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Assessment of Clinical Bioequivalence for Fedweed Pollen Extract: A Manufacturer's Proposal

This document outlines a manufacturer's request to change the approved production method for a standardized fedweed pollen extract. While CBER acknowledges the applicability of existing in vitro potency tests to the new formulation, they require additional demonstration of compositional similarity through a parallel line bioassay. The proposal suggests enlisting 4 to 6 subjects with varying sensitivity levels to fedweed pollen to ascertain if the preparations are compositionally similar based on slope differences in assay results. CBER emphasizes the need for robust subject numbers to prove equivalence.

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Assessment of Clinical Bioequivalence for Fedweed Pollen Extract: A Manufacturer's Proposal

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  1. Clinical bioequivalence

  2. 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

  3. Clinical bioequivalence

  4. Clinical bioequivalence

  5. 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, subjects…selectively sensitive to specific allergens in the crude mix should be selected…[I]n order to enhance detection of compositional differences, subjects can be selected who differ widely (10-10,000 fold) in their allergen skin test sensitivity…to the test of reference extracts.”

  6. 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

  7. Initial assumptions • Mean slope: 10 • Acceptable difference: 10% = 1 • SD slope: 1 •  = 0.05 • b = 0.2

  8. 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:

  9. For a = 0.05 and b = 0.2:

  10. 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

  11. Advisory Committee discussion CBER requests that the Committee discuss CBER’s current approach to clinical bioequivalence studies as it applies to allergen extract studies.

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