Comparing the FDA’s Pharmacogenomic Biomarkers and Pharmacogenetic Associations Tables

Pharmacogenomics (PGx), which considers the relationship between an individual’s genetics and their response to medications (i.e., drug-gene interactions), is expanding in clinical medicine. There are currently 25 evidence-based guidelines covering 20 different genes (biomarkers) related to 66 drugs. These guidelines have been developed by the Clinical Pharmacogenetics Implementation Consortium (CPIC), an international group of researchers, clinicians and academicians, with the common goal of facilitating the application of PGx in pharmacotherapy.

Other PGx guidelines have been developed by the Dutch Pharmacogenetics Working Group (DPWG), the Canadian Pharmacogenomics Network for Drug Safety (CPNDS), and other groups.^1,2 The impetus for development of a specific guideline often starts with data obtained during drug development, which is then noted, to various degrees in the U.S. Food and Drug Administration (FDA) approved drug labeling. This data includes patient outcomes, pharmacokinetic (PK), and pharmacodynamic (PD) information. Whether related to an adverse drug reaction or drug efficacy, PGx information is an important component of drug labels, where clinicians can gain insight into drug-gene interactions.

Table of Pharmacogenomic Biomarkers in Drug Labeling

The FDA provides two different tables of information related to PGx. The “Table of Pharmacogenomic Biomarkers in Drug Labeling” (Biomarker Table) is a regularly updated resource noting drug-biomarker pairs for which biomarker information is provided in at least one section of the drug’s label. As of now, the Biomarker Table includes over 430 drug-biomarker pairs across therapeutic areas (Table 1).³

Table 1. Number of biomarkers in FDA-approved drug labels by therapeutic area

Therapeutic Area	Number of Biomarkers
Oncology	184
Psychiatry	38
Infectious Diseases	35
Neurology	32
Hematology	26
Anesthesia	23
Cardiology	18
Gastroenterology	16
Gynecology	10
Pulmonary	10
Rheumatology	10
Endocrinology	7
Urology	5
Dermatology	4
Other	13

Currently, applications of PGx by clinicians is mostly related to pharmacokinetics (PK), where drug metabolism phenotypes (i.e., ultrarapid, rapid, normal, intermediate, and poor) and transporter function phenotypes (i.e., increased, normal, decreased, and poor) are related to drug exposure.⁴ Drug exposure, in turn may be related to inefficacy or adverse drug reactions, where concentration-effect relationships have been established. Information gained in this context throughout drug development results in biomarker notation(s) in various sections of the drug label.

FDA-Approved Labels Containing Biomarker Information by Label

Table 2 presents the number of FDA-approved labels containing biomarker information by label section. Here it is clear that biomarkers can be noted in numerous label sections within a given label. Biomarker information provided in drug label sections helps clinicians understand the context of the potential impact of altered forms of biomarkers (e.g., variation in a drug metabolizing gene leading to altered drug exposure), which in turn, may be related to drug inefficacy or adverse reactions. Certainly, there are also biomarkers that are not related to PK that are independent of dose/concentration, such as HLA genes.

Table 2. Number of biomarkers in FDA-approved drug labels by label section

Label Section	Number of Biomarkers
Clinical Studies	191
Clinical Pharmacology	164
Precautions	126
Indications and Usage	119
Adverse Reactions	117
Warnings	115
Dosage and Administration	105
Warnings and Precautions	88
Use in Specific Populations	68
Drug Interactions	24
Contraindications	18
Patient Counseling Information	12
Boxed Warning	11
Overdosage	5

While the FDA provided the Biomarker Table, the agency realized that the vast majority of biomarker/PGx information in drug labels did not relate information in the context of patient outcomes. Therefore, in February of 2020, the agency published the “Table of Pharmacogenetic Associations” (Associations Table).⁵

The Table of Pharmacogenetic Associations

The Table of Pharmacogenetic Associations (Table 3) is updated on a continuous basis and consists of three sections including pharmacogenetic associations for which the data:

• support therapeutic management recommendations
• indicate a potential impact on safety or response
• demonstrate a potential impact on pharmacokinetic properties only

Table 3 presents information with higher levels of clinical evidence and the number of drug-gene pairs, to date, by section as presented in the Associations Table.⁵ It should be noted that the criteria for inclusion of drug-gene pairs in the Associations Table are not provided by the FDA.⁵ The affected “subgroups” are noted in Table 3 as well. The difference in the number of entries of drug-biomarker pairs in the Biomarker Table versus the number of entries of drug-gene pairs in the Associations Table speaks to the level of evidence related to a given pair.

