Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

88 Applying Pharmacogenomics in Therapeutics
has been approved and its usage is becoming increasingly common. Hopefully
these successes will encourage other drug companies to develop pharmacogenomic
testing services.
Pharmacogenomics can also be used during clinical studies to generate data
that predict whether patients respond well to a drug, regardless of whether they
have the target and/or genetic alterations that affect efficacy and toxicity. To allow
for this, patient specimens must be collected during phase I, II, and III trials (and
ideally postmarketing studies); once patient outcome is known (patient response to
the drug in terms of effectiveness and/or toxicity and, in some instances, chemoresistance),
correlations can be made between outcome and the presence/absence
of pharmacogenomic biomarkers. 73,74 Similar strategies and tests that are used for
target identification (target gene analysis and genome profiling) can be used to
identify these biomarkers. Again, this information and the development of pharmacogenomic
tests is beneficial to both patients and drug companies; it can be
used to guide patient selection and thereby maximize effectiveness and minimize
toxicity, making it more likely the drug is approved. 39,70 With regard to the latter,
postmarketing studies are encouraged as they allow for analysis in a large and
diverse population.
It is noteworthy that de novo mutations that occur in target genes, drug transporters,
and enzymes responsible for drug metabolism can cause resistance to targeted
therapies. This phenomenon occurs fairly frequently with cancer drugs due to high
incidence of genetic instability in cancer cells. The collection of patient biospecimens
throughout the clinical trial process can help identify these de novo mutations,
and allow for correlations with resistance to be made. This knowledge can then be
used to predict chemoresistance in patients and plan accordingly. For example, certain
de novo mutations in Bcr-Abl that alter its kinase domain can result in resistance
to imatinib. 75 This knowledge has led to the design of new tyrosine kinase inhibitors
that are not impacted by these mutations and can be used to treat CML patients who
have developed resistance to imatinib. 76,77
The FDA and European Medicines Agency (EMA) are the regulatory agencies
that oversee drug development and approval in the United States and in Europe,
respectively. The benefits that result from the usage of pharmacogenomics during
drug target identification and drug development studies support their mission
to ensure drug safety and efficacy, and to support innovations in drug discovery
and development; and as such, both agencies actively encourage the incorporation
of pharmacogenomics into both drug development and monitoring. They have
published several white papers that provide guidance to companies, and, in addition,
the FDA offers drug companies access to review staff in their Office of
Clinical Pharmacology who can help companies to devise a pharmacogenomic
plan for inclusion in their drug development pipeline. * In some instances, the
FDA may make approval of an NDA contingent on the inclusion of postmarketing
* EMA guidelines and concept papers: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/
general/general_content_000411.jsp&mid=WC0b01ac058002958e; FDA guidelines and concept papers:
http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/pharmacogenetics/default.htm