The implementation of the guideline for the management of pediatric off-label use of drugs in China: a cross-sectional study

Introduction

Off-label drug use in pediatrics is a global public health issue (1), with studies indicating that the prevalence of off-label drug use ranges from 3.2% to 95% in pediatrics and from 26% to 95% in infants (2,3). According to a systematic review, pediatric off-label prescription rates ranged from 22.7% to 51.2% in outpatient settings and 40.48% to 78.96% in hospitalized children in China (4). In our previous cross-sectional study of pediatric outpatient prescriptions in Gansu Province, 38.0% involved off-label use (5). The highest rate of off-label drug use in outpatient children’s prescriptions was 90.0% in a single-center study of antidepressant prescriptions in China (6). Therefore, developing evidence-based recommendations on the off-label use of drugs in pediatrics in China is crucial.

The Chinese Society of Pediatric Clinical Pharmacology, in conjunction with the Chinese Medical Association, has jointly published “the Expert Consensus on Off-label Drugs in Pediatrics in China” (7). Over the past 5 years, in tandem with the emergence of new evidence, the standards, guidelines, and consensus statements pertaining to the off-label use of drugs in pediatrics have undergone significant updates. Despite the global progress in addressing pediatric off-label drug use, a notable gap remains in China, where an updated consensus statement or guideline specific to this issue is yet to be established. This absence highlights a critical need for clinicians and policymakers to collaborate in developing evidence-based guildines that reflect the unique characteristics and needs of Chinese pediatric population. To address the need for standardized pediatric off-label drug use in China, the Chinese Society of Pediatric Clinical Pharmacology, alongside the Chinese Medical Association and the National Clinical Research Center for Child Health and Disorders, have partnered with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Center in China, developed the “Guideline for the Management of Pediatric Off-label Use of Drugs in China” (i.e., the Guideline) (Appendix 1) (8). This guideline consolidates the latest evidence to provide healthcare professionals with a clear framework for safely and effectively managing off-label drug use in pediatric, reflecting a significant step forward in pediatric healthcare in China.

Numerous studies have demonstrated that up to 70% of clinicians across most fields and nations fail to adhere to Clinical Practice Guidelines (CPGs) (9,10). According to studies in China, the implementation of evidence-based recommendations in CPGs among medical staff is even worse, around 50% (11). To the Expert Consensus on Off-label Drugs in Pediatrics in China, a study by Mei et al. concluded that using off-label drugs in pediatrics was common in Shanghai, but more than half of the respondents declared that they did not adhere to the process proposed in the consensus (12). Clinician attitudes, discrepancies between patient preferences and CPGs, and CPGs dissemination may affect guidelines’ adherence (13). Identifying research gaps contributes to health practice and policy implementation (14), and guideline developers should be proactive in identifying research gaps and suggesting ways to address them to facilitate clinical practice translation (15). Thus, guideline implementation and compliance barriers must be identified in advance to develop appropriate strategies for specific settings and target groups (16). To create strategies to promote evidence utilization, analyzing the facilitators and barriers to managing off-label drug use in children is required (17). Thus, this study aims to use a cross-sectional study to determine the degree of difficulty and urgency in implementing each recommendation of the Guideline, and identify factors impacting gaps, urgencies, and difficulties. We present this article in accordance with the SURGE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-24-198/rc).

Methods

Study design

A cross-sectional study using the survey method was conducted from March 1 to June 17, 2022.

Participants and setting

The study was pre-tested by 48 healthcare professionals, including pediatricians, pharmacists, nurses, and health administrators. However, according to the pre-test findings, nurses did not feel involved in implementing the Guideline’s recommendations. They had no experience with the survey items. As a result, the respondents in this study only included pediatricians, pharmacists, and health administrators from regionally representative secondary and tertiary hospitals in 31 provinces of Mainland China. The study adopted the principle of convenience sampling.

At a confidence level of 99% and a sampling error of 5%, a minimum sample of 666 is required. For failure and refusal rates, another 15% were added to the sample, so that a minimum sample of 766 was required to ensure the credibility of this study. We sent out a total of 920 questionnaires covering almost every province in China, selecting representative secondary and tertiary hospitals.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Gansu Provincial Hospital (No. 2022-152). All participants provided informed consent to participate in the study.

Questionnaire

The questionnaire included three sections. The first section included 13 demographic questions for respondents, such as gender, age, workplace, etc. The second section was developed based on the 21 recommendations in the Guideline. There were three types of questions for each recommendation: (I) whether it had been implemented or not (yes or no), (II) the urgency of implementation (using a 1-7 Likert scale with a gradual increase in the urgency), and (III) the difficulty of implementation (using a 1-7 Likert scale with a gradual increase in the difficulty). The last section was an open-ended question seeking comments on implementing the Guideline (Appendix 2).

Content validation and pre-test were conducted to determine the content of the questionnaire. Three pharmacologists, a clinical expert, a health statistics expert, and a health administration expert were requested to conduct a content validity test of the questionnaire. The second section’s content validity index (I-CVI) was 0.83–1.00. A pre-test of 48 healthcare professionals showed that the questionnaire was easy to comprehend, the questions were well phrased, and each questionnaire took between 15 and 25 minutes to complete.

Data collection

The electronic version of the questionnaires was disseminated nationally through affiliations of the Clinical Pharmacology Group of the Pediatric Society of the Chinese Medical Association and the National Clinical Research Center for Child Health. Completed questionnaires were collected manually and turned into an Excel file by the researchers. Two researchers independently validated the correctness of the completed questionnaire data to assure data quality. They reviewed all that were inconsistent with each other or with the facts. Then we excluded questionnaires in which any question was unanswered.

