Enhancing Safety Monitoring in Cancer Trials

The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

Ethan Basch, M.D., M.Sc.Memorial Sloan-Kettering Cancer Center

April 22, 2010

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 v4• 790 individual items

Standard Approach to AE Monitoring

CATEGORY EXAMPLE DATA SOURCE

Laboratory Neutropenia Laboratory report

Observable Retinal tear Clinical staff

Symptoms Nausea Clinical staff vs. patients

Basch: Lancet Oncol, 2006

Patient CTCAE Symptom Reports often Disagree with Paired Clinician Reports

Basch: NEJM, 2010Fromme: JCO, 2004

Clinicians systematically downgrade CTCAE symptoms compared with patients

Patient CTCAE symptom reports better correlate with functional status than clinician CTCAE symptom reports

Basch: JNCI, 2009

• N=393 (mixed tumor types)• Seen by 1st clinician in office, then 2nd clinician in chemo suite, an

average of 15 minutes later

Clinician CTCAE Symptom Reporting is Unreliable

Atkinson: SBM, 2010

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)

Patient Experiences

Symptom

ResearchDatabase

Clinician

Assign attribution; initiate expedited reporting

Patient direct reporting of symptoms (3)

Patient Experiences

Symptom

ResearchDatabase

Clinician

Assign attribution; initiate expedited reporting

Enhance clinical care

Patient direct reporting of symptoms (4)

Patient CTCAE Self-Reporting is Feasible• Most cancer patients are willing and able to

self-report symptoms at visits via computer– Including non-web avid, elderly, end-stage– Little attrition over time

Basch: JCO, 2005; 2007Velikova: JCO, 2002Farnell: Eur J Cancer, 2010

Patient Self-Reporting is Already Standard in Closely-Related Areas

• HRQL and symptom efficacy endpoints in cooperative group trials

• Gold standard for symptom endpoints in drug applications and labeling claims submitted to FDA

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdfz

Docetaxel Drug Label

45% of adverse reactions listed in cancer drug labels are symptoms

Development of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

• Contract initiated October 2008– Project Officer: Bryce Reeve– Awarded to MSKCC

NCI Contract HHSN261200800043C

Mission

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 software systems

Scope

1. Produce a White Paper2. Conduct stakeholder survey identifying

barriers and potential solutions for implementing patient AE reporting in cooperative group trials

3. Create patient adaptations of CTCAE symptom items (“PRO-CTCAE items”)

4. Build software platform5. Conduct a “validation” study6. Design cooperative group feasibility study

PRO-CTCAE Network

NCI

ADVISORS TECH

NETWORK

NCCCP

MSKCCCoordinating

Center

Dana-Farber

MD Anderson

Mayo

Duke

Penn

FDACooperative Groups Industry

Christiana

Hartford

OLOL

Spartanburg

St. Joseph - Orange

SemanticBits

PerceptivePatient

Advocates

DCPDCCPS DCTD CBIIT

Screenshot of wikihttps://wiki.nci.nih.gov/x/cKul

Progress to Date

Stakeholder Survey

729 RespondentsRole 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

Results (1)

General impressionsQUESTION AGREE NEUTRAL DISAGREE

Systems to collect patient-reported outcomes in clinical trials should be developed

89% 5% 6%

In clinical trials, adverse events should be reported by patients

88% 8% 4%

Patient-reported adverse events should be reported in clinical trial results and in drug labels

76% 15% 9%

Potential barriers to widely implementing a system for patient adverse event self-reporting in the cooperative groupsQUESTION AGREE NEUTRAL DISAGREE

Severe 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%

Results (2)

Solutions to perceived barriersQUESTION AGREE NEUTRAL DISAGREE

These barriers could be overcome with adequate funding

79% 13% 8%

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

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

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

Results (3)

Item Development (1)

• Approach to identifying CTCAE items amendable to patient self-reporting

Item Development (2)

• 78 CTCAE “adverse symptoms” identified• Preliminary lay terms selected for each

– Individual systematic reviews– Removed medical jargon

Peripheral sensory neuropathy

Numbness or tingling of your hands or feet

Item Development (3)

• Analyzed each source CTCAE item, relevant publications, and datasets to determine which “attributes” are appropriate to characterize for each symptom– E.g., Frequency, severity, interference

• Assigned 1 to 3 attribute items per symptom– Hierarchical, to allow for skip patterns when

administered electronically• Pain frequency severity interference

Item Development (4)

• For each attribute type, generic question structures were created based on existing questionnaires– Simple grading scales– Clear to patients from diverse backgrounds– Amenable to translation

Item Development (5)

Example: MucositisCTCAE v4 Term Grade 1 Grade 2 Grade 3 Grade 4Mucositis 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

Two PRO-CTCAE v1 Items Responses

What was the severity of your MOUTH OR THROAT SORES at their worst?

