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Asthma Stability Model for Inhaled Corticosteroid Dose-Response. Wallace P. Adams, PhD OGD/OPS/CDER/US FDA Advisory Committee for Pharmaceutical Science and Clinical Pharmacology 23 July 2008. Outline of the Presentation. Methods to establish BE Challenges to ICS BE

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asthma stability model for inhaled corticosteroid dose response

Asthma Stability Model for Inhaled CorticosteroidDose-Response

Wallace P. Adams, PhD

OGD/OPS/CDER/US FDA

Advisory Committee for Pharmaceutical Science and Clinical Pharmacology

23 July 2008

outline of the presentation
Outline of the Presentation
  • Methods to establish BE
  • Challenges to ICS BE
  • Asthma stability model: Pilot study
    • crossover vs parallel design
    • estimates of sample size for a BE study
  • Asthma stability model: FDA research
  • Pharmacodyamic study data analysis
methods for establishment of be
Methods for Establishment of BE
  • In vivo studies in humans comparing drug or active metabolite in an accessible biologic fluid
  • In vivo studies in humans comparing a pharmacodynamic endpoint
  • Comparative clinical trials to demonstrate BE
  • Comparative in vitro studies

21 CFR 320.24(b)

dose response

Response Equivalence

DOSE-RESPONSE

Reduced safety

Reducedefficacy

Adapted from JN Pritchard, ANZSRS Annual Meeting, Brisbane, 16-19 Mar 2001

inhaled corticosteroids ics
Inhaled Corticosteroids (ICS)
  • Dose-response*
    • Differences from placebo for each active dose are statistically significant
    • A dose-response generally exists
      • shallow
    • Lack of statistical significance in response between adjacent doses
      • high variability of response
    • 4-fold or greater dose differences generally required to detect statistical significance
  • Carryover between treatment periods is a concern for crossover study designs
    • Unequal carryover can bias the estimate of difference between treatment means

*PJ Barnes et al, AJRCCM 1998;157:S1-53

slide6

Dose-Response (D-R):

CFC vs HFA Beclomethasone Dipropionate

  • Subjects
  • age >18 yrs with asthma
  • 50-75% of predicted
  • N=50-59 per treatment
  • Treatments
  • BDP for 6 weeks
  • Parallel group design
  • Up to 28 day ICS washout
  • with placebo MDI
  • 100, 400 or 800 mcg daily
  • (BID dosing), blinded to
  • dose

WW Busse et al, JACI 1999;104:1215-22

slide7

Dose-Response (D-R):

CFC-BDP and HFA-BDP

WW Busse et al, JACI 1999;104:1215-22

slide8

Relative Potency of CFC-BDP and HFA-BDP

(Finney Bioassay Method)

WW Busse et al, JACI 1999;104:1215-22, cited in JA Vanden Burgt et al, JACI 2000;106:1209-1226

asthma stability after oral prednisone model
Asthma Stability after Oral Prednisone Model
  • Pilot study in 12 adult asthmatics
  • Randomized two period crossover study
  • Oral prednisone (40 mg BID) wash-in, 4-7 days
  • Two doses of HFA-BDP; 100, 800 mcg/day
  • 21 day treatment period with ICS
  • Periodic measurement of pulmonary function
  • Repeat wash-in (4-7 day), crossover ICS (21 day)

RC Ahrens et al, AJRCCM, 2001;164:1138-45

sample size estimates based on the ahrens pilot study
Sample Size Estimates(based on the Ahrens Pilot Study)
  • Assume
    • 2 by 2 study design (2 doses of each preparation)
    • Finney bioassay
    • 90% confidence interval
    • BE interval on the dose scale is 50 - 200%
    • power = 80%
    • parallel or crossover study design
  • Sample size estimates
    • based on ‘s’ and ‘b’ at end of treatment period
    • ‘s’ is SD for responses from ANOVA
    • ‘b’ is dose-response slope
    • low s/b ratio increases study power

RC Ahrens et al, AJRCCM, 2001;164:1138-45

slide11

Mean Responses by Study Treatment Day

Mean AM FEV1 Response

s/b ratios

RC Ahrens et al, AJRCCM, 2001;164:1138-45

slide12

Study Design: Parallel vs Crossover

RC Ahrens et al, AJRCCM, 2001;164:1138-45

asthma stability model fda study objectives
Asthma Stability Model:FDA Study Objectives
  • Oral prednisone versus high dose ICS
    • Effect on maximum FEV1 value during high dose run-in of each crossover treatment
    • Effect on observed D-R
  • Characterize D-R based on three treatment levels
  • Study efficiency of screening process for identifying subjects demonstrating sufficient D-R (study enrichment)
  • Examine D-R of primary and secondary outcome variables
  • Characterize D-R using linear, nonlinear and Emax modeling
design and conduct of the fda study
Design and Conduct of the FDA Study
  • Subjects
    • Persistent asthma, non-smoking
    • Exhibit dose-response during run-in
  • Run-In Study Periods
    • 14 day high-dose ICS run-in (220 mcg x 4 actuations BID)
    • 28 day low-dose ICS run-in (44 mcg x 1 actuation BID)
  • Study Treatment Periods
    • high dose corticosteroid burst
      • oral prednisone on two periods, or
      • ICS
      • randomly assigned
    • 4 randomized crossover periods
      • double-blind, double-dummy
      • 28 days per period
      • 44 mcg (1 actuation) , 88 mcg (2 actuations), 88 mcg, and 352 (8 actuations) mcg BID
design and conduct of the study
Design and Conduct of the Study

7 day prednisone

or 14 day FP

7 day

14 day

28 day

28 day

High dose

run-in

Low dose

run-in

Pre-study

HDCB

FP treatment

44, 88, 88,

352 mcg BID

N = up to 120 (est.)

N = 30

N = 24

  • Home spirometry: AM FEV1 and PM FEV1 every day
  • Office spirometry at each clinical visit
  • eNO at each clinic visit
slide16

BE Criteria on the Dose Scale: Theory

W Gillespie, ACPS Meeting, 16 Aug 1996

slide17

Dose Scale Approach to Estimate Relative BA

Drug X (hypothetical example)

for RLD

2 (180 mcg) puffs of RLD

Dose of RLD that would result in a

RLD

RLD MDI Dose (mcg)

Revised from W Gillespie, ACPS Meeting, 16 Aug 1996

acknowledgments
Acknowledgments
  • Project Advisory Group
    • Badrul Chowdhury, MD, PhD, Division of Pulmonary and Allergy Products, OND
    • Sally Seymour, MD, DPAD
    • Robert Lionberger, PhD, OGD/OPS
    • Bing Li, PhD, OGD/OPS
    • Wallace Adams, PhD, OGD/OPS
  • Lawrence Yu, PhD, OGD/OPS