1. Including the Patient Voice in Safety Reporting Ethan Basch, MD, MSc Health Outcomes Group Departments of Medicine and Epidemiology/Biostatistics Memorial Sloan-Kettering Cancer Center June 2009

2. 1.Background on PROs 2.PROs for Adverse Event Reporting –Research –Regulatory issues 3.CALGB 70501 Overview

3. What is a PRO? FDA Definition: “Any report that comes directly from a patient about a health condition or its treatment without interpretation of the patient’s response by a clinician or anyone else” - Guidance (2006)

4. FDA Definition of PRO Any experience the patient knows best –Symptoms –HRQL –Functional status –Therapy compliance –Satisfaction with care –Treatment preferences -Guide clinical practice -Support clinical trial endpoints -Safety monitoring -AEs in clinical trials -Postmarket surveillance

5. Essential activity in treatment trials To ensure patient safety To provide data about drug effects Core activity in routine cancer care To guide therapy and supportive care Adverse Event Monitoring

6. NCI-sponsored treatment trials: CTCAE ~1000 individual items, ordinal scale Standard Approach to AE Monitoring CATEGORYEXAMPLEDATA SOURCE LaboratoryAnemia (hemoglobin)Laboratory report ObjectiveBlood PressureClinical staff SubjectiveNauseaClinical staff or patients?

7. EXAMPLE: DIARRHEA

8. 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

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

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

11. Rationales for Using PROs for Adverse Symptom Monitoring in Oncology Improve efficiency, quality, completeness of data collection in clinical trials –Eliminating data collection steps, reducing errors –Providing more direct account of patient experience Improve delivery of clinical care –Enhancing patient-clinician communication –Providing capacity to monitor patients between visits –Enabling automated alerts to address toxicities earlier Trotti & Basch: J Clin Oncol, 2007

12. Developed Initial Patient Questionnaire Adaptations of CTCAE symptom items –Health literacy/patient education experts –Focus groups –Cognitive debriefing Basch: JCO, 2005

13. 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

14. STAR (1)

15. STAR (2)

16. STAR (3) --Patient Name--

17. STAR (4)

18. STAR (5)

19. Feasibility Studies Patients receiving chemotherapy 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 up to 1.5 years Basch, JCO, 2005 Basch, JCO, 2007

20. Satisfaction High patient satisfaction –Wish to continue using –Would recommend to others Clinician impressions and actions –Accurate portrayal of patient status –Altered chemotherapy doses based on patient- reported information

21. Implications If PROs were adopted for monitoring adverse symptoms in oncology, how might this alter the frequency or severity of documented toxicities? –Do patients report toxicities differently from clinicians?

22. Patient vs. Clinician Reporting (1) Paper survey 400 patient-clinician pairs –Cancer outpatient clinics Patients and clinicians answered the same CTCAE items Basch, Lancet Oncol, 2006

23. Patient vs. Clinician Reporting (2)

24. Longitudinal Reporting Patient-reporting Clinician-reporting CTCAE Grade-2 (Moderate)CTCAE Grade-3 (Severe) Patient-reporting Clinician-reporting Basch, JNCI, 2009

25. Clinician-reported CTCAE symptoms –More predictive of death and hospitalization Patient-reported CTCAE symptoms –More correlated with daily health status Complementary information –Both have value in characterizing patient experience with disease and treatment Basch, JNCI, 2009 Prediction Model

26. Drug Labels Should both be included in clinical trial results and labels? Would this cause confusion? Instructive to consider examples outside of healthcare

27. Metacritic.com

28. CNET Reviews

29. Tripadvisor

30. Docetaxel Drug Label

31. NCI HHSN261200800043C NCI Contract Awarded 9/08

32. NCI Survey 729 stakeholders –Administered at cooperative groups / NCI listservs 11/08-2/09 TOTAL N = 729N* NCI Representative41 FDA Representative26 Cooperative Group Leadership52 Cooperative Group Member130 Lead PI84 Investigator103 CRA161 Research Nurse185 Patient Advocate121 Industry30 *Not mutually exclusive

33. Survey Results QUESTION AGREENEUTRALDISAGREE Systems to collect PROs in clinical trials should be developed89%5%6% In clinical trials, AEs should be reported by clinicians and patients 88%8%4% Both patient and clinician reported AEs should be reported in clinical trial results and in drug labels 76%15%9%

34. 77 CTCAE Items Identified for PRO

35. NCI Contract Patient interviews Building technology Validation study

36. CALGB 70501 Stand-alone companion trial Linked to selected treatment trials

37. 70501 Aims 1.Assess feasibility of patient CTCAE reporting in cooperative group trials 2.Compare patient vs. clinician reporting Accrual goal: 175

38. Eligibility Any patient enrolling in a linked treatment trial can also enroll in 70501, anytime prior to cycle/visit #2 To participate, a site must be listed with CALGB (contact us or CALGB) Additional accrual / cancer control credit assigned for 70501 enrollment

39. Currently Linked Treatment Trials CALGB 30607: Randomized, phase III, double-blind placebo-controlled trial of sunitinib as maintenance therapy in non-progressing patients following an initial four cycles of platinum-based combination chemotherapy in advanced, stage IIIB/IV non-small cell lung cancer CALGB 30704: A randomized phase II study to assess the efficacy of pemetrexed or sunitinib or pemetrexed plus sunitinib in the second-line treatment of advanced non-small cell lung cancer CALGB 40502: A randomized phase III trial of weekly paclitaxel compared to weekly nanoparticule albumin bound nab-paclitaxel or ixabepilone combined with bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer CALGB 40503: Endocrine therapy in combination with anti-VEGF therapy: a randomized, double- blind, placebo-controlled phase III trial of endocrine therapy alone or endocrine therapy plus bevacizumab for women with hormone receptor-positive advanced breast cancer CALGB 40601: Randomized phase III trial of paclitaxel combined with trastuzumab, lapatinib, or both as neoadjuvant treatment of HER2-positive primary breast cancer CALGB 40603: Randomized phase II 2 x 2 factorial trial of the addition of carboplatin +/- bevacizumab to neoadjuvant weekly paclitaxel followed by dose-dense AC in hormone receptor- poor/HER2-negative resectable breast cancer CALGB 70604: A randomized, phase III study of standard dosing versus longer dosing interval of zoledronic acid in metastatic cancer CALGB 80405: A phase II trial of irinotecan/5-FU/leucovorin or oxaliplatin/5-FU/leucovorin with bevacizumab, or cetuximab (C225), or with the combination of bevacizumab and cetuximab for patients with untreated metastatic adenocarcinoma of the colon or rectum

40. Schema

41. Interested Sites for 70501 Contact: Ethan Basch (basche@mskcc.org) Laura Sit (sitl@mskcc.org)