FDA-Approved Drug Labels, Pharmacogenomics and PharmGKB Evaluation

FDA-approved drug label standardization and pharmacogenomics
People often use the wording "FDA drug labels" instead of "FDA-approved drug labels."  To be clear, the FDA does not write drug labels; it is the responsibility of the drug company to provide them.  The FDA reviews and approves labels, and has implemented rules to standardize them.  Since 2005, submitted labels are required to be in Structured Product Labeling (SPL) format.  Starting in 2006, label highlights are required to have bulleted boxed warnings, and include indications and a Table of Contents.  These requirements greatly improve the organization and readability of labels for humans, but stop short of standardization enabling automated parsing and interpretation of labels.  It remains difficult to use techniques like Natural Language Parsing (NLP) to automatically extract information from drug labels.  And even with the current rules, sometimes vital information remains missing from approved drug labels, such as data regarding toxicity and uncertainty regarding the net benefit,  and comparative effectiveness.

The language used in drug labels can be vague and often stops short of requiring action.  For example, the azathioprine label states "It is recommended that consideration be given to either genotype or phenotype patients for TPMT."  Do they recommend testing?  They don't mention testing anywhere on the label, only that consideration should be given to the genotype or phenotype.  With a new patient, how would you have this information without testing?

The FDA maintains a list of labels containing pharmacogenomic information, called the Table of Pharmacogenomic Biomarkers in Drug Labels.  It is important to note that this table is (1) not a complete list of labels that reference genes, nor does it reflect (2) all genes of importance on labels listed or (3) indicate that the genes that are listed in the table are important for prescribing the drug.  Here is an example of each case (as of 10/20/13):

(1) Many drug labels that discuss G6PD deficiency are not listed in the table (eg. glibenclamide, pegloticase, primaquine - this also mentions CYPB5R3 deficiency on the label!), but the chloroquine label mentioning G6PD deficiency is listed.  Why chloroquine is listed but not other drugs warning against G6PD deficient patients is unclear.

(2) The valproic acid (Depakene) label is listed in the table with NAGS, CPS1, ASS1, OTC, ASL, ABL2.  These are genes related to urea cycle disorder which is a contraindication of the drug, though the genes are not listed by name on the label.   However the label does specifically discuss POLG gene mutations that predispose patients to increased risk of liver failure and death. POLG is a mitochondrial DNA polymerase associated with hereditary neurometabolic syndromes such as Alpers Huttenlocher Syndrome, and the valproic acid label states "POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders."  POLG is not listed in the Biomarker table with this or any other drug.

(3) The prasugrel (Effient) label is listed in the table with CYP2C19 (no other genes).   The label states "There is no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of prasugrel's active metabolite or its inhibition of platelet aggregation." The drug-gene pair is likely in the table because CYP2C19 poor metabolizers may be poor responders to clopidogrel, another anti-platelet drug.  For these cases, prasugrel is a typical alternative because CYP2C19 variation does not affect prasugrel use in any way.   This is an example where a drug-gene pair on the Biomarker table does not indicated a relevant PGx relationship between the two.

When PharmGKB curators curate drug labels, they need to interpret them, and that can be subjective.   PharmGKB has recently reviewed the drug labels from the FDA's Biomarker Table and improved the label annotations.  Curators have tried to define clearly how they interpret the level of PGx information on labels, resulting in definitions that are really a rather long list of criteria.  These definitions may change over time as new label wording comes up and definitions need to adjust for these new cases.

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