ART-RIM Workshop National Cancer institute Ethan Basch, MD, MSc Memorial Sloan-Kettering Cancer Center Patient-reported Outcomes (PROs) January 22, 2010
Dec 30, 2015
ART-RIM WorkshopNational Cancer institute
Ethan Basch, MD, MScMemorial Sloan-Kettering Cancer Center
Patient-reported Outcomes (PROs)
January 22, 2010
“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.”- Final FDA PRO Guidance (December 2009)
Definition
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf
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
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
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
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
Considerations when Administeringa PRO Measure in a Trial
Population issues• Validity, literacy, language, cognitive abilities, PSStudy design issues• What concepts to measure, parsimony• Frequency and duration of administration• Method and location of administrationMissing data• Most ill and most well patients?• Backup data collection methods?
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
Patient vs. Clinician Reporting
Patient-reporting
Clinician-reporting
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 35 54 368 49% (180/368)Breast Cancer 32 78 616 36% (223/616)GERD 18 115 472 45% (213/472)Hyperlipidemia 28 82 365 43% (158/365) Osteoarthritis 39 94 684 41% (278/684)
Adverse Events in Current Labels
• Almost half are symptoms
Docetaxel Drug Label
Data from “Tax 327” pivotal trial
NCI HHSN261200800043C
NCI contract to develop a PRO version of the CTCAE Initiated 10/08
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
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
77 CTCAE Symptoms Identified
Abdominal pain Depression Edema – Limb Hot flashes Myalgia Rash Urticaria
Acne Dermatitis (Radiation)
Ejaculatory dysfunction
Hyper-pigmentation
Nail changes Rash: Hand-Foot
Vaginal discharge
Alopecia/hair loss Diarrhea Epistaxis (Nosebleeds)
Hypohidrosis Nausea Rigor/chills Vaginal dryness
Amenorrhea Distension/bloating, abdominal
Erectile dysfunction
Incontinence, anal
Neuropathy-sensory
Skin Breakdown
Vision – blurred
Anorexia Dizziness Fatigue Incontinence, urinary
Odor Striae Voice changes
Anxiety Dry mouth/ xerostomia
Flashing lights Injection site reaction
Orgasmic dysfunction
Sweating diaphoresis
Vomiting
Arthralgia (joint pain)
Dry skin Flatulence Insomnia Pain Taste alteration
Watery eye
Bronchospasm, wheezing
Dyspareunia Floaters Irregular menses
Painful urination
Tinnitus Decreased concentration
Chelilitis Dysphagia Gynecomastia Libido Palpitations Tremor Depression 2
Constipation Dyspnea Heartburn/dyspepsia
Memory impairment
Photo-sensitivity
Urinary frequency
Nail changes 2 (color)
Cough Easy bruising Hiccoughs Mucositis/stomatitis
Pruritus/ Itching
Urine color change
Nail changes 3 (shape)
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
Methodological Development
• Content validity study– Cognitive interviews
• Measurement properties study – Validity, reliability, sensitivity, recall
• Platform “usability” study• Feasibility study
Platform: Form Builder
Platform: Patient Interface
Platform: Study Calendar
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