1. caBIG Population Sciences SIG Ethan Basch, MD, MSc Memorial Sloan-Kettering Cancer Center PRO-CTCAE A system for patient self-reporting of adverse symptoms in oncology trials May 7, 2009

2. Overview 1.Background – Adverse Event reporting in oncology 2.PRO-CTCAE contract overview 3.System/functionality requirements 4.Demonstration

3. Essential activity in clinical 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. FDA DEFNITION OF PATIENT-REPORTED OUTCOME (PRO): “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” Increasing Regulatory Interest in PROs

9. 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

10. Patients willing and able to report CTCAE symptoms via computer at clinic visits Patient reporting is discrepant from clinician reporting – Patients generally self-report worse severity – Patient reports better reflect day-to-day experience Clinicians will accept patient-reported AEs for treatment decisions and documentation Prior Research Findings

11. Currently no standard approach or technology platform for collecting patent-reported adverse symptoms in oncology trials

12. 2-Year Contract – Started on 10/1/08 NCI Contract HHSN261200800043C

13. Overall Mission of Project Employ rigorous scientific methods to create a system for patient self-reporting of adverse symptoms in cancer trials (called the PRO-CTCAE), which is widely accepted and used; generates useful data for investigators, regulators, clinicians and patients; and is compatible with existing adverse event reporting systems

14. SOW Multiple Interrelated Tasks 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

15. Task-Based Framework for Project

16. Expert Investigative Team and Subcontracts

17. Overview of Project Brief review of relevant non- technology tasks of project

18. Progress to Date (1) 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

19. Progress to Date (2) 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%

20. Progress to Date (3) 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%

21. Progress to Date (4) 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%

22. Progress to Date (5) 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

23. 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)

24. Progress to Date Task 2: Develop Items For each symptom, evaluate multiple dimensions – Frequency, severity, interference with activities Developed structure of questionnaire items

25. Generic Structure of Items FREQUENCY: How OFTEN did you have XXXX: Never, Rarely, Occasionally, Frequently, Almost Constantly SEVERITY: At its worst, what was SEVERITY of your XXXX: None / Mild / Moderate / Severe / Very severe INTERFERENCE: How much did XXXX INTERFERE with your (daily activities): Not at all / A little bit / Somewhat / Quite a bit / Very much

26. Task 5: Platform Development Envisioned a system to allow PIs to create forms for electronic administration of PRO- CTCAE items to patients at clinic visits

27. Platform Components/Functionality Components – Form builder – Study calendar – Patient interface – Study-level reports – Patient-level reports – Automated alerts/notifications Skip pattern rules User-level access/permissions Interoperability with caAERS

28. Publishing Tool and FormBuilder

29. Task 5: Approach Subcontract to SemanticBits LLC Weekly teleconferences since 10/08 – Committee: investigators, research study personnel, oncologists, patient representatives, psychometricians, FDA representatives, NCI representatives DEMONSTRATION: – Ram Chilukuri, SemanticBits LLC