Clinical bioequivalence

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Clinical bioequivalence
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Specific example

• A manufacturer wishes to change its approved
  production method for standardized fedweed pollen
  extract
• CBER acknowledges that existing in vitro potency
  tests will be applicable to the new preparation.
  However, CBER requests that the manufacturer
  demonstrate compositional similarity by parallel
  line bioassay

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Clinical bioequivalence
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Clinical bioequivalence
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Clinical bioequivalence

• At least 4 subjects are required per assay. One
  or more test extracts are to be compared against
  a reference in each subject.
• For evaluating compositional differences,
  subjectsselectively sensitive to specific
  allergens in the crude mix should be
  selectedIn order to enhance detection of
  compositional differences, subjects can be
  selected who differ widely (10-10,000 fold) in
  their allergen skin test sensitivityto the test
  of reference extracts.

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Manufacturer proposal

• Based on the 1993 protocol, the manufacturer
  proposes to enlist 4 to 6 study subjects of
  varying levels of sensitivity to fedweed pollen
• If the slopes of the two preparations are not
  significantly different in these study subjects,
  the manufacturer will conclude that the two
  preparations are compositionally similar

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Initial assumptions

• Mean slope 10
• Acceptable difference 10 1
• SD slope 1
• ? 0.05
• b 0.2

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• To determine the number of subjects (n) required
  to detect a difference d with confidence a and
  power 1 - b with the two one-sided test approach,
  use the following

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• For a 0.05 and b 0.2

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Conclusions

• The failure to demonstrate a difference is not
  sufficient to demonstrate equivalence
• Given that, for the parallel line bioassay, s ?
  d, the number of study subjects required to
  demonstrate equivalence will usually exceed 4-6

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Advisory Committee discussion

• CBER requests that the Committee discuss CBERs
  current approach to clinical bioequivalence
  studies as it applies to allergen extract
  studies.