# Presentation: 679889

## Bioequivalence of Highly Variable Drugs: Regulatory Perspectives

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

## 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

## 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

## 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

## 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.*, 75-133%)

- *Note for Guidance on the Investigation of Bioavailability and
-   Bioequivalence, January 2002

## 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.

## Performance of FDA Criteria

- Survey of ANDA Applications (1996-2001)
- Evaluated distribution of Cmax and AUC T/R mean ratios (point estimates)

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## 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

## Available OptionsBioequivalence of Highly Variable Drugs

- Scaling based on intra-subject variability (Cmax, AUC)
- Expansion of regulatory limits

## Scaling Approaches

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

## 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

## Expansion of LimitsStudy: Hauck et al.*

- AUC: 90% Confidence Interval Limits 80-125%
- Cmax: 90% Confidence Interval Limits 70-143%
- 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)

## 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

## Q & A

- Dale Conner, Pharm.D.