Presentation on theme: "Clinical bioequivalence. Specific example n A manufacturer wishes to change its approved production method for standardized fedweed pollen extract n CBER."— Presentation transcript:
Specific example n A manufacturer wishes to change its approved production method for standardized fedweed pollen extract n 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
“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.”
Manufacturer proposal n Based on the 1993 protocol, the manufacturer proposes to enlist 4 to 6 study subjects of varying levels of sensitivity to fedweed pollen n 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
Initial assumptions n Mean slope: 10 n Acceptable difference: 10% = 1 n SD slope: 1 n = 0.05 = 0.2 = 0.2
Conclusions n The failure to demonstrate a difference is not sufficient to demonstrate equivalence Given that, for the parallel line bioassay, , the number of study subjects required to demonstrate equivalence will usually exceed 4-6 Given that, for the parallel line bioassay, , the number of study subjects required to demonstrate equivalence will usually exceed 4-6
Advisory Committee discussion CBER requests that the Committee discuss CBER’s current approach to clinical bioequivalence studies as it applies to allergen extract studies.