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.