More progress, fewer barriers for PGx testing

Karen Titus

January 2024—Sometimes even superb ideas can also turn out to be quite, well, bothersome. Zoom meetings. Bridal showers. Bike lanes. Parking apps. QR menu codes. And—if laboratories aren’t careful—the same can be true of pharmacogenomic testing.

Just ask Ann Moyer, MD, PhD, associate professor, laboratory medicine and pathology, Mayo Clinic. When it comes to pharmacogenomic testing, laboratory medicine brings significant expertise to the table. But in clinical settings, physicians who prescribe the medications need to be familiar with how to use the test results. They also need to work with the lab to decide which tests, for which genes or gene-drug pairs, will be most helpful for their patients, she says.

“Especially if you’re going to start incorporating clinical support alerts into the EHR,” adds Dr. Moyer, who was chair of (until Dec. 31; she is now advisor to) the CAP/ACMG Biochemical and Molecular Genetics Committee. “If the practice doesn’t actually want them, then you’re just going to end up annoying them.”

It’s a lesson Stuart Scott, PhD, learned the hard way. In his previous position at Icahn School of Medicine at Mount Sinai, New York, he and his laboratory colleagues developed a comprehensive pharmacogenomics panel “that we were very proud of,” recalls Dr. Scott, who is now at Stanford University, where he is professor, Department of Pathology, and director of the clinical genomics laboratory. “We put a lot of time and energy into making sure it was scientifically valid and sound and high-evidence content.”

So thorough was their work, in fact, that the report generated by the panel was a 30- to 40-page PDF file. Which, needless to say, didn’t work. “It was way too much information,” says Dr. Scott.

Happily, it can also be taken as a sign of progress that pharmacogenomic testing is now large enough to be an irritant. The field, young but not new, has seen earlier barriers to its use fall in recent years. What might have once been a lengthy steeplechase event has now settled into the more routine laps around the track. “We’re seeing more progress, rather than new barriers,” is how Dr. Moyer characterizes the field.

One of the issues that’s dropped away, Dr. Moyer says, is that in the past it was possible to test for only one gene at a time—hardly a cost-effective or efficient approach. Most of these genes are involved in drug metabolism, with some drugs metabolized by multiple enzymes encoded by multiple genes. “If you can only do one test for one gene at a time, you’re really limited in how a patient can actually use that information.”

Now that gene panels are available, one barrier has fallen.

Other barriers have dropped away as electronic health records and clinical decision support alerts have evolved to accommodate pharmacogenomic testing. Solid data alone isn’t enough—physicians need seamless ways to access it, both in the short and long term.

“Really, the dream is for this to be testing that you do up front,” Dr. Moyer says, with results available for use at different points in a patient’s life—acknowledging, of course, that the tests will change and improve over time.

But if the results are in a PDF, they can easily become buried in the EHR, “and no one can ever find them again,” she says.

That’s a lesson Dr. Scott and his Mount Sinai colleagues learned the hard

way.

“It just didn’t work,” Dr. Scott says. “It was too much information.” Even the best information is useless if no one can find it. Clinical colleagues worried about who was responsible for managing pharmacogenomic results and possibly missing crucial information. What would happen if one physician ordered pharmacogenomic testing, and then a year or so later, another physician prescribed a medication for that patient but missed relevant pharmacogenomic information?

A more immediate practical problem arose as well. When Dr. Scott and colleagues were translating their pharmacogenomic research into clinical implementation, back in 2009 and 2010, “We thought it was going to be the next big thing. But there was very little appetite from the providers. That was understandable in retrospect, because they just didn’t know what to do with the results.”

Now it’s possible to put pharmacogenomic, or PGx, data into discrete fields in the EHR. Much work has also gone into refining clinical decision support alerts to make PGx results more user-friendly. It’s now possible for the PGx testing to remain effectively invisible to the prescribing physician. “It’s just there in the background,” says Dr. Moyer. The alerts can then be set up “so that when the patient has an actionable genotype, it fires; if they don’t, it leaves them alone.”

Having a more integrated EHR-based reporting, coupled with clinical decision support, is crucial. “You remove the massive burden of giving all that information at once to any one provider,” Dr. Scott says. As it turns out, comedy isn’t the only field where timing is everything.

Even the most organized and finely tuned system will sputter, however, if physicians lack basic PGx knowledge.

“The person prescribing the medication has to be at least somewhat familiar with pharmacogenomics, or be able to find the information they need to use it,” Dr. Moyer says. She’s seen improvement—another hurdle falling—in recent years, as education has expanded for clinicians and pharmacists. “That’s helped quite a bit.”

The biggest improvement she’s seen at Mayo came from its Right 10K study, involving more than 10,000 patients across numerous specialties and focused on using genomic data to individualize treatment. “That meant that many different physicians throughout the practice, and pharmacists, would be exposed to pharmacogenomic data on their patients,” Dr. Moyer says. “They could kind of get a taste of, ‘Well, what is this? Is it helpful?’” The effort included educational campaigns, Dr. Moyer says, “so people would know what to do when the data appeared, since they weren’t ordering the tests themselves.”

