ACPS Meeting, October 19-20, 2004ACPS Meeting, October 19-20, 2004ACPS Meeting, October 19-20, 2004ACPS Meeting, October 19-20, 2004

BioINequivalence:Concept and Definition

Lawrence X. Yu, Ph. D.Lawrence X. Yu, Ph. D.

Director for ScienceDirector for Science

Office of Generic Drugs, OPS, CDER, FDAOffice of Generic Drugs, OPS, CDER, FDA

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Bioavailability: Rate and Extent of Bioavailability: Rate and Extent of Drug Absorption Drug Absorption

ln C

once

ntr

atio

n

AUC

Time

100

1100

2100

3100

4100

5100

6100

7100

0 5 10 15 20 25

Cmax

Time

Con

cent

rati

on

Tmax - time of maximum concentration

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BioequivalenceBioequivalence

“ “the absence of a significant difference in the rate the absence of a significant difference in the rate and extent to which the active ingredient or and extent to which the active ingredient or active moiety in pharmaceutical equivalents or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available pharmaceutical alternatives becomes available at the site of drug action when administrated at at the site of drug action when administrated at the same molar dose under similar conditions in the same molar dose under similar conditions in an appropriately designed study…” (21 CFR an appropriately designed study…” (21 CFR §§320.1)320.1)

“ “the absence of a significant difference in the rate the absence of a significant difference in the rate and extent to which the active ingredient or and extent to which the active ingredient or active moiety in pharmaceutical equivalents or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available pharmaceutical alternatives becomes available at the site of drug action when administrated at at the site of drug action when administrated at the same molar dose under similar conditions in the same molar dose under similar conditions in an appropriately designed study…” (21 CFR an appropriately designed study…” (21 CFR §§320.1)320.1)

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BioequivalenceBioequivalence

90% confidence interval for AUC and Cmax 90% confidence interval for AUC and Cmax

between 80-125%between 80-125%

Passing (among others) allows market access Passing (among others) allows market access Generic: ANDA approvalGeneric: ANDA approval

Innovator: Demonstrates to be marketed formulation Innovator: Demonstrates to be marketed formulation

is equivalent to clinical formulationis equivalent to clinical formulation

90% confidence interval for AUC and Cmax 90% confidence interval for AUC and Cmax

between 80-125%between 80-125%

Passing (among others) allows market access Passing (among others) allows market access Generic: ANDA approvalGeneric: ANDA approval

Innovator: Demonstrates to be marketed formulation Innovator: Demonstrates to be marketed formulation

is equivalent to clinical formulationis equivalent to clinical formulation

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Why define BioINequivalence?Why define BioINequivalence?

FDA receives studies that attempt to reverse a FDA receives studies that attempt to reverse a

previous finding of bioequivalence.previous finding of bioequivalence. Need standard to evaluate the claimNeed standard to evaluate the claim

Published claims of BioINequivalencePublished claims of BioINequivalence

FDA receives studies that attempt to reverse a FDA receives studies that attempt to reverse a

previous finding of bioequivalence.previous finding of bioequivalence. Need standard to evaluate the claimNeed standard to evaluate the claim

Published claims of BioINequivalencePublished claims of BioINequivalence

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What Should Bioinequivalence Mean?What Should Bioinequivalence Mean?

Bioequivalence leads to market accessBioequivalence leads to market access A study that demonstrates bioequivalence is clear and A study that demonstrates bioequivalence is clear and

convincing evidence of equivalenceconvincing evidence of equivalence

Bioinequivalence may lead to market exclusionBioinequivalence may lead to market exclusion A study that demonstrates bioinequivalence is clear A study that demonstrates bioinequivalence is clear

and convincing evidence of a problemand convincing evidence of a problem

Bioequivalence leads to market accessBioequivalence leads to market access A study that demonstrates bioequivalence is clear and A study that demonstrates bioequivalence is clear and

convincing evidence of equivalenceconvincing evidence of equivalence

Bioinequivalence may lead to market exclusionBioinequivalence may lead to market exclusion A study that demonstrates bioinequivalence is clear A study that demonstrates bioinequivalence is clear

and convincing evidence of a problemand convincing evidence of a problem

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Possible Outcome of BE StudiesPossible Outcome of BE Studies

T/R (%)80% 125%

Demonstrate BE

Fail to Demonstrate BE

Fail to Demonstrate BIE

Demonstrate BIE Demonstrate BIE

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Fail to Demonstrate vs. DemonstrateFail to Demonstrate vs. Demonstrate

T/R (%)80% 125%

Demonstrate BIE

?

