CTEP Program MeetingPatient-Reported Outcomes (PROs)

in Cancer Treatment Trials

Ethan Basch, MD, MScMemorial Sloan-Kettering Cancer Center

PROs for Adverse Event Reporting

March 18, 2008

Overview

1. Background2. Rationale for using PROs for AE Reporting3. Prior and ongoing research

(outside scope of PRO-CTCAE contract)• Questionnaire and platform development• Feasibility• Patient vs. clinician reporting

Essential activity in treatment trials• To ensure patient safety • To provide data about drug effects

– Trialists, regulators, clinicians, patients

Core activity in routine cancer care• To guide therapy and supportive care

Adverse Event Monitoring

NCI-sponsored treatment trials: CTCAE v3 ~1000 individual items

Standard Approach to AE Monitoring

CATEGORY EXAMPLE DATA SOURCE

Laboratory Anemia (hemoglobin) Laboratory report

“Objective” Blood Pressure Clinical staff

“Subjective” Nausea Clinical staff and patients

Patient Experiences

Symptom

Clinician Interprets Symptom

Clinician interviews patient at visit

Chart Representation

of SymptomClinician writes in chart

Data ManagerInterpretation of SymptomData manager

abstracts chart

ResearchDatabase

Manualdata entry

Current Model for Adverse Symptom Reporting in Oncology Trials

Patient Experiences

Symptom

ResearchDatabase

Patient direct reporting of symptoms (1)

Patient Experiences

Symptom

ResearchDatabase

Clinician

Patient direct reporting of symptoms (2)

Rationales for Patient-Reported Outcomes Approach to Adverse Symptom Reporting

• Improve efficiency of data collection– Eliminating data collection steps, reducing errors

• Provide more direct account of patient experience– Eliminating filtering of patient reports by others

• Engage patients as active participants in trials • Enable real-time data capture (ePROs)

– Automated alerts, between-visit reporting

• Provide subsequent patients with AE information reported by their peers, not clinical staff

• Harmonize CTCAE with current standards for symptom measurement using PROs– Eg, FDA guidance

Trotti, Colevas, Setser, Basch: JCO, 2007

Research Prior to PRO-CTCAE Contract

• Created initial adaptations of CTCAE symptom items for pilot testing

• “STAR” items

Basch: JCO, 2005

EXAMPLE: DIARRHEA

Basch: JCO, 2005

Items Loaded to Web Platform

• Online interface– Patient self-reporting– Longitudinal report– Automated alerts

• Administration– Touchscreen kiosks and wireless tablet computers in

clinic waiting areas– Home computers between visits

Basch: J Am Med Informatics Assoc, 2007

STAR Lung Page

STAR Report Page--Patient Name--

Symptom Reported Page

Feasibility Studies

• Outpatients with lung, gynecologic, and genitourinary malignancies receiving chemotherapy

• Intervention: – Selected CTCAE symptoms– 10-minute training– Encouraged to login at follow-up visits– Access to website from home (voluntary)– Reports printed for clinicians at visits– Alerts nurses for grades 3-4

Basch, JCO, 2007

Results

Feasible• Most patients are willing and able to self-

report CTCAE symptoms at clinic visits– Including non-web avid, elderly, and

end-stage with high symptom burdens – No attrition in login rates after up to 2 years

or up to 40 clinic visits

Basch, JCO, 2007

Satisfaction

• High patient satisfaction– Wish to continue using– Would recommend to others

• High clinician satisfaction– Accurate portrayal of patient status– Useful as basis for clinical decisions

57 email alerts(25 different patients)

15 from clinic-based computers

42 from home

computers

Patient’s location

4chemotherapy

holds

7 tel contacts 3 med changes 3 appts made

Clinician actions

Basch, JCO, 2005

Toxicity Alerts for Grade 3-4 (n=80)

Conclusions

• Most patients receiving chemotherapy are willing and able to self-report adverse symptom information at clinic visits

• Clinicians find information valuable and will use it to guide treatment decisions

Real-World Question

• If PROs became a standard approach for reporting adverse symptoms in oncology, how might this alter the frequency or severity of documented toxicities?– Do patients report adverse symptoms

differently from clinicians?

