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