That turned out to have a leveling effect among all providers. In the past, some specialties have been quicker to adopt pharmacogenomics than others, in part for historical reasons, Dr. Moyer says. It depends in part, too, on the number of actionable drugs in a clinical specialty.

Another early barrier was outsized enthusiasm. Early adopters were understandably excited, perhaps “to the point that maybe as a field we weren’t all as realistic as we should have been,” Dr. Moyer concedes.

In practice, pharmacogenomics is focused primarily on drug metabolizing enzymes, and at present to a lesser extent on drug targets, Dr. Moyer says. “In general we can predict how the drug is going to be metabolized differently from one person to another. In those cases, we generally are able to predict toxicities, and maybe patients who needed an adjusted dose.

“But,” she continues, “we’re not at the point yet where we can say, ‘This is the drug you need to take.’ But early on, when the field was younger, I think people got the impression that it was going to be this magic bullet that would tell you exactly what drug to use. I think that’s jaded some clinical specialties to some extent.”

Some specialties, on the other hand, have shown great progress, with guidelines in place and high rates of adoption. Take, for example, the HIV drug abacavir. For patients who are positive for HLA-B*5701, it’s recommended that they not take the medication because they’re at higher risk for severe cutaneous reactions. In this area of medicine, Dr. Moyer says, it’s typical for PGx testing to be done up front prior to the medication being prescribed.

In other fields, knowing that a patient is a poor metabolizer of certain drugs may mean only a dose adjustment rather than a different drug. “It’s not always black and white,” she says.

Another earlier barrier, lack of reimbursement, is also dropping away, with a CPT code now available for PGx panel testing as payers recognize its benefits, says Dr. Moyer.

That’s been helped along by the strength and visibility of the Clinical Pharmacogenetics Implementation Consortium (https://cpicpgx.org), Dr. Scott says, with a growing literature acknowledging that medications that have CPIC guidelines have a level of evidence that warrants reimbursement. Though it’s limited to specific genes and medications, “just the fact they’ve come around to be more supportive is a huge change in the field.”

While individual institutions continue to make progress, the field has been pushed forward by larger entities such as CPIC that are doing some much-needed heavy lifting.

On a practical level, says Dr. Scott, CPIC answers the question uppermost in clinicians’ minds: If PGx testing is performed, how should they use the results clinically? CPIC has been publishing (in Clinical Pharmacology & Therapeutics) clinical practice guidelines for gene-drug pairs over the past dozen or so years.

All are structured the same way, Dr. Scott says: They include a section on the gene, one on the drug, and then a section containing the evidence supporting that association. They also have tables that link a particular genotype to the recommendation. CPIC does not advocate for or against testing. (“That’s a whole other debate,” Dr. Scott says.) But CPIC’s mantra, so to speak, is that because at some point all this data will become available—whether it’s driven by individual physicians ordering clinical tests, institutionwide endeavors, or even patients providing results from ancestry testing—providers will need help acting on results, Dr. Scott says.

These guidelines have become valuable for the whole PGx field, he says, because multiple professional societies have endorsed them and the authorship is international. “It’s a central place to see the evidence being curated systematically,” he says.

In a field where not all guidance travels at the same speed, CPIC “has done a really good job of providing level of evidence guidelines,” agrees Karen Weck, MD, director of molecular genetics and pharmacogenomics, professor of pathology and laboratory medicine, and professor of genetics, University of North Carolina at Chapel Hill. CPIC assigns levels of evidence for genes-drugs (for example, 1A, 1B, 2A, 2B) based on the strength of the literature. “Many places, including ours, have strongly considered doing testing for all the level 1A CPIC recommendations, because CPIC does make specific dosing or therapeutic drug recommendations. That can be very helpful for clinicians when they order pharmacogenomic testing.”

CPIC is part of the Pharmacogenomics Knowledge Base, PharmGKB (https://www.pharmgkb.org/), an interactive tool funded by the National Institutes of Health that is also an excellent general resource for all things related to pharmacogenomics, says Dr. Weck, who is also director of the molecular genetics laboratory, McLendon Clinical Laboratories, UNC Hospitals. It provides links to the CPIC recommendations, gives prescribing information and clinical annotations, and lists all variants in a particular gene and their effects. “It’s well referenced, well annotated, and often updated. And it’s very user-friendly.”

It was the opportunity to work with PharmGKB and some of its developers, including Teri Klein, PhD, that drew Dr. Scott to Stanford. “It’s probably the single largest knowledge base for pharmacogenomics in the world,” he says.

He and Dr. Klein are also working to set up a comprehensive PGx sequencing panel in the clinical laboratory at Stanford, working hand in hand with IT. The goal is to deliver panel-based results directly into the patient’s chart and use EHR functionality to provide clinical decision support. “It really takes the burden off the physician,” he says.

Another catalyst is the Food and Drug Administration, which continues to include pharmacogenomic information on some drug labels.

Despite the criticisms the agency has historically received for not updating its labels, says Dr. Moyer, “I’ve definitely seen where they’ve gone back and added pharmacogenetics to a drug label when the evidence suggests they should.” She cites one example: the addition of NUDT15 to the thiopurine labels that previously included only TPMT.