Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002Thursday, 17 January 2002

ADVAIR and FLOVENT DISKUSADVAIR and FLOVENT DISKUSSupplements for the COPD indication:Supplements for the COPD indication:

SUMMARY and QUESTIONS SUMMARY and QUESTIONS

Mary Purucker, MD, PhDMary Purucker, MD, PhDMedical Team LeaderMedical Team Leader

Division of Pulmonary and Allergy Drug ProductsDivision of Pulmonary and Allergy Drug ProductsCDER, USFDACDER, USFDA

ADVAIR and FLOVENT DISKUSADVAIR and FLOVENT DISKUSSupplements for the COPD indication:Supplements for the COPD indication:

SUMMARY and QUESTIONS SUMMARY and QUESTIONS

Mary Purucker, MD, PhDMary Purucker, MD, PhDMedical Team LeaderMedical Team Leader

Division of Pulmonary and Allergy Drug ProductsDivision of Pulmonary and Allergy Drug ProductsCDER, USFDACDER, USFDA

Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002Thursday, 17 January 2002

OVERVIEWOVERVIEW

• Efficacy Summary• Safety Summary– Corticosteroid-related Issues• Pivotal Trials• Supportive Trials• Non-Application Data (with caveats)

• Wrap-up• Discussion Points for PADAC

Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002Thursday, 17 January 2002

EFFICACY SUMMARYEFFICACY SUMMARY

• Flovent Diskus– 250 g BID

• Primary endpoint not replicated– 500 g BID

• Effect size 0.050 L, 0.113 L

• Advair Diskus (pre-dose FEV1)– 250/50 g BID

• “Effect size” 0.164 L– 500/50 g BID

• “Effect size” 0.160 L

Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002Thursday, 17 January 2002

SAFETY ISSUESSAFETY ISSUES

• Corticosteroid moiety common to the 2 products• Dose-related CS AE’s observed in pivotal trials• Systemic availability and activity demonstrated

– PK studies show dose-related effect on HPA-axis

• Potential for CS systemic effects should be assumed (on bone, eyes, connective tissue, and metabolism)

• Pivotal and supportive studies not designed or powered to detect a difference in many aspects of CS systemic safety

Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002Thursday, 17 January 2002

ICS and COPD: AERS DatabaseICS and COPD: AERS Database

• Search by indication (COPD, emphysema, chronic bronchitis) for all ICS (including fluticasone)

• 206 cases accounted for 213 AE’s – All but 14 cases after 1997– Mean age 68.8 years, 50% female

• Adverse Events– > 50% worsening COPD/ lack of effectiveness– cataract - 5, bone - 6, HPA-axis - 8, skin - 4, fungal

infection - 8, hyperglycemia - 8

Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002Thursday, 17 January 2002

ICS Systemic Effects: Bone (1)ICS Systemic Effects: Bone (1)

• Chronic systemic CS can lead to osteoporosis• ICS are systemically available bone effects may

occur and ideally should be quantified• Bone/BMD not studied in 3 pivotal trials or other-

wise reported in these sNDAs for this population• Supportive trials, FLTA3001, FLTA3017

– Different population: • Younger (18 - 50 yrs)• Pre-menopausal • Asthmatics (mild/moderate)

BMD in LS (FLTA3001) BMD proximal femur (FLTA3017)

Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002Thursday, 17 January 2002

ICS Systemic Effects: Bone (2)ICS Systemic Effects: Bone (2)

• LHS II showed decline in BMD over 3 years:– Lumbar spine (p=0.007), N=328 – Femur (p<0.001), N=359

• Asthma: – Israel, NEJM 2001; 3-yr. prospective cohort study of pre-

menopausal women dose-related BMD at hip– Wong, Lancet 2000; cross-sectional study of young

adults, mean exposure 6 yrs cumulative dose-related decrease in BMD at hip and LS

• IMPORTANT CAVEATS:– Different Moiety, Formulation (TAA vs. FP)– Different Populations

Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002Thursday, 17 January 2002

ICS Systemic Effects: HPA AxisICS Systemic Effects: HPA Axis

• FLTA3025: Serum Cortisol AUC12 + PK (4 wks)– FP 250 g BID: 10% vs. placebo– FP 500 g BID: 21% vs. placebo

• SFCA3006, 3007: ACTH stimulation testing in a subset

• ISOLDE (FLTA78): AM Cortisol– FP 500 g BID X 36 months: 10-15% mean AM Cortisol

for FP vs. placebo at all time-points (p<0.01)– 20% FP had Cortisol “shift” from N to L (9% placebo)

• FLTA1003 (PK/PD study): Urinary Cortisol– Single dose, crossover, normals – FP 1000 g single dose: 35% - 59% vs. pre-dose

Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002Thursday, 17 January 2002

ICS Systemic Effects: OcularICS Systemic Effects: Ocular

• CAVEATS:– Epidemiologic studies not RCT– ICS in general, not FP specifically– All cataracts not just PSC

• Australian study (Cumming, NEJM 1997)– ICS users age 49 - 82 years– 2-fold in PSC, further with cumulative lifetime dose

• Canadian study: (Garbe, NEJM 1998)– ICS-users age 70 yrs with 3 years – 3-fold in cataract extraction, dose response

Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002Thursday, 17 January 2002

ConclusionsConclusions

• Efficacy has been closely studied, substantial data, open to clinical interpretation. If approval recommended, labeling issues remain but are not insurmountable

• Safety database for this population is limited in describing long-term risks. How to adequately label for the potential long-term effects, particularly with regard to bone?

Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002Thursday, 17 January 2002

Agency Concerns for Discussion by PADAC: Agency Concerns for Discussion by PADAC: EFFICACYEFFICACY

• Patient population– Representative of COPD population? Reversibility– Supportive of broad indication of “…long-term twice-

daily maintenance treatment of COPD (including chronic bronchitis and emphysema)”?

• Primary Endpoint: Change from baseline in FEV1

– Clinical relevance with regard to meaningful benefit to the patients?

– Adequately supported by secondary endpoints?• Not just spirometry• COPD exacerbation• HRQL

Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002Thursday, 17 January 2002

Agency Concerns for Discussion by PADAC: Agency Concerns for Discussion by PADAC: SAFETYSAFETY

• Fluticasone is systemically available (by PK) and impact on HPA axis can be measured after single dose in normals, 4 wks in COPD– Other systemic CS effects should be assumed

• Are data sufficient for labeling with regard to impact on:– Bone (BMD or fractures)?– Ocular structures (PSC/cataracts, IOP)?– HPA-axis? – Connective tissue, metabolic, or other systemic events?

Pulmonary and Allergy Drugs Advisory Committee Pulmonary and Allergy Drugs Advisory Committee Thursday, 17 January 2002Thursday, 17 January 2002

AcknowledgementsAcknowledgements• Don Collier• Tayo Fadiran• James Gebert• Lydia Gilbert-McClain• Ted Guo• Ladan Jafari• Claudia Karwoski• Charles Lee• Robert Meyer• Sandra Suarez • Kimberly Topper• Joyce Weaver