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FDA Nasal BA/BE Guidance Overview. AAPS Workshop on Regulatory Issues Related to Drug Products for Oral Inhalation and Nasal Delivery Washington, DC 4 June 1999 Wallace P. Adams, Ph.D. Office of Pharmaceutical Science CDER/FDA

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fda nasal ba be guidance overview

FDA Nasal BA/BEGuidance Overview

AAPS Workshop on Regulatory Issues Related to Drug Products for Oral Inhalation and Nasal Delivery

Washington, DC

4 June 1999

Wallace P. Adams, Ph.D.

Office of Pharmaceutical Science

CDER/FDA

These slides represent the personal opinions of the speaker and do not necessarily represent the views or policies of US FDA.

draft guidance coverage
Draft Guidance Coverage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
  • Covers locally acting drug products only
approaches to measure ba and establish be
Approaches to Measure BA and Establish BE
  • Pharmacokinetic
  • Pharmacodynamic
  • Clinical
  • In vitro
locally acting drug products ladp

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
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
general ba and be approach
General BA and BE Approach
  • Formulation equivalence (BE):
    • Q1 (excipients qualitatively the same)
    • Q2 (excipients quantitatively the same)
  • Functional comparability of devices (BE)
  • Solutions
    • In vitro BA and BE
  • Suspensions
    • In vitro BA and BE
    • In vivo studies (two)
in vitro ba and be data
In Vitro BA and BE Data
  • Apply to all aerosols and sprays
  • Considered to be more sensitive indicators of differences in drug delivery to nasal sites than are clinical data
  • 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
In Vitro BA and BE Data:Specific Tests
  • 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 vivo ba and be data
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 vivo data requested for suspension formulations only
clinical study for local delivery
Clinical Study for Local Delivery
  • BA (NDA):
    • may use the same studies used to establish safety (S) and efficacy (E) of the drug product
  • BE (NDA):
    • may use the same comparative studies used to establish S and E of the drug product
  • BE (ANDA):
    • Three suggested clinical BE study designs
  • Sensitivity based on dose-response
systemic exposure or systemic absorption
Systemic ExposureorSystemic Absorption
  • Preferred study:
    • PK study in healthy subjects
  • Alternative when PK not feasible:
    • PD or clinical study in healthy subjects
importance of in vitro data for establishing be
Importance of In Vitro Datafor Establishing BE
  • BE studies with PD or clinical endpoints will not be sufficient in the event of in vitro BE studies that fail to meet the criteria
  • Clinical studies are highly variable and relatively insensitive to product differences
number and type of batches draft recommendation
Number and Type of Batches (Draft Recommendation)
  • BA (in vitro studies):
    • 30 (min); 10 cans or bottles from each of three batches
      • pivotal clinical trial (PCT) batch
      • primary stability batch
      • production scale batch (if feasible)
  • BE (in vitro studies):
    • 30 (min) for TEST; 10 x three batches
      • three different primary stability batches
    • 30 (min) for REFERENCE; 10 x three batches
      • three different batches from the marketplace
batches for clinical study for local delivery draft recommendation
Batches for Clinical Study for Local Delivery(Draft Recommendation)
  • NDA
    • Same pivotal clinical trial (PCT) batch used for in vitro BA studies
    • Same PCT batches used for in vitro BE studies
  • ANDA
      • Test and RLD batches used in the in vitro BE studies
batches for systemic exposure or systemic absorption study draft recommendation
Batches for Systemic Exposure or Systemic Absorption Study(Draft Recommendation)
  • NDA
    • A PCT batch, with in vitro BA data (preferable)
    • A batch similar to one used in a PCT, with in vitro BA data (alternative)
  • ANDA
    • Test and RLD batches used in the clinical study for local delivery, with in vitro BE data
draft nasal ba be guidance continuing work includes
Draft Nasal BA/BE Guidance:Continuing Work Includes -
  • Multiple batch data: statistical approaches
  • Establishing BE limits for comparative in vitro data
  • Interest in reduction in in vitro testing for certain measures
    • Objective vs subjective evaluation
    • Three batch data for statistical evaluation
    • Consideration of one batch test and RLD data for supportive characterization without statistical consideration
  • Response to public comments sent to docket
slide17

Decision Tree For Product Quality

BA and BE Studies For Nasal Aerosols and Nasal Sprays

NO

Is the formulation

a suspension?

In vitro studies only for solution formulations*

YES

Clinical study for local delivery

Clinical study for systemic absorption

In vitro studies

Is a PK study

feasible?

NO

YES

Clinical study for local delivery

PK study for systemic exposure

In vitro studies

*See Section II (A) regarding additional in vivo BA studies needed for solution and suspension formulations.

oral inhalation ba be guidance for ladp draft table of contents
Oral Inhalation BA/BE Guidancefor LADP: Draft Table of Contents
  • Introduction
  • Formulation and Device (MDIs and DPIs)
  • Documentation of BA and BE
    • Study design considerations
    • PD data: Increased emphasis for BE
    • Clinical data
    • In vitro data
      • DPIs and suspension formulation MDIs
      • Solution formulation MDIs (possible BE documentation with in vitro testing only with supporting pharmaceutic equivalence)
    • Systemic exposure: PK preferred
  • Statistical analyses
  • Multiple strengths
acknowledgments
Acknowledgments
  • Office of Pharmaceutical Science
  • Office of Generic Drugs
  • Office of Clinical Pharmacology and Biopharmaceutics
  • Division of Pulmonary Drug Products
  • Division of Testing and Applied Analytical Development
  • Division of Product Quality Research
  • Quantitative Methods and Research Staff
  • Thomas Jefferson University/Biostatistics Section