Allan T. Luskin, MD Associate Clinical Professor of Medicine, University of Wisconsin

Allan T. Luskin, MDAssociate Clinical Professor of Medicine, University of Wisconsin

Director, Respiratory Institute, Dean Medical CenterMadison, 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

Evolving Xolair Health Outcomes Data: What Does (or Should) it Mean to

Patients, Clinicians and Payors

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 syndromesyndrome, 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

Symptoms

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% 0.8%

NAEPP Guidelines

Pat

ien

t S

e lf-

Cla

s sif

icat

ion

Asthma in America, 2001

Who’s “Wrong”

“Control” vs. Symptoms

0

5

10

15

20

Very Well Quite Well Not VeryWell

Not at allWell

"Control"

None 1 to 2 3+ d/wk1) Most people “well controlled”2) Symptoms in many despite “control”

21%

34%

% T

otal

Sam

ple

35% 49% 11% 2%

“Control” vs. Bronchodilator Use

0

5

10

15

20

25

Very Well Quite Well Not VeryWell

Not at allWell

"Control"

None 1 to 2 3+ d/wk

24%

32%

% T

otal

Sam

ple

“Control” vs. Exacerbations

05

1015202530354045

Yes No Yes No Yes No

Noc Wake ED Visit Missed Social

Very Well Quite Well Not Very Not At All

% T

otal

Sam

ple

In Previous 3 months

42%

9%13%

Asthma Variability:“Moderate-Severe” Asthma on -Agonist Only

12 week: mean FEV1: 64%, -agonist: 4-5/day

0

10

20

30

40

50

60

70

80

Intermittent Mild Moderate Severe

Symptoms** Albuterol** PEF* All Criteria

**Intermittent, Mild, Mod-Severe*Intermittent-Mild, Moderate, SevereAlbuterol: 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

• ≤1 nocturnal awakening• No exacerbations• No ED visits• No therapy related adverse events

and

2 of 3

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)

0

20

40

60

80

100

FP FP/SM

Total Control

Well Controlled

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

20-32% not persistent “Lose Control”

N.B.: 19-36% never achieve control (89% adherence)

Exacerbations and Effect of Therapy

0

20

40

60

80

100

% Exacerbations

Prevented

COPD Asthma

ICS ICS + LABA

Different Exacerbations

or Different People(not all exacerbations and not all asthmatics

are the same)

Dimensions of ControlHow 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

0 2 4 6 8 10 12

physicallyunhealthy

mentallyunhealthy

activity limitation

unhealthy days

days/month

Asthma (7.5%) Never Asthma (89.5%)

147 million unhealthy

functioning days/year

Asthma-Specific HRQL and Costs:Asthma Costs over a 12 month Follow-up

$150

$175

$200

$225

$250

$275

$300

$325

Avg

. Cos

t/pe

rson

/yea

r

Excellent(90%-tile)

Mean + 10 Mean Mean - 10 Poor (10th %-

tile)

Clinical Predictors of HRQL

Clinical Outcomes

Mild Asthma Moderate-Severe Asthma

FEV1 No correlation No correlation

Rescue -agonist use

Some correlation

No correlation

Symptom intensity (SOB)

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

0 1000 2000 3000 4000 5000 6000

Nights inHospital

ER Visits

Oral SteroidBursts

UnscheduledContacts

Rate per 1000 person-years

0 Barriers (n = 497)1 Barrier (n = 581)2 Barriers (n = 902)3-4 Barriers (n = 938)

• No inflammation• Good lung

function• No urgent visits• Low costs

I can ...• Play ball • Stay at my friend’s

who has a dog• Forget my medicine

I can ...• Go out for a drink• Do work around

the house• Fool around with

my wife• Forget my medicine

“...the Asthma Is Controlled!”

Asthma Quality of Life (AQLQ) Questionnaire

32 items; 4 domains

activity limitationsasthma symptoms emotional function environmental exposure

Clinical relevance

+ 1.5 large

+ 1.0 moderate

+ 0.5 small

S

core

0

1

2

3

4

5

6

7

Higher scores

=less

impairmentin AQoL

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)

53.449.8

56.6 54.6 54.861.5 61.7

67.162.6

66.4

0

10

20

30

40

50

60

70

80

Activities Emotions Symptoms Exposure OverallScore

Placebo Omalizumab

*

18%

pat

ien

ts

* *

*P<0.05Kishiyama 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)

22.825.1

21 21.117.8

31.634.2 34.2 34.2 32.8

0

5

10

15

20

25

30

35

40

Activities Emotions Symptoms Exposure OverallScore

Placebo Omalizumab

% p

ati e

nts

* * ***

*P<0.05Kishiyama JL, et al. Allergy Clin Immunol International. 2000;Suppl 2:115. Abstract.

