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