Toward Integration of Pharmacogenomic Tests into Daily Clinical Practice: A General Survey for Polish Healthcare Workers
Pharmacogenomics (PGx) is an interdisciplinary translational science for primary care that focuses on the utilization of an individual’s genomic profile to predict therapy response and prevention of adverse drug reactions (ADRs) or severe adverse effects in patients, while improving therapeutic outcomes . PGx modifies patients’ prescriptions to adjust treatment decisions while considering the patients’ genomic profiles. In recent years, there were rapid developments in preparing PGx guidelines and annotations for many gene-drug interactions . However, while PGx tests have been described as an important area in clinical centers, still there are many challenges for the incorporation of such tests into the routine clinical setting . There are many obstacles for PGx tests to reach clinical utility and validity. These include, but are not limited to, a lack of background knowledge of general practitioners and physicians on the interpretation of a given PGx test result, absence of a comprehensive standardized program and/or recommendation to run PGx test in clinics (how the target patients must be selected, for example), small number of insurance providers for supporting the costs of such tests, and the need to provide a special infrastructure for cutting-edge panel-based PGx testing that can be implemented through any clinical center with the need for it . Notably, an interactive discussion and exchange on personalized medicine through clinicians and other healthcare providers and also researchers would help fill the gap between the current efforts in investigations and the requirements in clinical setting to ensure that PGx testing with clinical utility could be brought to every patient in need . Future research may emphasize preparation of more region-specific pharmacovariant (genomic variants in drug-related genes) evidences and target panel sequencing approaches aimed at distinct ethnic groups . Furthermore, widespread and easy access to local genomic databases plus the PGx data for people in a portable format, such as a specific card with a QR code linked to the database (eg, Ubiquitous Pharmacogenomics Consortium. Ubiquitous Pharmacogenomics [U-PGx] project’s PGx passport ), might be essential. To deal with the above-mentioned topics, timely novel and original studies and evaluations would be required. However, initial steps seem to be the use of a general analytical survey that measures the primary knowledge of doctors and clinicians along with their desire to order clinical PGx tests that would be beneficial for both the community and individuals across populations. The present research aimed to evaluate the level of awareness of PGx testing in clinicians and healthcare workers in the Republic of Poland. We aimed to demonstrate the associated difficulties and requirements for the implementation of such tests as part of the daily clinical practice through a specific questionnaire for the participants as well. Knowing about the main barriers of PGx testing is a fundamental phase for these genetic tests to be considered by the national healthcare system. To the best of our knowledge, this is the first direct assessment of the backgrounds and attitudes of Polish clinicians and healthcare workers toward the integration of PGx tests into a routine clinical context.   Anonymous questionnaires including information on participants’ level of education and whether they were involved in the healthcare system, and particularly if they were clinicians, were distributed online through every medical university and clinical center through an online platform of the Medical University of Białystok or via Poland’s medical chamber (Naczelna Izba Lekarska). According to the Bioethics Committee of the Medical University of Białystok, no institutional review board approval was applicable for our anonymous, publicly available survey on participants’ opinions of clinical PGx testing. Target participants were clinicians, physicians, and healthcare workers (employees/students). The healthcare workers who were paraclinical and/or administrative staff managing healthcare units were employees with executive roles in public clinical centers. Apart from medical personnel and Ph.D. students, the level of education for other contributors was divided into 2 main categories of “higher” and “medium” and was chosen by participants. The sorting was based on the Polish educational system nomenclature, in which higher education level means someone was educated in a university and possesses an academic degree such as a B.Sc., M.Sc., M.D., Ph.D., or Pharm.D., while medium education level indicates education up to high school. The main questions were as follows: (1) Whether participants had heard about PGx before (yes/no); (2) based on complementary explanations on the questionnaire’s page  or pre-existing background knowledge, whether participants believed it was worth implementing genetic testing for identification of actionable pharmacovariants to avoid possible ADRs (yes/no/I don’t know); and (3) what participants considered the main barrier(s) of PGx clinical testing for its integration into routine clinical practice in Poland. Options for the third question were as follows: (i) insufficient knowledge of doctors about the interpretation of the results of PGx tests; (ii) lack of standards and/or guidelines for the performance of PGx testing in hospitals; (iii) no reimbursement of the cost of performing PGx tests; (iv) lack of specialized infrastructure for PGx testing in hospitals; and (v) all of the above reasons. Furthermore, there was a separate yes/no question especially for clinicians at the end of our survey: Would you use PGx testing in daily practice, if available? Statistical Analysis Statistical analysis was performed in R v.4.1.2 (free open source, https://www.R-project.org ). The sample size with an effect size of 50% and taking into account an error type 1 of 5% and a power of 90% was approximately 315 people. The