Bioequivalence of Highly Variable Drugs: Regulatory Perspectives

Sam H. Haidar, R.Ph., Ph.D. Pharmacometrics Office of Generic Drugs

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Potential Advantages

Reduction in regulatory burden Facilitate market access for highly variable but safe and effective drugs Make it easier to approve a generic drug product which is significantly less variable than the reference listed drug
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Current BE* Requirements

Major Regulatory Agencies

U.S. Food and Drug Administration (FDA) Health Canada Committee for Proprietary Medicinal Products (CPMP), Europe National Institute of Health Sciences (NIHS), Japan
*BE = Bioequivalence
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Current BE Requirements
FDA*

AUC: 90% Confidence Interval Limits 80-125% Cmax: 90% Confidence Interval Limits 80-125% Criteria applied to drugs of low and high variability

*Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products- General Considerations
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Current BE Requirements
Health Canada

AUC: 90% Confidence Interval Limits 80-125% Cmax: Mean T/R ratio (point estimate) between 80-125% Criteria judged flexible enough to deal with highly variable drugs*

*Expert Advisory Committee on Bioavailability and Bioequivalence, June 26 27, 2003.

Current BE Requirements
CPMP*

AUC: 90% Confidence Interval Limits 80-125% Cmax: 90% Confidence Interval Limits 80-125% Cmax: In certain cases a wider interval is acceptable (e.g., 75133%)
*Note for Guidance on the Investigation of Bioavailability and Bioequivalence, January 2002
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Current BE Requirements
NIHS (Japan)*

AUC: 90% Confidence Interval Limits 80-125% Cmax: 90% Confidence Interval Limits 80-125% In cases of failure, add-on studies are acceptable (provided other criteria are met)
*Guideline for Bioequivalence Studies of Generic Drugs, December 22, 1997.
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Performance of FDA Criteria

Survey of ANDA Applications (19962001) Evaluated distribution of Cmax and AUC T/R mean ratios (point estimates)

40

30

Percent (%)

20

10

0 0.70

0.75

0.80

0.85

0.90

0.95

1.00

1.05

1.10

1.15

1.20

1.25

1.30
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AUC Point Estimate (T/R)

30

25

Percent (%)

20

15

10

0 0.70

0.75

0.80

0.85

0.90

0.95

1.00

1.05

1.10

1.15

1.20

1.25

1.30
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Cmax Point Estimate (T/R)

40

Highly Variable

40

30

30

Percent (%)

20

20

10

10

0 0.70 0.80 0.90 1.00 1.10 1.20 1.30 0.75 0.85 0.95 1.05 1.15 1.25 AUC Point Estimate (T/R)

0 0.70 0.80 0.90 1.00 1.10 1.20 1.30 0.75 0.85 0.95 1.05 1.15 1.25 11 AUC Point Estimate (T/R)

30 25
Highly Variable

25 20

Percent (%)

20 15

15

10

10

0 0.70 0.80 0.90 1.00 1.10 1.20 1.30 0.75 0.85 0.95 1.05 1.15 1.25 Cmax Point Estimate (T/R)

0 0.70 0.80 0.90 1.00 1.10 1.20 1.30 0.75 0.85 0.95 1.05 1.15 1.25 12 Cmax Point Estimate (T/R)

Summary

Although criteria allows for a mean difference of 20%, the vast majority of submissions were within 10%

This was also true with regard to highly variable drugs and drug products
Additional confirmation of greater variability associated with Cmax
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Available Options
Bioequivalence of Highly Variable Drugs

Scaling based on intra-subject variability (Cmax, AUC)

Expansion of regulatory limits

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Scaling Approaches

Reduction in sample size Limits are defined by degree of variability Need for point estimate constraint?

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Expansion of Limits

Cmax only, or Cmax and AUC

Fixed Limits (e.g., 70 143%) for drugs meeting high variability criterion
Need for point estimate constraint?

Major concern: How to classify borderline drugs and drug products

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Expansion of Limits
Study: Hauck et al.*

AUC: 90% Confidence Interval Limits 80125% Cmax: 90% Confidence Interval Limits 70143% Outcome: Sample size reduced by 60% Cmax ratios of 128% could pass using the 70-143% limit

*Hauck et al. Int J Clin Pharm Ther. 39 (8) pp. 350-355 (2001)

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Conclusion

If a need to make changes in the regulations is concluded: Either approach would result in significant reduction in sample size Additional criterion constraining point estimates may be needed

Based on prior experience, clustering around a T/R ratio of 1 would be expected for a modified BE criteria for highly variable drugs
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Q&A

Dale Conner, Pharm.D.

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