# Presentation: 726816

## ORALLY INHALED AND NASAL DRUG PRODUCTS FOR LOCAL ACTIONCurrent FDA BA/BE Background and Issues

**Wallace P. Adams, Ph.D.**
**OPS/CDER/FDA**
**OINDP Subcommittee of the**
**Advisory Committee for Pharmaceutical Science**
**Rockville, MD**
**26 April 2000**
***This presentation represents the personal opinions of the speaker***
*** ******and does not necessarily represent the views or policies of US FDA***

## ORALLY INHALED AND NASAL DRUG PRODUCTS FOR LOCAL ACTIONCurrent FDA BA/BE Background and Issues

**Wallace P. Adams, Ph.D.**
**OPS/CDER/FDA**
**Orally Inhaled and Nasal Drug Products Subcommittee of the Advisory Committee for Pharmaceutical Science ****	**
***This presentation represents the personal opinions of the speaker***
*** ******and does not necessarily represent the views or policies of US FDA***

## Two Product Quality Guidances  

*BA and BE Studies for Nasal Aerosols and Nasal Sprays for Local Action*
- draft issued June 1999
*BA and Be Studies for Orally Inhaled MDIs, DPIs and Inhalation Solutions for Local Action*
- in preparation

## Draft Guidances Coverage

- Bioavailability (BA) Measurement
- May be noncomparative
- Characterization (benchmark) studies
- PRODUCT QUALITY BA ONLY
- Additional PK/Bio studies are not covered
- Bioequivalence (BE) Establishment
- Comparative studies
- Cover locally acting drug products only

## Approaches to Measure BA and Establish BE

- Pharmacokinetic
- Pharmacodynamic
- Clinical
- In vitro

## Locally Acting Drug Products (LADP)

**The BA and BE Challenge:**
- Delivery to sites of action does not occur primarily after systemic absorption, hence
- Pharmacokinetic studies are inadequate to fully document BA and BE

## BA and BE Concepts for LADP

- Local delivery
- relates to efficacy
- Systemic exposure
- relates to safety
- may also relate to efficacy
- e.g., levocabastine nasal spray

## Formulation and Container/Closure System

- Formulation equivalence (BE):
- Q1 (excipients qualitatively the same)
- Q2 (excipients quantitatively the same)
- Functional comparability of devices (BE)

## In Vitro BA and BE Data

- Apply to all MDIs, DPIs, and nasal sprays
- Confidence intervals for comparative data of selected in vitro BE measures
- Statistics under development for the selected in vitro BE measures

## In Vitro BA and BE Data:Specific Tests for MDIs and Nasal Sprays

- Dose or spray content uniformity through container life
- Droplet size distribution
- Drug particle size distribution
- Spray pattern and plume geometry
- Priming and repriming
- Tail off

## In Vitro BE:Statistical Comparisons under Development

- Profile comparisons
- For cascade impactor data
- Based on chi-square differences, or
- Other possible statistics
- Nonprofile comparisons
- For dose content uniformity through container life and other in vitro tests
- Based on population BE criterion

## Proposed BE Criterion For CU

- Evaluate
- mean performance of T and R products
- variability of R product
- variability of T product
- Criterion based on
- difference between T and R means
- difference between T and R variances
- scaling of BE boundaries to RLD variance
- One-sided 95% upper confidence bound,

-  = 0.05

## Proposed BE Criterion for CU:

**In Vitro Population BE Criterion**
**and BE Limit**

## In Vivo BA and BE Data

- LOCAL DELIVERY based on clinical study
- SYSTEMIC EXPOSURE based on PK study, or
- SYSTEMIC ABSORPTION based on PD or clinical study
- In vitro data only requested for nasal solution formulations