analysis of the responses allowed us to determine whether the answers for particular questions were associated with descriptive variables, such as education level and employment in healthcare service. The data set was highly unbalanced. In particular, there were very few respondents with a medium education level; there were also few answers other than “yes” for the second question in the questionnaire: Is it worth implementing genetic testing for identification of actionable pharmacovariants to avoid possible ADRs? Therefore, we applied Fisher’s exact test for association between the answers and other variables instead of approximate methods like a chi-squared test. We tested the association between the answers and each descriptive variable as well as pairs of variables (education+work as healthcare provider). However, we did not find any significant pairwise interactions; therefore, the results of the pairwise tests are not mentioned further. Additionally, we tested if the answers for the 2 last questions depended on whether the respondent had heard about pharmacogenomics before.   Statistical analysis was performed in R v.4.1.2 (free open source, https://www.R-project.org ). The sample size with an effect size of 50% and taking into account an error type 1 of 5% and a power of 90% was approximately 315 people. The analysis of the responses allowed us to determine whether the answers for particular questions were associated with descriptive variables, such as education level and employment in healthcare service. The data set was highly unbalanced. In particular, there were very few respondents with a medium education level; there were also few answers other than “yes” for the second question in the questionnaire: Is it worth implementing genetic testing for identification of actionable pharmacovariants to avoid possible ADRs? Therefore, we applied Fisher’s exact test for association between the answers and other variables instead of approximate methods like a chi-squared test. We tested the association between the answers and each descriptive variable as well as pairs of variables (education+work as healthcare provider). However, we did not find any significant pairwise interactions; therefore, the results of the pairwise tests are not mentioned further. Additionally, we tested if the answers for the 2 last questions depended on whether the respondent had heard about pharmacogenomics before.   A total of 315 completed questionnaires were received from participants throughout the Republic of Poland. Each online answer sheet was meticulously evaluated to check if it was completed properly (for example, there were no cases of 2 selected options for 1 question, and that only clinicians completed the extra question at the end of the survey). All the answer sheets (100%) were confirmed to be correctly filled out. The education level profile of the respondents is shown in . Most participants had a higher education level; there were 7 participants with a medium education level and 70 students/Ph.D. students. Two-thirds of participants worked as healthcare providers. Question 1: Have You Ever Heard About Pharmacogenomic Tests? also show the distribution of prior knowledge about pharmacogenomics. About two-thirds of participants had heard about PGx tests before. Fisher’s exact test did not detect any significant dependence between the group of respondents and the answer. Question 2: Is It Worth Doing Pharmacogenomic Tests? For this question, “yes” was the most common answer in all groups of participants . Only 3 respondents answered “no” to this question. Employment in healthcare services was not significantly connected with support for the use of PGx . Conversely, there was a significant association between the answer to the question and both the level of education and prior knowledge about PGx. In particular, the respondents who had not heard about PGx before were more likely to answer “I don’t know” to the question. The respondents at the medium educational level were more likely to give a negative answer to the question (although the uncertainty of this effect was big due to the small number of such participants and only 1 negative answer). To investigate the details, we repeated the tests after removing some groups of answers/respondents . Removal of the answer “I don’t know” eliminated the dependence between the answer and the prior knowledge about PGx. The dependence on the education level disappeared after the removal of the group with medium education level. Question 3: Barriers to Implementation of Pharmacogenetic Tests and , show the frequency of particular answers to this question in different groups of participants. The most common answer in all the groups was “all of the above reasons”. The only association was found between education level and the answer. Namely, respondents with a higher education level were more likely to answer “all the barriers are important” than were other groups, and this difference was significant. However, students were more likely to give single answers (instead of “all the reasons”) for the third question, which asked about obstacles. Finally, we added 3 tests in the R script for the associations we found in the data. The result proved all the associations were significant as well .   also show the distribution of prior knowledge about pharmacogenomics. About two-thirds of participants had heard about PGx tests before. Fisher’s exact test did not detect any significant dependence between the group of respondents and the answer.   For this question, “yes” was the most common answer in all groups of participants . Only 3 respondents answered “no” to this question. Employment in healthcare services was not significantly connected with support for the use of PGx . Conversely, there was a significant association between the answer to the question and both the level of education and prior knowledge about PGx. In particular, the respondents who had not heard about PGx before were more likely to answer “I don’t know” to the question. The respondents at the medium educational level were more likely to give a negative answer to the question (although the uncertainty of this effect was big due to the small number of such participants and only 1 negative answer). To investigate the details, we repeated the tests after removing some groups of answers/respondents . Removal of the answer “I don’t know” eliminated the dependence between the answer and the prior knowledge about PGx. The dependence on the education level disappeared after the removal of the group with medium education level.   