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FDA Pharmacogenetic Labels A Clinical Perspective

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 .

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FDA Pharmacogenetic Labels A Clinical Perspective

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  1. 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

  2. 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

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

  4. UGT1A1 TA repeat associates with: irinotecan neutropenia/activity 50 P=0.007 45 40 35.7 35 30 % grade 4/5 neutropenia 25 16.3 20 15 8.6 10 5 0 6/6 6/7 7/7 UGT1A1 genotype 41.9 P=0.045 45 40 33.8 35 30 Objective response (%) 25 20 14.3 15 10 5 0 6/6 6/7 7/7 UGT1A1 genotype N=524 McLeod HL et al. 2004

  5. Vitamin K Carboxylase Genotype altered Warfarin Dose Rieder et al. N. Eng J. Med 2005;352: 2285-2293

  6. 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). <July 2005, Camptosar labeling; http://www.fda.gov/cder/foi/label/2005/020571s024,027,028lbl.pdf>

  7. 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

  8. 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

  9. A Clinical Perspective on Hierarchy of Pharmacogenetic Information

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

  11. 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

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

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

  15. 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

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

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

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

  19. A Fantasy Dosage and Administration Section for Warfarin

  20. 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

  21. 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

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