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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, 2005Rockville, MD

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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.”

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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

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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 StudiesSection

Clinical PharmacologySection

OR

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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

BoxedWarning

Clinical Studies

AdverseReactions

HIGHLIGHTS

LaboratoryTesting

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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

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

BoxedWarning

Clinical Studies

AdverseReactions

HIGHLIGHTS

LaboratoryTesting

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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

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If dose recommendations are different for subgroups of patients

with different genetic makeup

Example:irinotecan

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

BoxedWarning

Clinical Studies

AdverseReactions

HIGHLIGHTS

LaboratoryTesting

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Irinotecan

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

CLINICAL PHARMACOLOGYMetabolism 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

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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 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>

Action-Recommendations

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If individuals with certain genetic makeup are more sensitive to one of

the severe adverse eventsExample:irinotecan

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

BoxedWarning

Clinical Studies

AdverseReactions

HIGHLIGHTS

LaboratoryTesting

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Irinotecan

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

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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

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

BoxedWarning

Clinical Studies

AdverseReactions

HIGHLIGHTS

LaboratoryTesting

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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 ).

<July 2003, PDR labeling>

Action-Recommendations

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If individuals with certain genetic makeup had a higher rate of

adverse reactionsExample:

atomoxetine

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

BoxedWarning

Clinical Studies

AdverseReactions

HIGHLIGHTS

LaboratoryTesting

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Atomoxetine

ADVERSE EVENT

<adapted from STRATERRA labeling, electronic PDR, Jan 2004 update>

• ADR PM EM• decreased appetite 23% 16% • insomnia 13% 7% • sedation 4% 2% • depression 6% 2% • tremor 4% 1% • early morning awakening 3% 1%• pruritus 2% 1% • mydriasis 2% 1%

Descriptive info-

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When a specific laboratory test is available…….

Examples:atomoxetineazathioprine

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

BoxedWarning

Clinical Studies

AdverseReactions

HIGHLIGHTS

LaboratoryTesting

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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.

<STRATERRA labeling, electronic PDR, Jan 2004 update>

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Azathioprine

<July 2005, Imuran labeling; http://www.fda.gov/cder/foi/label/2005/016324s030,017391s013lbl.pdf>

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. …

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Device Labeling

Intended Use

Summary &Explanationof the Test

Test Procedure

Limitations

Summary of Expected Results

orPerformance

Characteristics

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Device Labeling

Intended Use

Summary &Explanationof the Test

Test Procedure

Limitations

Summary of Expected Results

orPerformance

Characteristics

..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

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Device Labeling

Intended Use

Summary &Explanationof the Test

Test Procedure

Limitations

Summary of Expected Results

orPerformance

Characteristics

..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

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Labeling Questions1. 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)

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Labeling Questions2. 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..)