1. CTEP Program Meeting Patient-Reported Outcomes (PROs) in Cancer Treatment Trials Ethan Basch, MD, MSc Memorial Sloan-Kettering Cancer Center PROs for Adverse Event Reporting March 18, 2008

2. Overview 1.Background 2.Rationale for using PROs for AE Reporting 3.Prior and ongoing research (outside scope of PRO-CTCAE contract) Questionnaire and platform development Feasibility Patient vs. clinician reporting

3. 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 Adverse Event Monitoring

4. NCI-sponsored treatment trials: CTCAE v3 ~1000 individual items Standard Approach to AE Monitoring CATEGORYEXAMPLEDATA SOURCE LaboratoryAnemia (hemoglobin)Laboratory report “Objective”Blood PressureClinical staff “Subjective”NauseaClinical staff and patients

5. 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 Research Database Manual data entry Current Model for Adverse Symptom Reporting in Oncology Trials

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

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

8. Rationales for Patient-Reported Outcomes Approach to Adverse Symptom Reporting Improve efficiency of data collection – Eliminating data collection steps, reducing errors Provide more direct account of patient experience – Eliminating filtering of patient reports by others Engage patients as active participants in trials Enable real-time data capture (ePROs) – Automated alerts, between-visit reporting Provide subsequent patients with AE information reported by their peers, not clinical staff Harmonize CTCAE with current standards for symptom measurement using PROs – Eg, FDA guidance Trotti, Colevas, Setser, Basch: JCO, 2007

9. Research Prior to PRO-CTCAE Contract Created initial adaptations of CTCAE symptom items for pilot testing “STAR” items Basch: JCO, 2005

10. EXAMPLE: DIARRHEA Basch: JCO, 2005

11. Items Loaded to Web Platform Online interface –Patient self-reporting –Longitudinal report –Automated alerts Administration –Touchscreen kiosks and wireless tablet computers in clinic waiting areas –Home computers between visits Basch: J Am Med Informatics Assoc, 2007

12. STAR Lung Page

13. STAR Report Page --Patient Name--

14. Symptom Reported Page

15. Feasibility Studies Outpatients with lung, gynecologic, and genitourinary malignancies receiving chemotherapy Intervention: – Selected CTCAE symptoms – 10-minute training – Encouraged to login at follow-up visits – Access to website from home (voluntary) – Reports printed for clinicians at visits – Alerts  nurses for grades 3-4 Basch, JCO, 2007

16. Results Feasible Most patients are willing and able to self- report CTCAE symptoms at clinic visits – Including non-web avid, elderly, and end-stage with high symptom burdens – No attrition in login rates after up to 2 years or up to 40 clinic visits Basch, JCO, 2007

17. Satisfaction High patient satisfaction – Wish to continue using – Would recommend to others High clinician satisfaction – Accurate portrayal of patient status – Useful as basis for clinical decisions

18. 57 email alerts (25 different patients) 15 from clinic-based computers 42 from home computers Patient’s location 4 chemotherapy holds 7 tel contacts 3 med changes 3 appts made Clinician actions Basch, JCO, 2005 Toxicity Alerts for Grade 3-4 (n=80)

19. Conclusions Most patients receiving chemotherapy are willing and able to self-report adverse symptom information at clinic visits Clinicians find information valuable and will use it to guide treatment decisions

20. Real-World Question If PROs became a standard approach for reporting adverse symptoms in oncology, how might this alter the frequency or severity of documented toxicities? – Do patients report adverse symptoms differently from clinicians?

21. Patient vs. Clinician Reporting Paper survey 400 patient-clinician pairs – Cancer outpatient clinics Patients and clinicians answered the same CTCAE items Basch, Lancet Oncol, 2006

22. Comparison of Paired Observations

23. Cumulative Incidence of Symptoms Patient-reporting Clinician-reporting CTCAE Grade-2 (Moderate)CTCAE Grade-3 (Severe) Patient-reporting Clinician-reporting Basch, ASCO, 2008

24. Which Perspective Should Be Standard? Treatment trials/drug labeling – Choosing one approach vs. the other could impact how toxic drugs look on paper “Clinician knows best” TOXICITY “Patient knows best”

25. Which Perspective in Trials and Labels? If continue clinician reports as standard – Will appear to systematically under-report and under-rate severity of symptoms compared to patient reports If adopt patient reports as standard – Frequency and severity of AE reports on labels will likely increase Or report both? – Might they be reflecting different phenomena?

26. Longitudinal Study Design Patients and clinicians reported the same CTCAE symptoms at each clinic visit for up to 1.5 years Analyzed associations of patient vs. clinician CTCAE reports with risk of death, hospitalization, and daily health status Findings Clinician CTCAE symptom reporting predicts death and hospitalization, while patient reporting does not Patient CTCAE reporting correlates more highly with daily health status than clinician reporting Basch, ASCO, 2008

27. Conclusion Clinicians and patients provide complementary information – Capture different aspects of the experience with disease and treatment

28. Drug Labels Would inclusion of both patient-based and clinician-based adverse symptom data in drug labels cause confusion? – Instructive to look at examples of ratings reporting approaches outside of healthcare

29. Metacritic.com

30. CNET Reviews

31. Tripadvisor

32. Docetaxel Drug Label

33. Ongoing Research Multi-center cooperative group study (CALGB) – Feasibility of patient CTCAE reporting, nested in 5 treatment trials – Cancer centers/CCOPs PRO study nested in Phase II trial – Patients self-report CTCAE symptoms via computer – Clinicians review patient reports on computer, then agree or disagree/reassign grades – Clinicians assign attribution

