Transcript Controlled

Evolving Xolair Health Outcomes Data:
What Does (or Should) it Mean to
Patients, Clinicians and Payors
Allan T. Luskin, MD
Associate Clinical Professor of Medicine, University of Wisconsin
Director, Respiratory Institute, Dean Medical Center
Madison, Wisconsin
Past Chair, Patient and Public Education Committee, NAEPP
Past Co-Chair, Managed Care Liaison, NAEPP
Committee on Asthma Measures, AMA
Asthma Expert Panel, JCAHO
Respiratory Measurement Advisory Panel, HEDIS/NCQA
Agenda
• Outcomes and variability of disease and
response to Rx and lack of correlation
between outcomes
• HRQOL with particular attention to newest
Xolair analysis
• Pharmacoeconomics: basics, specifics and
what current data does and doesn’t tell us
Asthma is a syndrome, not a disease
• The Asthma phenotype is highly variable
(clinically, pathologically and physiologically)
• Response to ALL therapy is highly variable
BHR and Reversible airflow obstruction does not predict
response to therapy
• Outcomes do not necessarily correlate with
each other
• There are Outcome phenotypes
Asthma Severity: Patient Perception
Who’s “Wrong”
Severe
Symptoms
None
4.8%
NAEPP Guidelines
Moderate Mild
Intermittant
10.4%
13.1%
48.6%
Mild
31.9% 47.2%
60.1%
42.3%
Moderate
41.3%
36.3%
22.1% 8.1%
Severe
21.9%
5.8%
4.5%
Asthma in America, 2001
0.8%
“Control” vs. Symptoms
None
2) Symptoms in many despite “control”
20
% Total Sample
11)
to 2Most
3+ d/wk
people “well controlled”
34%
15
10
21%
5
0
Very Well Quite Well Not Very Not at all
Well 11% Well 2%
35%
49%
"Control"
“Control” vs. Bronchodilator Use
None
% Total Sample
25
1 to 2
3+ d/wk
32%
20
15
10
24%
5
0
Very Well Quite Well Not Very
Well
"Control"
Not at all
Well
“Control” vs. Exacerbations
% Total Sample
Very Well
45
40
35 42%
30
25
20
15
10
5
0
Yes
Quite Well
Not Very
13%
9%
No
Noc Wake
Yes
Not At All
No
ED Visit
In Previous 3 months
Yes
No
Missed Social
Asthma Variability:
“Moderate-Severe” Asthma on b-Agonist Only
12 week: mean FEV1: 64%, b-agonist: 4-5/day
Symptoms**
80
70
Albuterol**
PEF*
All Criteria
**Intermittent, Mild, Mod-Severe
*Intermittent-Mild, Moderate, Severe
Albuterol: 59%
Symptoms: 45%
60
50
40
30
20
10
0
Intermittent
Mild
Moderate
Weeks in Category
Severe
Asthma is “Well” Controlled
if in a week….
• ≥5 days with DSS ≤1 (0-6 scale)
• ≥5days with no rescue b-agonist
• PEFRam ≥ 80% every day
2 of 3
and
•
•
•
•
≤1 nocturnal awakening
No exacerbations
No ED visits
No therapy related adverse events
all
AFD = DSS ≤1, no b-agonist, PEFR ≥80%, no noc awakening, no exacerbation, no ED
GOAL Study: Persistence of Control
(of those who achieved Control)
N.B.: 19-36% never achieve control (89% adherence)
20-32% not
persistent
“Lose Control”
100
80
60
40
Well Controlled
20
Total Control
0
FP
FP/SM
Bateman ED Am J Respir Crit Care Med 2004:170:836-844
Exacerbations and Effect of Therapy
ICS
ICS + LABA
100
Different
Exacerbations
or Different People
80
%
60
Exacerbations
Prevented 40
(not all exacerbations
and not all asthmatics
are the same)
20
0
COPD