Adelroth. JACI 2000;106:253-259

Anti-IgE: QOL in SAR

00.5

11.5

22.5

33.5

Omalizumab Placebo

AQLQ: Symptom Domain

0 0.5 1 1.5 2 2.5

Fighting for air

Sleep interference

Nighttime symptoms

Morning symptoms

Difficulty breathing

Clear throat

Chest heaviness

Coughing

Wheezing

Short of breath

Chest tightness

Placebo

Omalizumab

Luskin AT Annals of Allergy Asthma Immunol. 2004 abs

AQLQ: Activities Domain

0 0.5 1 1.5 2

Household activity

Walking

Exertion

All activities

Range of activities

Avoid smells

Avoid pollution

Avoid dust

Avoid smoke

Placebo

Omalizumab


AQLQ: Emotions/Environment Domain

0 0.5 1 1.5

Symptoms: Smells

Symptoms: Weather

Symptoms: Dust

Symptoms: Smoke

Fear: SOB

Fear: No Medication

Concerned: Medication

Frustrated with Asthma

Frustrated with Asthma

Placebo

Omalizumab


“Wake up in the morning with Symptoms”

0

0.5

1

1.5

2

2.5

ICS Stable ICS Reduction Extention

Omalizumab Placebo


“Overall Range of Activities”

0

0.2

0.4

0.6

0.8

1

1.2

1.4


Omalizumab Placebo


“Afraid of not having medication available”

0

0.2

0.4

0.6

0.8

1


Omalizumab Placebo


“Experience symptoms from dust”

0

0.2

0.4

0.6

0.8

1

1.2

1.4


Omalizumab Placebo


% Hardly Any or No Asthma-Related Limits

0 10 20 30 40 50 60 70 80

Morning Symptoms

Sleep Disturbance

Chest Tightness

All Activites

Exertion

Walks

Medication Fear

Dust Symptoms

Baseline Extension

*

**

*

*

*

*

*

*


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

0

0.5

1

1.5

2

2.5

3

Incidence rates/100

patient-years

Hospitalization ED Visits

Omalizumab 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

0

0.2

0.4

0.6

0.8

1

1.2

Daily Treatment

Costs

Hospital ED visits OV B-agonist ICS

Omalizumab Placebo


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


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


• 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


• 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 cost-effectiveness 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 “break-even” 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


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


Direct and Indirect Costs of Asthma

Asthma Severity

Meds Am. CareHospital

Use

Other Medical

*

Total Direct Costs

Indirect Costs**

Total Costs

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

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.

• Hospital Care– Inpatient $2B– ER $500M– Hosp outpatient $700M

• Physician Services– Inpatient care $110M– Office Visits $740M– Prescriptions $3.2B

• Pharmacist Services

Direct Costs

$7.4B (US)• Work Loss

– Employed $1.5B– At Home $800M

• Mortality $1.8B

• School Days Lost $1.1B

Indirect Costs

$5.3B (US)

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.

Economic Burden of Asthma in the U.S.

• 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

Cost to Patient ARQoL

Total Health Care ExpendituresModerate-Severe Asthma vs Non-Asthmatics

$0 $5,000 $10,000 $15,000 $20,000 $25,000

G-I

Depression

Sinusitis

Migraine

Allergies

Total Asthma Controls4,69210,890

Cost of Asthma to Employers

$0 $500 $1,000 $1,500 $2,000 $2,500 $3,000 $3,500

Asthma care

Other Respiratory

Other care

Respiratory

Other care

Medical Pharmacy Absenteeism Disability

Ast

hma

Con

trol

Work Loss in Parents of AsthmaticsChildren 6-16 y/o with persistent asthma (GINA ≥ 2)

0.0 2.0 4.0 6.0 8.0 10.0

Good

Moderate

Poor

Low

Moderate

High

OR

1 + Days 5 + Days

Severity

Control

30% lost work days13% lost > 5 work days

Kemp P Harvard Business Review. October 2004. Presented in part at AAAAI, 2001. Based on data from Bank One, Chicago, 2000

Cost of Illness

Med/RxLong-term DisabilityShort-term DisabiityAbsenteeismPresenteeism

Effect of Presenteeism

Effect of Presenteeism

Condition Prevalence Productivity Loss

Total annual loss

Migraine 12.0 % 4.9% $434,385

Arthritis 19.7 5.9 865,530

LBP 21.3 5.5 858,825

Allergies/sinus 59.8 4.1 1,809,945

Asthma 6.8 5.2 259,740

GERD 15.2 5.2 582,660

Dermatitis 16.1 5.2 610,740

Flu (past 2 wk) 17.5 4.7 607,005

Depression 13.9 7.6 786,600

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

0246

81012

141618

Medicare Medicaid Private NoInsurance

Total

1997 2002

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?

Documents

Allan T. Luskin, MD Associate Clinical Professor of Medicine, University of Wisconsin