NoneMildModerate SevereVery Severe

How much did MOUTH OR THROAT SORES interfere with your usual activities?

Not at allA little bitSomewhatQuite a bitVery much

Item Development (6)

• This represents a break in format and grading approach from the CTCAE itself

• Necessary for items appropriate to patient self-reporting, which would likely yield meaningful study results

• Oriented towards nuanced trial results reporting and drug labels– Can conclude the % of patients whose nausea is

severe but infrequent vs. mild but frequent

Item Refinement (1)

• Multicenter “cognitive interviewing” study to assure comprehension across diverse patient populations– Focus on lower education and regional diversity

• Status:– 2 of 3 rounds of interviews completed in >100

patients– Final round underway

Item Refinement (2)

• Adjustments necessary to verbiage of multiple items to clarify meaning

• Broad finding: – Patients often do not follow recall period

instructions– Led to modification of instructions with

emphasis on recall period

Software Platform

Hosted on NCI servers

Form Builder

Integrated Study Calendar

Planned future integration with Patient Study Calendar (PSC)

Simple Patient Interface

Secondary conditional

item

Reports

Real-Time Alerts

Software “Usability” Testing

• 3 cancer centers– 120 patients, 60 staff members

“Validation” Study

• Assessment of validity, reliability, sensitivity, of PRO-CTCAE items– Appropriate recall period– Relationship to clinician CTCAE reporting– Feasibility of questionnaire administration in

clinic via tablet computers, and from home via an automated telephone system (IVRS)

“Validation” Study

• Population– 900 patients with 7 cancer types receiving

chemotherapy and/or RT – 5 cancer centers, 5 NCCCP sites

• Accrual starting in May

Feasibility Assessment

• CALGB 70501 currently accruing– Pilot stand-alone study linked to selected

CALGB treatment trials– Prior version of items and software– Tablet computers at 27 sites– Patients self-report at 6 visits– Status: 60 of 175 patients enrolled

• Developed blueprint for integrating PRO-CTCAE system into cooperative group trials

Mounting Interest in PRO-CTCAE

• Requests to integrate items into 7 cooperative group trials– CALGB, RTOG, GOG, NCCTG

• Requests from investigators at 5 institutions to include items in studies

• Requests from industry– Genentech, Merck, NavigatingCancer.com

White Paper on Wiki

https://wiki.nci.nih.gov/x/X6_l

• Five areas of focus:1. Feasibility2. Methodology3. Technology4. Implementation5. Regulatory

• Barriers/limitations and strategies

White Paper Areas of Focus

Potential Impact• Clinical trials

– Improve efficiency of data collection and data quality – Generate real-time safety signals– Enhance understanding of patient experience with treatment

• Care delivery– Alert clinicians to issues meriting attention– Foster patient-clinician communication

• CER– Create infrastructure for standardized symptom data repository

• Consistent with recent IOM report– Goal II: incorporate innovative science/trial designs– Needs for 2015: efficiently incorporate new technologies;

develop innovative trial designs; address questions meaningful to patients; standardize data capture

AcknowledgmentsNCI DFCI MSKCC FDABryce Reeve Deb Schrag Jennifer Hay Laurie BurkeSteve Clauser Vish Viswanath Yuelin Li Gini KwitkowskiLori Minasian Josh Gagne Thomas Atkinson Ann Marie Trentacosti Diane St. Germain Lauren Becker Marwan Shouery Kathy FedenkoAndrea Denicoff Laura Sit Eugenio CarreraAnn O’Mara DukeJulia Rowland Amy Abernethy Moffitt SemanticBitsAnn Setser Lori Hudson Andy Trotti Ram ChilukuriAlice Chen John Ludenia Harsh AgarwalSonja Stringer Patient Advocates Paul BaumgartnerTed Trimble Mayo Cindy Geoghegan Mehul GulatiGordon Willis Jeff Sloan Diane Paul Vinay KumarShanda Finnigan Amylou DueckChristo Andonyadis Univ of Pennsylvania Perceptive InformaticsMike Montello MD Anderson Deb Bruner Keith WenzelJohn Speakman Charlie Cleeland Linda Hanisch Ali JafariGeorge Komatsoulis Tito Mendoza Hannah O’GormanDianne Reeves