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BMC Health Serv Res
BMC Health Serv Res
BMC Health Services Research
1472-6963
BioMed Central London

11535
10.1186/s12913-024-11535-6
Research
A national-wide survey on clinical implementation of PGx testing into precision therapeutics for Chinese children: a long way before standard clinical practice
Wu Wen-wen 12
Guo Hong-Li 1
Li Yue 1
Hu Ya-Hui 1
He Huan 3
Xu Jing njxujing@163.com

1
Wang Xiao-ling wangxiaoling@bch.com.cn

3
Chen Feng cy.chen508@gmail.com

1
1 https://ror.org/04pge2a40 grid.452511.6 Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, China
2 https://ror.org/01sfm2718 grid.254147.1 0000 0000 9776 7793 School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
3 grid.24696.3f 0000 0004 0369 153X Department of Pharmacy, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
18 9 2024
18 9 2024
2024
24 108910 4 2024
3 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Pharmacogenetics/pharmacogenomics (PGx) focuses on the genetic variation that causes the heterogeneity of pharmacokinetics and drug response among individuals and has the potential to predict individual efficacy and/or side effects. This study aims to investigate and understand the implementation of genetic testing for the personalized medication (GTPM) in children's hospitals in Mainland China.

Methods

A survey was conducted on 50 children's hospitals from 31 provinces, municipalities, and autonomous regions across Mainland China, and statistical analysis and recommendations were made.

Results

Questionnaire response was rate of 76.0% (38/50). Data from 15 hospitals conducting GTPM were included in this study, but only 6 hospitals had offered PGx tests for no less than five drug-related genes, and only 5 hospitals had covered more than ten drugs, which was a small scale overall. 20.0% of the laboratories did not conduct internal quality control, and 33.3% did not participate in inter-laboratory quality assessment. 46.7% of the practitioners did not receive external training. The primary goal for GTPM was to optimize drug dosage in the 15 hospitals, while the main challenge for GTPM was the implementation cost.

Conclusion

Although GTPM in pediatrics has made major progress in Mainland China in recent years, there were still various problems in terms of software, hardware configuration, personnel allocation, business scale, quality control, and result interpretation. This requires joint efforts of health administration, medical insurance departments, researchers, and hospitals to promote and improve GTPM.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12913-024-11535-6.

Keywords

Personalized medication
PGx testing
Children
Survey
China
Hospital Pharmacy Foundation of Jiangsu Pharmaceutical AssociationA202217 Grants from Jiangsu Research Hospital Association for Precision MedicationJY202108, JY202208 Specially-Appointed Medical Expert Project of Jiangsu Commission of Health2019 Science and Technology Innovation Project for Overseas Scholars from Nanjing Municipal Bureau of Human Resources and Social Security2020046 Chinese Pharmaceutical Association Hospital Pharmacy departmentNO.CPAZ05-ZC-2022-003 issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcIntroduction

In 2016, the State Council of the Central Committee of the Communist Party of China issued the “Health China 2030” [1]. Since then, "precision medicine (PM)", treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations [2], has been supported and advocated by Chinese national policies [1]. As a key element of PM, pharmacogenetics/pharmacogenomics (PGx) focuses on the genetic variation that causes the heterogeneity of pharmacokinetics and drug response among individuals and has the potential to predict individual efficacy and/or side effects [3]. Its clinical implementation can improve the effectiveness, safety, and cost-effectiveness of clinical drug treatments [4, 5]. Children have greater inter-individual differences at different ages, not only in height and body mass but also in pharmacokinetics and pharmacodynamics due to the difference in the development of various systems at different ages [6–9]. Therefore, personalized therapeutics in children assisted by drug-gene information is important to improve the safety and efficacy of medications in children [10–12].

PGx research in China began in the 1980s [13]. For more than 40 years, many experts in PGx have conducted systematic and in-depth research on individual drug differences and their genetic mechanisms. In 2004, the Third Xiangya Hospital of Central South University took the lead in initiating drug-gene-based personalized therapy, which opened the era of personalized drug therapy in China [14]. At present, hospitals and genetic testing institutions in China carry out personalized medication testing including anti-arrhythmic drugs, anti-hypertensive drugs, drugs for myocardial infarction, hypoglycemic drugs, and a dozen other related drugs [14]. Moreover, most of the reports on the status of PGx testing to guide personalized medication in China have been completed among adult's hospitals, but no similar studies have been conducted in children's hospitals [15–19]. This study aimed to investigate the present situation of genetic testing for the personalized medication (GTPM) in children's hospitals in China and to discuss how to support the development of accurate personalized medication use for Chinese children.

