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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

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bioequivalence of highly variable drugs regulatory perspectives

Bioequivalence of Highly Variable Drugs: Regulatory Perspectives

Sam H. Haidar, R.Ph., Ph.D.

Pharmacometrics

Office of Generic Drugs

potential advantages
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
Current BE* RequirementsMajor 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
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
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
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
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
Performance of FDA Criteria
  • Survey of ANDA Applications (1996-2001)
  • Evaluated distribution of Cmax and AUC T/R mean ratios (point estimates)
summary
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
Available OptionsBioequivalence of Highly Variable Drugs
  • Scaling based on intra-subject variability (Cmax, AUC)
  • Expansion of regulatory limits
scaling approaches
Scaling Approaches
  • Reduction in sample size
  • Limits are defined by degree of variability
  • Need for point estimate constraint?
expansion of limits
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
Expansion of LimitsStudy: 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
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
slide19
Q & A
  • Dale Conner, Pharm.D.