Asthma
Dimensions of Control
How the Disease Affects the Organism
•
•
•
•
•
Physiology
Symptoms (nocturnal, exercise)
Quality of life and Activities of Daily Living
Medications (adverse events, adherence)
Health Care Utilization (function of
exacerbations)
• Comorbidities
Outcomes
• Functional
– Symptoms/Medication Use
– Exacerbation
– Global: QOL, ADL
• Physiologic
– Lung function/BHR
• Progression
• Pathologic (Inflammation)
– Sputum eos/ eNO
• Economic
– Direct and indirect
Asthma and HRQOL: The Burden
Asthma (7.5%)
Never Asthma (89.5%)
unhealthy days
147 million
unhealthy
functioning
days/year
activity limitation
mentally
unhealthy
physically
unhealthy
0
2
4
6
days/month
8
10
12
Asthma-Specific HRQL and Costs:
Asthma Costs over a 12 month Follow-up
Avg. Cost/person/year
$325
$300
$275
$250
$225
$200
$175
$150
Excellent Mean + 10
(90%-tile)
Mean
Mean - 10
Poor
(10th %tile)
Clinical Predictors of HRQL
Clinical
Outcomes
Mild Asthma
ModerateSevere Asthma
FEV1
No correlation
No correlation
Rescue bagonist use
Some
correlation
No correlation
Symptom
Some
intensity (SOB) correlation
Some
correlation
The ATAQ Questionnaire: Scoring
• 1 barrier each if:
– NO or UNSURE to “did you feel your
asthma was well-controlled”
– YES or UNSURE to “missed
work/school/activities” in past 4 weeks or
12 months
– YES or UNSURE to “waking at night” in
past 4 weeks or 12 months
– Used 9 or more puffs of quick relief inhaler
• Total: 0 to 4 barriers
Rates (Unadjusted) of Acute Asthma Events by
Baseline Level of Asthma Control
0 Barriers (n = 497)
1 Barrier (n = 581)
2 Barriers (n = 902)
3-4 Barriers (n = 938)
Unscheduled
Contacts
Oral Steroid
Bursts
ER Visits
Nights in
Hospital
0
1000
2000
3000
4000
5000
Rate per 1000 person-years
6000
“...the Asthma Is Controlled!”
• No inflammation
• Good lung
function
• No urgent visits
• Low costs
I can ...
I can ...
• Play ball
• Stay at my friend’s
who has a dog
• Forget my medicine
• Go out for a drink
• Do work around
the house
• Fool around with
my wife
• Forget my medicine
Asthma Quality of Life (AQLQ)
Questionnaire
32 items; 4 domains
 activity limitations
 asthma symptoms
 emotional function
 environmental exposure
Clinical relevance
D Score
+ 1.5
large
7
6
5
4
3
2
+ 1.0 moderate
1
+ 0.5
small
Higher
scores
=
less
impairment
in AQoL
0
Juniper E et al., Am Rev Respir Dis 1993
% Patients with 0.5 Unit Change in AQLQ
From Baseline to End of Steroid-Reduction (Busse)
*
70
60
*
*
80
% patients
18
61.5
53.4
61.7
67.1
56.6
49.8
62.6
54.6
66.4
54.8
50
40
30
20
10
0
Activities
Emotions
Symptoms
Placebo
Exposure
Overall
Score
Omalizumab
*P<0.05
Kishiyama JL, et al. Allergy Clin Immunol International. 2000;Suppl 2:115. Abstract.
% of Patients With 1.5 Unit Change in AQLQ
From Baseline to End of Steroid Reduction (Busse)
40
35
31.6
30
25
22.8
*
*
*
*
34.2
34.2
34.2
*
32.8
25.1
21.1
21
17.8
20
15
10
5
0
Activities
Emotions
Symptoms
Placebo
Exposure
Overall
Score
Omalizumab
*P<0.05
Kishiyama JL, et al. Allergy Clin Immunol International. 2000;Suppl 2:115. Abstract.
