Why Highly Variable Drugs are Safer

1
Why Highly Variable 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 October
6, 2006
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I have made two previous presentations on this
topic to ACPS

• November 29, 2001
• Individual BioequivalenceHave the Opinions of
  the Scientific Community Changed?
• April 14, 2004
• Bioequivalence of Highly Variable (HV) Drugs
  Clinical ImplicationsWhy HV Drugs are Safer
• Many of the slides today are the same as
  presented in my previous appearances

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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 are considering another 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. (Nov. 29, 2001
  April 14, 2004)

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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 Carbamazepine 38 Conjugated
Estrogens 42
14-15 Cyclosporine (Neoral Package Insert)
20-50 9-21 Digoxin
52 Furosemide
59
15 Levothyroxine sodium 20
lt20 Phenytoin sodium 51
10-15 Theophyllin sustained release
31 11-14
Warfarin sodium 53
6-11 Black numbers (Benet,
Transplant. Proc. 31 1642-44. 1999)
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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 and proof
  nonexistent
• 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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Drug AThe Poster Drug for High Variability

• A repeat measures study of Drug A 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 Drug A Capsules, 200
  mg would require dosing in 300 postmenopausal
  women to achieve adequate statistical power

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Pharmacogenetics and Highly
Variable Drug Safety

• Should pharmacogenetics be considered in setting
  the criteria?
• For some drugs, high variability may be the
  result of genetic polymorphisms

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Can we make some general conclusions as to when
metabolic and transporter genetic polymorphisms
will be important clinically in terms of drug
disposition?

• ? CYP 2D6 For sure ? MDR1 No
• ? CYP 2C19 Yes ? OATPs Yes
• ? CYP 2C9 Yes ? OCTs Yes
• ? CYP 3A4 No ? OATs
  Probably
• ? CYP 1A2 Maybe ? MRP2 Maybe
• ? UGT 1A1 Maybe ? Other ABC
• ? NAT2 No
  transporters ??

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What are the Substrate Characteristics that
Result in Pharmacogenetic Variance Affecting
Pharmacokinetics?

• Substrate is BCS Class 1
• Genetic variants exhibit very wide differences in
  phenotype activity, preferable at one extreme
  marked effect and the other extreme no effect
• For an enzyme, protein is not present or not
  active extrahepatically, especially not present
  in the gut.
• For a Class 2, 3 or 4 substrate, efflux
  transporter effects are minimal.
• Compounds are primarily a substrate for a single
  metabolic enzyme, a single uptake transporter or
  a single efflux transporter
• The primary genetic variable potentially
  affecting substrate pharmacokinetics is not
  embedded.

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Cytochrome P450 2D6 Substrates

• Appear to be predominantly Class 1 substrates
• Therefore there will be no transporter interplay
  (We are unaware of a CYP2D6 substrate
  that has been shown to be an efflux transporter
  substrate)
• Therefore they will exhibit good absorption
• The enzyme shows marked genetic differences in
  enzyme activity between EMs and PMs
  (i.e., marked activity vs. no activity)
• There is no significant gut CYP2D6 activity
• Many CYP2D6 substrates have minimal metabolism by
  other enzymes
• All factors that minimize nongenetic
  variability

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Yet, many CYP 2D6 substrates have qualified
generic substitutes on the market

• The question should not be if such drugs are
  eligible for scaling in bioequivalence assessment
  or even if such drugs should be eligible for
  approval as generic equivalents
• Rather this is a labeling issue. If genetic
  polymorphisms are critical to drug dosing this
  should be true for the innovator as well as the
  generic

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Recommendationsof the FDA Expert Panel on
Individual Bioequivalence to this Advisory
Committee (April 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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My Recommendations April 14, 2004

• 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.

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It is important to note that when I presented the
recommendations of the Expert Panel (2001) as
well as my own recommendations (2004) to the
ACPS, the following were also stated

• There is no scientific basis or rationale for the
  point estimate recommendations
• 2. There is no belief that addition of the point
  estimate criteria will improve the safety of
  approved generic drugs
• 3. The point estimate recommendations are only
  political to give greater assurance to
  clinicians and patients who are not familiar
  (dont understand) the statistics of highly
  variable drugs

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Conclusions

• Highly variable narrow therapeutic index drugs
  are limited, at most, to a few cancer treatments
  but I am unaware of any documentation of highly
  variable narrow therapeutic index drugs.
• Highly variable drugs on the market are the
  safest drugs because marked swings in systemic
  drug levels have been shown to not affect safety
  and efficacy in individual patients
• High variability can result from a number of
  environmental and genetic factors, none of which
  appear to require any special considerations not
  already found in the labeling of the innovator
  drug