Patient-Reported Outcomes version of the Common

Terminology Criteria for Adverse Events

Sandra A. Mitchell, PhD, CRNPOutcomes Research Branch, DCCPS

Ethan Basch, MD, MScUniversity of North Carolina

September 9, 2013

Taxotere Drug Label

• Clinicians systematically miss adverse symptoms• Including at baseline in trials

Clinician vs. Patient AE Reporting

3

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

6

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 Clinician 5% 3% 0.1

PRO 3% 2% 0.4

Concentration problems

Clinician n/a n/a n/a

PRO 3% 3% 0.9

Symptom Arm Treatment Worsening from Baseline

P

Nausea Arm 1 43% 35% 0.004

Arm 2 38% 24%

Fatigue Arm 1 90% 47% 0.3

Arm 2 89% 50%

Diarrhea Arm 1 72% 45% <0.001

Arm 2 64% 31%

8

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 Arm 1 90% 47% 58% 0.3

Arm 2 89% 50% 70%

Diarrhea Arm 1 72% 45% 65% <0.001

Arm 2 64% 31% 56%

In label9

Better Detection of Baseline Symptoms Leads to Better Delineation of Cumulative AEs Between

Arms

10

Investigator Agreement with Patient CTCAE

in Phase 2 Trial

8%

8%

2%

14%

6%

2%

4%

85%

87%

96%

85%

93%

94%

95%

7%

5%

2%

2%

1%

4%

1%

0% 20% 40% 60% 80% 100%

KPS

Pain

Nausea

Fatigue

Dyspnea

Cough

Anorexia

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

NCI PRO-CTCAE Study GroupNCI PRO-CTCAE Study Group Supported through NCI contracts HHSN261200800043C and HHSN261201000063C

• PRO-CTCAE Team:

• Organizational Affiliations: NCI Community Cancer Centers Program (NCCCP), RTOG, Alliance, FDA

• We gratefully acknowledge our study participants and patient representatives!

PRO-CTCAE Symptom Library

CTCAE vs. PRO-CTCAE Item Structures CTCAE

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

-

PRO-CTCAEPlease 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

Patient Interface

Write-Ins for Additional Symptoms

Form Builder

Questionnaire Scheduling

Email Alerts

Reports and Data Export

Early Adopters

• Early adopters in academia and industry testing PRO-CTCAE in trials and observational studies

• Cooperative group trials

• Collaboration agreements

1. Identifying best-tolerated dose or schedule

2. Comparing tolerability between products• E.g. Gleevec vs. interferon; pazopanib vs. sunitinib

3. Identifying baseline symptoms and changes from baseline

• General screening of AEs to characterize risk profile

Potential Uses

24

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