PROMIS Measures and the NIH Toolbox
for Phase 2 and 3 Trials
Raymond Dionne, DDS, PhD
Disclaimers
Overview of Analgesic Drug Discovery and Development
• Classic approach: basic studies to elucidate analgesic
mechanisms, high throughput pharma R&D, clinical studies
to evaluate safety and efficacy
• Venturing into exploratory methods: genomic methods for
unbiased identification of symptoms pathways in humans
• Embracing uncertainty: use of genome-wide methods to
identify molecular-genetic basis of symptoms in humans
• Future Directions: ‘deep phenotyping’ and molecular-genetic
dissection of multi-symptom disorders to advance
understanding of symptoms biology leading to novel targets
for intervention
Prerequisite: quantify patient reported outcomes to identify
sub-groups for genomic interrogation and provide
individualized therapeutics (‘one size does not fit all patients’)
Complexity of Pain at the Level of Individual Patients
Prior Experience
Expectations
Mood
Sociocultural
Environment
Idiosyncrasy
Genomic Variation
Physiology
Inflammation
CNS Plasticity
Genomic Variation
Sensory Input
Kim & Dionne, Pain/Clinical Updates, 2005
Genomic Variation
Visual analogue sc ale (mm )
Wide Variation in Response to Experimental Stimuli Across Individuals
100
Response to Noxious Heat to Skin
80
60
40
20
0
1
100
200
300
400
500
Number of subjects
Kim H et al., Pain 2004
Wide Inter-Individual Variation in Responses to Drugs
 Post-surgical intravenous morphine titration
 Mean dose for adequate pain relief = 13.3 mg
 Dose range: 1- 48 mg (0.02 - 0.83 mg/kg)
 Predicted outcome for a fixed dose across a patient
population:
• Inadequate pharmacological effect
• Adequate efficacy with acceptable side effect liability
• Excessive pharmacological effect with adverse drug
reactions and less safety
! Alternative – evaluate symptoms biology and
therapeutic responses at the patient level patient to
ultimately individualize therapy (efficacy, safety)
Time to Shift the Paradigm for Analgesic R&D?
 Large unmet therapeutic need for chronic pain
 Modest therapeutic innovation in pain over past 50 years
 Pharmaceutical industry is abandoning drug discovery for
neurologic diseases due to poor return on investment
 Biomarkers considered to be ‘obligatory’ for drug discovery
 Target validation is best done in humans
 High variability in pain, analgesic efficacy and safety of analgesic
drugs
 Scientific opportunity knocks: genomic methods are
‘commodities’, PROMIS and NIH Toolbox now available
✓ Time for alternative research strategies using patient
reported outcomes and validated biomarkers in humans
Evaluating Pathways and Mechanisms of Radiation-Induced Fatigue
Piper Fatigue Scale
Severe
fatigue
Moderate
fatigue
Mild
fatigue
No fatigue
9
8
7
6
5
4
3
2
1
0
Range
Mean
Day 0
Day 1
Day 7
Day14
Day 21
Day 42
Day 72
Saligan, Hsiao, Wang et al. Brain Behavior Immunity, 2013
Top 10 Up- and Down-Regulated Genes
Top Upregulated Genes
Top Downregulated Genes
Genes Symbol
Gene Name
Expression
Value
Genes
Symbol
Gene Name
Expression
Value
IFI27
Interferon alpha-inducible
protein 27
0.774
MS4A1
B-lymphocyte antigen CD20
-0.821
CA1
Carbonic anhydrase 1
0.705
IGHM
Ig mu chain C region
-0.816
HBD
Hemoglobin subunit delta
0.640
PAX5
Paired box protein Pax-5
-0.791
XK
X-linked Kx blood group
0.534
FCRLA
Fc receptor-like A
-0.669
HBG2
Hemoglobin subunit gamma-2
0.513
TTC3
Tetratricopeptide repeat protein
3
-0.647
RHCE/RHD
Blood group Rh(CE)
polypeptide
0.507
NSUN5C
NOP2/Sun domain family,
member 5C
-0.642
AHSP
Alpha hemoglobin stabilizing
protein
0.496
POU2AF1
POU domain class 2-associating
factor 1
-0.636
GYPB
Glycophorin B
0.483
CCR7
C-C chemokine receptor type 7
-0.632
SNCA
Alpha synuclein
0.470
FAIM3
Fas apoptotic inhibitory
molecule 3
-0.613
ISCA1
Iron-sulfur cluster assembly 1
homolog
0.464
BLK
B lymphoid tyrosine kinase
-0.612
Differential Expression of MitochondriaRelated Genes
Differentially Expressed Genes
High Fatigue vs Low Fatigue (1 yr post EBRT)
n = 15
n = 22
Theory of Fatigue Development
a-syn
(expressed in synapses)
IFI27
Lysosomal pathway
BCL2
FIS1
SCL25A37
Mitochondrial crisis
Vision-Mission:
• Vision
– The Patient-Reported Outcomes Measurement
Information System (PROMIS), funded by the
National Institutes of Health, aims to provide clinicians
and researchers access to efficient, precise, valid,
and responsive
adult- andtitle
child-reported
Click
to edit Master
style measures
of health.
• Mission
– PROMIS uses measurement science to create an
efficient state-of-the-art assessment system for
self-reported health.
