1. 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

2. 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

3. Data Sources Differ By Type of AE CATEGORYEXAMPLEDATA SOURCE Laboratory valueAnemiaLab report Clinical observation/measurementRetinal tearClinical staff SymptomNauseaClinical staff vs. patients

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

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

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

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

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

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

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

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

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

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/GuidanceComplianceR egulatoryInformation/Guidance s/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 Diarrhea in Arm 1 (IFL) Dueck: Unpublished Data, 2010

21. 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 3278616 36% (223/616) Asthma 3554368 49% (180/368) GERD 18115472 45% (213/472) Hyperlipidemia 2882365 43% (158/365) Osteoarthritis 3994684 41% (278/684) Many adverse reactions in drug labels are symptoms

22. Docetaxel Drug Label

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

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 NCI ADVISORS TECHTECH NETWORKNETWORK NCCCPNCCCP MSKCC Coordinating Center Dana-Farber MD Anderson Mayo Duke Penn FDA Cooperative Groups Industry Christiana Hartford OLOL Spartanburg St. Joseph - Orange SemanticBits Perceptive Patient Advocates DCPDCCPSDCTD CBIIT

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 CTCAE v4 TermGrade 1Grade 2Grade 3Grade 4 Mucositis 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 ItemsResponses What was the severity of your MOUTH OR THROAT SORES at their worst? None Mild Moderate Severe Very Severe How much did MOUTH OR THROAT SORES interfere with your usual activities? Not at all A little bit Somewhat Quite a bit Very much

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. Survey 729 Stakeholders in Cooperative Groups QUESTIONAGREENEUTRALDISAGREE Systems to collect PROs in trials should be developed89%5%6% In trials, adverse events should be reported by patients88%8%4% POTENTIAL BARRIERSAGREENEUTRALDISAGREE Lack of computers69%15%16% Limited personnel57%18%25% SOLUTIONS TO OVERCOME BARRIERSAGREENEUTRALDISAGREE Funding (for personnel, dedicated space, training)79%13%8% Computers72%21%7% Bruner et al: ISOQOL, 2010

36. 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