Ethan Basch , M.D., M.Sc. Memorial Sloan-Kettering Cancer Center April 22, 2010

1. Enhancing Safety Monitoring in Cancer TrialsThe 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

2. Adverse Event Monitoring 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

3. Standard Approach to AE Monitoring NCI-sponsored treatment trials: CTCAE v4 • 790 individual items vs. patients

4. Patient CTCAE Symptom Reports often Disagree with Paired Clinician Reports • Basch: Lancet Oncol, 2006

5. Clinicians systematically downgrade CTCAE symptoms compared with patients • Basch: NEJM, 2010 • Fromme: JCO, 2004

6. Patient CTCAE symptom reports better correlate with functional status than clinician CTCAE symptom reports • Basch: JNCI, 2009

7. Clinician CTCAE Symptom Reporting is Unreliable • N=393 (mixed tumor types) • Seen by 1st clinician in office, then 2nd clinician in chemo suite, an average of 15 minutes later • Atkinson: SBM, 2010

8. Patient Experiences Symptom Current Model for Adverse Symptom Reporting in Oncology Trials Clinician Interprets Symptom Clinician interviews patient at visit Chart Representation of Symptom Clinician writes in chart Data Manager Interpretation of Symptom Manual data entry Data manager abstracts chart Research Database

9. Patient Experiences Symptom Patient direct reporting of symptoms (1) Research Database

10. Patient Experiences Symptom Clinician Patient direct reporting of symptoms (2) Research Database

11. Patient Experiences Symptom Clinician Patient direct reporting of symptoms (3) Assign attribution; initiate expedited reporting Research Database

12. Patient Experiences Symptom Clinician Enhance clinical care Patient direct reporting of symptoms (4) Assign attribution; initiate expedited reporting Research Database

13. 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; 2007 Velikova: JCO, 2002 Farnell: Eur J Cancer, 2010

14. 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

15. 45% of adverse reactions listed in cancer drug labels are symptoms Docetaxel Drug Label

16. NCI Contract HHSN261200800043C 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

17. 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

18. Scope • Produce a White Paper • Conduct stakeholder survey identifying barriers and potential solutions for implementing patient AE reporting in cooperative group trials • Create patient adaptations of CTCAE symptom items (“PRO-CTCAE items”) • Build software platform • Conduct a “validation” study • Design cooperative group feasibility study

19. 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

20. Screenshot of wiki https://wiki.nci.nih.gov/x/cKul

21. Progress to Date

22. Stakeholder Survey 729 Respondents *Not mutually exclusive

23. Results (1) General impressions

24. Results (2) Potential barriers to widely implementing a system for patient adverse event self-reporting in the cooperative groups

25. Results (3) Solutions to perceived barriers

26. Item Development (1) • Approach to identifying CTCAE items amendable to patient self-reporting

27. 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

28. 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

29. 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

30. Item Development (5)

31. Example: Mucositis

32. 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

33. 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

34. 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

35. Software Platform Hosted on NCI servers

36. Form Builder

37. Integrated Study Calendar Planned future integration with Patient Study Calendar (PSC)

38. Simple Patient Interface Secondary conditional item

39. Reports

40. Real-Time Alerts

41. Software “Usability” Testing • 3 cancer centers • 120 patients, 60 staff members

42. “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)

43. “Validation” Study • Population • 900 patients with 7 cancer types receiving chemotherapy and/or RT • 5 cancer centers, 5 NCCCP sites • Accrual starting in May

44. 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

45. 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

46. White Paper on Wiki https://wiki.nci.nih.gov/x/X6_l

47. White Paper Areas of Focus • Five areas of focus: • Feasibility • Methodology • Technology • Implementation • Regulatory • Barriers/limitations and strategies

48. 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

49. Acknowledgments