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Scientific Considerations for
FDA Draft Guidance on Dry Powder Inhalers of
Fluticasone Propionate and Salmeterol Xinafoate
Sau (Larry) Lee, Ph.D.
Office of Pharmaceutical Science
Office of Generic Drugs
Orlando Inhalation Conference:
Approaches in International Regulation
March 18, 2014
1
Disclaimer
This presentation reflects the views of the
author and should not be construed to
represent FDA’s views or policies
2
Acknowledgment
• OGD
–
–
–
–
–
–
Bhawana Saluja
Stephanie Kim
Bing Li
Dale Conner
Robert Lionberger
Kathleen Uhl
• OPS
– Lawrence Yu
• DPARP
–
–
–
–
Badrul Chowdhury
Lydia Gilbert McClain
Sally Seymour
Susan Limb
• ONDQA
– Prasad Peri
– Craig Bertha
• Gur Jai Pal Singh
• Wallace Adams
3
Outline
• Recent progress on FDA Guidance on
Bioequivalence of Locally Acting Inhalation
Products
• Regulatory considerations of generic DPIs
– Device and formulation
– In vitro and in vivo BE studies
• Future plan
4
Recent Progress on Bioequivalence of
Locally Acting Inhalation Products
• Complex dosage forms consisting of formulation and
device components
– Defining device similarity for generic inhalation devices
– Demonstrating equivalent local drug delivery in the lung
• The first individual product guidance for a MDI
– http://www.fda.gov/downloads/Drugs/GuidanceComplia
nceRegulatoryInformation/Guidances/UCM346985.pdf
• The first individual product guidance for a DPI
– http://www.fda.gov/downloads/Drugs/GuidanceComplia
nceRegulatoryInformation/Guidances/UCM367643.pdf
5
Draft BE Guidance on
Fluticasone Propionate; Salmeterol Xinafoate
6
Advair Diskus
• Three Strengths
– 100/50
– 250/50
– 500/50
• Treatment of asthma in patients aged 4 years
and older.
• Maintenance treatment of airflow obstruction
and reducing exacerbations in patients with
chronic obstructive pulmonary disease (COPD).
7
Regulatory Considerations for
Generic FP and SX DPIs
Comparative
Pharmacokinetic
Studies
Comparative
In Vitro Studies
Bioequivalence
Comparative
Clinical Endpoint Studies
Device and Formulation Design
8
In Vitro Considerations
• Emitted dose (ED) and aerodynamic particle size
distribution (APSD)
– Critical attributes that are believed to affect the total and
regional deposition of drugs in the lung
• ED and APSD dependent on and sensitive to productand process-related factors
– Physicochemical properties of API(s) and carrier (e.g., particle
size, shape and amorphous content)
– Device properties (e.g., internal geometry and electrostatic
charge)
– Process conditions (e.g., micronization, material conditioning,
and blending)
• Comparison of ED and APSD for all three strengths
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Emitted Dose
(% of the nominal labeled dose)
Effect of Flow Rate on
DPI Performance
A Palander et al. Clin Drug Invest 2000; 20:25-33
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In Vitro Considerations
• Equivalent ED and APSD at various flow rates
– Three different flow rates
– Labeled flow rate (e.g., 60 LPM), 50% of labeled flow rate
(e.g., 30 LPM), and 150% of labeled flow rate (e.g., 90 LPM)
– Expect to reasonably cover different inspiratory flow rates
generated by relevant patient populations
• Equivalent ED and APSD at various lifestages
– For ED, beginning, middle and end lifestages for each of
the three flow rates
– For APSD, beginning and end lifestages for each of the
three flow rates
– e.g., for 60 doses, beginning lifestage = 1st dose, middle
lifestage = 30th dose, and end lifestage = 60th dose
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Device Resistance = ∆P1/2/Flow Rate
∆P1/2 (kPa1/2)
5
5
4
4
3
3
2
2
Inhalator
Series2
Turbuhaler
Series1
1
1
Series3
Diskus
Series4
Rotahaler
0
00
25
25
50
50
75
75
100
100
Flow Rate (LPM)
125
125
150
150
Modified from AR Clark et al. J Aerosol Med 1993; 6:99-110
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In Vitro Considerations
• Comparable device resistance between the test
and reference device
– Patient compliance
• Ensures that the targeted patient population is able to
operate the test device effectively and receive proper
medication without any significant change in their
inspiratory effort
– Increase the likelihood of establishing equivalence of
ED and APSD
• Potential impact on the dependence of ED and APSD on flow
rate
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In Vivo Considerations:
Pharmacokinetics
OIDPs
GI Tract
Site of
Action (Lung)
Systemic
Circulation
The sampling site for PK studies (plasma) is a compartment
that is downstream of the site of action (the lung)
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Pharmacokinetic Studies
• PK BE Study design
– Single-dose studies in healthy subjects for all strengths
– Dose based on minimizing the number of inhalations but
justified by assay sensitivity
– PK measurements feasible, e.g., inhaled fluticasone propionate
(ICS) and salmeterol (LABA) (LLOQ = 1 pg/mL)
• Equivalence criteria
– 90% CI: 80% – 125% for AUC and Cmax
– Reference scaling if within-subject variability ≥ 30%
• No PK BE study waiver of low strengths
– The relationship among PK dose proportionality across
multiple strengths, in vitro performance (i.e., ED and
APSD) and product characteristics (e.g., formulation) not
well understood for DPI drug products
LI Harrison et al. J Aerosol Med Pul Drug Del 2011; 24:1-8
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In Vivo Considerations:
Pharmacodynamics
• It is a part of the weight-of-evidence approach to
support equivalent local drug delivery
• Historically, a dose-response PD BE study is generally
preferred over a BE study with a clinical endpoint
• The dose-response PD study for CFC-based Albuterol
MDI includes:
– Bronchodilatation model
– Bronchoprovocation model (methacholine challenge)
