A A 11

Pulmonary-Allergy Drugs Pulmonary-Allergy Drugs Advisory Committee MeetingAdvisory Committee Meeting

July 13, 2005July 13, 2005

Safety of Long-acting BetaSafety of Long-acting Beta22-Agonists-Agonists

A A 22

Long-Acting BetaLong-Acting Beta22-Agonist-Agonist

Salmeterol Salmeterol

C. Elaine Jones, PhD. C. Elaine Jones, PhD.

Vice PresidentVice President

Respiratory Regulatory Affairs Respiratory Regulatory Affairs

GlaxoSmithKlineGlaxoSmithKline

A A 33

Burden of Asthma in the USBurden of Asthma in the US

• Affected an estimated 20 million Americans in 2002Affected an estimated 20 million Americans in 200211

• Significant morbidity and mortalitySignificant morbidity and mortality– 484,000 hospitalizations in 2002484,000 hospitalizations in 200211

– 4,261 deaths in 20024,261 deaths in 200211

• Risk factors for asthma-related mortalityRisk factors for asthma-related mortality– Over-use of rescue medicationOver-use of rescue medication

– Under-use of ICSUnder-use of ICS

– Disease severityDisease severity

– Delay in seeking careDelay in seeking care

– Ethnic originEthnic origin

– GenderGender

– AgeAge

– Substance AbuseSubstance Abuse

– PollutionPollution

1National Center for Health Statistics website, http://www.cdc.gov/nchs/products/pubs/pubd/hestats/asthma/asthma.htm

A A 44

Salmeterol Approval HistorySalmeterol Approval History

• First approved in the United Kingdom, 1990First approved in the United Kingdom, 1990

• Approved in over 100 countriesApproved in over 100 countries

200320021998COPD

200019971994Asthma

ADVAIR DISKUS®

SEREVENT® DISKUS®

SEREVENT® Inhalation Aerosol

US Approval History

A A 55

Salmeterol ExposureSalmeterol Exposure

• Worldwide exposure estimated to be 45.2 Worldwide exposure estimated to be 45.2 million patient-years million patient-years

– 24.3 million patient-years for salmeterol 24.3 million patient-years for salmeterol

– 20.9 million patient-years for salmeterol 20.9 million patient-years for salmeterol administered with fluticasone propionate in a administered with fluticasone propionate in a single devicesingle device

A A 66

NHLBI Asthma Treatment GuidelinesNHLBI Asthma Treatment Guidelines

Severity Class

Step 4Severe Persistent

Step 3Moderate Persistent

Step 2Mild Persistent

Step 1Mild Intermittent

Symptoms

Continual

Daily

>2/week but <1x/day

2 days/week

Daily Medications

• Preferred treatment:High-dose ICS + LABA

• Preferred treatment:Low-to-medium dose ICS + LABA

• Preferred treatment:Low-dose ICS

• No daily medication needed

FEV1

60%

>60% - <80%

80%

80%

LABA = Long-Acting Beta-AgonistGuidelines for the Diagnosis and Management of Asthma—Update on Selected Topics 2002. NIH, NHLBI. June 2002. NIH publication no. 02-5075.

A A 77

Salmeterol for theSalmeterol for theTreatment of AsthmaTreatment of Asthma

• Established as an important Established as an important pharmacologic therapy pharmacologic therapy

• Extensive clinical experienceExtensive clinical experience

• Exhibits a favorable benefit to risk Exhibits a favorable benefit to risk profileprofile

A A 88

Salmeterol ReviewSalmeterol Review

Katharine Knobil, M.D.Katharine Knobil, M.D.

Vice PresidentVice President

Respiratory Clinical DevelopmentRespiratory Clinical Development

GlaxoSmithKlineGlaxoSmithKline

A A 99

Salmeterol ReviewSalmeterol ReviewAsthmaAsthma

• Benefits of salmeterolBenefits of salmeterol

• Safety of salmeterolSafety of salmeterol

– Post-marketing safety surveillance studies Post-marketing safety surveillance studies

– Epidemiology studiesEpidemiology studies

• Ongoing StudiesOngoing Studies

• SummarySummary

A A 1010

BetaBeta22-Agonists:-Agonists:

