Pharmacogenetics:
Global Regulatory Issues
ASENT 13th Annual Meeting
Bethesda, MD
February 26, 2011
Issam Zineh, PharmD, MPH
Associate Director for Genomics
Office of Clinical Pharmacology
Center for Drug Evaluation and Research/US FDA
Overview
• What is Pharmacogenetics and Why
Do We Care?
• Policy, Drug Development, and (a few)
Regulatory Question Marks
• Race, Ethnicity, and Variable Drug
Response
• Summary and Conclusions
These are my views and not necessarily FDA’s; no conflicts of interest to report.
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Problem Statement:
Predicting Drug Response is a Game of Chance
Effectiveness Rate
Modified from Spear at al 2001 [PMID 11325631]
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Pharmacogenomics/genetics
• Pharmacogenomics (PGx): The study of
variations of DNA and RNA characteristics as
related to drug response.
• Pharmacogenetics (PGt): A subset of PGx;
the study of variations in DNA sequence as
related to drug response.
ICH E15: Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding
Categories. April 2008.
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Why Else Do We Care?
60%
37%
50%
Kola and Landis 2004 [PMID 15286737] | Arrowsmith 2011 [PMID 21283095]
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CDER Genomics Group
Review Activity: 2008 - 2010
Submission Volume
250
200
150
100
50
0
2008
2009
2010
BLA
2
5
18
NDA
17
42
54
IND
37
92
138
Calendar years; NDAs and BLAs include supplements
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Regulatory Guidance
2005
Guidance on PG Data Submissions
Concept Paper on Drug-Diagnostic Co-Development
2007
Companion Guidance on PG Data Submissions
Guidance on PG Tests and Genetic Tests for Heritable Markers
2010
ICH E16 Concept Paper on PG Biomarker Qualification: Format and
Data Standards
Guidance on Chronic Hepatitis C Virus Infection: Developing
Direct-Acting Antiviral Agents for Treatment
Guidance on Qualification Process for Drug Development Tools
2011
Guidance on Clinical PG: Premarketing Evaluation in Early Phase
Clinical Studies
Preparation
Guidance on Clinical Trial Designs Employing Enrichment Designs
to Support Approval of Human Drugs and Biological Products
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FDA and EMA Position on PG in
Early Phase Trials
Condition
FDA
EMA
Collect and retain DNA
◘
◘
Consent for exploratory studies
◘
◘
◘
□
■
◘
+ PG interaction (PK or PD) – prospectively exclude,
dose-adjust, stratify
◘
■
Genome-wide/ comprehensive ADME genotyping
Retrospective exposure/response, population PK
◘
◘
◘
◘
DDI studies – exclude poor metabolizers
◘
◘
Polymorphic metabolism (major) – pro/retrospective
Variable PK, safety concerns, ethnic differences,
prodrugs – pro/retrospective
■ required
◘ recommended
□ not addressed
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Pharmacogenomic Maneuvers
in Drug Development
Experimental
evidence for
PGx
interaction
Major
polymorphic
pathways
---------- Optimize efficacy - - - Minimize risk ---------Restricted
FIH/DDI/HV
trials
Enriched/
stratified
trials*
Stratified
dose-finding
Stratified
dosing
Labeling
Nonclinical
Phase 1
Metabolism,
transport
Drug-target
interactions
Nonclinical
safety
ADME
Intrinsic/
extrinsic
factors
Safety
* Can also be retrospectively derived
Phase 2
Phase 3
Efficacy
Safety
D/R, C/R
Intrinsic/ extrinsic factors
Phase 4
K
n
o
w
l
e
d
g
e
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Dosing
1. Under what circumstances should we prospectively
require genotype-guided dosing (e.g., risk-based)?
2. Are retrospective/population PK analyses adequate
to guide PGx-dosing decisions?
3. How do we accrue an adequate safety database in
Phase 1/2 to inform Phase 3 design and dosing
decisions?
4. Co-development imperative?
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Subgroups, Stratification, Enrichment, Safety
1. At what point does the Agency determine what is
“prospective-retrospective” (considering missing
data, bias, multiplicity and confounding)?
2. How can claims of superiority be obtained for drug
responder subgroups (or nonresponders to the
comparator)?
3. When is stratified randomization and fallback
testing indicated, preferred?
4. How much data are needed in the “biomarkernegative” subgroup to support the biomarker’s
utility?
5. How much confirmatory evidence is required for
safety biomarkers relative to efficacy biomarkers?
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Overview
• What is Pharmacogenetics and Why
Do We Care?
• Policy, Drug Development, and (a few)
Regulatory Question Marks
• Race, Ethnicity, and Variable Drug
Response
• Summary and Conclusions
These are my views and not necessarily FDA’s; no conflicts of interest to report.
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Race/Ethnicity as an Added Dimension
Huang and Temple 2008 [PMID 18714314]
13
BiDil:
Meditations on Race and Ethnicity
↓43%
Taylor et al 2004 [PMID 15533851]
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Is it Wrong to “Biologize” Race?
• Not understanding the reasons for the difference in
treatment effect by race did not justify withholding the
treatment from those who could benefit from it.
– Imperfect, crude proxy (but temporarily useful)
– FDCA requirement for effectiveness
• Race and other demographic characteristics have long
been important to consider in analysis of trials and as
a matter of equity and justice.
– Subgroup analyses per guidance
– Differences are expected
Temple and Stockbridge 2007 [PMID 17200223]
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Race/Ethnicity may be a Proxy
for Drug Response Heritability
• CYP2C19 PMs
2% Caucasian
4% AA
14% Chinese
• BiDil Marker
40% Caucasian
68% AA
87% African
pharmgkb.org
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Maximizing the Explanatory
Power of Genetics
• Heterogeneity in drug response, exposure, or AEs by race
and/or study country is not uncommon
– Trial designs
– Eligibility criteria
– Patient characteristics
– Differences in SOC or background treatment
– Differences in prevalence of important gene variants
• Particularly relevant in global research
• ICH E15
– Characterization in a population relevant to the new region of the PK, and where
possible, PD and dose response for PD endpoints. This characterization could
be performed in the foreign region in a population representative of the new
region or in the new region.
ICH E15: Ethnic Factors in the Acceptability of Foreign Data
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Summary
• Genetic variability is determinant of variable
drug response
• Race, ethnicity, and genetic background are
related and important considerations in
drug development (e.g., in interpretation of
data from and planning of “foreign” trials)
• Regulatory policy and drug development
practices are evolving with respect to PGx
• The hope is to enhance product
development, regulatory review, and clinical
use
These are my views and not necessarily FDA’s; no conflicts of interest to report.
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