Materials and methods

Questionnaire design

The research group designed the first version of the questionnaire based on comprehensive literature research. We relied on the Futang Research Center of Pediatric Development (FRCPD) platform to carry out demonstration, invited 5 experts with strong expertise to revise the overall design of the questionnaire and form a revised questionnaire. The research group responded to experts' comments one by one to form the final questionnaire. The questionnaire consisted 33 questions in nine major categories (Supplementary materials) [20–25] .

The questionnaire also conducted a survey on the personal profiles of individuals engaged in GTPM work, making it easy to calculate the total number of such workers. Due to differences in education level, professional title, work experience, etc., the total number of personnel under corresponding stratified conditions can also be calculated. For example, the total number of GTPM professionals with different educational backgrounds should be equal to the total number of personnel engaged in this work at this hospital. This can indirectly assess the reliability of data collection. Therefore, this study ensures the reliability and authenticity of the questionnaire through the cross-verification of such data.

Study area and sampling

This study surveyed 50 member hospitals of the FRCPD with a high level of diagnosis and treatment of pediatric diseases, covering regions in East China, North China, Northwest China, Southwest China, South China, Northeast China, and Central China. The questionnaire was uploaded to the online professional survey platform named "Wenjuanxing" (www.wjx.cn) for data collection. The survey link online was conducted via the social media platform WeChat. The survey was conducted between 2022-12-01 and 2023-01-31. Questionnaires were excluded from the study if that were not returned within the above survey period.

It was also noted that the questionnaire should be completed by an institution that responsible for conducting GTPM and be submitted after review by the dean of the Pharmacy Department of the hospital. Participants should be responsible for the accuracy of the survey data, and make sure the survey data authentic.

Data analysis

The returned questionnaires were checked for completeness by two individual researchers. Thereafter, the questionnaires were collated and reviewed by statisticians, and statistical analysis was performed using Excel 2013 software. Response frequencies were calculated for each item in the survey. The statistical analysis primarily involved descriptive methods and was presented in both figure and narrative formats.

Results

General information of 15 children's hospitals that implemented GTPM

As shown in Fig. 1 and 15 of 50 questionnaires were finally included in this study for further analysis. Of note, the 15 hospitals that implemented GTPM were all tertiary-level A children's hospitals. The Wuhan Children's Hospital was the first to implement GTPM and has accumulated 24 years of clinical practice experience. Since 2014, an increasing number of children's hospitals have begun to implement GTPM. Particularly in 2019, more hospitals started offering these PGx testing services (Fig. 2A).Fig. 1 Flow diagram of survey response

Fig. 2 Time and Geographical Distribution of GTPM in 15 Children's Hospitals in Mainland China. (A) Time of GTPM in 15 hospitals. (B) Geographical distribution of 15 hospitals. Fig 2A/2B: ① in "Fig 2A" corresponds to ②in "Fig 2B". It means that the map numbers on the left correspond to the numbers in front of the hospital names on the right

In addition, children's hospitals implementing GTPM exhibited significant regional variations. Among them, 6 hospitals are located in East China, ranking first. Followed by 4 hospitals in North China, and 3 hospitals in Central China. On the other hand, South China and Southwest China each had 1 hospital, while there are no children’s hospitals implementing GTPM in Northwest and Northeast regions (Fig. 2B).

GTPM Quality Control and Laboratories Certification

Twelve of the 15 hospitals (80%) established an internal quality control system and 13 (86.7%) established standard operating procedures (SOPs) for genetic testing (Fig. 3A/B). Meanwhile, to ensure the quality of GTPM, laboratories should participate in external quality assessment (EQA). Among the 15 hospitals, 7 (46.7%) and 3 (20%) hospitals participated in national and provincial EQAs, respectively, but 5 (33.3%) hospitals did not participate in EQAs at any level (Fig. 3C).Fig. 3 GTPM Quality Control and Laboratory Certification in 15 Children's Hospitals in Mainland China. (A) Internal Quality. (B) SOP. (C) External Quality. (D) PCR Certification

The laboratories of the 15 hospitals that completed the questionnaire survey were most not established and certified according to the requirements of "Management of Clinical Gene Amplification Laboratories in Medical Institutions". Among the 7 hospitals using polymerase chain reaction (PCR) testing methods, only 5 (71.4%) have PCR certification, and only one hospital, Guangzhou Women's and Children's Medical Center, had both PCR accreditation and ISO15189 recognition (Fig. 3D).