Albuterol and SalmeterolAlbuterol and Salmeterol

CHCH2NH-C

OHHOH2C

HO CH3CH3

CH3

Albuterol

Salmeterol

OCH2CH2CH2CH2NHCH2CH2CH2CH2CH2CH2CHCH2

OHHOH2C

HO

A A 1111

Improvement in FEVImprovement in FEV11

Treatment Day 1

Per

cent

Pre

dict

ed F

EV

1

Salmeterol 42mcg (n=184)

Albuterol 180mcg (n=185)

Placebo (n=187)60

70

80

90

0 1 2 3 4 5 6 7 8 9 10 11 12.5

HoursSecond albuterol dose

Per

cent

Pre

dict

ed F

EV

1

Treatment Week 12 (Day 84)

Hours

Salmeterol 42mcg (n=152)

Albuterol 180mcg (n=152)

Placebo (n=150)

60

70

80

90

0 1 2 3 4 5 6 7 8 9 10 11 12.5

Second albuterol dose

Pearlman et al. NEJM 1992;327:1420-25D’Alonzo et al. JAMA 1994;271(18):1412-16

A A 1212

Maintenance of Bronchodilator EffectMaintenance of Bronchodilator Effect

Salmeterol Diskus 50mcg BID (n=176)

Placebo (n=176)

12 H

r F

EV

1 A

UC

BL

(Lite

r H

ours

)

6

2

1

0Day 1 Week 8 Week 20 Week 48

3

4

5

7

*p<0.001 vs. placeboKemp et al. J Allergy Clin Immunol 1999;104:1189-97

**

**

A A 1313

Reduction in Symptom ScoresReduction in Symptom Scores

† p<0.05 Salmeterol vs Placebo‡ p<0.05 Salmeterol vs Albuterol QIDPearlman et al. NEJM 1992;327:1420-25D’Alonzo et al. JAMA 1994;271(18):1412-16

-46

0

-8

-46

-5-8

-33

-9 -9

-29

-14 -14

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

Salmeterol 42mcg BID (n=184)Albuterol 180mcg QID (n=185)Placebo (n=187)

Per

cent

Cha

nge

from

Bas

elin

eChest

TightnessShortnessof Breath Wheezing Cough

† ‡ † ‡

† ‡

‡

A A 1414

Salmeterol, 50mcg BID + BDP, 200mcg BID(n=220)

BDP, 500mcg BID + Placebo(n=206)

0

5

10

15

20

25

30

35

0 1 5 9 13 17 21

Weeks

Cha

nge

in P

EF

(Li

ters

/min

)

*** p< 0.001** p< 0.01* p< 0.05

***

**

**

***

***

Improvement in Lung Function vs. Improvement in Lung Function vs. Increased-Dose Inhaled CorticosteroidsIncreased-Dose Inhaled Corticosteroids

Greening et al. Lancet 1994;344:219-24

A A 1515

Reduction in ExacerbationsReduction in Exacerbations

p < 0.05 vs. FP 220

1.00

0.95

0.90

0.85

0.80

0.75

Time to First Exacerbation (weeks)

Pro

bab

ility

of

No

Exa

cerb

atio

n

Salmeterol + FP 88mcg BID (n=467) FP 220mcg BID (n=458)

240 1442 6 10 168 18 20 2212

Matz et al. J Allergy Clin Immunol 2001;107:783-789

0

A A 1616

Improvement in Quality of LifeImprovement in Quality of Life

Limitation Function ExposureSymptoms

Mea

n C

hang

e in

AQ

LQ

0

0.5

1

1.5

2

Activity Asthma Emotional Environment Global score

Salmeterol 42mcg BID (n=240)

Placebo (n=234)

AQLQ = Asthma Quality of Life Questionnaire*p0.005, salmeterol vs. placebo for all assessmentsLockey et al. Chest 1999;115:666-673

*

**

*

*

A A 1717

Post-MarketingPost-MarketingSurveillance Studies Surveillance Studies

A A 1818

Salmeterol MDI 42mcg BID + Usual Care

(n=16,787)• Requirement for regular bronchodilator

• No run-in• 69% concurrent ICS

Albuterol MDI 180mcg QID + Usual Care

(n=8,393)

Day 0Visit 1

Week 4 Week 8 Week 16

SereventSerevent Nationwide Nationwide Surveillance Study (SNS)Surveillance Study (SNS)