34. CTCAE Patient Level Report (1)

35. CTCAE Patient Level Report (2)

36. Patients are willing and able to report CTCAE symptoms via computer Patient reporting is discrepant from clinician reporting – PROs more reflective of day-to-day experience Clinicians will accept patient-reported AEs for treatment decisions and documentation Reporting of both patient and clinician AE grades is reasonable in treatment trial results and labels – Would provide additional information about toxicity Summary

37. What are the barriers to widely implementing such a system? What AEs are appropriate for patient reporting? How should this work operationally? – Should clinicians use PROs to inform their own grades? – How often should patients self-report Only at visits? Between visits (eg, weekly)? Issues addressed in PRO-CTCAE contract Remaining Questions

38. CTEP Program Meeting Patient-Reported Outcomes (PROs) in Cancer Treatment Trials Ethan Basch, MD, MSc Memorial Sloan-Kettering Cancer Center Overview of PRO-CTCAE Contract March 18, 2008

39. 2-Year Contract – Started on 10/1/08 NCI Contract HHSN261200800043C

40. Overall Mission of Project 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 systems

41. SOW Generate White Paper identifying barriers, ideal conditions, and solutions to implement PRO-CTCAE Create PRO-CTCAE items Build/evaluate electronic PRO-CTCAE platform Evaluate measurement properties of items Develop training materials Design cooperative group study YEAR 1 YEAR 2

42. Task-Based Framework for Project

43. Expert Investigative Team and Subcontracts

44. How the Work is Done Committee for each Task – Under direction of each task leader – Regular teleconferences for each – Vigorous work between calls – Documentation archived on wiki https://wiki.nci.nih.gov/x/cKul Timelines – Oriented around RFP-specified deliverables

45. Progress to Date Task 1: Create White Paper Survey of 729 stakeholders RoleN* NCI Representative41 FDA Representative26 Cooperative Group Leadership52 Cooperative Group Member130 Lead PI84 Investigator103 CRA161 Research Nurse185 Patient Advocate121 Industry30 *Not mutually exclusive

46. Progress to Date Task 1: Create White Paper Survey results QUESTIONAGREENEUTRALDISAGREE Systems to collect PROs in clinical trials should be developed89%5%6% In clinical trials, AEs should be reported by clinicians and patients88%8%4% Both patient and clinician reported AEs should be reported in clinical trial results and in drug labels 76%15%9%

47. Progress to Date Task 1: Create White Paper Potential barriers to CTCAE PROs QUESTIONAGREENEUTRALDISAGREE Severe illness/debilitation of patients88%6% Caregiver/proxy reporting should be permitted70%12%18% Lack of computers69%15%16% Limited time58%19%23% Limited personnel57%18%25% Limited clinic space48%21%29%

48. Progress to Date Task 1: Create White Paper Solutions: funds and new computers QUESTIONAGREENEUTRALDISAGREE These barriers could be overcome with adequate funding79%13%8% My site has clinic staff who could assist patients to self-report66%18%16% My site has clinic areas that could be used for patient reporting47%28%25% My site has computers that could be used for patient reporting24%25%51% My site would need new computers72%21%7% Wireless computers are feasible at my site58%12%19% Paper-based reporting is feasible at my site86%14%4%

49. Progress to Date Task 2: Develop Items 77 CTCAE symptoms identified amendable to patient self-reporting PRO-CTCAE items created – Different in format from CTCAE – Can be viewed on Wiki

50. PRO-CTCAE Item List Abdominal painDepressionEdema – LimbHot flashesMyalgiaRashUrticaria Acne Dermatitis (Radiation) Ejaculatory dysfunction Hyper- pigmentation Nail changes Rash: Hand- Foot Vaginal discharge Alopecia/hair lossDiarrhea Epistaxis (Nosebleeds) HypohidrosisNauseaRigors/chillsVaginal dryness Amenorrhea Distension/ bloating, abdominal Erectile dysfunction Incontinence, anal Neuropathy- sensory Skin Breakdown Vision – blurred AnorexiaDizzinessFatigue Incontinence, urinary OdorStriaeVoice changes AnxietyDry mouth/ xerostomiaFlashing lights Injection site reaction/ extravasation Orgasmic dysfunction Sweating (diaphoresis) Vomiting Arthralgia (joint pain) Dry skinFlatulenceInsomniaPain Taste alteration Watery eye Bronchospasm, wheezingDyspareuniaFloatersIrregular menses Painful urination Tinnitus Decreased concentration ChelilitisDysphagiaGynecomastiaLibidoPalpitationsTremorDepression 2 ConstipationDyspnea Heartburn/ dyspepsia Memory impairment Photo- sensitivity Urinary frequency Nail changes 2 (color) CoughEasy bruisingHiccoughsMucositis/ stomatitis Pruritus/ ItchingUrine color change Nail changes 3 (shape)

51. Progress to Date Task 4: Cognitive Interviews A protocol has been developed to interview patients to assure comprehension of the new items – Undergoing IRB review at NCI and four cancer centers

52. Progress to Date Task 5: Platform Development A computer platform is in development with SemanticBits – Developer of other caBIG software including caAERS

53. Form Builder

54. Patient Interface

55. Study Calendar

56. Summary Other tasks in startup phases Future work beyond the contract – Assess patient reporting between visits – Translation into non-English – Site-by-site feasibility assessment – Evaluate this approach outside of clinical trial setting for post- market surveillance – Measure impact of this approach on quality of care