In a recent study published in The Lancet, researchers performed an implementation study of a 12-gene pharmacogenetic panel across seven European countries to investigate whether a gene-drug interaction-guided prescribing strategy could prevent its adverse reactions.
The study was named Pre-emptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions (PREPARE). It is the first-of-its-kind prospective clinical study set in real-world settings outside the United States of America (USA).
To date, the USA remains a hub for studies investigating the clinical implementation of pharmacogenetics. However, these studies have remained focused on evaluating the clinical implementation of single drug–gene pairs in highly specialized settings. Accordingly, when the researchers extensively searched PubMed in August 2022 for prospective studies assessing the clinical utility of a pharmacogenetic panel, their search fetched zero results.
About the study
In the present study, researchers investigated the advantages of a pharmacogenetic panel strategy along with the Dutch Pharmacogenetics Working Group (DPWG) guidelines across diverse European health organizations in seven European nations.
DPWG continuously reviews published scientific literature to update its guidelines covering more than 100 drug-gene pairs periodically. Testing for a pharmacogenetic panel comprising several actionable variants in the 12 major pharmacogenes detects a minimum of one actionable genotype in 90 to 95% of individuals spanning numerous populations. Therefore, this approach appears to be the most effective.
Initially, the study panel comprised 50 germline-variant alleles within 12 genes, labeled as the pharmacogenetic passport. However, the study design was not static, and changes in it represented a real-world situation more closely.
The researchers clustered countries and randomized them in block sizes of two to begin genotype-guided drug prescribing or standard clinical care. This divided all seven countries into study and control groups, which they exchanged after 19 months. The study group patients aged 18 years or older received the first prescription for a drug in the past 12 months, thus, called an index drug. At enrollment, the team collected blood or saliva samples for isolating their deoxyribonucleic acid (DNA) from patients in both groups.
In the study group, all patients had a Medication Safety Code card with a Quick Response (QR) code that encoded the patient’s pharmacogenetic test results and led to a website showing relevant DPWG recommendations related to the index drug. They returned this to the treating healthcare provider within seven days of index drug initiation. This card could also guide dose and drug selection for any subsequently prescribed drugs.
The team followed up with all patients up to 18 months maximum post initiation of the index drug to determine the incidence of causal and clinically relevant adverse drug reactions during the follow-up period.
During the preparatory phase, the researchers selected germline-variant alleles systematically based on predefined criteria, for instance, having 1% or higher minor allele population frequency (MAF). They considered an actionable drug–gene interaction test as positive if the DPWG commended a conversion to standard drug treatment. Note that the PREPARE study included all drugs for which the DPWG had an actionable drug–gene interaction.
The researchers used educational videos, games, and brochures to educate the healthcare professionals actively implementing pharmacogenetics. Similarly, they educated local participants during a site visit.
The study encompassed 6944 patients from seven countries, namely Austria, the Netherlands, Greece, Slovenia, Italy, Spain, and the United Kingdom. Also, the study covered several diseases and drug therapies.
Of the study population of 6944 patients, 3342 and 3602 patients received genotype-guided drug treatment and standard care, respectively. In the study and control groups, 152/725 and 231/833 patients experienced clinically relevant adverse drug reactions. The overall incidence of adverse drug reactions was 628/2923 and 934/3270 patients of the study and control groups, respectively.
These results confirmed that pharmacogenetics-guided drug prescribing could decrease the frequency of clinically relevant adverse drug reactions by 30%. More importantly, the study results highlighted the benefits of implementing a standardized pharmacogenetic-test system favoring pharmacogenetics-guided decision-making at the point of care.
The authors suggested that a truly pre-emptive study investigating the use of a pharmacogenetic panel would require at least a 10 to 20 times larger sample size. Also, the real-world design of the current study made the gene panel, list of eligible drugs, and DPWG recommendations prone to changes.
To summarize, the study results demonstrated the feasibility and benefits of a pharmacogenetic-panel strategy in real-world settings. Most importantly, it evidenced that the large-scale implementation of panel-based pharmacogenetics testing could make drug treatments safer in the future.