Toxicogenomics – A Drug Development Perspective - Genomic Biomarkers for Pharmaceutical Development - page 142

( http: // www.fda.gov / downloads / RegulatoryInformation / Guidances / ucm126957.pdf , accessed
on Jan. 8, 2013). The guidance itself encourages the integration of biomarkers in drug develop-
ment and their appropriate use in clinical practice. It is believed that this approach will help to
alleviate stagnation and to foster innovation in the development of new medical products, and,
ultimately, lead to better medicine. Furthermore, the guidance offers the FDA's current view on
pharmacogenomics and what the regulatory agency believes are the scientific grounds for eval-
uating such information as it relates to voluntary versus required submission of data. Many
principles found in this guidance apply to toxicogenomic studies. In particular, the identifica-
tion, evaluation, and validation of biomarkers are critical components of every pharmacog-
enomic and toxicogenomic case study in regulatory decision making. The guidance is general
and encompasses both genetic and genomic biomarkers; e.g., a CYP2D6 (cytochrome P450
2D6) mutation and an increase in HER2 (human epidermal growth factor receptor 2) expres-
sion can be viewed as a genetic and a genomic biomarker, respectively. The VGDS program
emphasized by the guidance creates a forum for scientific data exchanges and discussions with
the FDA outside of the regular review process. This is necessary, since future data submissions
will contain many more complex gene expression profiles and large-scale single nucleotide pol-
ymorphism maps (e.g., from whole genome scans), which will present new challenges in defin-
ing the analytical and clinical validity of such new and highly complex biomarker sets. Based
on the knowledge on genomics data related to drug safety, the FDA has approved 117 drugs
so far with pharmacogenomics information in their label ( http: // www.fda.gov / drugs / sciencer-
esearch / researchareas / pharmacogenetics / ucm083378.htm , last accessed on Feb. 18. 2013).
Although good progress has been made in recent years, additional proof-of-principle
studies are needed for the regulatory community to become more acceptant of using toxicog-
enomic data as part of the regulatory decision-making process. It will be important to dem-
onstrate, for instance, that toxicogenomics not only can confirm what is already known about
specific compounds and toxic end points (i.e., phenotypic anchoring), but also can accurately
predict toxicity for unknown compounds.
6.9 THE FUTURE PERSPECTIVE OF TOXICOGENOM ICS
The excitement that surrounded toxicogenomics when it was a new field has waned in
recent years [33] . While its objectives and goals have so far remained unchanged, a shift in
emphasis can be anticipated in the future. It is our view that toxicogenomics will remain
a valuable tool for mechanistic studies. However, toxicogenomics will need to fully take
advantage of data richness from enabling technologies with improved tools for knowledge
discovery. Specifically, the development of modernized data mining capability and systems
toxicology should be a future focus, especially methodologies to effectively extract and dis-
cover knowledge from very large data sets, to maintain high quality data and provenance
information, and to promote use and sharing of public data. Besides the need for developing
effective knowledge discovery tools, technology innovations will also impact the application
of toxicogenomics in the future. Notably, RNA-Seq is a newly emerging technology for both
mapping and quantifying transcriptome. Compared with earlier methods, massively parallel
RNA sequencing has vastly increased the throughput of RNA sequencing and allowed global
measurement of transcript abundance without the constraint of probes on the chip. The most