What It Takes: Bringing Pre emptive Pharmacogenomic Testing into Routine Clinical Practice

Currently when a patient presents with trigeminal neuralgia or painful neuropathy, doctors would need to do a genotyping test for the human leukocyte antigen B gene’s 1502 allele (HLA-B*1502) prior to the initiation of carbamazepine (CBZ) therapy. This is because patients who carry the HLA-B*1502 allele are at higher risk of experiencing CBZ-induced Stevens-Johnson syndrome and toxic epidermal necrolysis, which can be life-threatening and even prove fatal.[1]

The need for genotyping prior to starting therapy typically means that patients need to wait days to weeks for the return of their pharmacogenomics (PGx) testing results before commencing on their prescriptions.

For Professor Goh Boon Cher, Department of Haematology-Oncology, National University Cancer Institute, Singapore; Associate Professor Wee Hwee Lin, Saw Swee Hock School of Public Health, National University of Singapore; and Dr Elaine Lo, Principal Clinical Pharmacist, Clinical Support Services, Pharmacy, National University Hospital, they are piloting a project to study how patients and clinicians can potentially start therapy confidently and with little delay or wait time.

“Just imagine—if we can screen a broad panel of multiple genes for multiple drugs and make the test results readily available and accessible in our electronic medical records (EMR) system, clinicians will be able to make prompt prescription decisions at the point-of-care,” said Prof Goh. “But before that can happen, we’ll need to understand why, despite increasing availability of clinical guidance on how prescribing should be modified based on PGx test results, the uptake remains low.”

“Pre-emptive PGx testing is presently not widely adopted due to barriers such as a lack of awareness and guidance, long turnaround time, counter-intuitive workflows, and the additional costs of testing itself. Hence, our goal with this clinical implementation pilot (CIP) is to find ways to navigate around these issues—and optimise drug therapy outcomes for patients at the same time,” said Dr Lo.

Tackling Cost Concerns

In a study A/Prof Wee conducted in 2018 at the Singapore General Hospital, it was noted that the total cost of 81 admissions caused by adverse drug reactions (ADRs) was S$770,000. It was noted that the breakeven cost of a pre-emptive PGx test for patients taking warfarin, clopidogrel, chemotherapeutic and neuropsychiatric drugs was S$154 per patient.[2] A/Prof Wee said, “We just need to put these numbers side by side, and it becomes immediately clear that pre-emptive PGx testing is not only cheaper to the patient, but likely also the healthcare system.”

Prof Goh added, “The cost of genotyping today is relatively affordable because of more powerful testing equipment and more efficient process workflow. Additionally, in pre-emptive PGx testing, we are testing for common variants in the population. They are neither diagnostic nor prognostic—and no pre- and post-genetic counselling is required; there is less concern about cascade screening too.” 

Dr Lo continued, “Also, although we are only looking at a PGx panel of about 30 drug-gene pairs, the impact goes beyond 30 genes because many drugs are metabolised by just a few specific enzymes—so it is actually very economical. A multi-gene panel saves the trouble of patients having to go through multiple single-gene testing in their lives.” 

Increasing Awareness Among Clinicians and Patients

“We found that when we are able to explain the merits of pre-emptive PGx testing, share the costs and assure patients that all we need is a simple blood draw, patients are usually quite receptive. And if the advice came from a doctor, there is a high chance that patients will agree to do the test,” Prof Goh shared. 

Besides costs, another key limitation to the adoption of pre-emptive PGx testing is clinicians’ awareness and knowledge about the types of tests available, when they are required, and how to order, interpret and incorporate PGx test results in the context of other clinical variables.

“PGx is a relatively new tool in medicine—and many practising clinicians haven’t had much exposure in this area during their time in school. However, it is nothing that cannot be overcome. Some education and encouragement to try will be a good first step. Then when the clinicians realise that this helps them with their drug dosing and achieve more positive patient outcomes, they will be interested,” Prof Goh said. “That is why part of our focus now is to score some early wins so as to get the implementation off to a steady state. But as CIP investigators, we are also careful to set the right expectations and understanding. For example, pre-emptive PGx can help to reduce the odds of ADRs, but provided that it is used appropriately.”

Enabling Smoother Clinical Workflows

As part of the CIP, the team is also thinking about the sustainability of pre-emptive PGx information as part of the clinical practice. Dr Lo explained, “Today, whenever a patient does a PGx test, the clinic not only needs to trace the patient’s sample and test results to ensure that they are returned, they will also need to follow up with the patient to inform them of the outcome and whether they can start their prescribed medicine. This is disruptive to the process at clinics. That is why sometimes clinicians choose not to order the PGx test or avoid drugs that require PGx tests altogether.”

Prof Goh said, “That’s right. This is where the EMR plays an integral role to our implementation. We want to make it such that every patient’s PGx information is available to the clinician at the point of prescription. Then taking it one step further, the PGx information also has to be relevant to the particular episode and easily seen at a glance—because clinicians are seeing many patients within a session so anything that takes up extra time or hinders the flow of their clinical consultations is not going to be sustainable. I can attest to that first-hand as a clinician myself.”

“To Prof Goh’s point—that’s primarily why we take great effort in ensuring that information is presented succinctly and language use is moderated so that healthcare professionals assessing the EMR don’t over- or under react. We hope to build a workflow that can minimise doctors’ workload—so the doctors would be prompted with the PGx information when there is an important drug interaction and they won’t have to remember what to do with the drug,” Dr Lo elaborated.

Dr Lo continued, “Ultimately, I believe that if we can produce evidence of how pre-emptive PGx can benefit clinicians to do their job better, and patients in terms of reducing side effects and optimising efficacy, we would have a good case for implementing pre-emptive PGx as a precision medicine tool.”

“Yes—we know we have succeeded if all doctors can confidently select the best drug and dose so that patients do not lose the chance of response or is subjected to a preventable toxicity, and yet they will receive the best potential therapeutic outcomes,” Prof Goh concluded.

Click here to read how Prof Goh, A/Prof Wee and Dr Lo are transforming Singapore’s clinical practice to benefit us here.

This project is supported by the National Research Foundation, Singapore, through the Singapore Ministry of Health’s National Medical Research Council and the Precision Health Research, Singapore (PRECISE), under PRECISE’s Clinical Implementation Pilot grant scheme.

[1] https://www.hsa.gov.sg/announcements/safety-alert/recommendations-for-hla-b-1502-genotype-testing-prior-to-initiation-of-carbamazepine-in-new-patients

[2] Chan SL, Ng HY, Sung C, Chan A, Winther MD, Brunham LR, Wee HL. Economic burden of adverse drug reactions and potential for pharmacogenomic testing in Singaporean adults. Pharmacogenomics J. 2019 Aug;19(4):401-410. doi: 10.1038/s41397-018-0053-1. Epub 2018 Sep 24. PMID: 30250149