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The June 1999 Draft BA/BE Guidance for Nasal Aerosols and Nasal Sprays: History, Recommendations and Local Delivery Issues. Wallace P. Adams, Ph.D. OPS/CDER/FDA Orally Inhaled and Nasal Drug Products (OINDP) Subcommittee of Advisory Committee for Pharmaceutical Science Rockville, MD

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The June 1999 Draft BA/BE Guidance for Nasal Aerosols and Nasal Sprays:History, Recommendations and Local Delivery Issues

Wallace P. Adams, Ph.D.

OPS/CDER/FDA

Orally Inhaled and Nasal Drug Products (OINDP) Subcommittee of Advisory Committee for Pharmaceutical Science

Rockville, MD

17 July 2001

nasal aerosols mdis and nasal sprays

NASAL AEROSOLS (MDIs) AND NASAL SPRAYS*

Corticosteroids

Anticholinergics

Antihistamines

Cromones

*Draft FDA Guidance for Industry: BA and BE Studies for Nasal Aerosols and Nasal Sprays for Local Action, June 1999

outline
OUTLINE
  • History
  • Guidance Recommendations for BE
    • formulation and device
    • in vitro studies
    • in vivo studies
  • Local Delivery BE Issues
history a
History (a)
  • Patent or exclusivity expiration dates
    • Beconase AQ (Glaxo)- 27 July 1990
  • September 1993
    • GDAC with PADAC Representation meeting
    • BE of nasal solution formulations may be established with in vitro testing only
  • April 1995
    • CDER internal memo
      • For BE of generic aqueous suspension nasal sprays
        • Q1 and Q2 sameness
        • comparative in vitro data
        • multiple dose PK study
history b
History (b)
  • December 1996 letter to FDA
    • OGD requirements for BE of aqueous suspension nasal sprays do not require data on drug PSD, thus are inadequate to assure BE
    • Drug PSD affects rate and extent of dissolution and absorption from aqueous suspension nasal sprays to sites of action
  • May 1997
    • OINDP Technical Committee organized
  • June 1999
    • Issuance of draft guidance, BA and BE Studies for Nasal Aerosols and Nasal Sprays for Local Action
    • AAPS Workshop on Regulatory Issues Related to Drug Products for Oral Inhalation and Nasal Delivery
history c
History (c)
  • November 1999
    • OINDP Expert Panel organizational meeting
  • April 2000
    • OINDP Subcommittee of ACPS meeting
  • November 2000
    • OINDP Subcommittee report to ACPS
methods for documentation of be
METHODS FOR DOCUMENTATION 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 bioequivalence
  • Comparative in vitro studies
  • See 21 CFR 320.24 for details
application of be studies
APPLICATION OF BE STUDIES
  • FOR NDA’s
    • To-be-marketed product comparable to clinical trial product
  • FOR ANDA’S
    • Generic product BE to innovator product
  • FOR NDA’s and ANDA’s
    • Certain postapproval changes
be recommendations formulation equivalence
BE RECOMMENDATIONSFormulation Equivalence
  • Qualitative sameness (Q1)
    • identical active and inactive ingredients as in the RLD
  • Quantitative sameness (Q2)
    • inactive ingredients within ± 5% of the concentrations in the RLD
be recommendations the device
BE RECOMMENDATIONSThe Device
  • Assurance of equivalence:
    • is greatest when T uses the same brand and model (particularly the metering valve or pump and actuator) as used in R.
    • if not feasible, valve or pump, and actuator designs should be as close as possible in all critical dimensions (e.g., metering chamber volume, actuator orifice diameter)
be recommendations comparable in vitro performance a
BE RECOMMENDATIONS Comparable In Vitro Performance (a)
  • Dose content uniformity through container life
  • Droplet and particle size distribution
be recommendations comparable in vitro performance b
BE RECOMMENDATIONS: Comparable In Vitro Performance (b)
  • Spray pattern
  • Plume geometry
  • Priming and repriming
  • Tailoff characteristics
local delivery clinical endpoint in sar patients
LOCAL DELIVERYClinical Endpoint in SAR Patients
  • Dose-response
    • To document sensitivity
  • Traditional treatment study
  • Day(s) in the park study
  • Environmental Exposure Unit (EEU) study
systemic exposure study pk
SYSTEMIC EXPOSURE STUDY (PK)
  • Randomized, two-way crossover
  • Healthy (non-SAR) subjects
  • Single or multiple dose
  • Multiple actuations per dose to achieve measurable plasma concentrations, if necessary
    • minimize drug loss from fluid drainage
  • AUC and Cmax measures
  • Two one-sided tests procedure (ANOVA)
systemic absorption study pd
SYSTEMIC ABSORPTION STUDY (PD)
  • When PK study is not feasible -HPA axis suppression study for nasal corticosteroids
    • Healthy, nonallergic subjects
    • Randomized, placebo-controlled, parallel group study
    • Conduct at maximum labeled dose for 14 days
    • 24-hr urinary free cortisol or 24-hr serum cortisol, data baseline-adjusted
be recommendations overview
BE RECOMMENDATIONS(OVERVIEW)
  • Q1 and Q2 sameness
  • Device recommendations
  • Comparable in vitro performance
  • Comparable in vivo performance for local delivery
    • suspension formulation nasal sprays and nasal aerosols only
  • Comparable in vivo performance for systemic exposure or absorption
    • suspension formulation nasal sprays and nasal aerosols only
the local delivery issues
THE LOCAL DELIVERY ISSUES*
  • Clinical study may be crucial to establish BE for local delivery
  • Dose-response relationship
    • may not be possible to show
    • may not be consistently reproducible
  • Clinical study should document sensitivity
    • between different doses
    • doses may differ by two to fourfold
    • minimum dose not less than one spray per nostril daily
  • *Draft FDA Guidance for Industry: BA and BE Studies for Nasal Aerosols and Nasal Sprays for Local Action, June 1999
dose response

