FDA Pharmacogenetic Labels A Clinical Perspective

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FDA Pharmacogenetic LabelsA Clinical
Perspective

• David A Flockhart MD, PhD
• Indiana University School of Medicine

Clinical Pharmacology Subcommittee of the
Advisory Committee for Pharmaceutical Science
FDA, CDER November 14th, 2005
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The Purpose of Pharmacogenomics

• To predict response and thereby improve
  prescribing and the public health
• To elucidate drugs mechanism of action
• To identify targets
• choke points
• genes
• receptors/enzymes/transporters

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FDA labeling Progress

• TPMT labelling
• Irinotecan labelling
• Cytochrome P450 Amplichip approval
• UGT1A1 test approval for irinotecan

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UGT1A1 TA repeat associates with irinotecan
neutropenia/activity
41.9
P0.045
45
40
33.8
35
30
Objective response ()
25
20
14.3
15
10
5
0
6/6
6/7
7/7
UGT1A1 genotype
N524
McLeod HL et al. 2004
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Vitamin K Carboxylase Genotype altered Warfarin
Dose
Rieder et al. N. Eng J. Med 2005352 2285-2293
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Irinotecan
DOSAGE AND ADMINISTRATION - Dosage in Patients
with Reduced UGT1A1 Activity When administered
in combination with other agents, or as a
single-agent, a reduction in the starting dose by
at least one level of CAMPTOSAR should be
considered for patients known to be homozygous
for the UGT1A128 allele (See CLINICAL
PHARMACOLOGY and WARNINGS). However, the precise
dose reduction in this patient population is not
known and subsequent dose modifications should be
considered based on individual patient tolerance
to treatment (see tables 10-13).
ltJuly 2005, Camptosar labeling
http//www.fda.gov/cder/foi/label/2005/020571s024,
027,028lbl.pdfgt
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Barriers to Effective Pharmacogenetic Labels

• Time in Clinical Settings is Limited
• Information Overload is the Norm
• Very few prescribers read labels
• Lawyers do
• Simplicity, Accuracy of Presentation Not
  Negotiable
• A Picture is Worth a Thousand Words

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1
All clinically relevant information on effect of
polymorphic variation in drug metabolizing
enzymes, transporters, receptors and/or other
proteins on pharmacokinetics, pharmacodynamics,
clinical responses (both safety and efficacy
Clinical Studies Section
Clinical Pharmacology Section
OR
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A Clinical Perspective on Hierarchy of
Pharmacogenetic Information
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Potential Problems with Pharmacogenetic Labels
that Could Compromise Future Useof Valuable
Tests, Reimbursement and Medical Care

• Clinically Relevant is over-interpreted

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The Purpose of Pharmacogenomics

• To predict response and thereby improve
  prescribing and the public health
• To elucidate drugs mechanism of action
• To identify targets
• choke points
• genes
• receptors/enzymes/transporters

12
Potential Problems with Pharmacogenetic Labels
that Could Compromise Future Useof Valuable
Tests, Reimbursement and Medical Care

• Clinically Relevant is over-interpreted
• Iterative value of tests is not presented
• Simplicity, Accuracy of Presentation Not
  Negotiable

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Clinical Value Decreases when Current Predictive
Ability is High
Cancer Chemotherapy
Clinical Value of a Pharmacogenetic Test
Antidepressants/5HTR
Azathioprine/TPMT
ß-blockade/ß Receptor for HTN
Current Clinical Ability to Predict Response
Meyer UA and Flockhart DA, 2005
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Value Decreases when Current Predictive Ability
is High
Mechanistic Value of a Pharmacogenetic Test
Current Understanding of Mechanism
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Potential Problems with Pharmacogenetic Labels
that Could Compromise Future Useof Valuable
Tests, Reimbursement and Medical Care

• Clinically Relevant is over-interpreted
• Iterative value of tests is not presented
• Simple Genetic Tests are going to get more
  complicated
• Simplicity, Accuracy of Presentation Not
  Negotiable

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The Future of Pharmacogenetic Testing Multiple
Variants Contribute to one Phenotypic Response
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A Clinical Perspective on Drug Labels
Dosage Administration
Indications and Usage
Adverse Reactions and Contraindications
Clinical Pharmacology Section
Clinical Studies Section
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Dosage and Administration Section

• Dose Changes recommended in text form
• Graph of dose vs Genotype Recommendations where
  possible

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A Fantasy Dosage and Administration Section for
Warfarin
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Indications and Usage Section

• Data on Specific Genetic Populations
• E.g. Herceptin is indicated in women with
  Her2neu-positive breast cancer

Adverse Reactions and Contraindications Section

• Clear Genotypes or Genotypic Patterns to be
  Avoided

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Recommendations for Drug Labels

• Include in the Label
• Specificity and Sensitivity Data
• Incidence in Ethnic Subpopulations
• A Description of Clinical Context
• A listing of currently approved predictive tests
  in the Clinical Studies Section
• An Attempt to Quantitate the Iterative Value of a
  pharmacogenetic test in at least the Clinical
  Pharmacology Section
• A Clear Clinical Consequence
• Change in Dose
• Consider an Alternative Drug