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Guest Editorial
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Toxicogenomic Applications to Drug Risk Assessment I.Y. Rosenblum |
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Genomic technologies have the potential of expanding
accessible biomarkers across test species in toxicology studies. One of the major
goals is to discover biomarkers that bridge preclinical and clinical studies.
Over the past several years, genomic technologies have evolved that enable
the simultaneous analysis of the expression of hundreds to thousands of genes.
This capability has completely changed the types of questions and the quality
of information that can be queried by biomedical scientists. The functional
status of a living cell can be characterized at the molecular level by its gene
expression patterns. Cells belonging to different tissues and organs, cells
in various developmental stages, cells in different metabolic states, cells
under the influence of specific chemicals (whether natural or synthetic, endogenous
or exogenous), cells within a diseased tissue or tumor--all may differ by their
gene expression patterns at any given point in time.
Of the various applications of genomic technologies, toxicology is one of
the most pragmatic in terms of its role in the safety assessment of new therapeutic
candidates. The analysis and evaluation of gene and protein expression changes
that modulate toxic responses has been named toxicogenomics and toxicoproteomics,
respectively. These emerging disciplines promise to revolutionize the field
of toxicology by aiding and supplementing our mechanistic understanding of how
drug treatments in animals and humans induce toxic insults in one or more tissues
or organs. With the possible exception of very rapid cell death, it is believed
that gene expression changes underlie all drug-induced toxic events. The question
is will analysis of drug-induced gene expression changes lead to a better understanding
of the mechanism of toxicity? And if so, can investigators use this knowledge
to design a safer drug without compromising the drug's beneficial (therapeutic)
effects? Will genomic analysis lead to the identification of useful biomarkers
of toxicity, i.e., a biological signal that can be measured in patients that
will accurately report or, better yet, predict the onset of drug-induced toxicity?
Will genomic analysis lead to gene expression or protein expression patterns
that become the "signature" of toxic potential for that particular drug? If
the answer is "yes," then can genomic patterns become useful screens applied
in the early drug discovery stages, leading to less toxic "lead candidates"
that enter drug development? These questions and others are being intensely
and actively investigated by nearly every major pharmaceutical and biotechnology
company as well as by the U.S. Food and Drug Administration (FDA), the National
Institute of Environmental Health Sciences, and numerous academic laboratories.
Over the past several years, a number of forums involving the pharmaceutical
and biotechnology industries, regulatory agencies, and academia have been organized
to address some of these challenges. In mid-1999 the Health and Environmental
Sciences Institute (HESI) of the International Life Sciences Institute (ILSI)
(http://hesi.ilsi.org/) formed a project committee to develop a collaborative
scientific program to identify and address some of the key issues arising from
the emerging application of toxicogenomics to drug safety risk assessment. The
investigational studies conducted and reported by this consortium (Hamadeh et
al. 2002; ILSI/HESI 2003) created a path for several other forums focused on
this and related topics. An active HESI consortium now exists for the search,
characterization, and validation of biomarkers of drug-induced toxicity. Immediate
goals include the design and conduct of studies that will identify early predictive
biomarkers of nephrotoxicity, cardiotoxicity, and testicular toxicity.
It is now apparent that one major application of toxicogenomics in drug development
is the identification and characterization of early predictive biomarkers of
toxicity. More sensitive and specific biomarkers will contribute not only to
the understanding of the mechnisms involved in drug-induced toxic responses
but also to improving human risk assessment that is fundamental to the drug
approval process by the FDA or other regulatory agencies. Many of the conventional
biomarkers used in preclinical drug safety studies are either insensitive, nonspecific,
or they appear late in the pathogenesis of the lesion and, as such, qualify
only as reporters or indicators of toxicity. Other criticisms of conventional
biomarkers include their noninvasive accessibility, their limited species specificity,
and their relevance to human risk. Genomic-derived biomarkers have the potential
of appearing early in the pathogenesis of the lesion, possibly serving as predictors
as opposed to indicators of toxicity (Goodsaid 2003; Guerreiro et al. 2003).
