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 doesnt tell us

Asthma is a syndrome,
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

Patient Self-Classification

Whos Wrong

NAEPP Guidelines

Severe

Moderate Mild

Intermittant

None

4.8%

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%

Symptoms

Asthma in America, 2001

0.8%

Control vs. Symptoms

1) Most people well controlled
2) Symptoms in many despite control
% Total Sample

34%

21%

35%

49%

11%

2%

Control vs. Bronchodilator Use

% Total Sample

32%

24%

% Total Sample

Control vs. Exacerbations

42%

9%

In Previous 3 months

13%

Asthma Variability:
Moderate-Severe Asthma on -Agonist Only
12 week: mean FEV1: 64%, -agonist: 4-5/day

**Intermittent, Mild, Mod-Severe

*Intermittent-Mild, Moderate, Severe

Albuterol: 59%
Symptoms: 45%

Weeks in Category

Asthma is Well Controlled

if in a week.
5 days with DSS 1 (0-6 scale)
5days with no rescue -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 -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

Bateman ED Am J Respir Crit Care Med 2004:170:836-844

Exacerbations and Effect of Therapy

Different
Exacerbations
or Different People
(not all exacerbations
and not all asthmatics
are the same)

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

6
days/month

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 agonist use

Symptom
intensity (SOB)

Some
correlation

No correlation

Some
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

...the Asthma Is Controlled!

No inflammation
Good lung
function
No urgent visits
Low costs

I can ...

I can ...

Play ball
Stay at my friends
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
6
asthma symptoms
emotional function
5
environmental exposure
Clinical relevance
Score

+ 1.5

large

+ 1.0 moderate
+ 0.5

small

4
3
2
1

Higher
scores

=
less
impairment
in AQoL

0
Juniper E et al., Am Rev Respir Dis 1993

18

% Patients with 0.5 Unit Change in AQLQ

From Baseline to End of Steroid-Reduction (Busse)
*

% patients

*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)
*

% patients

*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

AQLQ: Symptom Domain

Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

AQLQ: Activities Domain

Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

AQLQ: Emotions/Environment Domain

Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

Wake up in the morning with Symptoms

Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

Overall Range of Activities

Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

Afraid of not having medication available

Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

Experience symptoms from dust

Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

% Hardly Any or No Asthma-Related Limits

*
*
*
*
*
*
*
*

Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

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

Oba Y J Allergy Clin Immunol 2004;114:265-9

Cost of Therapy
~0.5 exacerbations/pt/year (~1 in pts on po CS) compared to pl

Oba Y J Allergy Clin Immunol 2004;114:265-9

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 long-term
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, asthmarelated 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
4,692
10,890

Asthma

Control

Cost of Asthma to Employers

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

Severity

Control

Cost of Illness

Kemp P Harvard Business Review. October 2004.

Effect of Presenteeism

Effect of Presenteeism
Condition

Prevalence Productivity
Loss

Total annual
loss

Migraine
Arthritis
LBP
Allergies/sinus
Asthma
GERD
Dermatitis
Flu (past 2 wk)
Depression

12.0 %
19.7
21.3
59.8
6.8
15.2
16.1
17.5
13.9

$434,385
865,530
858,825
1,809,945
259,740
582,660
610,740
607,005
786,600

4.9%
5.9
5.5
4.1
5.2
5.2
5.2
4.7
7.6

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

NHISSurveys

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?