Compelling Evidence for Preemptive Pharmacogenetic Testing

An implementation study recently published in The Lancet examined the clinical utility of a 12-gene pharmacogenetic (PGx) panel to reduce adverse drug reactions throughout Europe. The PREPARE study represents the first of its kind to investigate the impacts of a preemptive panel approach in a large population across multiple institutions in conjunction with the Dutch Pharmacogenetics Working Group (DPWG) guidelines. As the article details, previous studies have focused on single gene-drug combinations to elucidate the benefits of pharmacogenetics; however, a preemptive approach has been minimally studied.

Often a challenge faced in demonstrating benefit in PGx studies is being able to narrow in on patients with actionable gene-drug interactions during the study period. PGx results can be utilized for the lifetime of the patient, and therefore changes to medication management may not be able to be captured in the short timeline that a study allots, and large sample sizes are necessitated. The researchers overcame this barrier by applying a unique and carefully crafted methodology of enrolling patients receiving a first-time prescription for a drug (i.e. index drug) with a known actionable gene-drug interaction with recommendations available from DPWG guidelines. All drugs with a recommendation provided by DPWG for a specified gene-drug combination were included, with the exception of abacavir, omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, and drugs containing estrogen.

Participants were assigned to either the control group which consisted of standard clinical care or the study group in which PGx test results were made available to healthcare providers within 7 days of the index drug initiation. To have an appropriate balance of index drugs for inclusion and prevent one or a few drugs from driving the result, each drug was capped at 10% of all initial prescriptions in the study and control groups. Participants in the study group received a “Medication Safety Code” card containing a quick response (QR) code, which provided information regarding the patients’ PGx results and DPWG recommendations and participants in the control group received a card denoting their participation in the PREPARE study. Participants were excluded if they previously underwent genetic testing relevant to the index drug, the medication had a planned duration of less than 7 consecutive days, and/or severe renal or hepatic insufficiency. Additionally, the study was designed to reflect real-world situations, consequently providers did not have to adhere to DPWG guideline recommendations and changes were allowed to the panel based on new literature and/or updates to guidelines. Although, it was found that 69.9% of the DPWG recommendations were implemented. Researchers’ primary outcome was the occurrence of “causal and clinically relevant adverse drug reactions reported for the index drug within the 12-week follow-up period”.

The study consisted of 6,944 patients from seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK) with 3,342 (48.1%) in the study group and 3,602 (51.9%) in the control group. The study demonstrated that PGx has the potential to impact a large percentage of patients, with 6,495 of the 6,944 (93.5%) participants carrying at least one actionable variant and 1,558 (25.2%) of 6,193 participants with an actionable variant for their index drug. In respect to the index drug, the most common was atorvastatin (n=716), followed by clopidogrel (n=619), and tacrolimus (n=472). For the primary outcome, the incidence of adverse drug reactions in patients with an actionable PGx variant was 21% in the study group and 28% in the control group, demonstrating a significant reduction of 30% in adverse drug reactions.

The PREPARE study is a seminal study for the advancement and implementation of PGx into standard of care. This study establishes that the use of PGx in clinical care is not only practical and attainable for multiple practice settings and in various disease states but can reduce adverse drug reactions experienced by patients. In the U.S., it is estimated that adverse drug reactions account for roughly 1.3 million emergency department visits and 350,000 hospitalizations each year and around $3.5 billion is spent each year on medical costs related to adverse drug reactions.2,3 The utilization of PGx has the potential to reduce these adverse drug reactions for patients; this study represents a major step forward for PGx and advocating for medication safety for patients. Researchers of the PREPARE study plan to conduct a cost-effectiveness analysis of panel-based preemptive PGx testing based on these results.

This study represents an important step in building evidence for making pharmacogenetic testing the standard of care.


  1. Swen JJ, van der Wouden CH, Manson LE, Abdullah-Koolmees H, Blagec K, Blagus T, Böhringer S, Cambon-Thomsen A, Cecchin E, Cheung KC, Deneer VH, Dupui M, Ingelman-Sundberg M, Jonsson S, Joefield-Roka C, Just KS, Karlsson MO, Konta L, Koopmann R, Kriek M, Lehr T, Mitropoulou C, Rial-Sebbag E, Rollinson V, Roncato R, Samwald M, Schaeffeler E, Skokou M, Schwab M, Steinberger D, Stingl JC, Tremmel R, Turner RM, van Rhenen MH, Dávila Fajardo CL, Dolžan V, Patrinos GP, Pirmohamed M, Sunder-Plassmann G, Toffoli G, Guchelaar HJ; Ubiquitous Pharmacogenomics Consortium. A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study. Lancet. 2023 Feb 4;401(10374):347-356. doi: 10.1016/S0140-6736(22)01841-4. PMID: 36739136.
  2. Shehab N, Lovegrove MC, Geller AI, Rose KO, Weidle NJ, Budnitz DS. US emergency department visits for outpatient adverse drug events, 2013-2014. JAMA 2016;316:2115-25.
  3. Institute of Medicine. Committee on Identifying and Preventing Medication Errors. Preventing Medication Errors, Washington, DC: The National Academies Press 2006.