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TRAINING WORKSHOP ON PHARMACEUTICAL QUALITY, GOOD MANUFACTURING PRACTICE

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TRAINING WORKSHOP ON PHARMACEUTICAL QUALITY, GOOD MANUFACTURING PRACTICE & BIOEQUIVALENCE Introduction to the Discussion of Bioequivalence Study Design and Conduct – PowerPoint PPT presentation

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Title: TRAINING WORKSHOP ON PHARMACEUTICAL QUALITY, GOOD MANUFACTURING PRACTICE


1
TRAINING WORKSHOP ON PHARMACEUTICAL QUALITY, GOOD
MANUFACTURING PRACTICE BIOEQUIVALENCE
  • Introduction to the Discussion of Bioequivalence
    Study Design and Conduct
  • Presented by
  • John Gordon, Ph.D.
  • Consultant to WHO
  • e-mail john_gordon_at_hc-sc.gc.ca

2
BackgroundFirst Product to Market
  • Innovators Product
  • Quality
  • Safety and efficacy
  • Based on extensive clinical trials
  • Expensive
  • Time consuming

3
BackgroundOther products with same medicinal
ingredient
  • Subsequent-entry products
  • Generic products
  • Multisource products
  • How do these products gain marketing
    authorization?

4
Pharmaceutical equivalence
  • Same amount of the same active pharmaceutical
    ingredient
  • Salts, esters
  • Same dosage form
  • Comparable dosage forms
  • e.g., tablet vs. capsule
  • Same route of administration
  • Is pharmaceutical equivalence enough?

5
Sometimes pharmaceutical equivalence is enough
  • Aqueous solutions
  • Intravenous solutions
  • Intramuscular, subcutaneous
  • Oral solutions
  • Otic or ophthalmic solutions
  • Topical preparations
  • Solutions for nasal administration
  • Powders for reconstitution as solution
  • Gases

6
Sometimes it is not enough
  • Pharmaceutical equivalence by itself does not
    necessarily imply therapeutic equivalence
  • Therapeutic equivalence
  • Pharmaceutically equivalent
  • Same safety and efficacy profiles after
    administration of same dose

7
Pharmaceutical Equivalents
Test
Reference
  • Possible Differences
  • Drug particle size
  • Excipients
  • Manufacturing Equipment or Process
  • Site of manufacture

Could lead to differences in product performance
in vivo
8
Additional data is required
  • Oral immediate release products with systemic
    action
  • Generally required for solid oral dosage forms
  • Critical use
  • Narrow therapeutic range
  • Bioavailability problems associated with the
    active ingredient
  • Problematic polymorphism, excipient interaction,
    or sensitivity to manufacturing processes

9
Additional data is required
  • Oral modified release products with systemic
    action
  • Fixed dose combination products with systemic
    action
  • When at least one component requires study
  • Non-oral / non-parental products with systemic
    action
  • Non-solution products with non-systemic action

10
Marketing authorization of multisource products
  • Extensive clinical trials to demonstrate safety
    and efficacy
  • Interchangeability?
  • Demonstration of equivalence to reference
    (comparator) product
  • Interchangeability
  • Therapeutic equivalence

11
Marketing authorization through equivalence
  • Suitable methods for assessing equivalence
  • Comparative pharmacokinetic studies
  • Comparative pharmacodynamic studies
  • Comparative clinical trials
  • Comparative in vitro tests

12
Comparative Pharmacokinetic Studies
  • In vivo measurement of active ingredient
  • Some relationship between concentration and
    safety/efficacy
  • Product performance is the key
  • Comparative bioavailability

13
Bioavailability
  • The rate and extent to which a substance or its
    active moiety is delivered from a pharmaceutical
    form and becomes available in the general
    circulation.
  • Reference
  • intravenous administration 100 bioavailability

14
Important Pharmacokinetic Parameters
  • AUC area under the concentration-time curve ??
    measure of the extent of bioavailability
  • Cmax the observed maximum concentration of drug
    ? measure of both the rate of absorption and the
    extent of bioavailability
  • tmax the time after administration of drug at
    which Cmax is observed ? measure of the rate of
    absorption

