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

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

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

Reliability of Clinician CTCAE Symptom Reports

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

Patient-Reported Gr3 Diarrhea Between study arms

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

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%

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

Investigator Agreement with Patient CTCAE in Phase 2 Trial

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

4/26/2017 NCI PRO-CTCAE Study Group Supported through NCI contracts HHSN261200800043C and HHSN261201000063C 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

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

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

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

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

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

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

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

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

4/26/2017 Email 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 e-mail. National Cancer Institute

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

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

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

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