Castle et al. Br Med J 1993:306;1034-1037

2:1

A A 1919

OutcomeSalmeterol

(n=16,787)Albuterol

(n=8393)Relative Risk

(P value)

Asthma-related Deaths 12 (0.07%) 2 (0.02%) 3.0 (P=0.105)

Asthma-related Hospitalizations 193 (1.15%) 102 (1.22%) 0.95 (P=0.651)

Asthma-related Withdrawals 488 (2.91%) 318 (3.79%) 0.77 (P=0.0002)

All Serious Events & Withdrawals 4272 (25.5%) 2209 (26.3%) 0.97 (P=0.200)

SNS ResultsSNS Results

Castle et al. Br Med J 1993:306;1034-1037

A A 2020

Salmeterol MDI 42mcg BID + Usual Care

(n=13,176)• No inhaled long-acting beta2-agonist

• > 12 years of agePlacebo MDI BID + Usual Care

(n=13,179)

Clinic Visit

28 week treatment periodPhone contact every 4 weeks

28 week supply of study medication provided

R

SMARTSMARTSalmeterol Multicenter Asthma Research TrialSalmeterol Multicenter Asthma Research Trial

Nelson et al. Chest 2005 (In Press)

A A 2121

SMART Study EndpointsSMART Study Endpoints

• Primary EndpointPrimary Endpoint– Combined respiratory-related deaths or life-threatening Combined respiratory-related deaths or life-threatening

experiences (intubation and ventilation)experiences (intubation and ventilation)

– Target sample size increased from 30,000 to 60,000 Target sample size increased from 30,000 to 60,000 patientspatients

• Key Secondary EndpointsKey Secondary Endpoints– Respiratory-related deaths Respiratory-related deaths

– Combined asthma-related deaths or life-threatening Combined asthma-related deaths or life-threatening experiencesexperiences

– Asthma-related deathsAsthma-related deaths

A A 2222

Phone contacts, spontaneous reports

Case Reports of Serious Adverse

EventsMMRC

DSMB

Study oversightInterim analysis

Recommendations to GSK

Adjudication of Serious Adverse Adjudication of Serious Adverse Events from SMARTEvents from SMART

MMRC= Mortality and Morbidity Review CommitteeDSMB= Data Safety Monitoring Board

MMRC reviewed all events:Determined if respiratory-

and/or asthma-related

• Unrelated

• Unlikely related

• Possibly related

• Almost certainly related

A A 2323

SMART Interim AnalysisSMART Interim Analysis

• SMART did not reach predetermined stopping SMART did not reach predetermined stopping criteria at the interim analysiscriteria at the interim analysis

• DSMB recommendedDSMB recommended

– Timely completion (within two years)Timely completion (within two years)

If this was not possible:If this was not possible:

– Discontinuation of study and rapid dissemination of Discontinuation of study and rapid dissemination of the interim resultsthe interim results

• SMART was discontinued due to difficulties in SMART was discontinued due to difficulties in enrollment and findings in African American enrollment and findings in African American patientspatients

A A 2424

Salmeterol

(n=13,176)

Placebo

(n=13,179)

Age, mean 39.2 39.1

Sex, n (%) Female

Male

8334 (64)

4703 (36)

8337 (64)

4686 (36)

Ethnic Origin, n (%)

Caucasian

African American

Hispanic

Asian

Other

9281 (71)

2366 (18)

996 (8)

173 (1)

230 (2)

9361 (72)

2319 (18)

999 (8)

149 (1)

224 (2)

Baseline CharacteristicsBaseline Characteristics

Peak Expiratory Flow (% Predicted) 84.0 83.8

A A 2525

Asthma Medications at BaselineAsthma Medications at Baseline

Salmeterol PlaceboConcurrent Medications, n (%) n=13,176 n=13,179

Subjects using asthma medicationsat Baseline 12,715 (97) 12,660 (96)

Subjects with no asthma medicationsat Baseline 461 (3) 519 (4)

Inhaled or oral beta2-agonists

(excluding inhaled LABAs) 12,059 (92) 12,043 (91)

Inhaled corticosteroids 6127 (47) 6138 (47)

Methylxanthines 1766 (13) 1767 (13)

Leukotriene modifiers 1437 (11) 1402 (11)