15
Plasma concentration time profile
concentration
Cmax
AUC
time
Tmax
16
Bioequivalence
  • Two products are bioequivalent if
  • they are pharmaceutically equivalent
  • bioavailabilities (both rate and extent) after
    administration in the same molar dose are similar
    to such a degree that their effects can be
    expected to be essentially the same

17
Therapeutic Equivalence
  • Therapeutic equivalence
  • Pharmaceutically equivalent
  • Same safety and efficacy profiles after
    administration of same dose bioequivalent
  • Interchangeability

18
Comparative Pharmacodynamic Studies
  • Not recommended when
  • active ingredient is absorbed into the systemic
    circulation
  • pharmacokinetic study can be conducted
  • Local action / no systemic absorption

19
Comparative Clinical Studies
  • Pharmacokinetic profile not possible
  • Lack of suitable pharmacodynamic endpoint
  • Typically insensitive

20
Comparative in vitro Studies
  • May be suitable in lieu of in vivo studies under
    certain circumstances
  • Requirements for waiver to be discussed

21
When are bioequivalence studies employed?
  • Multisource product vs. Innovative product
  • Pre-approval changes
  • Bridging studies
  • Post-approval changes
  • Additional strengths of existing product

22
Bioequivalence StudiesBasic Design
Considerations
  • Minimize variability not attributable to
    formulations
  • Minimize bias
  • REMEMBER goal is to compare performance of the
    two products

23
Gold Standard Study Design
  • Single-dose, two-period, crossover
  • Healthy volunteers
  • Subjects receive each formulation once
  • Adequate washout

24
Multiple-dose Studies
  • More relevant clinically?
  • Less sensitive to formulation differences

25
Multiple-dose Studies may be employed when
  • Drug is too potent/toxic for administration in
    healthy volunteers
  • Patients / no interruption of therapy
  • Extended/modified release products
  • Accumulation using recommended dosing interval
  • In addition to single-dose studies

26
Multiple-dose Studies may be employed when
  • Non-linear pharmacokinetics at steady-state
    (e.g., saturable metabolism)
  • Assay not sufficiently sensitive for single-dose
    study

27
Crossover vs. Parallel Designs
  • Crossover design preferred
  • Intra-subject comparison
  • Lower variability
  • Generally fewer subjects required
  • Parallel design may be useful
  • Drug with very long half-life
  • Crossover design not practical

28
Parallel Design Considerations
  • Ensure adequate number of subjects
  • Adequate sample collection
  • Completion of Gastrointestinal transit /
    absorption process
  • 72 hours normally sufficient

29
Fasted vs. Fed Designs
  • Fasted study design preferred
  • Minimize variability not attributable to
    formulation
  • Better able to detect formulation differences

30
Fed Study Designs may be employed when
  • Significant gastrointestinal (GI) disturbance
    caused by fasted administration
  • Product labeling restricts administration to fed
    state

31
Fed Study Design Considerations
  • Fed conditions depend on local diet and customs
  • Dependent on reason for fed design
  • Avoiding GI disturbance
  • Minimal meal to minimize impact
  • Required due to drug substance / dosage form
  • Modified-release products

32
Fed Study Design Considerations cont.
  • Required due to drug substance / dosage form
  • Complicated pharmacokinetics
  • Known effect of food on drug substance
  • Fed conditions designed to promote maximal
    perturbation
  • High fat
  • High Calorie
  • Warm

33
Replicate vs. non-replicate designs
  • Standard approach
  • Non-replicated
  • Single administration of each product
  • Average bioequivalence

34
Replicate Designs
  • Typically four-period design
  • Each product administered twice
  • Intra-subject variability
  • Subject X formulation interaction
  • Different approaches possible
  • Average bioequivalence
  • Individual bioequivalence

35
Replicate Designs
  • Advantages
  • More information available
  • Different approaches to assessment possible
  • Disadvantages
  • Bigger commitment for volunteers
  • More administrations to healthy volunteers
  • More expensive to conduct

36
Discussion
  • Questions
  • Comments
  • Opinions
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