Practitioners of GTPM

The GTPM operation, data analysis, and interpretation of PGx results are highly trained, and the overall quality and professionalism of the practitioners are crucial to the entire GTPM work. Among the 15 children's hospitals, the personnel involved in implementing GTPM generally have accumulated around 5 years of work experience in this field, with a small proportion having 6–10 years of experience (Fig. 4A). In addition, the majority of these practitioners have obtained a master's degree, while the proportion of practitioners with a bachelor's or doctoral degree is relatively close but less common (Fig. 4B).Fig. 4 GTPM Practitioner Qualifications in 15 Children's Hospitals in Mainland China. (A) Work Experience of Practitioners. (B) Practitioner's Qualifications. (C) Practitioners' Titles. (D) Practitioner's Training. A total of 81 GTPM practitioners in 15 hospitals

In terms of practitioner's professional titles, similar to the distribution of educational qualifications, the majority of practitioners hold intermediate-level positions (49.4%), while junior and associate senior positions account for 28.4% and 18.5% respectively. The number of individuals with senior positions was significantly low, with only 3 people (Fig. 4C). Furthermore, nearly 63% of GTPM practitioners have not received any external training at the national or provincial level (Fig. 4D). This indicates that the qualifications of personnel involved in pediatric GTPM are still not optimal.

Drugs-genes and scale of GTPM

This questionnaire presents the key areas and scale of GTPM implementation in children's hospitals in China through 4 categories of data: clinical departments, drug varieties, the number of genes tested, and the annual testing volume. The findings revealed that among the 15 children's hospitals, 13 hospitals have implemented GTPM in the Hematology and Neurology departments, while 10 hospitals have implemented GTPM in the Kidney Disease Department. Furthermore, Neurology Department has the highest number of GTPM implementations with 15 drugs, followed by Hematology, Oncology, and Respiratory departments with 8 drug varieties each (Fig. 5).Fig. 5 No. of Hospitals and Specific Drug Variety Corresponding to the Clinical Departments carried out by GTPM in 15 Children's Hospitals in Mainland China

As shown in Fig. 6, the 15 hospitals offered PGx testing for a total of 44 drugs. Among them, tacrolimus was the most commonly tested drug, implemented by 11 hospitals. Four drugs were implemented in GTPM by more than 5 hospitals, including methotrexate (9 hospitals), carbamazepine (9 hospitals), oxcarbazepine (8 hospitals), and mercaptopurine (7 hospitals). Additionally, tacrolimus was tested in 5 departments (Hematology, Oncology, Rheumatology,  Kidney Disease, and Neurology), glucocorticoids in 5 departments (Kidney Disease, Rheumatology, Endocrinology, Respiratory Medicine, and Neurology), and mercaptopurine in 4 departments (Hematology, Oncology, Gastroenterology, and Neurology) within these hospitals.Fig. 6 No. of Hospitals and Clinical Departments Corresponding to the Specific Drug Variety carried out by GTPM in 15 Children's Hospitals in Mainland China. PND: Pediatric Neurology Department. PND*: Pediatric Neurosurgery Department

As shown in Fig. 7, the questionnaire results also found that the Children's Hospital of Nanjing Medical University offered the highest number of PGx testing services, covering 8 drug-related genes. Kunming Children's Hospital and Hunan Children's Hospital were next in line, both providing testing for 7 genes. Indeed, among the 15 hospitals, a total of 14 drug-related genes were tested. The MTHFR PGx testing was offered by the highest number of hospitals, with 11, followed by CYP3A5, CYP2C9, and HLA-B genes.Fig. 7 Specific Genes and Corresponding Hospitals carried out by GTPM in 15 Children's Hospitals in Mainland China. (A) Hospital--No. of Genes. (B) Hospital--Specific Genes. (C) Gene--No. of Hospitals. Fig 7A/7B: 1* in "Fig 7A" corresponds to 1* in "Fig 7B". It means that Tianjin Children's Hospital provided one gene testing, this gene was HLA-B

