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FDA Advisory Committee for Pharmaceutical Science and Clinical Pharmacology Office of Generic Drugs

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ICS-Containing Inhaled Products in the US (MAT 5/08) ... Therefore, there is a need for achievable guidelines to be developed to allow ... – PowerPoint PPT presentation

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Title: FDA Advisory Committee for Pharmaceutical Science and Clinical Pharmacology Office of Generic Drugs


1
FDA Advisory Committee for Pharmaceutical Science
and Clinical PharmacologyOffice of Generic
DrugsFood and Drug Administration
  • Paul M Dorinsky, M.D.
  • VP, Global Respiratory Clinical Research
  • TEVA Pharmaceuticals

2
ICS-Containing Inhaled Products in the US (MAT
5/08)
  • Approximately 31 Million Prescriptions/Year
  • Approximately 7 Billion Annually
  • Therefore, there is a need for achievable
    guidelines to be developed to allow generic
    products to reach the US market

3
Presentation Outline
  • Background
  • Overview of Dose-Response Data for Inhaled
    Corticosteroids (ICS) in Asthma
  • Implications of shallow ICS dose response for
    evaluating ICS bioequivalence
  • Alternative proposal for demonstrating ICS
    bioequivalence

4
Background
Test ICS Dose A
Reference ICS Dose A
Test ICS Dose B
Reference ICS Dose B
  • Scientific rationale for Dose-Response as a
    method for establishing ICS Dose Equivalence
  • Internal Study Validity Assay Sensitivity
  • Establishment of Dose Relationship Between Test
    and Reference ICS

5
Overview of Dose-Response Data for Inhaled
Corticosteroids (ICS) in Asthma
  • Phase IIb dose response studies have generally
    been conducted by investigating different doses
    in distinct populations rather than evaluating
    the full range of doses in the same patient
    population
  • In general, even the lowest dose of an ICS has
    significant activity that is close to the maximum
    effect of the drug
  • MICE Study ACRN study by Szefler et al JACI
    2002
  • ICS Evaluated
  • BDP CFC (n15) at doses of 168, 672 and 1344 mcg
    per day
  • Fluticasone propionate CFC (n15) at doses of 88,
    352, and 704 mcg per day
  • Near maximal FEV1 and PC20 effects occurred at
    low to medium doses for both ICS
  • The high dose did not significantly increase
    efficacy for either ICS
  • Dose response extremely shallow

6
Dose Response Studies Where ICS Dose Response was
Minimal
7
Dose Response Studies Where ICS Dose Response was
Observed
8
Interim Summary
  • Although some studies did discriminate between
    ICS dose levels, no design has been shown to be
    reproducibly useful in demonstrating an ICS dose
    response
  • Regardless of the design or endpoint utilized,
    clinically relevant and statistically significant
    differences between ICS doses is generally minimal

9
Implications of shallow ICS dose response for
evaluating ICS bioequivalence Finney Assay
Change in FEV1
Change in FEV1
Log Dose of ICS
With a shallow dose response curve, the CI will
be wider as compared with a dose response curve
that is steep
10
Simulation Relating Total Sample Size and Slope
of Log Dose Response When Limits for 95
Confidence Interval of Relative Potency is 0.8 to
1.25
N 175
N 500
  • What type of dose response can be expected for
    an ICS?
  • . Based on the MICE study Szefler et al JACI
    2002 using methacholine response
  • Slope for BDP 0.18
  • Slope for FP 0.07

11
Alternative proposal for demonstrating ICS
bioequivalence Key Principles
  • Following In Vitro Characterization demonstrating
    bioequivalence of the Test and Reference ICS, The
    clinical Program will
  • Ensure Internal Study Validity Assay
    Sensitivity
  • Ensure the Relationship Between Test and
    Reference ICS is characterized
  • Ensure Adequate Assessment of Safety and
    Efficacy in Relevant Populations

12
Key Elements of the Clinical Program
  • For the development of generic 505(j) inhaled
    corticosteroid products, TEVA proposes
  • Clinical Pharmacology study
  • Randomized, two-way, crossover study in healthy
    volunteers or patients for each dose
  • Equivalence for AUC0-t, and Cmax, ( 90
    confidence interval between limits of 0.80 to
    1.25)
  • Clinical Efficacy Study Adults and Adolescents
  • Randomized, parallel group, 12-week study in
    asthma patients (one study per strength)
  • Placebo or active comparator for assay
    sensitivity
  • Pre-Dose FEV1 or other established efficacy
    measure as primary endpoint
  • Non-inferiority of the test product and the
    reference product and superiority to placebo
  • Safety assessed via adverse events and other
    safety measures as appropriate (e.g., clinical
    labs, ECGs, etc)
  • Clinical Safety Study - Pediatrics
  • Extrapolation of efficacy from adults to children
  • Safety study (and or PK study) evaluating the
    test and reference product to show comparable
    safety (and or systemic exposure) of the two
    products.
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