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
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
• 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