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):
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
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.