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

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

35.7

16.3

8.6

0

5

10

15

20

25

30

35

40

45

50

6/6 6/7 7/7

P=0.007

UGT1A1 genotype

% g

rad

e 4/

5 n

eutr

op

enia

N=524

41.9

33.8

14.3

05

1015202530354045

6/6 6/7 7/7

UGT1A1 genotypeO

bje

ctiv

e re

spo

nse

(%

)

P=0.045

McLeod HL et al. 2004

Vitamin K Carboxylase Genotype altered Warfarin Dose

Rieder et al. N. Eng J. Med 2005;352: 2285-2293

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>

Barriers to Effective Pharmacogenetic Labels

o Time in Clinical Settings is Limitedo Information Overload is the Normo Very few prescribers read labels

- Lawyers do

Simplicity, Accuracy of Presentation Not NegotiableA 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 StudiesSection

Clinical PharmacologySection

OR

SNPs that change clinical outcome

SNPs that change drug response

SNPs that change pharmacokinetics

SNPs that change activity in vitro

Non-conservative amino acid changes

Non-synonymous SNPs in exons

Exon-based changes

All SNPs

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-interpretedIterative value of tests is not presented

Simple Genetic Tests are going to get more complicated

Simplicity, Accuracy of Presentation Not Negotiable

SNPs that change clinical outcome

SNPs that change drug response

SNPs that change pharmacokinetics

SNPs that change activity in vitro

Non-conservative amino acid changes

Non-synonymous SNPs in exons

Exon-based changes

All SNPs

The Future of Pharmacogenetic Testing:

Multiple Variants Contribute to one Phenotypic Response

Clinical StudiesSection

Clinical PharmacologySection

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

Recommended Starting Dose (mg)

12

34

56

78

910

0

2

4

6

8

10

12

A B C D E F G H I J

Genotype

Sta

rtin

g D

ose

(m

g)

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