Anti-IgE: QOL in SAR
Adelroth. JACI 2000;106:253-259
ta
l
To
n
ot
io
es
Ey
N
os
e
Placebo
Em
A
ct
iv
iti
e
s
3.5
3
2.5
2
1.5
1
0.5
0
N Slee
on
p
-n
os
e/
ey
e
Pr
ac
tic
al
Omalizumab
AQLQ: Symptom Domain
Chest tightness
Short of breath
Wheezing
Coughing
Chest heaviness
Placebo
Omalizumab
Clear throat
Difficulty breathing
Morning symptoms
Nighttime symptoms
Sleep interference
Fighting for air
0
0.5
1
1.5
Luskin AT Annals of Allergy Asthma Immunol. 2004 abs
2
2.5
AQLQ: Activities Domain
Avoid smoke
Avoid dust
Avoid pollution
Avoid smells
Placebo
Omalizumab
Range of activities
All activities
Exertion
Walking
Household activity
0
0.5
1
Luskin AT Annals of Allergy Asthma Immunol. 2004 abs
1.5
2
AQLQ: Emotions/Environment Domain
Frustrated with Asthma
Frustrated with Asthma
Concerned: Medication
Fear: No Medication
Placebo
Omalizumab
Fear: SOB
Symptoms: Smoke
Symptoms: Dust
Symptoms: Weather
Symptoms: Smells
0
0.5
1
Luskin AT Annals of Allergy Asthma Immunol. 2004 abs
1.5
“Wake up in the morning with Symptoms”
Omalizumab
Placebo
2.5
2
1.5
1
0.5
0
ICS Stable
ICS Reduction
Luskin AT Annals of Allergy Asthma Immunol. 2004 abs
Extention
“Overall Range of Activities”
Omalizumab
Placebo
1.4
1.2
1
0.8
0.6
0.4
0.2
0
ICS Stable
ICS Reduction
Luskin AT Annals of Allergy Asthma Immunol. 2004 abs
Extention
“Afraid of not having medication available”
Omalizumab
Placebo
1
0.8
0.6
0.4
0.2
0
ICS Stable
ICS Reduction
Luskin AT Annals of Allergy Asthma Immunol. 2004 abs
Extention
“Experience symptoms from dust”
Omalizumab
Placebo
1.4
1.2
1
0.8
0.6
0.4
0.2
0
ICS Stable
ICS Reduction
Luskin AT Annals of Allergy Asthma Immunol. 2004 abs
Extention
% Hardly Any or No Asthma-Related Limits
Baseline
Extension
*
Dust Symptoms
*
Medication Fear
Walks
*
Exertion
*
All Activites
*
Chest Tightness
*
*
Sleep Disturbance
*
Morning Symptoms
0
10
20
30
Luskin AT Annals of Allergy Asthma Immunol. 2004 abs
40
50
60
70
80
Summary and Conclusions
• Consistent and positive impact of
omalizumab on AQLQ overall and domain
scores (p<0.05)
• Specific drivers of improvement in each of
the domains were noted
• Correlations between AQLQ and other
clinical outcomes were low-moderate
– r=0.14 to r=0.60
Summary and Conclusions (cont)
• Symptoms Domain:
– “Waking with symptoms in the morning”
– p<0.001
• Activities Domain
– “all activities done”
– p<0.001
• Emotions Domain
– “fear of not having medication available”
– p<0.01
• Environment Domain
– “symptoms from being exposed to dust”
– p<0.001
Summary and Conclusions (cont)
• ARQL assessment provides non-overlapping
information on clinical benefit distinct from other
outcomes
• Examination of variability in mean scores reveals
item-level responses strongly influence symptom and
activity improvement
• Symptoms likely to be important to patients are
significantly improved by omalizumab compared to
placebo in patients with mod-severe asthma
Health-Care Utilization:
Omalizumab vs. Placebo
Omalizumab
Placebo
3
2.5
2
Incidence
rates/100 1.5
patient-years
1
0.5
0
Hospitalization
Oba Y J Allergy Clin Immunol 2004;114:265-9
ED Visits
Cost of Therapy
~0.5 exacerbations/pt/year (~1 in pts on po CS) compared to pl
Omalizumab
Placebo
1.2
1
0.8
Daily
Treatment 0.6
Costs
0.4
0.2
0
Hospital
ED visits
Oba Y J Allergy Clin Immunol 2004;114:265-9
OV
B-agonist
ICS
Cost of Symptom Free Day
ICS
$3.35-$7.50
Zafirlukast
$5.71-$12.08
Sal/FP
$3.79-$9.06
Omalizumab
$523
Omalizumab (>0.05 AQLQ) $378
Oba Y J Allergy Clin Immunol 2004;114:265-9
Xolair Cost-Effectiveness:
Issues with Current Data
• RCT data not representative of “real-world”
– Overestimates placebo arm
– Underestimates active drug arm
• Placebo and Protocol effect
– 67% of placebo patients improved at 1 year
– ED visits and likely hospitalizations lower
because of use of study investigator and with
more frequent OV than usual
Xolair Cost-Effectiveness:
Issues with Current Data
