October 18, 2022
Significance of Pharmacogenomic Biomarkers in Biological Drug Labeling: A USFDA Perspective

In the era of personalized medications, precision medicine revolutionized the delivery of biologicals, ensuring safety and efficacy by comprehending the product’s effect at an individual level. Pharmacogenomics (PGx) is one of the components of precision medicine owing to its role in optimal dose selection and effective, dose-responsive, individual identification that can avoid adverse reactions.

Furthermore, with the advent of PGx biomarkers, the fate of biologicals in terms of pharmacokinetics and pharmacodynamics can be assured. Life Sciences companies manufacturing biologicals provide information on the PGx biomarkers in the labeling section, which assists healthcare practitioners and patients during their administration. The genesis of the inclusion of PGx biomarkers details can be traced back to early 2013 with the United States Food and Drug Administration’s (US FDA’s) guidance titled ‘Clinical Pharmacogenomics: Premarket Evaluation in Early-phase Clinical Studies and Recommendations for Labeling.’ It mentioned that the PGx labeling must describe the genomic marker and functional effects of genomic variants after drug administration.

As per a survey conducted in early 2021, the US FDA witnessed a threefold (3x) increase in the biological approvals containing PGx biomarker labeling for therapeutic and congenital anomalies from 2000 to 2020. Statistically, the increase went from 10.3% in 2000 to 28.2% in 2020. This approval upsurge indicates the adherence of the pharmaceutical companies to the guidance and inclusion of PGx biomarkers’ labeling to ensure public health. Although the inclusion of PGx information in drug labels was noticed for all clinical areas, they were prominent in some therapeutic areas.

The significance of PGx biomarker labeling can give insights to the stakeholders on the following points:

  1. Mechanism of drug action
  2. Associated adverse events
  3. Genotypic information on dosing
  4. Clinical response variability across individuals through drug exposure
  5. Polymorphic drug targets and disposition genes
  6. Clinical trials adopted during the development

In August 2022, the US FDA released data tabulating the list of PGx biomarkers, drugs, therapeutic areas, and instructions to be incorporated in the labeling section. The table below is an excerpt from the published comprehensive biomarkers list with their corresponding labeling sections instructions/warnings.

Sr. No.

Labeling Sections

Biomarkers

1.

Adverse Reactions

  • TPMT
  • Chromosome 7
  • Chromosome 13
  • CYP2C19
  • ROS1

2.

Adverse Reactions, Clinical Studies

  • BCR-ABL1 (Philadelphia chromosome)
  • HBB
  • BRAF
  • ERBB2 (HER2)
  • MYD88

3.

Boxed Warning, Warnings and Precautions, Use in Specific Populations, Patient Counselling Information, Contraindications

  • CYP2D6
  • HLA-B
  • CYP2C19
  • Non-specific (Congenital Methemoglobinemia)
  • Chromosome 5q

4.

Clinical Pharmacology

  • UGT1A1
  • CYP2C9
  • IFNL3 (IL28B)
  • CYP2C19
  • SLCO1B1

5.

Clinical Studies

  • Gene Signature (T-effector)
  • KIT, CD274 (PD-L1)
  • CBL
  • PTPN11
  • PGR (Hormone Receptor)

6.

Contraindications

  • Non-specific (Genetic Susceptibility to Malignant Hyperthermia)
  • PROC
  • PROS1
  • SERPINC1 (Antithrombin III)
  • LEP

7.

Indications and Usage, Adverse Reactions, Clinical Studies

  • ESR (Hormone Receptor)
  • ERBB2 (HER2)
  • CPS1
  • OTC (Urea Cycle Disorders)
  • Microsatellite Instability

8.

Indications and Usage, Dosage and Administration, Adverse Reactions, Clinical Studies

  • Homologous Recombination Repair
  • EGFR,
  • RCA
  • Genomic Instability (Homologous Recombination Deficiency)
  • CD274 (PD-L1)

9.

Indications and Usage, Dosage and Administration, Adverse Reactions, Use in Specific Populations, Clinical Studies

  • BCR-ABL1 (Philadelphia chromosome)
  • TNFRSF8 (CD30)
  • MS4A1 (CD20 antigen)
  • RET
  • LEPR

10.

Indications and Usage, Dosage and Administration, Warnings and Precautions, Adverse Reactions, Use in Specific Populations, Clinical Studies

  • AMACR
  • AKR1D1
  • CYP7A1
  • HSD3B2 (Bile Acid Synthesis Disorders)
  • BCR-ABL1 (Philadelphia chromosome

11.

Warnings

  • HLA-B
  • G6PD
  • Non-specific (Congenital Methemoglobinemia)
  • HLA-A
  • ESR

Figure 1. Labeling instructions for respective biomarkers, an excerpt from the US FDA website

With the inclusion of PGx biomarker labeling for drugs and biologicals, it is essential to adhere to and comply with global labeling standards. Precision medicine-based labeling requires tailor-made business strategies and expertise to sail through Regulatory processes. Check now for more updates on Freyr's in-depth and proven expertise.

Author:

Varunesh Tambe
Management Trainee