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

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The June 1999 Draft BA/BE Guidance for Nasal
Aerosols and Nasal SpraysHistory,
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

• 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

• History
• Guidance Recommendations for BE
• formulation and device
• in vitro studies
• in vivo studies
• Local Delivery BE Issues

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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

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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• Issuance of draft guidance, BA and BE Studies for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

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History (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

• 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

• FOR NDAs
• To-be-marketed product comparable to clinical
  trial product
• FOR ANDAS
• Generic product BE to innovator product
• FOR NDAs and ANDAs
• Certain postapproval changes

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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

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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)

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BE RECOMMENDATIONS Comparable In Vitro
Performance (a)

• Dose content uniformity through container life
• Droplet and particle size distribution

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BE RECOMMENDATIONS Comparable In Vitro
Performance (b)

• Spray pattern
• Plume geometry
• Priming and repriming
• Tailoff characteristics

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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

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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)

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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

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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

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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

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DOSE-RESPONSE
Reduced safety
Reduced efficacy
Adapted from JN Pritchard, ANZSRS Annual Meeting,
Brisbane, 16-19 Mar 2001
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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

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ACKNOWLEDGMENTS
FDA/CDER OINDP Technical Committee Helen
Winkle Ajaz Hussain, Ph.D. Roger Williams, M.D.
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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 Inhalatio
n 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
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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
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RELATIVE BIOAVAILABILITY "RESPONSE SCALE" vs
"DOSE SCALE (PHARMACODYNAMIC STUDIES)
GJPS 3/30/2000
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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