1. ART-RIM Workshop National Cancer institute Ethan Basch, MD, MSc Memorial Sloan-Kettering Cancer Center Patient-reported Outcomes (PROs) January 22, 2010

2. “A PRO is any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else.” Definition http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInfor mation/Guidances/UCM193282.pdf - Final FDA PRO Guidance (December 2009)

3. Examples Symptoms – Severity, frequency, interference, bother, etc. Quality of life – Various domains Subjective impressions of improvement/change Treatment preferences Satisfaction with care Compliance with treatment

4. Standards Rigorous standards for development, administration, analysis, and reporting of patient-reported data have emerged, and are codified in the FDA Guidance – Technically only apply when measuring effects of treatment with the intention of making a labeling claim, but have been widely accepted beyond the regulatory setting – Nonetheless, poorly designed measures are still common in protocols and publications

5. Scrutiny Questions for patients should not simply be “made up” and administered at occasional or inconsistent intervals Concepts that are best known by patients should not be reported by clinicians

6. Considerations in Developing or Selecting a PRO Measure Measurement properties of instruments Reliability – Test-retest – Internal consistency Validity – Content validity (qualitative) – Construct validity (discriminant) Ability to detect change Recall period

7. Considerations when Administering a PRO Measure in a Trial Population issues Validity, literacy, language, cognitive abilities, PS Study design issues What concepts to measure, parsimony Frequency and duration of administration Method and location of administration Missing data Most ill and most well patients? Backup data collection methods?

8. PROs for Measuring Adverse Symptoms Standard approach to measuring AEs in NCI- sponsored clinical trials: CTCAE – CTCAE v4: >800 items; ~10% are “symptoms” CTCAE items are reported by clinicians – But clinicians underestimate the frequency and severity of patient symptoms – Therefore, with clinician-only reporting, we have an incomplete picture of toxicity

9. Patient vs. Clinician Reporting Patient-reporting Clinician-reporting

10. Indication # of U.S. Approved Drug Labels Average # of AEs per Label Total # of Unique AEs across Labels Proportion of AEs which Are Symptoms Asthma 3554368 49% (180/368) Breast Cancer 3278616 36% (223/616) GERD 18115472 45% (213/472) Hyperlipidemia 2882365 43% (158/365) Osteoarthritis 3994684 41% (278/684) Adverse Events in Current Labels Almost half are symptoms

11. Docetaxel Drug Label Data from “Tax 327” pivotal trial

12. NCI HHSN261200800043C NCI contract to develop a PRO version of the CTCAE Initiated 10/08

13. Mission of PRO-CTCAE Initiative 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

14. PRO-CTCAE Scope Create PRO-CTCAE adverse symptom items Evaluate measurement properties of items Build electronic administration platform Assess feasibility Nine interdisciplinary task committees assembled Including NCI and FDA representatives

15. 77 CTCAE Symptoms Identified Abdominal painDepressionEdema – LimbHot flashesMyalgia Rash Urticaria Acne Dermatitis (Radiation) Ejaculatory dysfunction Hyper- pigmentation Nail changes Rash: Hand- Foot Vaginal discharge Alopecia/hair lossDiarrhea Epistaxis (Nosebleeds) HypohidrosisNauseaRigor/chills Vaginal dryness Amenorrhea Distension/ bloating, abdominal Erectile dysfunction Incontinence, anal Neuropathy- sensory Skin Breakdown Vision – blurred AnorexiaDizzinessFatigue Incontinence, urinary OdorStriaeVoice changes Anxiety Dry mouth/ xerostomia Flashing lights Injection site reaction Orgasmic dysfunction Sweating diaphoresis Vomiting Arthralgia (joint pain) Dry skinFlatulenceInsomniaPain Taste alteration Watery eye Bronchospasm, wheezing DyspareuniaFloaters Irregular menses Painful urination Tinnitus Decreased concentration ChelilitisDysphagiaGynecomastia Libido PalpitationsTremorDepression 2 ConstipationDyspnea Heartburn/ dyspepsia Memory impairment Photo- sensitivity Urinary frequency Nail changes 2 (color) CoughEasy bruisingHiccoughsMucositis/ stomatitis Pruritus/ Itching Urine color change Nail changes 3 (shape)

16. Possible Attributes of Each Symptom Frequency Severity Interference with usual activities Present/Not present Separate items for each attribute – Between 1 and 3 attribute items per symptom – Selected based on attributes included in original CTCAE items, and nature of each symptom – 122 total items representing the 77 symptoms

17. Methodological Development Content validity study – Cognitive interviews Measurement properties study – Validity, reliability, sensitivity, recall Platform “usability” study Feasibility study

18. Platform: Form Builder

19. Platform: Patient Interface

20. Platform: Study Calendar

21. Summary Patient self-reporting is the gold standard for symptom assessment Guidance for developing and administering PRO instruments is available in the FDA document The PRO-CTCAE provides a lexicon of adverse symptom items which are being developed in keeping with rigorous methodological criteria