FDA Pharmacogenetic Labels A 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 14 th, 2005

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

FDA labeling Progress TPMT labelling Irinotecan labelling Cytochrome P450 Amplichip™ approval UGT1A1 test approval for irinotecan

UGT1A1 TA repeat associates with: irinotecan neutropenia/activity /66/77/7 P=0.007 UGT1A1 genotype % grade 4/5 neutropenia N= /66/77/7 UGT1A1 genotype Objective response (%) P=0.045 McLeod HL et al. 2004

Vitamin K Carboxylase Genotype altered Warfarin Dose Rieder et al. N. Eng J. Med 2005;352:

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 UGT1A1*28 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).

Barriers to Effective Pharmacogenetic Labels oTime in Clinical Settings is Limited oInformation Overload is the Norm oVery few prescribers read labels -Lawyers do Simplicity, Accuracy of Presentation Not Negotiable A Picture is Worth a Thousand Words

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

A Clinical Perspective on Hierarchy of Pharmacogenetic Information

Potential Problems with Pharmacogenetic Labels that Could Compromise Future Use of Valuable Tests, Reimbursement and Medical Care “Clinically Relevant” is over-interpreted

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

Potential Problems with Pharmacogenetic Labels that Could Compromise Future Use of Valuable Tests, Reimbursement and Medical Care “Clinically Relevant” is over-interpreted Iterative value of tests is not presented Simplicity, Accuracy of Presentation Not Negotiable

Current Clinical Ability to Predict Response Clinical Value of a Pharmacogenetic Test Clinical Value Decreases when Current Predictive Ability is High Meyer UA and Flockhart DA, 2005 Azathioprine/TPMT β-blockade/β Receptor for HTN Cancer Chemotherapy Antidepressants/5HTR

Current Understanding of Mechanism Mechanistic Value of a Pharmacogenetic Test Value Decreases when Current Predictive Ability is High

Potential Problems with Pharmacogenetic Labels that Could Compromise Future Use of 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

The Future of Pharmacogenetic Testing: Multiple Variants Contribute to one Phenotypic Response

Clinical Studies Section Clinical Pharmacology Section Indications and Usage Dosage & Administration A Clinical Perspective on Drug Labels Adverse Reactions and Contraindications

Dosage and Administration Section Dose Changes recommended in text form Graph of dose vs Genotype Recommendations where possible

A Fantasy Dosage and Administration Section for Warfarin

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

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