara Perez
Richard Piekarz
Liora Pollick
Katherine Ramsey
Bryce Reeve
Lauren Rogak
Dave Rothfarb
Sean Ryan
Daniel Satele
Martin Schoen
Deborah Schrag
Ann Setser
Eve Shalley
Mary Shaw
Marwan Shouery
Laura Sit
Jeff Sloan
Diane St. Germain
Ann Marie Trentascosti
Ted Trimble
Andy Trotti
Andrea Vinard
Vish Viswanath
Gordon Willis
Jennifer Wind
PRO-CTCAE Team:
Organizational Affiliations: NCI Community Cancer Centers Program (NCCCP), RTOG, Alliance, FDA
We gratefully acknowledge our study participants and patient representatives!
National Cancer Institute

13. PRO-CTCAE Symptom Library
4/26/2017
PRO-CTCAE Symptom Library
There are 80 symptoms represented in the PRO-CTCAE symptom library---and the symptom categories map to both the CTCAE and to MEDRA. Not every symptomatic adverse event is relevant for every trial. The system is designed to be comprehensive enough to be used in trials across all types of treatment, while simultaneously allowing a tailored and targeted approach to surveillance for symptomatic adverse events for each clinical trial and even at different phases of the trial. For example, with more comprehensive surveillance for symptoms to establish the pre-treatment baseline of disease-related symptoms and thereby better isolate treatment-emergent adverse effects, o, surveillance for the emergence of late toxicities during long term follow-up)
National Cancer Institute

14. CTCAE vs. PRO-CTCAE Item Structures
Adverse Event
Grade 1 2 3 4 5
Mucositis oral
Asymptomatic or mild symptoms; intervention not indicated
Moderate pain; not interfering with oral intake; modified diet indicated
Severe pain; interfering with oral intake
Life-threatening consequences; urgent intervention indicated -
CTCAE grades integrate symptom severity, interference, and clinical intervention whereas PRO-CTCAE items are designed specifically to capture the patient experience, providing distinct measurement of frequency, severity, and interference as they relate to each symptom.
PRO-CTCAE
Please think back over the past 7 days:
What was the severity of your MOUTH OR THROAT SORES at their WORST?
None / Mild / Moderate / Severe / Very severe
How much did MOUTH OR THROAT SORES interfere with your usual or daily activities?
Not at all / A little bit / Somewhat / Quite a bit / Very much

15. Scientifically Rigorous Development
Extensive cognitive testing in patients
Large U.S. validation study
Software developed and hosted at NCI
Translations underway
Pilot integration into clinical trials

16. System for Electronic Data Capture
4/26/2017
System for Electronic Data Capture
Flexible system for electronic data capture with a number user-centered features. Participants can select English or Spanish and can chose to respond using the web, or their telephone key pad
National Cancer Institute

17. 4/26/2017
Patient Interface
However if they answer that numbness or tingling was mild, they are asked how that numbness or tingling interfered with usual or daily activities.
National Cancer Institute

18. Write-Ins for Additional Symptoms
4/26/2017
Write-Ins for Additional Symptoms
There is a feature that allows patients to nominate additional symptoms that they may be experiencing, and their write-in is mapped to a suitable MEDRA term
National Cancer Institute

19. 4/26/2017
Form Builder
For each clinical trial, investigators build a customized survey that may include core adverse treatment effects such as GI symptoms, fatigue, and peripheral neuropathy, as well as specific side effects that may be anticipated based on prior research or knowledge of the adverse effects that are generally associated with a particular class of agents or modification of a specific molecular pathway
National Cancer Institute

20. Questionnaire Scheduling
4/26/2017
Questionnaire Scheduling
To accommodate the frequent changes in patient schedules and needs that commonly occur during cancer treatment, the system permits clinicians to reschedule survey administration, place surveys on hold, print forms for paper and pencil administration, as well as to manually enter the responses for patients
National Cancer Institute

21. 4/26/2017
Alerts
The system allows you to customize alert routines, specifying which symptoms and which attribute thresholds will trigger alerts as well as specifying those clinicians and investigators who will receive the alerts by .
National Cancer Institute

22. Reports and Data Export
4/26/2017
Reports and Data Export
The system allows you to export data in either an adobe acrobat or excel format, and offers a number of different reporting formats to be viewed or printed
Here you see reporting by date, symptom term and attribute presented in a wide format
National Cancer Institute

23. Early Adopters
Early adopters in academia and industry testing PRO-CTCAE in trials and observational studies
Cooperative group trials
Collaboration agreements

24. Potential Uses 1. Identifying best-tolerated dose or schedule
4/26/2017
Potential Uses
1. Identifying best-tolerated dose or schedule
2. Comparing tolerability between products
E.g. Gleevec vs. interferon; pazopanib vs. sunitinib
Identifying baseline symptoms and changes from baseline
General screening of AEs to characterize risk profile
National Cancer Institute

25. Discussion and Path Forward
4/26/2017
Discussion and Path Forward
Interest to identify early-phase trials to integrate PRO- CTCAE to assess:
Feasibility of using PRO-CTCAE
Value in dose-finding and decision rules
Optimal workflow for adding PRO-CTCAE into trials
Role of investigators in using PRO-CTCAE data
Mapping of PRO-CTCAE to CTCAE grades
National Cancer Institute