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drug-labeling). In February 2020, they published a table of pharmacogenetic associations (https://www.
fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations) to highlight drug-
gene associations that are likely to have altered metabolism and, in certain cases, differential therapeutic
effects such as risks for adverse events and therapeutic failures. This is a living document and the FDA
has an open docket for stakeholders to offer specific comments about inclusion of other pharmacogenetic
associations along with the rationale and supportive evidence. It is unclear at this point how often this
table will be updated. While CPIC has published their process for robust and systematic evidence review to
[47]
develop their peer-reviewed guidelines ; the FDA does not explicitly discuss the evidence base underlying
the recommendations presented in their table of pharmacogenetic associations.

Dutch Pharmacogenetics Working Group
In 2005, the Royal Dutch Pharmacists Association established the DPWG with the objective of developing
pharmacogenomic-based therapeutic and dose recommendations. Thus far, recommendations have been
developed for over 80 drugs covering various therapeutic classes covered in both the CPIC and FDA
databases. These guidelines are updated every 3 months and are available to all physicians and pharmacists
in the Netherlands. They have also been integrated into the clinical decision support systems in the
Netherlands and serve as the main source of pharmacogenetic-guided recommendations used in U-PGx in
Europe [6,36] .

Of note, the FDA, CPIC, and DPWG guidelines offer similar recommendations for most drug-gene
pairs; however, differences in the guidelines’ development processes and/or allele and phenotype
[48]
classifications have resulted in discordance in some recommendations . For instance, pharmacogenetic-
guided recommendations for aripiprazole, clozapine, and gefitinib, among others, vary across all three
[49]
platforms. CPIC and DPWG are currently working on standardization of alleles and phenotypes . The
recent CYP2D6 genotype-phenotype term standardization project is one of the most important efforts
[50]
in this area . Using standardized terms and harmonizing the guidelines are likely to facilitate clinical
implementation efforts and data sharing across health systems around the world.

The Canadian Pharmacogenomics Network for Drug Safety
The Canadian Pharmacogenomics Network for Drug Safety (CPNDS) is an innovative, national program
[51]
that aims to reduce serious adverse drug reactions in children and adults . They have developed their
own specific “drug biotransformation” testing panel which contains variants of genes that are known to
influence the way a patient responds to a given medication or may predispose a patient to an adverse drug
reaction. Having a national health care system in Canada with an active surveillance network facilitates the
integration and dissemination of CPNDS guidelines to accelerate adoption of pharmacogenetics.

OTHER PERTINENT CLINICAL CONSIDERATIONS
Assessment of pharmacogenetic results for clinical applications should also account for non-genetic clinical
and environmental factors to evade incomplete conclusions and misguided recommendations. Drug-
drug interactions, disease states, organ function, hormonal status, and considerations of additional patient
specific factors are regularly taken into consideration for medication and dose selection. Drug-drug-
gene interactions should be duly considered as the efficacy and incidence of adverse events are chiefly the
result of parent compound and metabolite concentrations. In this section, we will review the concept of
phenoconversion, considerations for switching medications, and guidance for special populations including
transplant and pediatric patients as well as pregnant women. Other disease states have also been found
to modulate the activity of metabolizing enzymes, though with less clarity for clinical actionability and
therefore will not be covered here .
[52]