Home Health Care FDA study offers new tool to make sense out of pharmacogenetics data

FDA study offers new tool to make sense out of pharmacogenetics data

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In the late 1990s and early 2000s, healthcare providers and researchers noticed that some patients with HIV (approximately 5%) experienced a severe hypersensitivity reaction to the drug abacavir, in some cases causing multiple organ failure, anaphylactic shock and even death. They were eager to determine why only certain patients were affected so they could continue to prescribe this highly effective therapy while minimizing the risk of potential harm. Early research urged providers to closely monitor patients taking abacavir and discontinue the therapy if signs of a reaction occurred.

Researchers set out to see if a genetic variant or polymorphism was associated with hypersensitivity to abacavir. By early 2002, the first studies associating a variant with abacavir hypersensitivity were published. Today, all patients must undergo genetic testing for the high-risk genetic variant before starting abacavir therapy.

These discoveries were major milestones in an emerging and rapidly growing area of precision medicine that has since identified numerous other associations between genetic variation and optimal drug response or adverse reaction profile. More specifically, the field of pharmacogenetics, which uses a patient’s genetic test results to identify the most effective, lowest-risk drug therapies for their individual conditions, has become an increasingly recognized optimization strategy for prescribing decisions.

An emerging field

Each year, more findings emerge about how our DNA influences how we respond to drugs. This data has been accumulating at such a rapid rate that the FDA now offers two informational resources for prescribers: Table of Pharmacogenomic Biomarkers in Drug Labeling and a Table of Pharmacogenetic (Pharmacogenetics) Associations, which lists gene-drug interactions that the agency has determined to have sufficient scientific evidence to suggest that there are gene-based differences in drug response. The lists, however, cover different aspects of pharmacogenetic information. While there is some overlap between the resources, the scope of information is different, and neither is comprehensive.

The desire for a more complete and organized view of pharmacogenetic information is the main reason why my pharmacist colleagues and I decided to review, analyze and break down the information in the FDA resources. We grouped the pharmacogenetic information referenced in the tables into seven categories that described the nature of the drug-gene interaction.  Additionally, we determined whether the gene was known to impact drug safety (adverse reaction risk), drug efficacy (risk of reduced effectiveness), neither or both. The study, “Characterization of Pharmacogenetic Information in Food and Drug Administration Drug Labeling and the Table of Pharmacogenetic Associations,” was published in the peer-reviewed journal Annals of Pharmacotherapy.

We wanted to have a structured and systematic approach to reviewing pharmacogenetic information in order to appreciate the full breadth of the nature and potential clinical impact of the information. This can lay the foundation for structuring meaningful pharmacogenetic information into the prescriber’s clinical decision-making process. After all, only 9% of primary care physicians report ordering a pharmacogenetics (PGX) test according to the results of a 2020 survey, and less than 4% report that they feel confident in their ability to interpret the results. At the same time, however, 80% of respondents reported they would be likely or very likely to consult a pharmacogenetics-trained pharmacist for help interpreting a report. Educating all stakeholders about pharmacogenetics information and including such information in clinical decision support guidance could help protect more patients and improve outcomes.

Driving safe and effective decisions

Clinicians’ time is limited, and pharmacogenetics (PGX) test result reports are often lengthy and complex, so it is not surprising that few of the survey respondents were eager to include such information in their decision making. The FDA supplies pharmacogenetics information, but again, few providers have the time to carefully review it for relevancy to their individual patients.

Our study attempts to provide an organized view of the types and outcomes of clinically relevant FDA-reviewed pharmacogenetics information. We analyzed individual FDA-approved prescribing information listed in the Table of Biomarkers in Drug Labeling (first released in 2008) as well as the Table of Pharmacogenetic Associations (first released in 2020). The FDA created the latter table in response to claims from some pharmacogenetics testing firms that were “not adequately supported by sound science,” according to a statement from the agency.

Our review began with more than 400 drug-gene pairs, but our list was narrowed to 308 pairs once we eliminated drug-gene pairs with information that did not describe an effect of genetic variation on drug disposition or response. Although most drugs studied were used in oncology, the drugs spanned a variety of other therapeutic areas including psychiatry, neurology, infectious disease and cardiology. Our categories of pharmacogenetic information were:

  • polymorphism-affecting drug metabolism
  • polymorphism-affecting drug transport
  • polymorphism affecting a drug’s direct protein target
  • variant associated with increased adverse drug reaction susceptibility
  • variant associated with poor therapeutic effect
  • biomarker-defined drug indication
  • biomarker-defined adverse drug reaction

Nearly all (97%) of the drug-gene pairs were associated with either a biomarker-defined drug indication (36%), polymorphic drug metabolism (33%) or increased adverse reaction susceptibility (28%). Examples of the latter category include increased risk for abacavir hypersensitivity in individuals who carry the HLA-B *57:01 gene or increased risk for hemolytic anemia in individuals with deficiency in a certain enzyme (glucose-6-phosphate dehydrogenase). Our characterization showed that 87% of the drug-gene pairs were associated with a safety or efficacy-related outcome, and most drugs were affected by variation in just a single gene.

Just the beginning

We expect pharmacogenetics data will become commonplace in select prescribing decisions in the near future.  Increasingly, research is demonstrating the “clinical utility” of including gene-based recommendations in prescribing decisions, thus making genetic testing more accessible, and health care payers more willing to support test coverage and reimbursement. Certainly, genetic information is used today to drive some decisions, but the relevancy and quality of the data are only part of the reason for its limited adoption thus far.

Prescribers need a pharmacogenetics knowledge base to determine a safe and effective medication and dosage for their patients, but they also need pharmacogenetics test information to be easily accessible, interpretable and meaningful. Our study is just one of many steps toward meeting the challenge of delivering pharmacogenetics information at or near the point of ordering so prescribers can easily and efficiently make optimal therapeutic decisions for their patients.

Photo: ipopba, Getty Images

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