A A 2626

Baseline Asthma Characteristics in Baseline Asthma Characteristics in Caucasians and African Americans Caucasians and African Americans

Caucasian(n=18,642)

African American(n=4685)

Peak expiratory flow (% predicted) 85% 78%

Baseline ICS Use 49% 38%

Nocturnal symptoms present 57% 64%

6% 15%1 hospitalization last 12 months

30% 44%1 hospitalization lifetime

4% 8%1 intubation for asthma lifetime

59% 72%1 ER visit lifetime

22% 41%1 ER visit last 12 months

A A 2727

SMART ResultsSMART ResultsAll Patients and Ethnic SubgroupsAll Patients and Ethnic Subgroups

RR (95% CI) SAL n PLA n1° Endpoint

7.26 (0.89, 58.94) 7 1

4.92 (1.68,14.45) 19 4

3.88 (0.83, 18.26) 8 2

5.82 (0.70, 48.37) 6 1

1.08 (0.55, 2.14) 17 16

2.29 (0.94, 5.56) 16 7

4.10 (1.54, 10.90) 20 5

1.05 (0.62, 1.76) 29 28

Asthma Death

AsthmaDeath or LifeThreateningExperience

RespiratoryDeath

4.37 (1.25, 15.34) 13 3

1.71 (1.01, 2.89) 37 22

2.16 (1.06, 4.41) 24 11

RespiratoryDeath or LifeThreateningExperience

1.40 (0.91, 2.14) 50 36

Total N=13176 N=13179Caucasian N=9281 N=9361African American N=2366 N=2319

.031.062.125.25 .5 421 168 6432 128

2° Endpoints

A A 2828

Total N=13176 N=13179ICS N=6127 N=6138Non-ICS N=7049 N=7041

RR (95% CI) SAL n PLA n1° Endpoint

Asthma Death

AsthmaDeath or LifeThreateningExperience

RespiratoryDeath or LifeThreateningExperience

SMART ResultsSMART ResultsAll Patients and by ICS Use at BaselineAll Patients and by ICS Use at Baseline

.031.062 .25 .5 421 168 6432 128

9 0

2.39 (1.10, 5.22) 21 9

2.28 (0.88, 5.94) 14 6

1.60 (0.87, 2.93) 27 17

1.35 (0.30, 6.04) 4 3

1.24 (0.60, 2.58) 16 13

2.01 (0.69, 5.86) 10 5

1.21 (0.66, 2.23) 23 19

4.37 (1.25, 15.34) 13 3

1.71 (1.01, 2.89) 37 22

2.16 (1.06, 4.41) 24 11

1.40 (0.91, 2.14) 50 36

RespiratoryDeath

2° Endpoints

.125

A A 2929

RR (95% CI) SAL n PLA n

Asthma Death

AsthmaDeath or LifeThreateningExperience

RespiratoryDeath or LifeThreateningExperience

SMART ResultsSMART ResultsEthnic Subgroups by ICS Use at BaselineEthnic Subgroups by ICS Use at Baseline

African American ICS (SAL N=906, PLA N=785)African American Non-ICS (SAL N=1460, PLA N=1444)

Cauc. ICS (SAL N=4586, PLA N=4637)Cauc. Non-ICS (SAL N=4695, PLA N=4724)

.031.062.125 .25 .5 421 168 6432 128

3.02 (0.82, 11.11) 9 35.61 (1.25, 25.26) 11 2

1.25 (0.60, 2.60) 16 130.88 (0.42, 1.84) 13 15

3.12 (0.33, 29.92) 3 14.43 (0.52, 37.89) 5 1

2.29 (0.70, 7.42) 9 42.31 (0.60, 8.93) 7 3

3.02 (0.82, 11.11) 9 310.46 (1.34, 81.58) 10 1

1.62 (0.63, 4.17) 11 70.68 (0.24, 1.90) 6 9

4 03.12 (0.33, 29.92) 3 1

5 00.96 (0.06, 15.35) 1 1

RespiratoryDeath

2° Endpoints

1° Endpoint

A A 3030

SMART SummarySMART Summary

• More events occurred in patients receiving More events occurred in patients receiving salmeterolsalmeterol

– Suggestion of higher risk in African AmericansSuggestion of higher risk in African Americans

