Title: The June 1999 Draft BA/BE Guidance for Nasal Aerosols and Nasal Sprays: History, Recommendations and Local Delivery Issues
1The 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
2NASAL 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
3OUTLINE
- History
- Guidance Recommendations for BE
- formulation and device
- in vitro studies
- in vivo studies
- Local Delivery BE Issues
4History (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
5History (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- Issuance of draft guidance, BA and BE Studies for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
6History (c)
- November 1999
- OINDP Expert Panel organizational meeting
- April 2000
- OINDP Subcommittee of ACPS meeting
- November 2000
- OINDP Subcommittee report to ACPS
7METHODS 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
8APPLICATION 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
9BE 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
10BE 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)
11BE RECOMMENDATIONS Comparable In Vitro
Performance (a)
- Dose content uniformity through container life
- Droplet and particle size distribution
12BE RECOMMENDATIONS Comparable In Vitro
Performance (b)
- Spray pattern
- Plume geometry
- Priming and repriming
- Tailoff characteristics
13LOCAL DELIVERYClinical Endpoint in SAR Patients
- Dose-response
- To document sensitivity
- Traditional treatment study
- Day(s) in the park study
- Environmental Exposure Unit (EEU) study
14SYSTEMIC 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)
15SYSTEMIC 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
16BE 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
17THE 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
18DOSE-RESPONSE
Reduced safety
Reduced efficacy
Adapted from JN Pritchard, ANZSRS Annual Meeting,
Brisbane, 16-19 Mar 2001
19PROPOSAL 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
20ACKNOWLEDGMENTS
FDA/CDER OINDP Technical Committee Helen
Winkle Ajaz Hussain, Ph.D. Roger Williams, M.D.
21BCC 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
22THE END
23PROPOSED 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
24PROPOSED BE CRITERION FOR NONPROFILE DATA In
Vitro Population BE Criterion and BE Limit
25RELATIVE BIOAVAILABILITY "RESPONSE SCALE" vs
"DOSE SCALE (PHARMACODYNAMIC STUDIES)
GJPS 3/30/2000
26DATA 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