Standardization of Clinical PGx Testing
Pharmacogenetics practice guidelines aim to increase concordance among laboratories
Victoria M. Pratt, PhD, FACMG, is associate professor and director of Pharmacogenetics and Molecular Genetics Laboratories at Indiana University School of Medicine. She graduated with a Ph.D. in medical and molecular genetics from Indiana University School of Medicine in 1994. Prior to joining Indiana University, she was chief director, molecular genetics, for Quest Diagnostics Nichols Institute. She is a medical and clinical molecular geneticist board-certified by the American College of Medical Genetics. Currently, Dr. Pratt serves as the president of the Association for Molecular Pathology and PGx Working Group chair.
Q: Can you briefly describe what pharmacogenetic (PGx) testing is? When and why is it performed?
A: Pharmacogenetic testing focuses on the identification of genomic variants that can influence how an individual will react to specific medications. Pharmacogenetic testing results or insights help enable healthcare providers to optimize drug dosage and potentially reduce the risk of adverse drug events.
Q: How has PGx testing affected patient care in recent years?
A: During the past decade, advances in genome analysis techniques and technologies have enabled scientists to identify thousands of genetic variations that are associated with disease susceptibility and drug responses. These findings have significantly improved our understanding of the mechanisms underlying disease pathogenesis and drug responses.
Q: What are the major challenges that limit adoption of PGx testing in routine clinical care? What steps need to be taken to overcome them?
A: Despite the fact that many commercial platforms are available, clinical laboratories often develop their own laboratory tests for CYP2C9 genotyping. Consistency in clinical genotyping panels among clinical laboratories could further promote the utilization of these important clinical PGx practice guidelines.
Q: What factors are to be considered when choosing PGx tests to guide treatment decisions?
A: There are a number of important factors involved, including the patient’s clinical scenario and the pharmacokinetics and metabolic pathway of the medication. There is also the potential functional impact of pharmacogenomic variants on the therapeutic agents being considered, and allele frequencies in different populations and ethnicities. The PGx testing platform selected should ensure that clinically important alleles are being tested.
Q: How does health insurance for PGx test panels work?
A: Reimbursement for pharmacogenomics testing involves many constantly moving parts and varies depending on the type of test and code the laboratory obtains. In general, laboratories seek to obtain a Current Procedural Terminology (CPT) code, where evidence (i.e., clinical validity) is reviewed. Once a CPT code is obtained, a value is assigned. Then payers, whether governmental or private, decide whether or not to cover and reimburse the pharmacogenomics test (or panel). For clinical laboratory tests, most insurers use the concept of reasonable and necessary to equate to clinical utility. While there is no standardized definition for clinical utility, in its simplest form it equates to a change in medical management. Testing for pharmacogenomic variants can change medical management in a number of ways such as determining if a medication is predicted to be effective at current dosage, should be discontinued, or if a dosing change is needed.
Q: Can you tell me a bit about the work being done by the Association for Molecular Pathology’s Pharmacogenomics working group?
A: AMP frequently leads and/or participates in collaborative professional society working groups to develop clinical practice guidelines. In this case, the AMP-led Pharmacogenetics Working Group included organizational representation from both the College of American Pathologists and the Clinical Pharmacogenetics Implementation Consortium. The AMP PGx Working Group is developing a series of guidelines designed to help standardize clinical testing for frequently used genotyping assays. The Working Group was formed to derive a minimum set of alleles/variants that should be included in clinical PGx genotyping test panels, and to define the key attributes of the selection of these alleles.
The latest CYP2C9 report follows a set of recommendations for clinical CYP2C19 genotyping allele selection that was previously published in May 2018. These reports define a minimum set of alleles/variants that should be included in clinical genotyping panels for two of the most important PGx genes. Since these genes are involved in the phase I metabolism of many commonly prescribed medications, this series of recommendations should be implemented with other clinical guidelines such as those issued by Clinical Pharmacogenetics Implementation Consortium, which focus primarily on the interpretation of genotyping results and therapeutic recommendations for specific drugs.
Q: As part of the working group, you have published recommendations for allele selection in diagnostic PGx assays. How did the group identify the most important variants to be included?
A: The AMP PGx Working Group started with CYP2C19 and CYP2C9 genotyping panels due to the widespread adoption of these tests and our desire to help physicians, pharmacists, researchers, and other stakeholders better understand what these panels include and what the test results mean. To determine variants for both CYP2C19 and CYP2C9 testing we considered a number of important factors, including the functional impact of the variants, allele frequencies in different populations and ethnicities, the availability of reference materials, as well as other technical considerations for PGx testing.
Q: How do you think standardization of alleles/variants will impact interpretation of tests and medication management in patients?
A: AMP members are among the early adopters of molecular diagnostic testing in clinical settings, and we are committed to continuously improving professional practice and patient care. In this latest report, we highly recommend that clinical laboratory professionals include our Tier 1 set of alleles that
- Have been well characterized and shown to significantly affect the function of the protein and/or gene leading to an alteration in a drug response phenotype.
- Have an appreciable minor allele frequency in a population/ethnicity group
- Have publicly available reference materials
For example—currently, CYP2C9 tests can produce variable results due to factors such as the choice of tested alleles, targeted testing of populations with varying ethnic backgrounds, as well as the technical performance of the various platforms. This latest report provides recommendations for a list of alleles that should be included in clinical CYP2C9 genotyping tests to help standardize testing and genotyping concordance among laboratories.
Q: How might standardization of genetic variants across clinical laboratories affect CLIA certification of PGx test panels or FDA drug labels?
A: The FDA recognizes the role of CYP2C9 genetic variability for a number of medications. However, very limited information is usually available in FDA product labels regarding the testing methods employed by drug manufacturers while conducting PGx studies. Specific considerations from a diagnostic laboratory perspective such as allele selection, testing platforms, and availability of reference materials have not been the focus of the consortia guidelines. Consistency in clinical genotyping panels among clinical laboratories could further promote the utilization of these important clinical PGx practice guidelines.
Q: How do you envision pharmacogenomics will evolve in the age of artificial intelligence and big data?
A: Pharmacogenetics is a rapidly changing field. We hope that with artificial intelligence (AI), pharmacogenetic testing results will be routinely incorporated into patient care. As pharmacogenetics evolves, we intend to update these recommendation documents as new technologies, data, or reference materials become available.