– Suggestion of higher risk in patients not reporting Suggestion of higher risk in patients not reporting ICS use at baselineICS use at baseline

• Low number of events prevents definitive Low number of events prevents definitive conclusionsconclusions

• No clear explanation from these dataNo clear explanation from these data

A A 3131

Dissemination of SMART ResultsDissemination of SMART Results

• Two ‘Dear Health Care Professional’ LettersTwo ‘Dear Health Care Professional’ Letters

– On the day SMART was stoppedOn the day SMART was stopped

– When the labels were updatedWhen the labels were updated

• Labeling RevisionsLabeling Revisions

– Boxed warning added; Clinical Trials and Warnings Boxed warning added; Clinical Trials and Warnings sections updated for sections updated for SereventSerevent and and AdvairAdvair

– Updated with final resultsUpdated with final results

A A 3232

WARNING: Data from a large placebo-controlled US WARNING: Data from a large placebo-controlled US study that compared the safety of salmeterol study that compared the safety of salmeterol (SEREVENT(SEREVENT®® Inhalation Aerosol) or placebo added Inhalation Aerosol) or placebo added to usual asthma therapy showed a small but to usual asthma therapy showed a small but significant increase in asthma-related deaths in significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks) versus those 13,176 patients treated for 28 weeks) versus those on placebo (3 of 13,179) (see WARNINGS in on placebo (3 of 13,179) (see WARNINGS in complete Prescribing Information).complete Prescribing Information).

Important Safety InformationImportant Safety Information

A A 3333

Dissemination of SMART ResultsDissemination of SMART Results

• Two ‘Dear Health Care Professional’ LettersTwo ‘Dear Health Care Professional’ Letters– On the day SMART was stoppedOn the day SMART was stopped

– When the labels were updatedWhen the labels were updated

• Labeling RevisionsLabeling Revisions– Boxed warning added; Clinical Trials and Warnings Boxed warning added; Clinical Trials and Warnings

sections updated for Serevent and Advairsections updated for Serevent and Advair

– Updated with final resultsUpdated with final results

• PublicationsPublications– Abstract at American College of Chest PhysiciansAbstract at American College of Chest Physicians

– Manuscript accepted for publication by ChestManuscript accepted for publication by Chest

A A 3434

Epidemiology StudiesEpidemiology Studies

A A 3535

Epidemiology StudiesEpidemiology Studies

• StrengthsStrengths

– Utilization of comprehensive medical and Utilization of comprehensive medical and pharmacy databasespharmacy databases

– Identification of a greater number of eventsIdentification of a greater number of events

• LimitationsLimitations

– Assignment of treatment is not randomAssignment of treatment is not random

– Potential confounding by differences in baseline Potential confounding by differences in baseline characteristicscharacteristics

A A 3636

Studies of Severe Asthma Outcomes Studies of Severe Asthma Outcomes and Salmeteroland Salmeterol

0.01

0.1

1

10

1Meier. Thorax 1997;52:612-7 (n=16,919)2Lanes et al. Am J Respir Crit Care Med 1998;158:857-61 (n=6533)3Williams et al. Thorax 1998;53:7-13 (n= 233)4Anderson et al. BMJ 2005;330:117-24 (n=1064)

RespDeathTheo1

0.33

RespDeathIpra1

0.55

ER2

0.69

Hosp2

1.09

ICU2

0.81

ICU3

1.42

AsthmaDeath4

0.97

Rel

ativ

e R

isk

TheoUsual Care

A A 3737

Ongoing Studies to Help AddressOngoing Studies to Help AddressSMART FindingsSMART Findings

Studies in African AmericansStudies in African Americans

• Exacerbations in African American SubjectsExacerbations in African American Subjects

– 1 year duration, 460 subjects1 year duration, 460 subjects

– FP/salmeterol vs. FPFP/salmeterol vs. FP

• Epidemiology study of African Americans Epidemiology study of African Americans and Caucasiansand Caucasians

– Medicaid data from 7 states, 1995 to 1999Medicaid data from 7 states, 1995 to 1999

– Association of asthma-related prescription Association of asthma-related prescription medication use and medication use and asthma morbidity and asthma morbidity and mortality mortality

A A 3838

Ongoing Studies to Help AddressOngoing Studies to Help AddressSMART FindingsSMART Findings