and , show the frequency of particular answers to this question in different groups of participants. The most common answer in all the groups was “all of the above reasons”. The only association was found between education level and the answer. Namely, respondents with a higher education level were more likely to answer “all the barriers are important” than were other groups, and this difference was significant. However, students were more likely to give single answers (instead of “all the reasons”) for the third question, which asked about obstacles. Finally, we added 3 tests in the R script for the associations we found in the data. The result proved all the associations were significant as well .   The main objective of this study was the evaluation of the background knowledge and attitudes of Poland’s clinicians and healthcare providers toward the implementation of the PGx test in the primary care setting. The use and distribution of such general questionnaires for reaching public opinion on specific clinical affairs (including genetic testing and particularly PGx tests) have been previously utilized in different parts of the world . As expected, in almost all such surveys, overall positive attitudes toward the incorporation of (pharmaco)genetic tests into local clinical settings were seen for people with higher educational levels and relative background knowledge in the field . During the present study, the same was also observed in the participants with higher levels of education, including doctors, clinicians, professional healthcare providers, medical students, and Ph.D. students. Whether in detail or not, most of the individuals had heard about PGx tests before (64.4%). Regarding the use of PGx tests for prevention of ADRs in patients, again most of the opinions were positive (93.3%). Increased awareness of the benefits of PGx incorporation into clinical practice in our target population means that more healthcare and legislative stakeholders would be knowledgeable as well. Once important decision makers become interested in implementing PGx, it would then be more readily accepted by the healthcare society. Educational initiatives for this group of individuals in payor organizations, alongside healthcare administrative workers, also need to be developed and implemented. While these individuals need to be targeted, it must be kept in mind that this could include non-clinical personnel as well. The perceived benefits of PGx implementation have been shown in previous studies to be the most important direct predictor of the intention to adopt PGx testing . Focusing educational initiatives should include factors such as specific patient case examples, data on PGx implementation effects on healthcare resource utilization, and financial benefits to payors and healthcare systems. Meanwhile, some of the educated but unaware participants (never heard about PGx before) were doubtful if it was worth doing such tests or not (“I don’t know” option). Addressing this may require structured and targeted instruction on the clinical utility of PGx tests in medical, pharmacy, nursing, and other health professional school curricula. In 2005, a recommendation was issued for such schools to incorporate PGx as an integral part of their core pharmacology curricula . Also, in a 2019 global survey, it was observed that significantly fewer programs in graduate schools reported PGx education as a part of pharmacology (15.4%) compared with M.D. (59.1%), pharmacy (50%) and nursing (66.7%) programs. Overall, most programs (63%) did offer at least the minimum recommended number of 3 to 4 hours of instruction . However, there is still room for improvement in this area. Since PGx is a hot topic for the implementation of personalized medicine by healthcare systems, both basic and advanced courses, particularly for healthcare providers, should be arranged if the system is interested in reducing the ADR burden and improving the cost effectiveness of drug therapy in their patient population . The next question was the selection of the most important obstacle(s) to performing PGx clinical tests throughout Poland. The response “all the above reasons” was chosen most often (67.6%). This may indicate that although most of the healthcare staff do understand and accept the importance of PGx technology and principles, the entire system needs more preparation for integration of such tests in everyday practice. Even though adding “all the above reasons” in our questionnaire may have created a biased answer to this question, all the barriers were observed throughout Poland’s healthcare system, and including the option was intended to offer the notion to participants, as they could think all the reasons exist together. However, according to this result, it seems Poland is not completely ready for routine implementation of PGx clinical tests. After the above (most popular) selected response, “having no reimbursement of the cost of performing PGx tests” and “insufficient background knowledge of doctors about the interpretation of the test results” were the most frequently selected answers, respectively (14.2% and 8.8%). Although including PGx tests in the list of services that are covered by insurance companies may require more effort , there are some strategies that could be helpful to bring the attention of such corporations to the need for supporting and covering the PGx tests. For instance, running the tests in population-specific local cohorts can add extra insights to unravelling ethnic group-dependent pharmacovariants, cost-effectiveness, clinical utility, and