AHRQ Annual Conference Patient-Reported Outcomes for Adverse Event Monitoring in Clinical Research

1. AHRQ Annual ConferencePatient-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

2. Adverse Event Monitoring 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

3. Data Sources Differ By Type of AE vs. patients

4. Anorexia Fatigue Nausea Vomiting Patient- reported Clinicians systematically downgrade symptoms compared with patients Clinician- reported Diarrhea Constipation Basch: NEJM, 2010 Months Months

5. Patient adverse symptom reports better correlate with functional status than clinician reportsBasch: JNCI, 2009

6. Clinician Adverse Symptom Reporting is Unreliable • N=393 • Seen by 1st clinician in office, then 2nd clinician ~15 minutes later Atkinson: SBM, 2010

7. Patient Experiences Symptom Clinician Interprets Symptom Clinician interviews patient at visit Current Model for Adverse Symptom Reporting in Clinical Trials Chart Representation of Symptom Clinician writes in chart Data Manager Interpretation of Symptom Manual data entry Data manager Abstracts chart, converts findings to standardized terminology Research Database

8. Patient Experiences Symptom Patient direct reporting of symptoms Research Database

9. Patient Experiences Symptom Clinician Patient direct reporting of symptoms Research Database

10. Available Technologies • Web-based • Handheld devices • IVRS • Paper • Text messaging • Interviewer • Mixed methods/modes catering to patients

11. Patient Experiences Symptom Clinician Assign attribution; initiate expedited reporting Patient direct reporting of symptoms Research Database

12. Patient Experiences Symptom Clinician Enhance clinical care Assign attribution; initiate expedited reporting Patient direct reporting of symptoms Research Database

13. 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

14. 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

15. Feasibility High rates of adherence in multi-center industry trials for patient-reported symptoms (IVRS) Meacham & Wenzel (Perceptive Informatics/ClinPhone): ISPOR, 2008

16. 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

17. 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

18. Clinician-Reported Diarrhea • Dueck: Unpublished Data, 2010

19. Patient-Reported Diarrhea • Dueck: Unpublished Data, 2010

20. Patient vs. Clinician Diarrheain Arm 1 (IFL) • Dueck: Unpublished Data, 2010

21. Adverse Symptoms Are Common • Many adverse reactions in drug labels are symptoms

22. Docetaxel Drug Label

23. NCI Contract HHSN261200800043C Development of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) • Initiated October 2008

24. 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

25. PRO-CTCAE Network CBIIT DCCPS DCP DCTD Dana-Farber Christiana N E T W O R K N C C C P NCI MD Anderson Hartford Mayo OLOL MSKCC Coordinating Center Duke Spartanburg Penn St. Joseph - Orange SemanticBits ADVISORS T E C H Cooperative Groups FDA Industry Patient Advocates Perceptive

26. 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

27. Example: Mucositis

28. 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

29. Software Platform

35. Survey729 Stakeholders in Cooperative Groups Bruner et al: ISOQOL, 2010

36. Conclusions • 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