• Establishing dose-response for inhaled corticosteroids
(fluticasone propionate) has been very challenging
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Dose-Response Relationships
ICS dose response
Response Scale T/R: 0.80
Dose Scale:
0.80
Response Scale T/R: 0.80
Dose Scale:
0.67
Response Scale T/R: 0.80
Dose Scale:
0.26
ED50 = Dose required to produce 50% the fitted maximum PD response
Singh et al. RDD 2005:115-126
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Proposed PD Model for
Dose Response of ICS
• Exhaled Nitric Oxide (eNO) Model
– Relevant marker of airway inflammation
– Not influenced by bronchodilators, therefore suitable for the
inhalation products containing ICS (e.g., Advair Diskus)
– Rapid onset and offset of ICS effect on eNO, therefore suitable
for a crossover study design
• Contracts
– eNO study at National Jewish Health, Denver, CO
– Fluticasone propionate
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NJH Pilot eNO Study for FP
• Phase I
–
14-day run-in period, followed by a 14-day treatment period (88 mcg BID) and a 14-day
washout period
• Phase II
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Multiple-dose, 4-way crossover
Flovent® HFA MDI, 44 mcg
Fluticasone propionate 44 mcg (1 inhalation), 88 mcg (2 inhalations; repeated), and 352
mcg (8 inhalations) BID
14 day treatment period and 14 day washout period
6 eNO measurements per treatment (generally Monday, Wednesday and Friday)
• Patients
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–
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Mild-to-moderate asthmatics
Exhaled NO ≥ 45 ppb
Return to baseline eNO (within one-half of the observed maximum percentage drop from
baseline to nadir due to each prior treatment period) on two consecutive visits during the
14-day washout period of Phase I
• 9 subjects completed the study
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eNO Data for BID Dosing of
Flovent HFA, 44 mcg
Dose
(mcg/day)
eNO
(ppb)
0
69.79
88
40.11
176
34.60
176
31.20
704
31.66
No evident dose-response relationship was observed
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Individual eNO Data for
BID Dosing of Flovent HFA, 44 mcg
88 mcg/day
704 mcg/day
Subject
ID
Dose (mcg/day)
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In Vivo Considerations:
Clinical Endpoints
• 100 mcg per day of FP is already near or on the
plateau region of the dose-response curve
– BID dosing of Flovent Diskus (50 mcg) and Flovent HFA
(44 mcg)
– QD dosing of Advair Diskus (100 mcg), not the FDAapproved lowest daily dose (100 mcg BID)
– Not suitable for the dose-scale analysis
• Similarly, no dose-response is observed for 50 mcg
of SX
• A clinical endpoint BE study is therefore
recommended in the current FDA draft guidance
for FP and SX
22
In Vivo Considerations:
Clinical Endpoints
• Clinical Endpoint BE Study design
– A randomized, multiple-dose, placebo-controlled,
parallel group design consisting of a 2 week run-in
period followed by a 4-week treatment period of the
placebo, T or R product
– Lowest strength only
• 100/50 (fluticasone propionate 100 mcg and
salmeterol 50 mcg powder for inhalation)
– 100/50, twice daily
– Males and non-pregnant females with asthma
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In Vivo Considerations:
Clinical Endpoints
• BE study endpoints
– Area under the serial FEV1-time curve calculated
from time zero to 12 hours (AUC0-12h) on the first
day of the treatment
– FEV1 measured in the morning prior to the dosing of
inhaled medications on the last day of a 4-week
treatment.
• Equivalence criteria
– The 90% CIs for the T/R ratios for the primary
endpoints within the limits of 80.00-125.00%
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Device Considerations
• The test FP and SX DPI should have the
following characteristics
–
–
–
–
Passive (breath-actuated) device
Pre-metered multi-dose format
60 doses
External operating procedures consisting of: (1) Open,
(2) Click, (3) Inhale, and (4) Close
– Similar size and shape to the R product
– Comparable device resistance to the R product
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Formulation Considerations
• Qualitative (Q1) consideration
– Same inactive ingredient(s)
• Critical to establishing equivalence between the test and
reference DPI products
• Lactose
• Quantitative (Q2) consideration
– Same inactive ingredient(s) but may differ in concentration
• Cannot exceed the levels used in other FDA approved products
administered by the same route of administration (i.e.,
inhalation)
• Effect of Q2 difference on bioequivalence assessed by in vitro
and in vivo BE studies
• Submit pharmaceutical development data to support the selected
test formulation
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Ongoing FDA Research Projects
• PK based approach
– Relationships between PK and local drug delivery in
the lung are still not understood
– University of Florida, Gainesville, FL (expected to be
completed in Sept 2014)
• Modeling and simulations
– Investigation of lung deposition for locally acting
inhaled drugs by computational fluid dynamics
– Virginia Commonwealth University, Richmond, VA
(expected to be completed in Sept. 2014)
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New Research
• Development of in vivo predictive dissolution
method for orally inhaled drug products
• Systematic evaluation of excipient effects on the
efficacy of metered dose inhaler products
• Investigate the sensitivity of pharmacokinetics in
detecting differences in physicochemical
properties of the active in suspension nasal
products for local action
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Conclusions
• Individual drug product BE guidances
• Scientific publications of OGD research projects in
inhalation areas
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