Demonstrate BE

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ObjectiveObjective

To develop bioinequivalence criteria that areTo develop bioinequivalence criteria that are

Scientifically soundScientifically sound Statistically validStatistically valid Fair to all partiesFair to all parties Easy to useEasy to use

To develop bioinequivalence criteria that areTo develop bioinequivalence criteria that are

Scientifically soundScientifically sound Statistically validStatistically valid Fair to all partiesFair to all parties Easy to useEasy to use

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April 14, 2004 ACPS MeetingApril 14, 2004 ACPS Meeting Does the ACPS agree with the distinction Does the ACPS agree with the distinction

between demonstrating bioINequivalence and between demonstrating bioINequivalence and failure to demonstrate bioequivalence? failure to demonstrate bioequivalence?

Committee’s comments: Committee’s comments: • 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.

Does the ACPS agree with the distinction Does the ACPS agree with the distinction between demonstrating bioINequivalence and between demonstrating bioINequivalence and failure to demonstrate bioequivalence? failure to demonstrate bioequivalence?

Committee’s comments: Committee’s comments: • 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.

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April 14, 2004 ACPS MeetingApril 14, 2004 ACPS Meeting Does the ACPS recommend a preferred method Does the ACPS recommend a preferred method

for evaluating the three pharmacokinetic for evaluating the three pharmacokinetic endpoints for bioINequivalence?endpoints for bioINequivalence?

If bioINequivalence is demonstrated for any one If bioINequivalence is demonstrated for any one pharmacokinetic endpoint, then bioINequivalence is pharmacokinetic endpoint, then bioINequivalence is demonstrated for the products.demonstrated for the products.

BioINequivalence must be demonstrated for all three BioINequivalence must be demonstrated for all three pharmacokinetic endpoints for bioINequivalence to be pharmacokinetic endpoints for bioINequivalence to be demonstrated for the products. demonstrated for the products.

There should be one pre-selected pharmacokinetic endpoint There should be one pre-selected pharmacokinetic endpoint used for bioINequivalence testing. If so, which one? used for bioINequivalence testing. If so, which one?

The three pharmacokinetic endpoints should be evaluated for The three pharmacokinetic endpoints should be evaluated for bioINequivalence with statistical corrections to the level of bioINequivalence with statistical corrections to the level of significance for each endpoint in order to maintain an overall significance for each endpoint in order to maintain an overall significance level of 0.05. significance level of 0.05.

Does the ACPS recommend a preferred method Does the ACPS recommend a preferred method for evaluating the three pharmacokinetic for evaluating the three pharmacokinetic endpoints for bioINequivalence?endpoints for bioINequivalence?

If bioINequivalence is demonstrated for any one If bioINequivalence is demonstrated for any one pharmacokinetic endpoint, then bioINequivalence is pharmacokinetic endpoint, then bioINequivalence is demonstrated for the products.demonstrated for the products.

BioINequivalence must be demonstrated for all three BioINequivalence must be demonstrated for all three pharmacokinetic endpoints for bioINequivalence to be pharmacokinetic endpoints for bioINequivalence to be demonstrated for the products. demonstrated for the products.

There should be one pre-selected pharmacokinetic endpoint There should be one pre-selected pharmacokinetic endpoint used for bioINequivalence testing. If so, which one? used for bioINequivalence testing. If so, which one?

The three pharmacokinetic endpoints should be evaluated for The three pharmacokinetic endpoints should be evaluated for bioINequivalence with statistical corrections to the level of bioINequivalence with statistical corrections to the level of significance for each endpoint in order to maintain an overall significance for each endpoint in order to maintain an overall significance level of 0.05. significance level of 0.05.

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April 14, 2004 ACPS MeetingApril 14, 2004 ACPS Meeting Committee’s comments: Committee’s comments:

The Committee agreed on a general understanding of The Committee agreed on a general understanding of bioINequivalence to move forward by recognizing it bioINequivalence to move forward by recognizing it is not a simple matter. In addition, the members felt is not a simple matter. In addition, the members felt this is an important concept, especially how it this is an important concept, especially how it applies to the entire regulatory scenario. There was applies to the entire regulatory scenario. There was no consensus at this point as to a final criteria no consensus at this point as to a final criteria pertaining to the three pharmacokinetic endpoints. pertaining to the three pharmacokinetic endpoints.

Committee’s comments: Committee’s comments: The Committee agreed on a general understanding of The Committee agreed on a general understanding of

bioINequivalence to move forward by recognizing it bioINequivalence to move forward by recognizing it is not a simple matter. In addition, the members felt is not a simple matter. In addition, the members felt this is an important concept, especially how it this is an important concept, especially how it applies to the entire regulatory scenario. There was applies to the entire regulatory scenario. There was no consensus at this point as to a final criteria no consensus at this point as to a final criteria pertaining to the three pharmacokinetic endpoints. pertaining to the three pharmacokinetic endpoints.