The pharmacogenes and methods employed are very similar in all the countries analysed. Table 1 shows the most commonly employed pharmacogenes. The table includes two Spanish examples because of the availability of detailed information. In total, 16% of the pharmacogenes analysed are transport proteins, 39% are metabolism proteins, and 45% are therapeutic targets. Thus, 55% of the pharmacogenes are bioavailability pharmacogenes (transport and metabolism) and 45% are therapeutic targets. The treatments involved show that the main therapeutic areas are antitumoral (23%), neurological (18%), immunosuppressant (11%), antiretroviral (10%), anticoagulant (8%), antihypercholesterolemic (8%), antidiabetic (8%), and biological (5%). These results are consistent with those depicted in Fig. 1 for services which offer PGx.

Fig. 1.

Implementation of PGx by clinical area (Spain). Numbers represent the number of hospitals offering PGx services. Data obtained from the SEFH.27

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The number of variants analysed per gene is relatively small, and in most cases is limited to one. The “rs” reference numbers are shown in Table 1, allowing access to the description of each variant in the dbSNP database26 (https://www.ncbi.nlm.nih.gov/snp).

The main analytical method used is PCR and, to a lesser extent, arrays (results not shown). In the analysis of arrays, ad hoc variant panels are mainly used in Spain, whereas commercially available fixed panels are in wide use in other countries. Next-Generation Sequencing (NGS) is rarely used, except in research settings. Two types of sequencing are used: Whole Exome Sequencing (WES) analyses around 1%–2% of the genome and is the most common method; and Wide Genome Sequencing (WGS) analyses the entire genome. A unique aspect of NGS is the number of reads or fragments into which the DNA is divided. These are sequenced simultaneously (bulk sequencing) and then sorted to obtain the sequence of the sample.28 The most commonly used NGS is Long-Read Sequencing (LRS) with reads of up to 45 000.

The implementation of PGx in hospital settings is widespread, whereas it remains limited in the community setting. This situation is similar in other countries. In Spanish hospitals, pharmacogenetics units have been set up to meet the demands of different clinical areas, especially oncohematology (Fig. 1).27 In community pharmacies, the implementation of PGx is at an early stage and is very uneven. Unlike the situation in hospitals, there appears to be a lack of infrastructure and testing is outsourced to specialised laboratories.

PGx is being developed within the framework of specific programs or projects. In other countries, development is at its most advanced in the United States, with initiatives such as the Cleveland Clinic's Personalised Medication Program, the CLIPMERGE PGx Program, the eMERGE-PGx initiative, IGNITE, INGENIOUS, the 1200 Patients Project, and PREDICT.29,30 In Europe, the Netherlands has gone furthest in developing PGx. In fact, this country was the first to publish clinical guidelines (by the DPWG) and develop systems in which prospective data on a set of key pharmacogenes are collected and included in patients' electronic medical records.31 In Spain, noteworthy programs include those conducted by the Instituto de Salud Carlos III,25 la Sociedad Española de Farmacogenética y Farmacogenómica,32 Hospital de la Princesa,24 and the MedeA Project.33

In the Spanish autonomous communities, PGx development remains uneven34 (see Fig. 2). An analysis of the key elements of implementation shows that the most important factor is the existence of government plans and strategies, followed by public–private collaboration and training. The existence of a critical mass of well-trained PGx specialists and infrastructure is much less influential.

Fig. 2.

Precision medicine in Spain and key elements in its development. Data obtained from the Roche report.34 1) Cantabria, 2) Castilla La Mancha, 3) Canary Islands, 4) Aragon, 5) La Rioja, 6) Principality of Asturias, 7) Balearic Islands, 8) Extremadura, 9) Community of Valencia, 10) Navarra, 11) Madrid, 12) Region of Murcia, 13) Castilla y León, 14) Galicia, 15) Basque Country, 16) Andalusia, and 17) Catalonia. PGx, pharmacogenetics/pharmacogenomics; PM, personalised medicine.

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PGx has evolved from the creation of specific units in hospitals to solve specific clinical problems to the study of panels or mass sequencing of population groups in centralised laboratories at regional and national levels. In this sense, a noteworthy initiative is the Collaborative Spanish Variability Server (CSVS),35 which is a database that has collected genomes and exomes of individuals allowing us to determine the prevalence of pharmacogenomic variants in the Spanish population.