Patient vs. Clinician Reporting

• Paper survey

• 400 patient-clinician pairs– Cancer outpatient clinics

• Patients and clinicians answered the same CTCAE items

Basch, Lancet Oncol, 2006

Basch, Lancet Oncol, 2006

Comparison of Paired Observations

Cumulative Incidence of Symptoms

Patient-reporting

Clinician-reporting

CTCAE Grade-2 (Moderate) CTCAE Grade-3 (Severe)

Patient-reporting

Clinician-reporting

Basch, ASCO, 2008

Which Perspective Should Be Standard?

• Treatment trials/drug labeling– Choosing one approach vs. the other could impact how

toxic drugs look on paper

“Clinician knows best”

TOXICITY “Patient knows best”

Which Perspective in Trials and Labels?

• If continue clinician reports as standard– Will appear to systematically under-report and under-rate

severity of symptoms compared to patient reports

• If adopt patient reports as standard– Frequency and severity of AE reports on labels will likely

increase

• Or report both?– Might they be reflecting different phenomena?

Longitudinal Study

Design• Patients and clinicians reported the same CTCAE symptoms at

each clinic visit for up to 1.5 years• Analyzed associations of patient vs. clinician CTCAE reports with

risk of death, hospitalization, and daily health status

Findings• Clinician CTCAE symptom reporting predicts death and

hospitalization, while patient reporting does not• Patient CTCAE reporting correlates more highly with daily

health status than clinician reporting

Basch, ASCO, 2008

Conclusion

• Clinicians and patients provide complementary information– Capture different aspects of the experience with

disease and treatment

Drug Labels

• Would inclusion of both patient-based and clinician-based adverse symptom data in drug labels cause confusion?

– Instructive to look at examples of ratings reporting approaches outside of healthcare

Metacritic.com

CNET Reviews

Tripadvisor

Docetaxel Drug Label

Ongoing Research

• Multi-center cooperative group study (CALGB)– Feasibility of patient CTCAE reporting, nested in 5

treatment trials– Cancer centers/CCOPs

• PRO study nested in Phase II trial– Patients self-report CTCAE symptoms via computer– Clinicians review patient reports on computer, then

agree or disagree/reassign grades– Clinicians assign attribution

CTCAE Patient Level Report (1)

CTCAE Patient Level Report (2)

• Patients are willing and able to report CTCAE symptoms via computer

• Patient reporting is discrepant from clinician reporting – PROs more reflective of day-to-day experience

• Clinicians will accept patient-reported AEs for treatment decisions and documentation

• Reporting of both patient and clinician AE grades is reasonable in treatment trial results and labels– Would provide additional information about toxicity

Summary

• What are the barriers to widely implementing such a system?

• What AEs are appropriate for patient reporting?• How should this work operationally?

– Should clinicians use PROs to inform their own grades?– How often should patients self-report

• Only at visits?• Between visits (eg, weekly)?

Issues addressed in PRO-CTCAE contract

Remaining Questions

CTEP Program MeetingPatient-Reported Outcomes (PROs)

in Cancer Treatment Trials

Ethan Basch, MD, MScMemorial Sloan-Kettering Cancer Center

Overview of PRO-CTCAE Contract

March 18, 2008

• 2-Year Contract– Started on 10/1/08

NCI Contract HHSN261200800043C

Overall Mission of Project

• Employ rigorous scientific methods to create a system for patient self-reporting of adverse symptoms in cancer trials, which is widely accepted and used; generates useful data for investigators, regulators, clinicians and patients; and is compatible with existing adverse event reporting systems

SOW

• Generate White Paper identifying barriers, ideal conditions, and solutions to implement PRO-CTCAE

• Create PRO-CTCAE items• Build/evaluate electronic PRO-CTCAE platform• Evaluate measurement properties of items• Develop training materials• Design cooperative group study

YEAR 1

YEAR 2

Task-Based Framework for Project

Expert Investigative Team and Subcontracts

How the Work is Done

• Committee for each Task– Under direction of each task leader– Regular teleconferences for each– Vigorous work between calls– Documentation archived on wiki