As shown in Fig. 8, there was a significant variation in the annual average quantity of PGx testing among the 15 hospitals. Nearly half of the hospitals (47%) had fewer than 500 tested genes, and a majority (66%) had fewer than 500 samples tested annually. Additionally, the annual average revenue for these services is mostly below 100,000 CNY (It refers to the legal tender issued by the People's Bank of China) (60%). Furthermore, we also observed significant regional disparities in the fee rates for GTPM services. The hospital with the highest number of PGx tests conducted an average of 9,630 genes and used samples from 2,705 individuals over the past three years. However, the annual average revenue for this hospital fell within the range of 100,000 to 500,000 CNY. On the other hand, the second-ranked hospital conducted tests for 7,227 genes and utilized samples from 3,600 individuals, but its annual average revenue exceeded 2.01 million CNY.Fig. 8 Business Scale of GTPM in 15 Children's Hospitals in Mainland China. (A) No. of Genes. (B) No. of People. (C) Amount of Testing.

Sample Source and Assay Analysis Method of GTPM

Fifteen hospitals had whole blood as the sample source for GTPM, while two other hospitals had oral swabs as the sample source.

Detection of genetic polymorphism mostly uses traditional methods such as PCR and restriction fragment length polymorphism (RFLP) [26]. With the rapid development of genetic diagnosis, high-throughput, rapid, and accurate genetic polymorphism detection methods have been gradually developed, such as gene chip method and next-generation sequencing technology. This study found that 15 hospitals utilized a total of six genetic testing methods (fluorescence in situ hybridization, fluorescence quantitative PCR, in situ hybridization (ISH), PCR combined with hybridization technology, PCR-direct sequencing, and gene chip method), and one hospital has already implemented the use of the gene chip method for GTPM in children. Furthermore, three hospitals offered multiple PGx testing methods, while the remaining 12 hospitals can only provide a single testing method.

Interpretation of GTPM results

The results of this study revealed that all 15 hospitals provided interpretations of PGx tests results, and the interpretation reports included medication recommendations based on the results of the genetic tests. The individuals responsible for interpreting genetic testing results had diverse professional backgrounds. There were genetic testing practitioner (8 individuals), clinical pharmacists (9 individuals), and even clinical doctors (1 individual). Indeed, clinical pharmacists had a better understanding of the patient's actual condition compared to those specifically involved in genetic testing technology.

Furthermore, clinical pharmacists possess specialized knowledge in pharmacy, including the impact of genetic polymorphisms on drug metabolism. They are often more knowledgeable in this field compared to clinical physicians. However, the number of clinical pharmacists in Chinese healthcare institutions is limited, which hinders the interpretation and application of GTPM results to some extent [27].

Cost of GTPM

In this study, only one of the 15 hospitals (6.7%) was fully reimbursed by health insurance, six hospitals (40.0%) were partially reimbursed, and eight hospitals (53.3%) were fully self-funded. Differences in healthcare coverage systems had also led to differences in the cost of genetic testing across provinces and cities.

Furthermore, there is currently no standardized pricing for PGx testing in China, resulting in significant cost disparities among the 15 participating hospitals in the survey. For the same PGx testing, some hospitals charged as high as 1900 CNY, while others charge as low as 50 CNY. Indeed, no hospital has conducted any economic studies on the cost-effectiveness of GTPM.

Purposes and barriers of GTPM

The primary goal for GTPM was to optimize drug dosage in the 15 hospitals, and the second purpose's was to prevent and reduce adverse drug reactions (ADR). While the main challenge for GTPM was the implementation cost, and the second barrier's was the insufficient recognition (Fig. 9).Fig. 9 Purposes and Barriers of GTPM in 15 Children's Hospitals in Mainland China

Discussion

This is the first study to investigate the current status of GTPM in children's hospitals in Mainland China, and the findings from the survey could be used to improve the implementation of PGx in pediatric patients.

The first finding of this survey was that the major challenge for the implementation of GTPM was technical test availability. On the one hand, our survey revealed that there were certain problems in laboratory quality control and personnel training (Figs. 3 and 4D), and the standardization needed to be strengthened. Many studies have shown that the main barriers to the implementation of PGx testing internationally are primarily focused on the clinical application [22, 23, 28–32], such as financial barriers (costs), insufficient evidence (lack of guidelines), healthcare providers' skepticism and insufficient knowledge [33–38]. However, the results in our survey showed that some barriers in China remain at the most fundamental technical level.

