Risa Hayes, PhD
Research Advisor
Eli Lilly and Company
May 22, 2012
Patient-Reported Outcome (PRO) Measures
 A patient-reported outcome (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.
 A PRO instrument is used to measure treatment
benefit or risk in medical product clinical trials.
 A PRO is a clinical outcome assessment (COAs)
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Patient-reported outcome assessments (PROs)
Clinician-reported outcome assessments (ClinROs)
Observer-reported outcome assessments (ObsROs)
2
URINARY INCONTINENCE
Labeling claim for ANTUROL Claim first approval:07 December 2011
Patients treated with ANTUROL (84 mg)
experienced a statistically significant decrease in
the number of urinary incontinence episodes per
week from baseline to endpoint (the primary
efficacy endpoint) compared with placebo
(p=0.0445) and patients treated with the 56 mg
dose did not show statistically significant efficacy.
Statistically significant improvements in daily
urinary frequency (p=0.0010) and urinary void
volume (p<0.0001) were also seen with
ANTUROL (84 mg) relative to placebo. The mean
difference from placebo for ANTUROL (84 mg)
was -2.3 for urinary incontinence episodes per
week in a group of patients with a mean of
greater than 40 incontinence episodes per week
at baseline. Mean and median change from
baseline in weekly incontinence episodes
(primary endpoint), daily urinary frequency, and
urinary void volume (secondary endpoints)
between placebo and ANTUROL are summarized
in Table 3.
Source: PROLabels
PRO Measures to Support Labeling
 The Food and Drug Administration (FDA) reviews
and evaluates existing, modified, or newly created
patient-reported outcome (PRO) instruments to
support labeling claims
 Two methods for development of PRO instruments
but one standard of evidence
PRO Instrument Development to Support
Labeling Claims
NDA/IND process?
DDT Qualification process?
Guidance for Industry
Guidance for Industry
Patient-Reported Measures:
Use in Medical Product Development
to Support Labeling Claims
Patient-Reported Measures:
Use in Medical Product Development
to Support Labeling Claims
Guidance for Industry
Qualification Process for
Drug Development Tools
PRO Consortium
Industry Members
Working Groups
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 Asthma
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Abbott Laboratories
Actelion Pharmaceuticals Ltd.
Amgen Inc.
Astellas Pharma US, Inc.
AstraZeneca Pharmaceuticals
Boehringer Ingelheim Pharmaceuticals, Inc.
Bristol-Myers Squibb Company
Daiichi Sankyo, Inc.
Eisai
Eli Lilly & Company
Forest Research Institute
GlaxoSmithKline
Ironwood Pharmaceuticals, Inc.
Janssen Pharmaceutical Companies of Johnson &
Johnson
Merck Sharp & Dohme
Novartis Pharmaceutical Corporation
Novo Nordisk, Inc.
Pfizer, Inc.
Roche
Sanofi
Shire Corp.
Sunovion Pharmaceuticals Inc.
Takeda Pharmaceuticals US
UCB Pharma Ltd.
 Cognition
 Depression
 Functional Dyspepsia
 Irritable Bowel Syndrome
 Non-Small Cell Lung Cancer
 Rheumatoid Arthritis
Team for PRO Measure Development
 Medical
 Regulatory
 Outcomes research
 Statistics
 Data management
 Marketing
PRO Instrument Development within an
Individual Drug Development Program
Pre-IND/Phase 1
Define
Concept of
Measurement
and
Context of Use
Phase 2A
Establish
Content
Validity
(e.g.,
Qualitative
Research, Mixed
Methods)
Phase 2B
Phase 3
Establish other
measurement
properties
(e.g., Quantitative
Longitudinal
Research)
NDA Submission
PRO dossier
submitted as
part of
NDA/IND
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Treatment Benefit
The impact of treatment on how patients survive,
feel, or function
• Efficacy (e.g., improvement or delay in the
development of symptoms)
• Comparative safety (e.g., reduction or delay in
treatment-related toxicity)
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Concept of Measurement to Support
Direct Evidence of Treatment Benefit
Disease-defining
concepts
Core signs,
symptoms
or
decrements in
functioning
Proximal disease
Impact concepts
General
psychological
functioning
Related
functioning
Related
S/Ss
Proximal concept to
treatment benefit
Distal disease
Impact concepts
Additional
functioning
Additional
S/Ss
Disease impact on general
life concepts
Productivity
Health status
General
physical
functioning
Social
functioning
Health-related
quality of life
Satisfaction
with
health
Distal concept to
treatment benefit
Example: Direct Evidence of Treatment Benefit
in Non-Small Cell Lung Cancer*
Disease –defining
concepts
Proximal disease impact
concepts
Weight loss
Cough