## Clinical End Point Studies
Traditional Treatment Study:
Single-blind placebo lead-in period (1-14 days), two-week treatment duration, symptom assessment twice daily and at the end of dosing interval, safety measurements (lab tests)
Day(s) in the Park Study:
Baseline establishment, park exposure for specified periods over 1-2 days.  Nasal symptoms assessment to characterize the onset of drug action and end-of-dosing interval efficacy.  Safety assessment (adverse events reporting)
EEU study:
Controlled indoor environment, Screening by repeated pretreatment exposure, EEU exposure to establish baseline, EEU exposure for specified periods over 1-2 days, Nasal symptoms assessment to characterize the onset of drug action and end-of-dosing interval efficacy.  Safety assessment (adverse events reporting)

_**Traditional Treatment Study**_:
- Single-blind placebo lead-in period (1-14 days), two-week treatment duration, symptom assessment twice daily and at the end of dosing interval, safety measurements (lab tests)
_**Day(s) in the Park Study**_:
- Baseline establishment, park exposure for specified periods over 1-2 days.  Nasal symptoms assessment to characterize the onset of drug action and end-of-dosing interval efficacy.  Safety assessment (adverse events reporting)
_**EEU study**_:
- Controlled indoor environment, Screening by repeated pretreatment exposure, EEU exposure to establish baseline, EEU exposure for specified periods over 1-2 days, Nasal symptoms assessment to characterize the onset of drug action and end-of-dosing interval efficacy.  Safety assessment (adverse events reporting)

**BE Studies for Nasal Sprays**

- GJPS  3/30/2000

## Equivalent Systemic Exposure
Study Design:  Randomized, two-way 				crossover
Subjects:  Generally healthy volunteers
BE Metrics
PK (preferred):  	   	 AUC and Cmax
PD (if PK not feasible):  Varies with the drug

- Study Design:  Randomized, two-way 				crossover
- Subjects:  Generally healthy volunteers
- BE Metrics
- PK (preferred):  	   	 AUC and Cmax
- PD (if PK not feasible):  Varies with the drug

**BE Studies for Nasal Sprays**

- GJPS  3/30/2000

## PD Endpoints 
Based on the ability of albuterol to dilate airways
Forced expiratory volume in one second (FEV1)
Based on the ability of albuterol to protect airways from bronchospasm induced by challenge agents
Provocative dose or concentration of the agent  required to reduce a given FEV1 value by 20% (PD20 or PC20)

- Based on the ability of albuterol to dilate airways
- Forced expiratory volume in one second (FEV1)
- Based on the ability of albuterol to protect airways from bronchospasm induced by challenge agents
- Provocative dose or concentration of the agent  required to reduce a given FEV1 value by 20% (PD20 or PC20)

**PD BE Studies for Inhalation Aerosols (Albuterol MDI)**

- GJPS  3/30/2000

## Study Design
 Randomized, crossover studies
Treatments
Minimum
T1 T2,  R1 R2 
Preferred
T1 T2 T3,  R1 R2 R3

-  Randomized, crossover studies
**Treatments**
- Minimum
- T1 T2,  R1 R2
- Preferred
- T1 T2 T3,  R1 R2 R3

**PD-BE Studies for Inhalation Aerosols (Albuterol MDI)**

*T = test product, R = reference product*
*1, 2 & 3 = Number of actuation doses*

- GJPS  3/30/2000

## BE Studies for Inhalation Aerosols

**Equivalent Systemic Exposure or Systemic Absorption**
- Study Design:	Randomized, two-way 				crossover
- Subjects:	Generally healthy volunteers
- BE Metrics
- PK (preferred):  	    	  AUC and Cmax
- PD (if PK not feasible):   Varies with the drug

- GJPS  3/30/2000

## Data Analysis

**Clinical BE Studies**
- Study design dependent
- Analyses suitable for noncontinuous (categorical) data
**PD BE Studies**
- “Dose Scale” analysis
**Systemic Exposure Studies (PK)**
- Two one-sided tests procedure (ANOVA)

- GJPS  3/30/2000