Transcript ITOX Guidance PERI 2003 - Chemical Toxicity Testing: The US and

The Future of Chemical
Toxicity Testing in the U.S.
Toxicity Testing in the 21st Century
June 21, 2010
David Jacobson-Kram, Ph.D., DABT
Office of New Drugs, CDER, FDA
Food and Drug Administration
Risk Assessment: Pharmaceuticals
vs. Environmental Contaminants
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Pharmaceuticals are designed to have beneficial
health effects, risk versus benefit weighed.
Environmental contaminants present only risk to
exposed individual.
Drugs are taken at pharmacologic doses,
exposure to pollutants generally at
subpharmacologic doses.
EPA performs quantitative risk assessments to
determine safe or acceptable exposure levels,
FDA either approves or does not approve a
drug. Safety data provided in label.
Food and Drug Administration
FDA has data that can facilitate
extrapolation to human toxicity
Toxicity in cultured cells
Toxicity in intact animals
Toxicity in humans
Food and Drug Administration
A Proposed Vision on the Future
of Carcinogenicity Testing
FDA is completely committed to the “3Rs”.
 All ICH safety guidelines have 3R
considerations as a top priority.
 We are making progress in the short term
and dramatic changes in the not too
distant future.
 Current focus is carcinogenicity studies.
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Food and Drug Administration
The Perfect Carcinogenicity Test
Would:
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identify all materials that could potentially
induce cancer in human beings.
have 100% sensitivity (no false negatives)
and 100% specificity (no false positives).
rank carcinogens in order of potency.
identify target organs/tissues and types of
tumors,e.g. small cell carcinoma of the
lung vs. squamous cell carcinoma of the
skin.
provide results rapidly and at low cost.
Food and Drug Administration
State of the art: 2-year
carcinogenicity studies in rodents
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Protracted, 2-year in-life, 3 month preliminary doserange finding studies, 4 - 6 month post-life, 3+ years
to get answer.
Expensive, depending on route of exposure, can cost
from one to several million dollars.
Hazard assessment is imperfect. While most human
carcinogens are identified by this assay, many false
positives are suspected, especially those that induce
tumors in only one species, one sex and/or one site.
Quantitative risk assessments tend to exaggerate
risks to humans.
Many animals are required. Typically, 50+/sex/dose
plus vehicle controls. More animals for TK
Positive data provide little or no mechanistic
information about the material.
Food and Drug Administration
Near-term future of
carcinogenicity testing
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Carcinogenicity battery:
Negative genetox battery
 Negative 6-month transgenic mouse
 Lack of preneoplastic lesions and lack of hormonal
perturbation in rat chronic study
 Negative in silico prediction
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Two year studies not required
Food and Drug Administration
How can the “omics” revolution
help risk assessment for cancer
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Shorten time required to determine if drug or a
chemical is potentially carcinogenic
Lower cost of testing will allow more compounds
to be tested
Improve extrapolation of animal data to humans
Improve extrapolation from experimental high
dose to human exposure dose
Reduce animal usage
Provide insight into mechanisms of action
Food and Drug Administration
Research Objectives of the
Carcinogenicity Working Group
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Short Term Objectives:
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Identify and evaluate the utility of genomic biomarkers
to provide an early prediction of carcinogenicity,
especially by non-genotoxic compounds
Develop an assay platform and test protocol to enable
the early prediction and mechanistic assessment of
carcinogens
Long Term Objectives:
A.
Determine if genomic data combined with other subchronic/chronic toxicity endpoints can reduce the
reliance on life-time rodent cancer bioassays
- see Jacobson-Kram (2008) Vet Pathol 45:707
Food and Drug Administration
Predictive Toxicogenomics Approaches
Reveal Underlying Molecular Mechanisms
of Nongenotoxic Carcinogenicity
Nie et al. Molec. Carc. 45:914, 2006
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Examined over 100 “paradigm compounds” to develop
signature for nongenotoxic carcinogens.
Male rats given a single high dose (30 to 50% of
published LD50) of each chemical and the livers were
removed 24 hrs after dosing.
A training set consisting of 24 nongenotoxic carcinogens
and 28 noncarcinogens was used to identify a six gene
signature which identified nongenotoxic carcinogens with
an accuracy of 88%.
This was the case whether or not the liver was the
ultimate target organ.
Food and Drug Administration
A Gene Expression Biomarker Provides Early
Prediction and Mechanistic Assessment of
Hepatic Tumor Induction by Nongenotoxic
Chemicals
Fielden, et al. Tox. Sci. 99 90-100, 2007
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Rats treated for 5 days with one of 100 structurally and
mechanistically diverse nongenotoxic hepatocarcinogens
and nonhepatocarcinogens
Novel multigenebiomarker (i.e., signature) was derived
to predict the likelihood of nongenotoxic chemicals to
induce liver tumors in longer term studies
Independent validation of the signature on 47 test
chemicals indicates an assay sensitivity and specificity of
86% and 81%, respectively
Not too bad!
Food and Drug Administration
Outcome of Interlaboratory
Evaluation
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Food and Drug Administration
Interlaboratory Evaluation of Genomic
Signatures for Predicting Carcinogenicity
in the Rat
Fielden et al., Tox. Sci. 103:28, 2008
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Examined data from short term rat studies on
over 150 compounds
Merged data sets indicated that the accuracy of
the Fielden et al. and Nie et al. signatures was
approximately 65% and 60%, respectively
Differences in study design and different
microarray platforms resulted in reduced
predictivity relative to internal validation
estimates reported in the individual studies
Food and Drug Administration
Conclusions
Current tools for cancer hazard and risk
assessment are imperfect.
 In the near term reduce dependence on
two-year carcinogenicity studies using
“battery” approach.
 In the longer term omics technology may
provide faster and mechanistically-based
risk assessments.
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Food and Drug Administration