1. 1 How New Insights into Pharmacogenomics Lead to Revisions of Product Labels Shiew-Mei Huang, Ph.D. Deputy Director for Science Office of Clinical Pharmacology & Biopharmaceutics CDER, FDA huangs@cder.fda.gov Advisory Committee for Pharmaceutical Science -Clinical Pharmacology Subcommittee- November 14, 2005 Rockville, MD

2. 2 21 CFR 201.57 “…if evidence is available to support the safety and effectiveness of the drug only in selected subgroups of the larger population with a disease, the labeling shall describe the evidence and identify specific tests needed for selection or monitoring of patients who need the drug.”

3. 3 Drug and Biologics/Device Labeling -Recommendations- [Section] [Content] Topic 1A backgrounder: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4194B1_00_TOC.htm

4. 4 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

5. 5 When the information has important implications for safe and effective use, the consequences of the genetic differences and/or recommendations may be placed in Indications and Usage AND/ OR Dosage & Administration Precautions/ Warnings Contra- indications Boxed Warning Clinical Studies Adverse Reactions HIGHLIGHTS Laboratory Testing

6. 6 If a drug is indicated only for a population with a certain genetic makeup, and a genotypic or phenotypic test needs to be conducted prior to prescription and administration Example: Herceptin

7. 7 Trastuzumab (Herceptin) INDICATIONS & USAGE indicated for..metastatic breast cancer whose tumor overexpress the HER2 protein….... Patients whose tumor evaluated with an assay validated to predict HER2 http://www.fda.gov/cder/foi/label/2005/009218s101lbl.pdf Required

8. 8 If dose recommendations are different for subgroups of patients with different genetic makeup Example: irinotecan

9. 9 Irinotecan CLINICAL PHARMACOLOGY Metabolism and Excretion: … SN-38 is subsequently conjugated predominantly by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite. UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism. Approximately 10% of the North American population is homozygous for the UGT1A1*28 allele. In a prospective study, in which irinotecan was administered as a single-agent on a once-every-3-week schedule, patients who were homozygous for UGT1A1*28 had a higher exposure to SN-38 than patients with the wild-type Descriptive info- rationale

10. 10 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). Action- Recommendations

11. 11 If individuals with certain genetic makeup are more sensitive to one of the severe adverse events Example: irinotecan

12. 12 Irinotecan WARNINGS Patients with Reduced UGT1A1 Activity Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of CAMPTOSAR treatment. A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele (see DOSAGE & ADMINISTRATION). Heterozygous patients (carriers of one variant allele and one wild-type allele which results in intermediate UGT1A1 activity) may be at increased risk for neutropenia; however, clinical results have been variable and such patients have been shown to tolerate normal starting doses.

13. 13 If individuals with certain genetic makeup are more sensitive to one of the life threatening adverse events that may not be managed via dose reduction Example: thioridazine

14. 14 Thioridazine CONTRAINDICATIONS … elevated levels of thioridazine would be expected to augment the prolongation of the QTc interval associated with thioridazine and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes-type arrhythmias. …. Therefore, thioridazine is contraindicated …. in patients, comprising about 7% of the normal population, who are known to have a genetic defect leading to reduced levels of activity of P450 2D6 (see WARNINGS and PRECAUTIONS ). WARNINGSPRECAUTIONS Action- Recommendations

15. 15 If individuals with certain genetic makeup had a higher rate of adverse reactions Example: atomoxetine

16. 16 Atomoxetine ADVERSE EVENT ADRPMEM decreased appetite23% 16% insomnia 13% 7% sedation 4% 2% depression 6% 2% tremor4% 1% early morning awakening 3% 1% pruritus 2% 1% mydriasis2% 1% Descriptive info-

17. 17 When a specific laboratory test is available……. Examples: atomoxetine azathioprine

18. 18 Atomoxetine LABORATORY TEST Laboratory Tests : Laboratory tests are available to identify CYP2D6 PMs …….higher blood levels in PMs lead to higher rate of some adverse effects of STRATTERA.

19. 19 Azathioprine Laboratory Tests: TPMT Testing: It is recommended that consideration be given to either genotype or phenotype patients for TPMT. Phenotyping and genotyping methods are commercially available. The most common non- functional alleles associated with reduced levels of TPMT activity are TPMT*2, TPMT*3A and TPMT*3C. Patients with two non-functional alleles (homozygous) have low or absent TPMT activity and those with one non-functional allele (heterozygous) have intermediate activity. …

20. 20 Device Labeling Intended Use Summary & Explanation of the Test Test Procedure Limitations Summary of Expected Results or Performance Characteristics

21. 21..an in vitro diagnostic test for detection and genotyping of the *1 (TA6) and *28 (TA7) alleles of ….the UGT1A1 gene....aid in identification of patients with greater risk for decreased UGT activity Example: UGT1A1 molecular assay

22. 22..can be used to identify patients that may require dose modifications for drugs that are metabolized by UGT1A1..patients who possess the UGT1A1*28 genotype are at greater risk for irinotecan-induced toxicities… Example: UGT1A1 molecular assay

23. 23 Labeling Questions 1. what is the best way to present genetic information in the labeling (section and content) for use by providers and patients? Progression of labeling (recent examples): - atomoxetine: CYP2D6 PM (2003) - 6-MP: TPMT*2, *3A, *3C (2004) - irinotecan: UGT1A1*1, *28 (2005) - thioridazine: genetic defect… reduced activity of 2D6 (2003) - azathioprine: TPMT*2, *3A, *3C (2005)

24. 24 Labeling Questions 2. How should the results of a genotype test be reported when technology allows measurement of genotypes where clinical significance is uncertain or incomplete? - irinotecan: UGT1A1*1 (TA6), *28 (TA7) *1 (TA6/6) *28 homozygous (TA7/7) *28 heterozygous (TA6/7) Other (including 5, 8..)