Response Equivalence

DOSE-RESPONSE

Reduced safety

Reducedefficacy

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

proposal for be study nasal suspension aerosols and sprays
PROPOSAL FOR BE STUDYNASAL SUSPENSION AEROSOLS AND SPRAYS
  • Formulation recommendations
  • Device recommendations
  • In vitro studies
  • In vivo studies
    • rhinitis study (lowest active dose)
    • PK study (high dose)
      • alternate: PD study
acknowledgments
ACKNOWLEDGMENTS

FDA/CDER OINDP Technical Committee

Helen Winkle

Ajaz Hussain, Ph.D.

Roger Williams, M.D.

slide21

BCC and CMC CC

Locally Acting Drug Products

Oral Inhalation and Nasal Drug Products

Wallace Adams (Chair)

Working Groups

Badrul Chowdhury Mary Fanning

Lydia Gilbert-McClain Robert Meyer

Gur Jai Pal Singh (Chair)

Wallace Adams Dale Conner

Stella Machado Robert Meyer

Donald Schuirmann Sandra Suarez

Eugene Sullivan

Wallace Adams (Chair)

James Allgire Charles Brownell

Dale Conner Moheb Nasr

Rabindra Patnaik Pradeep Sathe

Gur Jai Pal Singh Yi Tsong

Guirag Poochikian (Chair)

Craig Bertha Timothy McGovern

Robert Meyer Michael Smela

Donald Hare

Debra Birenbaum Tien-Mien (Albert) Chen

Young Moon Choi Dale Conner

Robert Meyer Gur Jai Pal Singh

Sandra Suarez

Comparative

Clinical

Pharmacodynamic

In Vitro

Bioavailability/

Bioequivalence

Inhalation Drug

Products*

Comparability of Inactive Ingredients

Comparative Systemic

Absorption (Safety) Study

* A CMC CC Working Group

23 April 2001

proposed be criterion for nonprofile data
PROPOSED BE CRITERION FOR NONPROFILE DATA
  • Evaluates
    • mean performance of T and R products
    • variability of R product
    • variability of T product
  • Based on
    • difference between T and R means
    • difference between T and R variances
    • scaling of BE boundaries to RLD variance
  • Uses one-sided 95% upper confidence bound
    • alpha = 0.05
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PROPOSED BE CRITERION FOR NONPROFILE DATA:

In Vitro Population BE Criterion

and BE Limit

slide25

RELATIVE BIOAVAILABILITY

"RESPONSE SCALE" vs "DOSE SCALE”

(PHARMACODYNAMIC STUDIES)

GJPS 3/30/2000

data analysis
DATA ANALYSIS
  • Clinical Study (Rhinitis)
    • Under discussion
      • Change from baseline data have continuous and noncontinuous (categorical) aspects
  • HPA Suppression Study (PD)
    • To be drafted
  • Systemic Exposure Study (PK)
    • Two one-sided tests procedure (ANOVA)

GJPS 3/30/2000

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