• https://wiki.nci.nih.gov/x/cKul

• Timelines– Oriented around RFP-specified deliverables

Progress to DateTask 1: Create White Paper

• Survey of 729 stakeholdersRole N*

NCI Representative 41

FDA Representative 26

Cooperative Group Leadership 52

Cooperative Group Member 130

Lead PI 84

Investigator 103

CRA 161

Research Nurse 185

Patient Advocate 121

Industry 30*Not mutually exclusive

Progress to DateTask 1: Create White Paper

• Survey resultsQUESTION AGREE NEUTRAL DISAGREESystems to collect PROs in clinical trials should be developed 89% 5% 6%

In clinical trials, AEs should be reported by clinicians and patients 88% 8% 4%

Both patient and clinician reported AEs should be reported in clinical trial results and in drug labels

76% 15% 9%

Progress to DateTask 1: Create White Paper

• Potential barriers to CTCAE PROsQUESTION AGREE NEUTRAL DISAGREESevere illness/debilitation of patients 88% 6% 6%

Caregiver/proxy reporting should be permitted 70% 12% 18%

Lack of computers 69% 15% 16%

Limited time 58% 19% 23%

Limited personnel 57% 18% 25%

Limited clinic space 48% 21% 29%

Progress to DateTask 1: Create White Paper

• Solutions: funds and new computersQUESTION AGREE NEUTRAL DISAGREEThese barriers could be overcome with adequate funding 79% 13% 8%

My site has clinic staff who could assist patients to self-report 66% 18% 16%

My site has clinic areas that could be used for patient reporting 47% 28% 25%

My site has computers that could be used for patient reporting 24% 25% 51%

My site would need new computers 72% 21% 7%

Wireless computers are feasible at my site 58% 12% 19%

Paper-based reporting is feasible at my site 86% 14% 4%

Progress to DateTask 2: Develop Items

• 77 CTCAE symptoms identified amendable to patient self-reporting

• PRO-CTCAE items created– Different in format from CTCAE– Can be viewed on Wiki

PRO-CTCAE Item ListAbdominal pain Depression Edema – Limb Hot flashes Myalgia Rash Urticaria

Acne Dermatitis (Radiation)

Ejaculatory dysfunction

Hyper-pigmentation

Nail changes Rash: Hand-Foot

Vaginal discharge

Alopecia/hair loss Diarrhea Epistaxis (Nosebleeds)

Hypohidrosis Nausea Rigors/chills Vaginal dryness

Amenorrhea Distension/bloating, abdominal

Erectile dysfunction

Incontinence, anal Neuropathy-sensory

Skin Breakdown

Vision – blurred

Anorexia Dizziness Fatigue Incontinence, urinary

Odor Striae Voice changes

Anxiety Dry mouth/ xerostomia Flashing lights Injection site reaction/

extravasation

Orgasmic dysfunction

Sweating (diaphoresis)

Vomiting

Arthralgia (joint pain)

Dry skin Flatulence Insomnia Pain Taste alteration

Watery eye

Bronchospasm, wheezing Dyspareunia Floaters Irregular menses Painful urination

Tinnitus Decreased concentration

Chelilitis Dysphagia Gynecomastia Libido Palpitations Tremor Depression 2Constipation Dyspnea Heartburn/

dyspepsiaMemory

impairmentPhoto-

sensitivityUrinary

frequencyNail changes 2

(color)

Cough Easy bruising Hiccoughs Mucositis/stomatitis

Pruritus/ Itching Urine color change

Nail changes 3(shape)

Progress to DateTask 4: Cognitive Interviews

• A protocol has been developed to interview patients to assure comprehension of the new items– Undergoing IRB review at NCI and four cancer

centers

Progress to DateTask 5: Platform Development

• A computer platform is in development with SemanticBits– Developer of other caBIG software including

caAERS

Form Builder

Patient Interface

Study Calendar

Summary

• Other tasks in startup phases• Future work beyond the contract

– Assess patient reporting between visits– Translation into non-English – Site-by-site feasibility assessment– Evaluate this approach outside of clinical trial setting for post-

market surveillance– Measure impact of this approach on quality of care