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AHRQ Annual Conference
Patient-Reported Outcomes for Adverse Event Monitoring in Clinical Research
Ethan Basch, M.D., M.Sc. Memorial Sloan-Kettering Cancer Center
September 28, 2010
No Financial Disclosures
Essential activity in Clinical Research• To ensure patient safety • To provide data about drug effects
– Trialists, regulators, payors, clinicians,
patients
Core activity in routine care• To guide therapy and supportive care
Adverse Event Monitoring
Data Sources Differ By Type of AE
CATEGORY EXAMPLE DATA SOURCE
Laboratory value Anemia Lab report
Clinical observation/measurement Retinal tear Clinical staff
Symptom Nausea Clinical staff vs. patients
Basch: NEJM, 2010
Nausea
Fatigue
Months
Anorexia
Vomiting
Diarrhea Constipation
Months
Patient-reported
Clinician-reported
Clinicians systematically downgrade symptoms compared with patients
• Patient adverse symptom reports better correlate with functional status than clinician reports
Basch: JNCI, 2009
• N=393 • Seen by 1st clinician in office, then 2nd clinician ~15 minutes later
Atkinson: SBM, 2010
Clinician Adverse Symptom Reporting is Unreliable
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, converts findings to standardized terminology
ResearchDatabase
Manualdata entry
Current Model for Adverse Symptom Reporting in Clinical Trials
Patient Experiences
Symptom
ResearchDatabase
Patient direct reporting of symptoms
Patient Experiences
Symptom
ResearchDatabase
Clinician
Patient direct reporting of symptoms
• Web-based• Handheld devices• IVRS• Paper• Text messaging• Interviewer
• Mixed methods/modes catering to patients
Available Technologies
Patient Experiences
Symptom
ResearchDatabase
Clinician
Patient direct reporting of symptoms
Assign attribution; initiate expedited reporting
Patient Experiences
Symptom
ResearchDatabase
Clinician
Assign attribution; initiate expedited reporting
Enhance clinical care
Patient direct reporting of symptoms
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
Criticisms of Patient-Reported AEs
• Not feasible– Patients not willing or able to report– Missing data when patients become ill– Too logistically cumbersome/expensive
• Will generate “noise”– Patients will broadly endorse symptoms if asked, making it
impossible to distinguish AEs between study arms– Will not be helpful in unmasking serious or unexpected AEs
Feasibility• High rates of adherence in multi-center industry trials for patient-reported symptoms (IVRS)
Meacham & Wenzel (Perceptive Informatics/ClinPhone): ISPOR, 2008
Feasibility
• Little attrition over time (web-based)– Including non-web avid, elderly, end-stage with high
symptom burdens
Basch: JCO, 2005; 2007
Velikova: JCO, 2002
Farnell: Eur J Cancer, 2010
PROs Can Distinguish between Study Arms and Identify Serious AEs
• NCCTG 9741: Phase III trial comparing three chemotherapy regimens for metastatic colorectal cancer
• Closed after 841/1,125 patients enrolled due to unexpected excess of early deaths in Arm 1 (“IFL”)– Associated with “GI syndrome” including severe diarrhea
• Diarrhea reporting:– Clinicians reported toxicities at each cycle (diarrhea required)– Patients reported diarrhea via in HRQL (SDS) every other cycle
Rothenberg: JCO, 2001
Clinician-Reported Diarrhea
Dueck: Unpublished Data, 2010
Patient-Reported Diarrhea
Dueck: Unpublished Data, 2010
Patient vs. Clinician Diarrheain Arm 1 (IFL)
Dueck: Unpublished Data, 2010
Adverse Symptoms Are Common
Indication # of U.S. Approved Drug
Labels
Average # of AEs per Label
Total # of Unique AEs across
Labels
Proportion of AEs which Are
Symptoms
Breast Cancer 32 78 616 36% (223/616)
Asthma 35 54 368 49% (180/368)
GERD 18 115 472 45% (213/472)
Hyperlipidemia 28 82 365 43% (158/365)
Osteoarthritis 39 94 684 41% (278/684)
• Many adverse reactions in drug labels are symptoms
Docetaxel Drug Label
Development of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)
• Initiated October 2008
NCI Contract HHSN261200800043C
Mission
Develop a system for patient electronic 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
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
Item Development
• Evaluated the standard lexicon for adverse event reporting in oncology (CTCAE)– Currently reported by clinicians
• Of 790 CTCAE items, 81 are amenable to patient self-reporting (“symptoms”)– To create patient versions of these items,
generic question structures were developed based on existing questionnaires
• Removed medical jargon• Attention to cultural literacy
Example: Mucositis
CTCAE 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 Refinement
• Multicenter “cognitive interviewing” study to assure comprehension across diverse patient populations
• National “validation” study underway to evaluate measurement properties of items
Hay: ASCO, 2010
Dueck: ASCO, 2010
Software Platform
Survey729 Stakeholders in Cooperative Groups
QUESTION AGREE NEUTRAL DISAGREE
Systems to collect PROs in trials should be developed 89% 5% 6%
In trials, adverse events should be reported by patients 88% 8% 4%
POTENTIAL BARRIERS AGREE NEUTRAL DISAGREE
Lack of computers 69% 15% 16%
Limited personnel 57% 18% 25%
SOLUTIONS TO OVERCOME BARRIERS AGREE NEUTRAL DISAGREE
Funding (for personnel, dedicated space, training) 79% 13% 8%
Computers 72% 21% 7%
Bruner et al: ISOQOL, 2010
• Electronic patient-reporting of adverse symptoms
in clinical trials is feasible and clinically valuable– Improve quality and efficiency of safety data collection– Enhance understanding of patient experience with treatment– Alert investigators and clinicians to issues meriting attention
• Appropriate for multiple contexts– Preapproval clinical trials– Postmarket surveillance– Comparative effectiveness research– Clinical practice
• Ongoing efforts to operationalize and pilot systems
Conclusions