• RCT data not representative of “real-world”
– Overestimates placebo arm
– Underestimates active drug arm
• Placebo and Protocol effect
– 67% of placebo patients improved at 1 year
– ED visits and likely hospitalizations lower
because of use of study investigator and with
more frequent OV than usual
Asche CV. JACI.2005
Xolair Cost-Effectiveness:
Issues with Current Data
• Hospitalization rate ~16% in the literature
– Placebo-3%
– Xolair-<1%
• Dropout rates for Rx failure not quantified
– 14:1 placebo:xolair
• QALY not used
– comparisons with other drugs not valid
• No data on economic benefit of AQLQ (QOL)
Asche CV. JACI.2005
• Conclusions reflect studies that were designed
to assess efficacy, rather than effectiveness
– Conclusions dependent on key assumptions
about dosing and efficacy in a controlled
clinical setting--not actual clinical practice
– Retrospective C-E analyses have limited
generalizability to actual clinical practice
– If the RCT underestimate benefits patients
achieve in actual clinical practice, then C-E
ratios for omalizumab are overestimated
• Without assessing cost and efficacy in the same
patient population, direct comparisons of costeffectiveness are misleading
– Incremental C-E ratios for other asthma
therapies should only provide context: ICS,
LTRAs, and ICS-LABA combination are
indicated for different patient populations
– Omalizumab is indicated for patients with
moderate-to-severe persistent IgE-mediated
asthma who have failed other therapy
• Identifying eligible patients based on “breakeven” criteria for cost-effectiveness would
exclude most patients the clinical benefit that
a therapy like omalizumab can deliver
– Omalizumab is intended to address the disease
process to prevent exacerbations and
related cascade of healthcare utilization
– Patients with persistent IgE-mediated asthma
who may benefit significantly from
omalizumab therapy are likely to be excluded
from receiving therapy
Public Health Impact of Omalizumab
in High-Risk Patients
• Risk difference: omalizumab prevented
exacerbations in about 17 additional patients
for every 100 treated
• Prevented fraction: 50% of potential
exacerbations were prevented by treatment
with omalizumab
• Number needed to treat: 5.7 patients needed to
be treated with omalizumab to maintain 1
patient free of an exacerbation
Holgate S, et al.Curr Med Res Opin. 2001;17(4):233-240.
Societal Burden of Asthma
• Calculating societal burden of asthma requires
assessment of both direct and indirect costs
• Direct costs include
– Costs attributed to medical care (office visits,
hospitalizations, emergency visits, medications, etc.)
• Indirect costs
– Dollars expended by the patient, family, employer,
and/or society because of illness (including loss of
productivity and quality of life)
• Can be determined using either a cost of illness
or cost of wellness approach
Stempel DA, et al. J Allergy Clin Immunol. 2003;111:1203-4.
Cost of Illness Approach
• Traditional view of government and other
third party payers
– Determines costs by multiplying average
medical costs for one person with asthma by
the total number of expected patients in the
population
– Focused on direct cost of care
– Minimal emphasis on prevention or longterm control
Stempel DA, et al. J Allergy Clin Immunol. 2003;111:1203-4.
Wall Street Journal, July 18, 2001
Cost of Wellness Approach
• Goal of wellness is to minimize expenses caused
by treatment failures and enhance productivity
– Direct costs targeted for preventative health care
and use of effective controller medications
• Indirect costs are used for environmental
control, lifestyle changes, and other
interventions that promote better health
• On balance, an investment in wellness
promotes
– Enhanced disease control
– Greater productivity at work or school
– Improved quality of life
Stempel DA, et al. J Allergy Clin Immunol. 2003;111:1203-4.