Table 3. Number of drug-gene pairs in the FDA Table of Pharmacogenetic Associations

Table Section	Affected Subgroups (n=number of drug-gene pairs per subgroup)	Number of Drug-Gene Pairs
Pharmacogenetic associations for which the data support therapeutic management recommendations.	Allele (gene variant) positive (n=2) Intermediate, poor metabolizers (n=15) Poor metabolizers (n=28) Ultrarapid metabolizers (n=2) Ultrarapid, intermediate, poor metabolizers (n=1) Ultrarapid, normal, intermediate, poor metabolizers (n=1) Variant carriers (n=2)	51
Pharmacogenetic associations for which the data indicate a potential impact on safety or response.	Allele (gene variant) positive (n=6) Intermediate, poor function transporters (n=1) Poor metabolizers (n=12)	19
Pharmacogenetic associations for which the data demonstrate a potential impact on pharmacokinetic properties only.	Intermediate, poor metabolizers (n=6) Poor function transporters (n=2) Poor metabolizers (n=19) Ultrarapid or poor metabolizers (n=1) Ultrarapid, intermediate, or poor metabolizers (n=9)	37

The Associations Table includes more drug-gene pairs than are presented in CPIC, DPWG, or any other clinical guidelines and raises the question as to what criteria are used by the FDA for inclusion in the table. For example, while there is a CPIC guideline related to the drug-gene pair of simvastatin-SLCO1B1 and the FDA includes the simvastatin-SLCO1B1 pair in the Associations Table, SLCO1B1 is not mentioned in the Biomarker Table. A discussion of the Associations Table relative to label and off-label use of drug-gene interaction data was recently published.⁶ Regardless, the FDA is now providing broader information related to drug-biomarker and drug-gene pairs that will assist clinicians in clinical decision support.

Conclusions

Guidance from the FDA relative to clinical pharmacogenomics was discussed in a previous blog, “What is Pharmacogenomics?” Following this guidance and including PGx in drug development leads to inclusion of biomarker information in drug labels and the Biomarker Table. If the evidence rises to a certain level, drug-gene pairs will be included in the Associations Table. Independently, CPIC, the DPWG, and other groups may work to develop clinical guidelines all of which supports clinicians in efforts to provide safe and effective pharmacotherapy through the application of PGx.

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References

1. The Clinical Pharmacogenetics Implementation Consortium. Guidelines. Found at: https://cpicpgx.org/guidelines/. Accessed August 19, 2020.
2. The Pharmacogenomics Knowledgebase. Clinical Guideline Annotations. Found at: https://www.pharmgkb.org/guidelineAnnotations. Accessed August 17, 2020.
3. U.S. Food and Drug Administration. Table of Pharmacogenomic Biomarkers in Drug Labeling. Found at: https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling. Accessed August 17, 2020.
4. Caudle KE, Dunnenberger HM, Freimuth RR, et al. Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genet Med. 2017;19(2):215-223. doi:10.1038/gim.2016.87.
5. U.S. Food and Drug Administration. Table of Pharmacogenomic Biomarkers in Drug Labeling. Found at: https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations. Accessed August 19, 2020.
6. Kisor DF, Monte AA, Müller DJ. Pharmacogenetic associations and evidence-based pharmacogenomics guidelines: supporting label and off-label use of drug-gene interaction data. Pharmacogenomics. 2020;21(7):427-430. doi:10.2217/pgs-2020-0017.