Methods
We downloaded all data on 14 April 2020, from which we extracted the
level tag and PGx. The SmPCs TMMDA-approved drugs retrieved from the
agency’s website and checked and updated according to the 2020 version
of RX Media Pharma Interactive Pharmaceuticals Information Source were
screened and analyzed for PGx content [20,21]. Then, we compared the
information provided in TMMDA-approved labels with that in the
Pharmacogenomics Knowledgebase (PharmGKB) database [22]. PharmGKB
annotates drug labels containing PGx approved by the FDA, EMA, Swiss
Agency of Therapeutic Product (Swissmedic),
Pharmaceuticals and Medical
Devices Agency, Japan (PMDA), and
Health Canada (Santé
Canada, HCSC). PharmGKB annotations provide a brief summary of the PGx
in the label, an excerpt from the label, and a downloadable highlighted
label PDF file. A list of genes and phenotypes found within the label is
mapped to label section headers and listed at the end of each
annotation. PharmGKB also attempts to interpret the level of action
implied in each label with the
”PGx Level” tag
[22]. There are four levels of actions:
1. Testing required, states or implies that some sort of gene, protein,
or chromosomal testing, including genetic testing, functional protein
assays, and cytogenetic studies, should be conducted before using this
drug.
2. Testing recommended, states or implies that some sort of gene,
protein or chromosomal testing, including genetic testing, functional
protein assays, and cytogenetic studies, is recommended before using
this drug.
3. Actionable PGx, may contain information about changes in efficacy,
dosage, metabolism, or toxicity due to gene/protein/chromosomal variants
or phenotypes (e.g., ”poor metabolizers”), or the label may mention
contraindications of the drug in a particular subset of patients with
particular variants/genotypes/phenotypes.
4. Informative PGx, contains information stating that particular
gene/protein/chromosomal variants or metabolizer phenotypes do not
affect a drug’s efficacy, dosage, metabolism, or toxicity, or states
that particular variants or phenotypes affect a drug’s efficacy, dosage,
metabolism, or toxicity, but this effect is not “clinically”
significant. Or, the label appears or appeared on the FDA Biomarker List
but does not currently meet the requirements to be assigned as “Testing
required,” “Testing recommended,” or “Actionable PGx.”
First being the highest level, we analyzed the consistency of
recommendations of labels approved by different agencies as well.
Statistical analysis: The data were presented as the percentage of the
drug labels approved by each agency and presented as numbers and
percentages. No statistical comparison was performed as the aim of this
study was to determine the discrepancies among agencies and the possible
effects of these discrepancies on ethical issues.