BE Issues of HVD

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BE Issues of HVD HVDP
Kamal K. Midha, Maureen Rawson Gordon McKay
John W. Hubbard
PharmaLytics Inc. A Non-Profit Institute of the
University of Saskatchewan Saskatoon, SK,
Canada, S7N 3R2
Advisory Committee for Pharmaceutical Sciences,
Nov 29 2001
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Highly Variable Drugs(HVD and HVDP)

• A drug with an ANOVA-CV ? 30 has been defined as
  an HVD
• A highly variable drug product is a formulation
  with an ANOVA-CV ? 30 and has been termed HVDP
• With an HVD/P, a very large number of subjects is
  required in a traditional ABE study, even when
  two samples from the same lot of the same ref
  formulation are compared

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HVDs

• Chlorpromazine (CPZ) is an example of an HVD
  which has an ANOVA-CV of 34 on AUC and 43 on
  Cmax.
• The following slide shows results of a 3-period
  ABE study on CPZ with 37 subjects
• The test product was given once and the ref
  product was given twice (two samples from the
  same lot of the ref product)

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CPZ 3-way ABE Study (n37)Test vs 2
administrations of Ref1991
CV Test vs Ref Ref
vs Ref GMR 90 CI GMR
90 CI AUC 34 108 95 - 123
102 90 - 116 Cmax 43 106
90 - 126 115 98 - 136
Based on log transformed data Probability of
passing (36 subjects 2-period study, GMR 115) is
ca 15 only
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Comments

• It is clear that 2 samples from the same lot of
  the reference product were not found BE with each
  other because the ANOVA-CV was 43 and GMR 115
• These (and other) data showed that the reference
  formulation was a good quality product (HVD not
  an HVDP)

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Comments

• Under the new recommendations of the Oct 2000
  Guidance, when stated a priori and after due
  consultation with the agency, scaled IBE based on
  a replicate design may be allowed for an HVD,
  HVDP.
• This is a reasonable proposal for HVD/Ps which
  should be maintained at least for a trial period
  of two years so as to foster the gathering of
  data to be acquired in BE studies with a
  reasonable number of subjects.

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Comments

• The use of scaling for HVD/Ps permits the the
  assessment of BE to be performed with a
  reasonable number of subjects without
  compromising either the consumer risk and/or the
  producer risk.

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Comments

• An additional advantage of IBE is that the study
  provides an assessment of the quality of the
  dosage forms under investigation
• The constraint that the GMR must fall within
  80-125 for scaled IBE is reasonable, and should
  be maintained

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Comments

• Increasing the constraint on GMR in IBE to
  lt125 (e.g. 115) would take us back a decade!
• Our plea is that we should not modify the
  recommendation in the Guidance until scientific
  evaluations of the scaled metrics are completed.