Shortness of breath
Shoulder Pain
Chest Pain
Tightness in chest
Difficulty breathing
Anxiety
Decreased
appetite
Difficulty swallowing
Memory
Concentration/clarity of
thinking
Depression
Hoarseness
Sleep disturbance
Phlegm
Wheezing
Swelling of the
face/neck
Proximal concept to
treatment benefit
Distal disease impact
concepts
Ambulation
Lack of energy
Loss of stamina
Distal impact on general
life concepts
Social
functioning
Overall impact
on HRQL
Life interference
Helplessness/
hopelessness
Independence
Difficulty with activities
of daily living
Distal concept to
treatment benefit
* Concepts identified through a cursory review of the literature. Graph will evolve based on findings from
qualitative research and clinician expertise
* Graph does not include concepts measured by biomarkers, ClinRO measures, or ObsRO measures
Context of Use
 Disease definition
 Target subpopulation (age, disease severity)
 Clinical trial design and objectives (targeted
claim)
 Geographic location of the study sites
 Language and culture
 Clinical practice variations
 Other (e.g., format)
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Endpoint Model
An Endpoint Model displays the role and hierarchy of relevant
outcome concepts in clinical trials (i.e., all primary and secondary
endpoints)
Endpoints hierachy
Primary
Concepts
Concept A
Weight loss
Secondary with
Hierarchy
Concept B
Blood pressure
Concept C
Ability to do
physical activities
Exploratory
Concept D
Self-esteem
COA/Biomarker/Survival
OA 1
% weight lost from baseline
to endpoint in kg
OA 2
Systolic/diastolic
OA 3
New PRO instrument
Other OA
New PRO instrument
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PRO Instrument Development within an
Individual Drug Development Program
Pre-IND/Phase 1
Define
Concept of
Measurement
and
Context of Use
Phase 2A
Phase 2B
Phase 3
NDA Submission
Establish
Content
Validity
(e.g.,
Qualitative
Research, Mixed
Methods)
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“Well Defined and Reliable” Measurement
Properties
 Documented in the targeted context of
use
 Content validity
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Includes qualitative research in target population
of responders
May include quantitative methods (e.g., Rasch,
IRT, classical test theory) to assess item function
Established before study of other measurement
properties
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Mixed Methods Approach to Assuring
Content Validity
 Quantitative methods
 Content validity state – exploratory
 Psychometric analysis stage – confirmatory
 Sample Size Considerations
 Samples as small as 30 individuals can provide
useful descriptive information
 Multivariate methods, such as factor analysis can
require larger samples
PRO Instrument Development within an
Individual Drug Development Program
Pre-IND/Phase 1
Define
Concept of
Measurement
and
Context of Use
Phase 2A
Establish
Content
Validity
(e.g.,
Qualitative
Research, Mixed
Methods)
Phase 2B
Phase 3
NDA Submission
Establish other
measurement
properties
(e.g., Quantitative
Longitudinal
Research)
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“Well Defined and Reliable” Measurement
Properties
 Documented in the targeted context of use
 Content validity
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
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Includes qualitative research in target population of responders
May include quantitative methods (e.g., Rasch, IRT, classical test theory)
to assess item function
Established before study of other measurement properties
 Construct validity
 Reliability (most critical: test-retest for PRO assessments)
 Sensitivity to change (consistent with study objectives)
 Responder definition
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PRO Instrument Development within an
Individual Drug Development Program
Pre-IND/Phase 1
Define
Concept of
Measurement
and
Context of Use
Phase 2A
Establish
Content
Validity
(e.g.,
Qualitative
Research, Mixed
Methods)
Phase 2B
Phase 3
Establish other
measurement
properties
(e.g., Quantitative
Longitudinal
Research)
NDA Submission
PRO dossier
submitted as
part of
NDA/IND
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Use of a Qualified COA in a Drug
Development Program
Pre-IND/Phase 1
Phase 2A
Phase 2B
Phase 3
NDA/BLA
NDA Submission
Submission
Reference to
the DDT PRO
qualification
specific
guidance and
submit as part
of NDA/IND
Define
Concept(s) &
Context of Use
Qualified DDT COA in
its targeted context of
use
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Thank you.