Advancing Patient-Centered Outcomes
PROMIS: A Common Source of PROs
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Clinical Practice
Surveys (CDC)
Clinical research
Clinic
Hospital
NIH
Industry
FDA
DOMAINS
A domain is the specific feeling,
function, or perception you
want to measure.
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Cuts across different diseases
DOMAINS vs. Diseases
• Diseases (common & rare) are combinations
of different mechanisms that impact domains
• Capturing multiple domains may be optimal
way to assess diseases
Click to editPRO
Master
title style
• Core-common
domains
are universally
applicable across diseases, ages and
ethnicities
• Core PRO domains can link common and rare
diseases
Mechanisms
PROs
Interleukins
Phys Fn
Fatigue
Social
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style
Sleep
Chemokines
Prostaglandins
Anxiety
Pain
The PROMIS Metric
T Score
Mean = 50
SD = 10
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Referenced to the US General
Population
PROMIS Fatigue Across Five Clinical Conditions
Cancer
w/ benefit
(2 mos)
N = 310
N = 229
Back PainBack Pain Back Pain
(3 mos) (1 mo)
(B)
Depression Depression Depression
(1 mo)
(3 mos)
(B)
N = 114
N = 64
Cancer
Chemo
(B)
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HF Post-transplant
HF Pre-transplant
Exacerbation to Stable
N = 125
COPD Stable (B)
35
40
45
50
55
Average for General Population
COPD Exacerbation (B
60
65
Computerized Adaptive Testing (CAT)
Click to edit
Integrates IRT with computers to
administer a PRO instrument
• selects questions on the basis
of a patient’s response to
previously administered
questions
• measurement is “adapted” to
Masterindividual
title style
• skips uninformative items to
minimize response burden
• allows determination of
person’s standing on a
domain without a loss in
measurement precision.
Computerized Adaptive Tests
Question #1
3
low
physical
function
1
0
Question #3
2
2
1
-3
-2
-1
0
2
Question #2
1
high
physical
function
Questionnaire
with a high
precision AND a
wide range
CAT Starts with an Item Bank
• Covers the whole range of the domain
• Items are “calibrated” (difficulty and
discrimination)
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PROMIS® Adult Banks: v1.0
Domains
Emotional Distress – Anger
Emotional Distress – Anxiety
Emotional Distress – Depression
Fatigue
Pain – Behavior
Click to edit Master title
Pain – interference
Physical Function
Satisfaction with Discretionary Social Activities
Satisfaction with Social Roles
Sleep Disturbance
Wake Disturbance (sleep related impairment)
Global Health
Items in
Bank
29
29
28
95
style39
41
125
12
14
27
16
Items in
Short
Form
8
7
8
7
7
6
10
7
7
8
8
10
PROMIS® Pediatric Banks: v1.0
Domains
Emotional Distress – Anger
Emotional Distress – Anxiety
Emotional Distress – Depression
Fatigue
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Pain – Interference
Physical Function-Mobility
Physical Function-Upper Extremity
Peer Relationships
Asthma
title
Items in
Bank
n/a
15
14
23
style
13
125
29
15
17
Items in
Short
Form
6
8
8
10
8
10
8
8
8
Assessment-Technology Center
• FREE online research management tool
• Enables study specific websites
– Secure data capture
• Clinical studies can be customized
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to
edit
Master
title
style
• Includes PROMIS instruments
– short forms, CATs and Profiles
• Detailed statistical/development history
• Real-time scoring
• www.assessmentcenter.net
Asessment
Center
Click to edit Master
titlesupports
style
different modes of
administration
CAT
Graph
Click to edit Master title style
Future Clinical Research & Individualized Care
• Precision – improved measurement precision
across the full range of patient-reported
outcomes
• Efficiency – less respondent burden
• Standardization
– more
interpretable
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title
style
research with standard terminology and metrics
• International clinical trial applications
• Common language between research and
practice fosters comparative effectiveness
research
Click to edit Master title style
Click to edit Master title style
PROMIS® combines:
• Item Response Theory (IRT) and Computer
Adaptive Testing (CAT)
• Together, IRT and CAT provide precise
measurement
individual
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titlesymptoms
style
PROMIS® Profile Short Forms (29-43-57 items) + pain intensity
8
Mental
Anxiety
29
Depression
28
Fatigue
95
Physical
Pain Interference
41
Sleep Disturbance
27
Physical Function
86
Social
Satisfaction with Roles
14
4
6
Pain Assessment Using the NIH Toolbox
 Instruments to measure pain selected on the
basis of ‘scholarly input from… diverse experts’
 Pain intensity measured on 0 to 10 NRS
 Pain interference measured on PROMIS 6-item
short form
 No specific measures recommended for
measuring pain intensity in children
 PROMIS pediatric pain interference measure
recommended as a supplemental measure
Cook KF et al. Neurology 2013; 80 (Suppl 3):549-53
Other NIH Toolbox Assessment tools
 Emotion
 Motor
 Cognition
 Audition
 Olfactory
 Vestibular function
 Gustation
 Somatosensation
 Visual
 Social support, companionship and distress
Neurology 2013; 80 (Suppl 3)
Molecular-Genetic Dissection of Chronic Pain Disorders
X-M Wang, M Hamza*, H Kim, L Saligan*
M-R Kim, RA Dionne