Studies Including Genetic EvaluationsStudies Including Genetic Evaluations

• Response by betaResponse by beta22-receptor genotype-receptor genotype

– 38-week duration, 540 subjects38-week duration, 540 subjects

– FP/salmeterol vs. salmeterolFP/salmeterol vs. salmeterol

• BetaBeta22-receptor and glucocorticoid pathway -receptor and glucocorticoid pathway

polymorphisms and clinical response polymorphisms and clinical response

– 1000 subjects from completed clinical trials1000 subjects from completed clinical trials

– FP/salmeterol vs. salmeterol vs. FPFP/salmeterol vs. salmeterol vs. FP

A A 3939

Ongoing Studies in PatientsOngoing Studies in Patientswith COPDwith COPD

• Mortality in patients with COPDMortality in patients with COPD

– 3-year duration, 6200 subjects3-year duration, 6200 subjects

– FP/salmeterol, salmeterol, FP vs. placeboFP/salmeterol, salmeterol, FP vs. placebo

• COPD ExacerbationsCOPD Exacerbations

– Two 1-year studies, 740 subjects eachTwo 1-year studies, 740 subjects each

– FP/salmeterol vs. salmeterolFP/salmeterol vs. salmeterol

A A 4040

Benefit to Risk SummaryBenefit to Risk Summary

• Asthma is a serious disease with significant Asthma is a serious disease with significant morbidity and mortalitymorbidity and mortality

• Salmeterol provides substantial therapeutic benefitsSalmeterol provides substantial therapeutic benefits– Improves lung function and asthma-related quality of lifeImproves lung function and asthma-related quality of life

– Reduces symptoms, use of rescue medication, and Reduces symptoms, use of rescue medication, and exacerbationsexacerbations

– Endorsed by evidenced-based treatment guidelinesEndorsed by evidenced-based treatment guidelines

• Salmeterol and serious asthma-related eventsSalmeterol and serious asthma-related events– Association observed in SNS and SMART Association observed in SNS and SMART

– No association observed in epidemiology studiesNo association observed in epidemiology studies

A A 4141

Benefit to Risk SummaryBenefit to Risk Summary

• Prescribing information provides guidance on Prescribing information provides guidance on use of salmeteroluse of salmeterol

– Should not be used to treat acute symptomsShould not be used to treat acute symptoms

– Is not a substitute for inhaled or oral Is not a substitute for inhaled or oral corticosteroidscorticosteroids

– Consideration should be given to adding anti-Consideration should be given to adding anti-inflammatory agents (e.g. corticosteroids)inflammatory agents (e.g. corticosteroids)

– Should not be initiated in patients with significantly Should not be initiated in patients with significantly worsening or acutely deteriorating asthma worsening or acutely deteriorating asthma

• Incorporation of SNS and SMART resultsIncorporation of SNS and SMART results

A A 4242

Benefit to Risk SummaryBenefit to Risk Summary

• Salmeterol is an important therapeutic optionSalmeterol is an important therapeutic option

–Remains a valuable medicationRemains a valuable medication

– Improves the level of careImproves the level of care

• Favorable benefit to risk profileFavorable benefit to risk profile

A A 4343

External ExpertsExternal Experts

• Professor Richard Beasley, MBChB, DM, FRCP Professor Richard Beasley, MBChB, DM, FRCP – Director of the Medical Research Institute of New Zealand Director of the Medical Research Institute of New Zealand

• Eugene Bleecker, M.D. Eugene Bleecker, M.D. – Professor of Medicine and Section Head Pulmonary, Critical Professor of Medicine and Section Head Pulmonary, Critical

Care, Allergy and Immunologic Diseases at Wake Forest Care, Allergy and Immunologic Diseases at Wake Forest University Health SciencesUniversity Health Sciences

– Co-Director, Center for Human GenomicsCo-Director, Center for Human Genomics

• George O’Connor, M.D., M.S.George O’Connor, M.D., M.S.– Professor of MedicineProfessor of Medicine

Division of Pulmonary and Critical Care MedicineDivision of Pulmonary and Critical Care MedicineBoston University School of MedicineBoston University School of Medicine

– Director, Adult Asthma Program, Boston Medical CenterDirector, Adult Asthma Program, Boston Medical Center