FDA

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FDAs Critical Path to Medical Product
DevelopmentOpportunities for Generic Drugs

• Lawrence X. Yu, Ph. D.
• Director for Science
• Office of Generic Drugs
• Food and Drug Administration

Advisory Committee for Pharm. Science October 19,
2004
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The Critical Path for Medical Product Development

• Ensuring Safety
• Demonstrating Medical Utility
• Industrialization Process

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President Bush on Health Care There are other
ways to make sure drugs are cheaper. One is to
speed up generic drugs to the marketplace,
quicker. October 8
Presidential Debate
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FDAs Critical Path Initiative

• Janet Woodcock, M.D. (June 4, 2004)
• A serious attempt to bring attention and focus to
  the need for targeted scientific efforts to
  modernize the techniques and methods used to
  evaluate the safety, efficacy and quality of
  medical products as they move from product
  selection and design to mass manufacture.

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Definition of a Generic Drug
A drug product that is therapeutically equivalent
to a brand-name drug Comparable to a brand-name
drug product in dosage form, strength, route of
administration, quality and performance
characteristics, and intended use.

• FDAs Critical Path
• Ensuring Safety
• Demonstrating Medical Utility
• Industrialization Process

Bioavailability/ Bioequivalence
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FDAs Critical Path - OGD

• Bioavailability/Bioequivalence Modeling and
  Prediction
• Bioequivalence of Locally Acting Drugs
• Product Design, Characterization, and in vitro
  Performance Testing

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e-ADME Predicting Bioavailability and
Bioequivalence
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Biopharmaceutics Classification System
Guidance for Industry Waiver of In Vivo
Bioavailability and Bioequivalence Studies for
Immediate Release Solid Oral Dosage Forms Based
on a Biopharmaceutics Classification System US
Department of Health and Human Services Food and
Drug Administration Center for Drug Evaluation
and Research (CDER) August 2000

• Waiver for BCS Class III drugs
• Excipient effect
• Transporters
• BCS Class boundaries
• Solubility
• Permeability

Molecular Pharm. 1356-362 (2004) J. Pharm. Sci.
931375-81(2004) Eur. J. Pharm. Sci.
22297-304(2004)
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Compartmental Absorption and Transit (CAT) Model

• An in silico mechanistic model describes
• How a drug gets into the blood
• How much it gets into the blood
• How fast it gets into the blood
• Research at OGD continues to identify critical
  bioavailability/ bioequivalecne factors

Int. J. Pharm. 270221-227 (2004) Molecular
Pharm. In press
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Quantitative Structure Bioavailability
Relationship (QSBR) Model
QSBR Model
Rat
Dog
Pharm. Res. 17639-644 (2000)
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Predicting Bioavailability/ Bioequivalence

• Biopharmaceutics Classification System
• Classification refinement and waiver extension
• Compartmental Absorption and Transit Model
• Understand critical absorption factors
• QSBR Model
• Very promising not widely used (due to )

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Bioequivalence Methods for Locally Acting Drugs

• Key Scientific Challenges
• Topical Dermatological
• Nasal Spray and Inhalation
• Gastrointestinal, vaginal, and ophthalmic
• Often require clinical testing
• Target research to provide a scientific basis for
  in vitro or in vivo bioequivalence methods

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Locally Acting Drugs
Site of Action
Dose
Effect
Plasma concentration is usually not relevant
to local delivery bioequivalence
Plasma
Concentration

• 21 CFR 320.24 allows alternatives
• in vivo pharmacodynamics
• in vivo clinical comparisons
• in vitro comparisons
• other appropriate approaches

Need for OGD Research Program
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Clinical Bioequivalence Studies

• Test, reference, placebo arms in patients
• 90 confidence interval on test reference cure
  rate
• Estimated CVs 100

N Cure Test Cure Ref 90CI
728 50 48 -12,16
453 46 40 -8,20
447 29 27 -9,13
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Bioequivalence of Locally Acting Drugs

• Barrier to generic competition
• Barrier to product improvement
• Need to demonstrate BE after formulation change
  or in product development
• Clinical endpoints have high variability
• Inefficient detection of formulation differences
• Unnecessary human testing

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Product Design and Characterization

• Same drug substance
• Pharmaceutical solid polymorphism
• Same dosage form
• Topical products
• Product quality
• Quality standards
• Adhesion tests for transdermal products
• Nasal and inhalation products
• Novel drug delivery systems

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Product Performance Testing
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Product Performance Testing

• Role of Dissolution Testing
• A quality control tool
• Monitor batch-to-batch consistency of the drug
  release from a product
• An in vivo performance test
• An in vitro surrogate for product performance
  that can guide formulation development and
  ascertain the need for bioequivalence tests

Are these goals consistent?
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Process Identification, Simulation, and
Optimization Tools

• Historically, pharmaceutical production involves
  the manufacture of the finished product using
  batch processes, followed by excessive laboratory
  testing and analysis to verify its quality
• Process identification, simulation, and
  optimization tools need to be developed for
  pharmaceutical batch processes so that any
  manufacturing process failure can be readily
  identified and corrected
• Product quality is assured by high quality of
  starting materials, robust manufacturing
  processes, and limited laboratory testing and
  analysis

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Future Directions

• Continue to build world class scientific
  expertise in predicting bioavailability/
  bioequivalence and process optimization
• Prioritize scientific efforts
• Pursue collaborations
• Within FDA (OTR, CBER, CDRH)
• With academia (U of Michigan, U of Kentucky, Ohio
  State U, U of Maryland, and CSM)
• With NIST and other government agencies
• With industry

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