Clinical bioequivalenceClinical bioequivalence

Specific exampleSpecific example

A manufacturer wishes to change its A manufacturer wishes to change its approved production method for approved production method for standardized fedweed pollen extractstandardized fedweed pollen extract

CBER acknowledges that existing in vitro CBER acknowledges that existing in vitro potency tests will be applicable to the new potency tests will be applicable to the new preparation. However, CBER requests that preparation. However, CBER requests that the manufacturer demonstrate compositional the manufacturer demonstrate compositional similarity by parallel line bioassay similarity by parallel line bioassay

Clinical bioequivalenceClinical bioequivalence

Clinical bioequivalenceClinical bioequivalence

Clinical bioequivalenceClinical bioequivalence

““At least 4 subjects are required per assay. One or more At least 4 subjects are required per assay. One or more test extracts are to be compared against a reference test extracts are to be compared against a reference in each subject. in each subject.

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

Manufacturer proposalManufacturer proposal

Based on the 1993 protocol, the Based on the 1993 protocol, the manufacturer proposes to enlist 4 to 6 study manufacturer proposes to enlist 4 to 6 study subjects of varying levels of sensitivity to subjects of varying levels of sensitivity to fedweed pollenfedweed pollen

If the slopes of the two preparations are not If the slopes of the two preparations are not significantly different in these study subjects, significantly different in these study subjects, the manufacturer will conclude that the two the manufacturer will conclude that the two preparations are compositionally similarpreparations are compositionally similar

Initial assumptionsInitial assumptions

Mean slope: 10 Mean slope: 10 Acceptable difference: 10% = 1Acceptable difference: 10% = 1 SD slope: 1SD slope: 1 = 0.05= 0.05 = 0.2= 0.2

1

21

21

11z

nn

yy

1

21

21

11z

nn

yy

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

2

211

22

zzn

For = 0.05 and = 0.2:

2

2

22

37.12842.0645.12

n

n0.05 0.2 1 2 500.05 0.2 1 1 130.05 0.2 1 0.57 5

0.05 0.2 2 2 130.05 0.2 3.5 2 5

2

211

22

zzn

ConclusionsConclusions

The failure to demonstrate a difference The failure to demonstrate a difference is not sufficient to demonstrate is not sufficient to demonstrate equivalenceequivalence

Given that, for the parallel line bioassay, Given that, for the parallel line bioassay, , the number of study subjects , the number of study subjects required to demonstrate equivalence required to demonstrate equivalence will usually exceed 4-6will usually exceed 4-6

Advisory Committee discussionAdvisory Committee discussion

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