Transcript BioINequivalence: Concept and Definition Lawrence X. Yu, Ph. D. Director for Science

BioINequivalence:
Concept and Definition
Lawrence X. Yu, Ph. D.
Director for Science
Office of Generic Drugs, OPS, CDER, FDA
ACPS Meeting, October 19-20, 2004
ln Concentration
Bioavailability: Rate and Extent of
Drug Absorption
Cmax
7100
Concentration
6100
5100
4100
AUC
3100
2100
Tmax - time of maximum concentration
Time
1100
100
0
2
5
10
15
Time
20
25

Bioequivalence
“the absence of a significant difference in the rate
and extent to which the active ingredient or
active moiety in pharmaceutical equivalents or
pharmaceutical alternatives becomes available
at the site of drug action when administrated at
the same molar dose under similar conditions in
an appropriately designed study…” (21 CFR
§320.1)
3
Bioequivalence

90% confidence interval for AUC and Cmax
between 80-125%

Passing (among others) allows market access
 Generic:
ANDA approval
 Innovator:
Demonstrates to be marketed formulation
is equivalent to clinical formulation
4
Why define BioINequivalence?

FDA receives studies that attempt to reverse a
previous finding of bioequivalence.
 Need

5
standard to evaluate the claim
Published claims of BioINequivalence
What Should Bioinequivalence Mean?

Bioequivalence leads to market access
A
study that demonstrates bioequivalence is clear and
convincing evidence of equivalence

Bioinequivalence may lead to market exclusion
A
study that demonstrates bioinequivalence is clear
and convincing evidence of a problem
6
Possible Outcome of BE Studies
Demonstrate BE
Fail to Demonstrate BIE
Fail to Demonstrate BE
Demonstrate BIE
80%
7
Demonstrate BIE
T/R (%)
125%
Fail to Demonstrate vs. Demonstrate
?
Demonstrate BE
Demonstrate BIE
80%
8
T/R (%)
125%
Objective

To develop bioinequivalence criteria that are
 Scientifically
sound
 Statistically valid
 Fair to all parties
 Easy to use
9
April 14, 2004 ACPS Meeting

Does the ACPS agree with the distinction
between demonstrating bioINequivalence and
failure to demonstrate bioequivalence?

Committee’s comments:
•
10
The Committee felt that there was a need to establish
criteria for bioINequivalence evaluation and the criteria
should not be just as failure of the bioequivalence test.
The members argued it was important to focus on the
clinical relevance with the therapeutic index. The
Committee discussed both Area under the Curve (AUC)
and Cmax as metrics important for bioequivalence and
bioINequivalence.
April 14, 2004 ACPS Meeting

Does the ACPS recommend a preferred method
for evaluating the three pharmacokinetic
endpoints for bioINequivalence?




11
If bioINequivalence is demonstrated for any one
pharmacokinetic endpoint, then bioINequivalence is
demonstrated for the products.
BioINequivalence must be demonstrated for all three
pharmacokinetic endpoints for bioINequivalence to be
demonstrated for the products.
There should be one pre-selected pharmacokinetic endpoint
used for bioINequivalence testing. If so, which one?
The three pharmacokinetic endpoints should be evaluated for
bioINequivalence with statistical corrections to the level of
significance for each endpoint in order to maintain an overall
significance level of 0.05.
April 14, 2004 ACPS Meeting

Committee’s comments:

12
The Committee agreed on a general understanding of
bioINequivalence to move forward by recognizing it
is not a simple matter. In addition, the members felt
this is an important concept, especially how it
applies to the entire regulatory scenario. There was
no consensus at this point as to a final criteria
pertaining to the three pharmacokinetic endpoints.