The June 1999 Draft BA/BE Guidance for Nasal Aerosols and Nasal Sprays:
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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


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NASAL AEROSOLS (MDIs) AND NASAL SPRAYS* 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


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OUTLINE Nasal Sprays:

  • History

  • Guidance Recommendations for BE

    • formulation and device

    • in vitro studies

    • in vivo studies

  • Local Delivery BE Issues


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History Nasal Sprays:(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


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History Nasal Sprays:(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    • Issuance of draft guidance, BA and BE Studies for Nasal Aerosols and Nasal Sprays for Local Action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


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History Nasal Sprays:(c)

  • November 1999

    • OINDP Expert Panel organizational meeting

  • April 2000

    • OINDP Subcommittee of ACPS meeting

  • November 2000

    • OINDP Subcommittee report to ACPS


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METHODS FOR DOCUMENTATION OF BE* Nasal Sprays:

  • 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


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APPLICATION OF BE STUDIES Nasal Sprays:

  • 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


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BE RECOMMENDATIONS Nasal Sprays:Formulation 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


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BE RECOMMENDATIONS Nasal Sprays:The 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)


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BE RECOMMENDATIONS Nasal Sprays: Comparable In Vitro Performance (a)

  • Dose content uniformity through container life

  • Droplet and particle size distribution


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BE RECOMMENDATIONS: Nasal Sprays: Comparable In Vitro Performance (b)

  • Spray pattern

  • Plume geometry

  • Priming and repriming

  • Tailoff characteristics


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LOCAL DELIVERY Nasal Sprays:Clinical Endpoint in SAR Patients

  • Dose-response

    • To document sensitivity

  • Traditional treatment study

  • Day(s) in the park study

  • Environmental Exposure Unit (EEU) study


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SYSTEMIC EXPOSURE STUDY (PK) Nasal Sprays:

  • 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)


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SYSTEMIC ABSORPTION STUDY (PD) Nasal Sprays:

  • 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


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BE RECOMMENDATIONS Nasal Sprays:(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


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THE LOCAL DELIVERY ISSUES* Nasal Sprays:

  • 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


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Response Equivalence Nasal Sprays:

DOSE-RESPONSE

Reduced safety

Reducedefficacy

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


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PROPOSAL FOR BE STUDY Nasal Sprays:NASAL 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


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ACKNOWLEDGMENTS Nasal Sprays:

FDA/CDER OINDP Technical Committee

Helen Winkle

Ajaz Hussain, Ph.D.

Roger Williams, M.D.


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BCC and CMC CC Nasal Sprays:

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


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THE END Nasal Sprays:


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PROPOSED BE CRITERION FOR NONPROFILE DATA Nasal Sprays:

  • 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: Nasal Sprays:

In Vitro Population BE Criterion

and BE Limit


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RELATIVE BIOAVAILABILITY Nasal Sprays:

"RESPONSE SCALE" vs "DOSE SCALE”

(PHARMACODYNAMIC STUDIES)

GJPS 3/30/2000


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DATA ANALYSIS Nasal Sprays:

  • 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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