On the other hand, lack of clinical practice guidelines and knowledge hindered to some extent the application of GTPM in clinical practice. This was similar to the findings of a study to assess the attitudes and opinions of psychiatric clinicians about the PGx testing, in which 84.5% were concerned about the lack of clear guidelines for use [23]. A study in China also showed that lack of guidelines was found to be one of the major factors for hindering PGx clinical application [39]. Similarly, another study showed that 78.5% (62/79) of health care professionals also listed the lack of clinical guidelines as a major barrier to implement PGx testing [31]. In fact, a number of studies had also pointed out that insufficient evidence and guidelines for the clinical utility of PGx testing was found to be a ubiquitous barrier to PGx implementation in clinical practice [22, 23, 25, 29, 31, 40, 41]. For example, Just et al. pointed out that most participants were only familiar with classical genetics, pharmacology, and pharmacokinetics, and the role of metabolic phenotypes However, they were less adept at applying PGx tests, interpreting test results, and using them in therapeutic recommendations [42, 43].

Another relevant observation of our study was that there was a large price difference between regions and hospitals. Cost was an important consideration for the healthcare systems and patients when applying PGx in clinical practice, and it was often listed as one of the major barriers to clinical implementation [20, 28–35, 37, 38]. A survey of GTPM barriers in children's hospitals across the United States showed that reimbursement, cost, and money were among the top three barriers [20]. Notably, of the 137 PGx associations outlined in the FDA table, they identified 44 economic evaluations, relating to 10 drugs. Out of these economic evaluations, 57% showed that PGx testing was beneficial, with 30% being cost-effective and 27% leading to cost-savings [44]. Another survey evaluated the cost-effectiveness of PGx-guided treatment for drugs recommended by the CPIC guidelines, and found that, of the 108 studies assessing 39 drugs, 77 (71%) showed PGx testing was either cost-effective or cost-saving, 21 (20%) showed that it was not cost-effective, and 10 (9%) were uncertain [32]. However, similar research was very uncommon in this area in China. The lack of evidence of clinical benefits has led to questions about the significance of PGx testing by medical insurance authorities.

One more concern needs to be further discussed. For those hospitals implementing GTPM, the scale of GTPM was also generally small. Compared to the developed children's hospitals such as St. Jude Children's Research Hospital, Minnesota Children's Hospital, and Boston Children's Hospital, there were gaps in the number of test genes (10/7/6) and test drugs (26/23/36) [45]. Therefore, pediatric GTPM in China is still in its infancy, and there is still a lot of room for growth.

Finally, our study has several limitations due to its survey-based nature. We only included the data from 15 hospitals, and the survey was completed by one individual at each hospital who may not have an accurate sense of some data. Indeed, the 15 hospitals could not be representative of all children's hospitals, but as they are from different provinces, we can at least roughly estimate the development of GTPM in Mainland China.

Conclusions

Collectively, this study provided important insight into the GTPM in pediatrics in Mainland China. Although it has made major progress, there were still various problems in terms of high cost, environmental requirements, and technical difficulties, limiting its clinical application. This necessitates the collaborative efforts of health administration, medical insurance departments, researchers, and hospitals to promote and enhance GTPM.

Electronic supplementary material

Supplementary Material 1.

Supplementary Material 2.

Acknowledgements

Thanks to the members of the FRCPD for their support of this study.

Author contributions

W.W. Wu had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: F. Chen, X.L. Wang, and J Xu. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: W.W. Wu, H.L. Guo and F. Chen. Critical revision of the manuscript: F. Chen. Administrative, technical, or material support: X.L. Wang, and J Xu. Supervision: F. Chen, X.L. Wang, and J Xu.

Funding

This study was supported by the Specially-Appointed Medical Expert Project of Jiangsu Commission of Health (2019), the Science and Technology Innovation Project for Overseas Scholars from Nanjing Municipal Bureau of Human Resources and Social Security (2020046), the Chinese Pharmaceutical Association Hospital Pharmacy department (NO.CPA-Z05-ZC-2022-003), grants from Jiangsu Research Hospital Association for Precision Medication (JY202108, JY202208), and the Hospital Pharmacy Foundation of Jiangsu Pharmaceutical Association (A202217 and A202313).

Data availability

The original data of this study are included in this published article and its supplementary materials.

Declarations

Ethics approval and consent to participate

The study was carried out following the guidelines of the Helsinki Declaration. Approval for the collection of medical data was granted by the Ethics Committee of the Children's Hospital of Nanjing Medical Univerisity (Protocol number 202310001-1). Due to the questionnaire nature of this study, no personal information of the participates was involved, so the requirement for consent to participate was waived by the ethics committee.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Wen-wen Wu and Hong-Li Guo contributed equally to this work.
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