Direct and Indirect Costs of Asthma
Other
Medical
*
Total
Indirect
Direct
Costs**
Costs
Total
Costs
Meds
Am. Care
Hospital
Use
Mild
47%
7%
4%
5%
$1681
22%
$2646
Moderate
39%
7%
5%
4%
$2473
33%
$4530
Severe
19%
7%
17%
8%
$6354
46%
$12,813
Asthma
Severity
N = 401 adults with asthma 18-50 yrs old
*transportation to ED and outpatient procedures, purchase of asthma-control products, asthma-related
home repairs, etc.
**Lost productivity at work and inability to perform daily activities
Cisternas, MG et al. J Allergy Clin Immunol. 2003;111:1212-8.
Economic Burden of Asthma in the U.S.
Direct
Costs
$7.4B (US)
• Hospital Care
– Inpatient $2B
– ER $500M
– Hosp outpatient $700M
Indirect
Costs
$5.3B (US)
• Work Loss
– Employed $1.5B
– At Home $800M
• Mortality $1.8B
• Physician Services
– Inpatient care $110M
– Office Visits $740M
– Prescriptions $3.2B
• Pharmacist Services
• School Days Lost $1.1B
Cost to
Patient
ARQoL
• Activity avoidance
• Mortality
• 16 Asthma deaths
per day
• Missing school
• Missing work
• Unscheduled office
visits and visits to ER
• Lifestyle disruptions
have become embedded
in patient expectations
for disease
Sullivan SD, and Weiss KB, Health economics of asthma and rhinitis, I and II. Assessing the value of interventions,
Current Reviews of Allergy and Clinical Immunology, January 2001, Volume 107, No. 1&2, p. 3-8 and 203-210.
Total Health Care Expenditures
Moderate-Severe Asthma vs Non-Asthmatics
Asthma
4,692
Total
Controls
10,890
Allergies
Migraine
Sinusitis
Depression
G-I
$0
$5,000
$10,000
$15,000
$20,000
$25,000
Cost of Asthma to Employers
Medical
Pharmacy
Absenteeism
Disability
Other care
Respiratory
Other care
Other Respiratory
Asthma care
$0
$500 $1,000 $1,500 $2,000 $2,500 $3,000 $3,500
Work Loss in Parents of Asthmatics
Children 6-16 y/o with persistent asthma (GINA ≥ 2)
30% lost work days
13% lost > 5 work days
1 + Days
5 + Days
High
Severity
Moderate
Low
Poor
Control
Moderate
Good
0.0
2.0
4.0
6.0
OR
8.0
10.0
Cost of Illness
Med/Rx
Long-term Disability
Short-term Disabiity
Absenteeism
Presenteeism
Kemp P Harvard Business Review. October 2004. Presented in part at AAAAI, 2001.
Based on data from Bank One, Chicago, 2000
Effect of Presenteeism
Effect of Presenteeism
Condition
Prevalence Productivity
Loss
Migraine
12.0 %
4.9%
Arthritis
19.7
5.9
LBP
21.3
5.5
Allergies/sinus 59.8
4.1
Asthma
6.8
5.2
GERD
15.2
5.2
Dermatitis
16.1
5.2
Flu (past 2 wk) 17.5
4.7
Depression
13.9
7.6
Total annual
loss
$434,385
865,530
858,825
1,809,945
259,740
582,660
610,740
607,005
786,600
Cost-Sharing
• In an attempt to reduce costs, payors will
shift costs to patients:
– “consumer-driven health plans”
– Utilization control and influence choice
• This will demand a FULLY educated
consumer
• We will need to help patient evaluate the
full cost-benefit (not just HCU but QOL)
Rx Noncompliance due to Costs
1997
2002
18
16
14
12
10
8
6
4
2
0
Medicare Medicaid
Private
No
Insurance
Total
NHIS Surveys
Discussion Questions
• Are the current outcomes that we consider in the
treatment algorithm for asthma adequate?
• If not, what else should we be considering?
• What are the benefits and challenges of looking
at these other outcomes?
• What endpoints would help clarify and
communicate the value proposition for Xolair?
Discussion Questions
• What indirect costs are most strongly associated with
poor control of asthma symptoms?
• With increasing focus on the concept of control,
should we rethink the conventional cost-effectiveness
approach for asthma interventions?
– Is an outcome measure other than the symptom free-day
warranted?
– Should analyses take into account the significant burden
associated with indirect costs that may be mitigated by
therapies that reduce activity limitations?