necessity of running the diagnosis tests in related clinical centers. The result could convince the insurance providers to cover the test in their panels. In fact, other strategies to improve the clinical outcomes of PGx tests in commercial markets were also investigated and reported . Such policies will promote the increased and faster integration of PGx tests throughout communities. To raise the education level of physicians and clinicians, adding PGx-oriented materials for educational goals, as mentioned earlier, should be considered and achieved. The educational initiatives for clinicians would need to be focused on PGx principles, terminology, interpretation of results, use of clinical guidelines, and patient case examples . While PGx clinical evidence can be easily found in major PGx databases and guidelines (PharmGKB; Clinical Pharmacogenetics Implementation Consortium; Dutch Pharmacogenetics Working Group), efforts need to be implemented to educate practicing clinicians on the interpretation of PGx test results. This would be the absolute way to ensure that patients get the most benefit out of the technology. On the other hand, more evidence-based clinical data (from local and international research groups) would make it more likely that the tests find their way into daily clinical settings, bringing the benefits for both the patients and the healthcare systems. Through this, more PGx tests would be ordered by relevant physicians and clinicians as well. This was obvious when we assessed the extra question for clinicians. Half of the participants were in this group and almost 90% agreed with ordering PGx tests if they were available. Finally, for addressing the 2 other barriers (lack of distinct guidelines for running PGx test in hospitals and less availability of necessary technologies for PGx genotyping), governmental authorities and policy making institutions must collaborate and encourage the investment by stakeholders and regulate research institutions to provide updated instructions for the standardization of the tests . To overcome the barriers for genotyping of drug-related genes, however, new high-throughput sequencing technologies with the ability to decode rare population-specific pharmacovariants are more recommended than other orthogonal tests, which cover only a few known markers . Today, a model of pre-emptive and/or re-active PGx tests are performed in many European countries through EU-funded implementation projects like U-PGx  and SafePolyMed . We also performed an EU-funded comprehensive study on pharmacogenetics and pharmacogenomics of local cardiovascular patients with ADRs at the University Clinical Hospital in Białystok . By taking the initial steps on this bright path, we may soon witness Poland joining such actions within Europe. The present study’s observations resulted in motivation for performing PGx testing throughout the Republic of Poland, where PGx is still not well known in healthcare settings. Moreover, decisions on including personalized medicine and PGx clinical tests within the medical/pharmacy study curriculum has already been accepted as a topic for discussion at upcoming events between head deputies and university rectors . Indeed, modern medical education as a response to the health needs of society must include individualized treatment as part of its long-term plans in Poland, and maybe the whole of Europe. Current reports can provide invaluable insight to the ministry of health in Poland, as drug programs are developed to decrease related expenditures , especially since our results confirmed the main outcomes of similar studies performed in other parts of the world . The revealed themes included that participants appreciated the clinical utility and value of PGx tests, were aware of the implementation challenges in clinical practice, and knew of the necessity for awareness by healthcare professionals and patients. Limitations To keep the data as private as possible and reduce participant hesitancy to share responses, we decided to not assess where the respondents were working or being educated. However, knowing about the workplace and place of study could also have been helpful in evaluating the depth and breadth of the responses. Also, the survey data collection was performed only for 4 months because we wanted to assess participants’ knowledge and attitudes in a very current timeframe. However, a longer period of time could have led to more collected data and a more meaningful result. Finally, the fact that only 1 question relied on background knowledge of participants and the depth of actual knowledge could not be assessed in a quick survey raises the issue of replacing the term “knowledge” with “awareness” of PGx.   To keep the data as private as possible and reduce participant hesitancy to share responses, we decided to not assess where the respondents were working or being educated. However, knowing about the workplace and place of study could also have been helpful in evaluating the depth and breadth of the responses. Also, the survey data collection was performed only for 4 months because we wanted to assess participants’ knowledge and attitudes in a very current timeframe. However, a longer period of time could have led to more collected data and a more meaningful result. Finally, the fact that only 1 question relied on background knowledge of participants and the depth of actual knowledge could not be assessed in a quick survey raises the issue of replacing the term “knowledge” with “awareness” of PGx.   This study revealed the positive trend and attitude among Poland’s clinicians and other healthcare system employees/students toward the integration of PGx tests in routine clinical practice. While the awareness and interest of the participants may encourage healthcare and legislative stakeholders to provide facilities with the necessities for wide scale clinical implementation of PGx tests, some main barriers remain. These need to be removed if the entire country wants to receive the benefits of personalizing drug therapy using genetic information.   