FDA Division of Biometrics; SEALD

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Nov 29, 2013 (3 years and 8 months ago)

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PRO
-
CTCAE FDA Meeting #1


FDA Division of Biometrics; SEALD



Ethan Basch, MD, MSc

PROs for Adverse Event Reporting


July 23, 2009

Invited Participants


Mandi Yu; Eugenio Andraca
-
Carerra; Chuck
Cooper; George Rochester; Gini Kwitkowski;
Judy Racoosin; Ann Marie Trentacosti; Laurie
Burke; Laura Sit; Ethan Basch


More than one
-
third of adverse events in drug labels
are symptoms (nausea, fatigue, sensory neuropathy)



In clinical trials, adverse symptom information is
reported by research staff, not directly by patients



Scientific evidence demonstrates health professionals
underestimate the incidence and severity of
symptoms compared to patients’ own accounts



Staff
-
based symptom assessments usually occur at
clinic visits, missing remote between
-
visit events

Adverse Symptom 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)

AEs in Labels Amenable to PRO

Cumulative Incidence of Symptoms

Patient
-
reporting


Clinician
-
reporting

Patient
-
reporting


Clinician
-
reporting


PRO measures are standard
for symptom endpoint
evaluation



Guidance: patients know
their symptoms best



Can extend this model to
safety reporting

Symptom Endpoint Evaluation


In oncology trials, AEs are often reported using CTCAE


Lexicon of >1000 terms (~75 symptoms)


Each term graded for severity via ordinal scale


New version mapped to MedDRA preferred terms


Like MedDRA, reporting by staff at visits

NCI PRO
-
CTCAE Initiative

Grade

NCI Description

Response Description

1

Mild

Mild pain not interfering with function.

2

Moderate

Moderate pain; pain or analgesics interfering
with function, but not interfering with ADL.

3

Severe

Severe pain; pain or analgesics severely
interfering with ADL.

4

Disabling

Disabling.

Example CTCAE Item: Pain


10/08: NCI issued contract to create PRO version of
CTCAE (“PRO
-
CTCAE”)


Create patient items


Conduct validation study


Develop technology platform for administration

NCI PRO
-
CTCAE Initiative

CTCAE Terms for PRO

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

Rigors/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/

extravasation

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

(color)

Cough

Easy bruising

Hiccoughs

Mucositis/

stomatitis

Pruritus
/
Itching

Urine color
change

Nail changes

(shape)


Up to 3 attributes per symptom


Frequency


Severity


Interference with daily activities

Adverse Symptom Attributes

Attributes


Overall PI determines PRO
-
CTCAE items for regular
administration via patient electronic CRF


Calendar for administration is set up
-
front


Default: weekly


Patients may add additional items when reporting


Notifications are sent to staff for missed reports


Data are aggregated

Reporting Model

Participant Report

Symptom Summary

Overall Mission of Project


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


Provide a more full picture of patient experience


Purpose is AE screening, not endpoint evaluation

Implications for Labeling


No regulatory requirement that staff vs. patients
serve as source of AE data



If PRO
-
CTCAE were implemented, likely both
clinicians and patients would report on same
symptoms, and investigators and regulators would
have both for analysis


Discrepant but complementary

Tripadvisor

CNET Reviews

Docetaxel

Drug Label

Discussion


How would this information fit into the current approach
to AE data analysis?


What is ideal way for applicants to deliver PRO safety
data

to FDA? (raw data; summary reports)?


Should adverse symptom data remain in CTCAE format or
be converted to MedDRA?


Approach to missing data; should sponsors collect
reasons for missed PROs for imputing data?


If clinician vs. patient report is discrepant, how will that
be considered?


Will PRO
-
CTCAE information be considered useful?


How will PRO
-
CTCAE information be shown in labels?