PGx has been implemented in hospitals, but could also be implemented at all levels of the healthcare system. In fact, much of PGx is focused on outpatient drugs, such as antidiabetics, statins, and so on. Cavallari et al have outlined a set of specific elements that should be considered when establishing a PGx service.38 These elements include patient selection, analytical genotyping procedures, computer systems, staff training, and quality control. Thus, hospitals are the preferred location for PGx implementation due to their operational facilities. There is also a historical reason for this situation: the majority of the initiatives have emerged from research projects, most of which have been hospital-based. Further PGx development is likely to occur mainly in out-of-hospital settings, and the increasing use of Internet-based gene panels may contribute to this trend. In this regard, the FDA has approved direct-to-consumers (DTC) genetic test kits, which assess risk markers for cancer (BRCA 1 and 2) and other diseases (G6PDH). Many of these tests can be done without prescription, and so there is a clear need to inform people with community pharmacies playing a key role.

However, despite significant advances in knowledge, it is striking that the implementation of PGx has been so slow, both in Spain and in other countries.39 The reasons given for this situation include a certain level of scepticism, technical difficulties, the lack of specialists, and budget constraints.31,40 Critics highlight the lack of clarity concerning pharmacogenes. Furthermore, genotyping tests and registration processes often lack standardisation. In addition, recognition by drug agencies, which employ varying different criteria, is relevant to PGx implementation. In Spain, at least those medicines for which the Spanish Agency of Medicines and Medical Devices and the EMA include PGx analysis in their data sheets should be included. Regarding technical difficulties, the issues primarily stem from managing the results rather than from the analyses themselves.41 Thus, the analysis of a vast amount of data to provide a solution necessitates reliable mathematical algorithms. This aspect has significantly improved with the evolution of artificial intelligence and the substantial increase in computational capacity, thus enabling the rapid identification and application of solutions. However, this aspect remains a challenge because many such databases lack structure and interoperability, rendering their integration nearly impossible. The analytical aspect has transitioned from the early, almost handcrafted techniques to today's easily applicable automated methods. Finding a laboratory is not difficult and, currently, the SEFF is drawing up a map of laboratories in Spain. In other countries, the availability of genetic testing is very widespread and can be consulted in the Genetic Testing Registry database.42 The number of specialists is gradually increasing and costs are steadily decreasing.

The implementation of PGx has paralleled progress in precision medicine, both in Spain and in other countries. Government plans and strategies have significantly shaped the development of precision medicine in Spain. For example, the Spanish strategy for personalised medicine was launched in 2020. Governments are investing heavily, especially in infrastructures such as the Spanish IMPaCT program.43 Another key aspect is collaboration between the public and private sectors. In the biomedical field, such collaboration has stemmed from government programs and the keen interest of private companies, which have recognised this field as a good business opportunity. Consequently, this synergy has contributed to the remarkable growth of biotech companies in Spain (https://www.asebio.com/en). This aspect, among others, has led to an increase in the use of biotechnological treatments and the associated increase in costs, which contrasts with the expected reduction following the implementation of PGx. Some authors have suggested that this trend could lead to social inequalities by limiting access to medicines for people in lower socioeconomic groups.44

PGx training is of particular concern as a critical mass of well-trained PGx specialists is needed for its implementation to become widespread. As mentioned, some biomarkers have strong scientific and clinical support, whereas others are merely statistical associations that have been proven to be misleading and to have clinical implications. Discriminating between them requires well-trained specialists. In both pharmacy and medicine, undergraduate training in PGx is very scarce and postgraduate training does not include PGx as a speciality. However, courses do exist, some of which are free of charge, such as those offered by the COPHELA consortium.45 The current trend is to form multidisciplinary teams in which pharmacists, with their training in pharmacokinetics and pharmacodynamics, should play a key role. In relation to PGx, pharmacists' responsibilities include promoting the optimal use and timing of PGx tests, interpreting PGx test results, and educating healthcare professionals, patients, and the general public about the field of pharmacogenomics.46,47 Setting up such teams in hospitals is straightforward and improving with the creation of translational medicine units. Although this aspect can be challenging in community pharmacy, it is not insurmountable, thanks to information and communication technology.

The concept of precision medicine and PGx have evolved simultaneously.44 Initially, the concept was captured by the term personalised medicine (i.e., where each person receives the most effective treatment while avoiding adverse effects). Subsequently, the concept was referred to as precision medicine, which includes population subgroups as well as individuals, thus avoiding the possible misinterpretation of the term “personalised”. The concept, which was originally based on genetics, has also evolved to include other factors. Medical records increasingly contain PGx data along with so-called Medically Actionable Predisposition conditions.23 Finally, there is a trend toward preventive medicine where PGx focuses on characterising populations in anticipation of possible treatments.48 This is a global trend,49 and a good example is provided by the GENOTRIAL project at the Hospital de la Princesa (Madrid, Spain). This approach is part of a broader global strategy to collect all the biomarkers that show variation.50 This new approach has been welcomed with great interest by the pharmaceutical industry for population selection in clinical studies.