In addition, genomic technologies have the potential of expanding accessible
biomarkers across test species in toxicology studies. One of the major goals
is to discover biomarkers that bridge preclinical and clinical studies.
A variety of recent forums have focused on the issue of genomic data submission
to support human risk assessment. The FDA and PhRMA (Pharmaceutical Research
and Manufacturers of America) have sponsored workshops focused on the generation
of guidelines for genomic data submission. The inaugural meeting, held spring
2002, created the framework for several follow-up meetings on this topic. The
FDA perspective is that genomic data will enrich new drug applications, and
the agency has encouraged sponsors to submit genomic data in drug submissions
under a "safe harbor" provision. The majority of sponsors are concerned that
the science of genomics is still developing and that the FDA is not prepared
to review or interpret genomics data. The fear is that submission of genomics
data will result in significant differences in data interpretation, resulting
in many questions that will delay FDA approvals. The Drug Information Association
(DIA) in collaboration with the FDA, PhRMA, the Biotechnology Industry Organization
(BIO), and the companies represented by the Pharmacogenomics Working Group (PWG)
has scheduled a workshop 13-14 November 2003 that will discuss and debate
the draft FDA guidelines titled "The Genomic Data Submission (GDS) Proposal"
(http://www.diahome.org).
Within the context of pharmaceutical drug development, the ultimate payoff
for toxicogenomics and toxicoproteomics can be enormous. However, we are not
ready for "prime time." Many challenges must be met to ensure scientific valid
and appropriate incorporation of these technologies into product development,
product evaluation, product regulation, and ultimately, medical practice. From
a regulatory viewpoint, several critical issues will likely affect the level
of scientific scrutiny of genomic-derived data. Key factors include the stage
or stages of drug development at which these technologies are applied. The FDA
emphasized that the level and rigor of scientific scrutiny of data will depend
on when in drug development these methods are applied and how the resultant
data intend to be used. The outcome of the DIA-FDA-PhRMA-BIO-PWG
workshop in November should help clarify many impending issues and pave the
way for new technological applications that can improve the risk assessment
process.
A tremendous effort of everyone will be needed to move rationally in the direction
of achieving scientific credibility, followed by regulatory and scientific consensus
of how and when to apply genomic data to drug development and the approval of
new medicines. The payoffs include a better understanding of human diseases,
safer and more effective drugs to treat diseases, and more efficient and quicker
development time for producing and marketing new therapeutic agents.
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I.Y. Rosenblum
Drug Safety
Schering-Plough Research Institute
Lafayette, New Jersey
E-mail: irwin.rosenblum@spcorp.com
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Dr. Rosenblum is group director of Drug Safety at the
Schering-Plough Research Institute, a division of Schering-Plough Pharmaceutical
Corporation. His current job responsibilities include general toxicology,
genetic and molecular toxicology, and safety pharmacology. His research
interests and experience include biochemical, pharmacological, and toxicological
aspects of drug development. He presently serves on the editorial boards
of the Journal of Regulatory Toxicology and Pharmacology and the EHP Toxicogenomics
section.
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References
Goodsaid FM. 2003. Genomic biomarkers of toxicity. Curr Opin Drug Discov Devel 6:41-49.
Guerreiro N, Staedtler F, Grenet O, Kehren J, Chibout S-D. 2003 Toxicogenomics in drug development. Toxicol Pathol 31:471-479.
Hamadeh HK, Knight BL, Haugen AC, Sieber S, Amin RP, Bushel PR, et al. 2002. Methapyrilene toxicity: anchorage of pathologic observations to gene expression alterations. Toxicol Pathol 30:470-482.
ILSI/HESI. 2003. Proceedings of workshop on Toxicogenomics in Risk Assessment: Assessing the Utility, Challenges, and Next Steps, 5-6 June 2003, Fairfax, VA. Washington, DC:International Life Sciences Institute, Health and Environmental Sciences Institute.
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