Bioequivalence of Highly Variable HV Drugs: Clinical Implications Why HV Drugs are Safer

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Bioequivalence of Highly Variable (HV) Drugs
Clinical ImplicationsWhy HV Drugs are Safer
Leslie Z. Benet, Ph.D. Professor of
Biopharmaceutical Sciences University of
California San Francisco FDA Advisory Committee
for Pharmaceutical Science Rockville, MD April
14, 2004
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The Current U.S. Procrustean Bioequivalence
Guidelines

• The manufacturer of the test product must show
  using two one-sided tests that a 90 confidence
  interval for the ratio of the mean response
• (usually AUC and Cmax) of its product to that
  of
• the reference product is within the limits of
  0.8 and 1.25 using log transformed data.
• (Procrustean ? marked by an arbitrary, often
  ruthless disregard for individual differences or
  special circumstances.)
• Note BCS is a non-Procrustean advance
• We should consider other non-Procrustean
  advances

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Bioequivalence IssuesWhat are we trying to solve?

• For all drugs, but particularly for NTI drugs,
  practitioners need assurance that transferring a
  patient from one drug product to another yields
  comparable safety and efficacy (switchability).
• For wide-therapeutic index, highly variable drugs
  we should not have to study an excessive number
  of patients to prove that two equivalent products
  meet preset (one size fits all) statistical
  criteria.
• To give patients and clinicians confidence that a
  generic equivalent approved by the regulatory
  authorities will yield the same outcome as the
  innovator product.

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Why is meeting bioequivalence criteria a
relatively minor concern for drugs with narrow
therapeutic indices?

• By definition, approved drugs
• with narrow therapeutic
• indices exhibit small
• intrasubject variability.
• If this were not true, patients
• would routinely experience
• cycles of toxicity and lack of
• efficacy, and therapeutic
• monitoring would be useless.

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NTI Drugs Frequently Proposed to Limit Generic
Substitution
CV Inter
Intra Subject Subject Carbamazepin
e 38 Conjugated Estrogens 42 14-15 Digoxin
52 Levothyroxine sodium 20 lt20 Phenytoin
sodium 51 10-15 Theophyllin sustained
31 11-14 release
Warfarin
sodium 53 6-11
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Individual Bioequivalence (IBE)
(µT - µR)2 ?D2 (?WT2 - ?WR2)
lt ? ?WR2

• Initial Promises for IBE
• Addresses the correct question (switchability)
• Considers subject by formulation interaction
  (?D )
• Incentive for less variable test product
• Scaling based on variability of the reference
  product
• both for highly variable drugs and for certain
  
• agency-defined narrow therapeutic range drugs
• Encourages use of subjects more representative
  of
• the general population

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• Re-examination of the Initial Promises for IBE
• Addresses the correct question
  (switchability)Necessity questionable
• Considers subject by formulation
  interactionUnintelligible parameter
• Incentive for less variable test productABE
  with scaling could also solve this issue
• Scaling based on variability of the reference
  product both for highly variable drugs and for
  certain agency-defined narrow therapeutic range
  drugs ABE with scaling could also solve this
  issue
• Encourages use of subjects more representative
  of the general populationFailed

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Highly Variable Drugs (CVgt30)
For wide-therapeutic index highly variable drugs
we should not have to study an excessive number
of patients to prove that two equivalent products
meet preset (one size fits all ) statistical
criteria. This is because ,by definition, highly
variable approved drugs must have a wide
therapeutic index, otherwise there would have
been significant safety issues and lack of
efficacy during Phase 3 Highly variable narrow
therapeutic index drugs are dropped in Phase 2
since it is not possible to prove either efficacy
or safety.
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ProgesteroneThe Poster Drug for High Variability

• A repeat measures study of Prometrium 2x200
  mg capsules in 12 healthy post-menopausal females
  yielded
• Intrasubject CV for AUC of 61
• Intrasubject CV for Cmax of 98
• A generic company calculated that a 2 period
  crossover BE study for Progesterone Capsules,
  200 mg would require dosing in 300 postmenopausal
  women to achieve adequate statistical power

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Recommendationsof the FDA Expert Panel on
Individual Bioequivalence to this Advisory
Committee on November 21, 2001

• Sponsors may seek bioequivalence approval using
  either ABE or IBE (with SxF deleted)
• Scaling of ABE should be considered.
• If an IBE study is carried out and the test
  product fails, the data or a subset of the data
  may not be reanalyzed by ABE for approval
• A point estimate criteria on mean AUCs of 15
  and on mean Cmax of 20 should be required for
  both ABE and IBE.
• Consideration should be given for narrower point
  estimate criteria for NTI drugs (e.g., AUC 10,
  Cmax 15)

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Recommendations

• Methodology should be developed to allow
  approvals based on weighting of average
  bioequivalence analyses for highly variable drugs
  (i.e., ?WRgt 30).
• A point estimate criteria on mean AUCs of 10
  and on mean Cmax of 15 should be required for
  NTI drugs where ?WR ? 20.
• A point estimate criteria on mean AUCs of 15
  and on mean Cmax of 20 should be required for
  all other drugs, including NTI drugs where ?WRgt
  20.