Statistical analysis

Descriptive data analysis was performed for the characteristics of the participating health professionals and the comments on the implementation. The descriptive analysis was calculated using Microsoft Excel 16.54, including the frequency, percentage, means, and standard deviations.

A chi-squared test was performed to determine the difference in the number of implementations of off-label drug use management between secondary and tertiary hospitals and between children’s hospitals and other types of hospitals, respectively. The effect of urgency and difficulty on recommendation implementation was studied using binary logistic regression. As scores (1–7 Likert scale) were regarded as continuous variables, linear regression was used for multivariate analysis, and the stepwise regression technique was used to screen the variables. Regional distribution, hospital level, hospital type, rater’s age group, degree, professional role, work experience, position, and management experience were included as the multivariate variables. Chi-squared analysis, multi-factor logistic regression, and linear regression were analyzed using SPSS 23.0. P values of 0.05 were regarded as statistically significant.

Likert scale scores for urgency and difficulty of recommendation were analyzed using means and standard deviations and were then ranked based on the values of means from most to least.

The Sankey diagram visualizes the flow of participants’ choices for each recommendation (18,19). For clarity, all cumulative statistics were labeled on the cumulative bars. In this study, the left and right flows came from the central cumulative bar, with the left column indicating difficulty scores and the right column showing urgency scores. Suppose a participant is selected to implement a recommendation, its urgency (right column) and difficulty (left column) scores are streamed from the “yes” column in the middle. Thus, we can see the cumulative flow of 18,249 selections and the proportion (869 participants × 21 recommendations =18,249). R software (version 1.3.1056) was used to develop Sankey.

Results

Characteristics of the participating health professionals

A total of 895 questionnaires were collected from 491 participating organizations across 31 provinces in mainland China. Eight hundred sixty-nine questionnaires were included after 26 invalid questionnaires were excluded. The response rate was 97.1%. The essential characteristics of the included health professionals are shown as in Table 1, and the demographic characteristics of the secondary and tertiary hospitals as Table S1.

Most participants were female (n=610, 70.2%), had the age of 30–39 years old (n=372, 42.8%), had a bachelor’s degree (n=463, 53.3%), had over 20 years of work experience (n=273, 31.4%), and had a senior position (n=360, 41.4%). The participating health professionals included 407 pediatricians (46.8%), 43 non-pediatrician clinicians (4.9%), 200 clinical pharmacists (23.0%), 163 non-clinical pharmacists (18.8%), and 56 health managers (6.4%). Six hundred thirty-one participants (72.6%) were from tertiary hospitals, and 238 (27.4%) were from secondary hospitals.

The current state of off-label drug use management in children

The top 5 recommendations were 8.2, 5.1, 1.2, 8.1, and 7.3. The percentage of all recommendations carried out ranged between 65.5% and 41.1%. More than half of the recommendations (57.14%, 12/21) had been implemented in China. The implementation of recommendations 1.1, 1.2, 2.1, 2.5, 3.2, 5.1, 7.1, 8.2, 2.2, 3.1, 4.2, and 8.1 in tertiary hospitals were conducted more than those in secondary hospitals. Except for recommendations 5.2, 6.2, 7.2, 7.3, 8.1, and 8.3, the other 15 recommendations were carried out much more in pediatric hospitals than in other types of hospitals. The guideline recommendations are shown in Appendix 1 and the management details have been presented in Table S2.

The urgency and difficulty of guideline implementation

The mean of urgency and difficulty scores were just of slight differences between the recommendations, respectively. Almost all of the 21 recommendations received difficulty scores above 4, and all 21 recommendations received urgency scores above 5. The mean of urgency and difficulty scores for recommendations 5.2 and 5.1 were the lowest, with a mean of 5.67 and 3.93, respectively. The top five recommendations for overall urgency are 1.1, 1.2, 6.1, 4.2, and 6.2. The top five recommendations for overall difficulty are 2.3, 6.2, 6.1, 4.1, and 3.2; the mean scores of 21 recommendations were over 4. Table S3 shows the scores and rankings (see Appendix 1 for the guideline recommendations).

The association of actual recommendation implementation with the urgency and difficulty of implementation

For recommendations 1.1, 5.2, 6.1, 7.3, 8.1, and 8.2, there were significant correlations between the Likert scale scores for implementation urgency and the actual recommendation implementation (see Appendix 1 for the guideline recommendations). For all recommendations, there were significant correlations between the Likert scale scores for implementation difficulty and the actual recommendation implementation. Raters who had not implemented recommendations scored higher difficulty scores than those who had implemented them. The details are shown in Table 2.

Figure 1 is a Sankey diagram describing participants for each recommendation who had recommendation implementation or did not (middle column: yes or no) and how to evaluate the implementation’s urgency (right column) and difficulty (left column). The total number of implemented recommendations was 9,474, with 8,775 being unimplemented. The urgent Likert scale values were 8,090 at 7, 4,057 at 6, 3,043 at 5, 2,117 at 4, 446 at 3, 265 at 1, and 231 at 2. The percentage of the most urgent was 44.33% (8,090/18,249), and the least urgent was 1.45% (265/18,249). The difficulty Likert scale values were 5,020 at 4, 3,982 at 5, 2,436 at 6, 2,196 at 7, 1,788 at 3, 1,420 at 2, and 1,047 at 1. The percentage of the most difficult was 12.03% (2,196/18,249), and the least difficult was 5.74% (14,075/18,249). 27.51% (5,020/18,249) of respondents believed the guideline’s implementation was generally difficult.

Figure 1 The association of actual recommendation implementation with the urgency and difficulty.

Multi-factor analysis of the urgency and difficulty of guideline implementation

Factors impacting the urgency and difficulty of guideline implementation were different, but the common influencing factors included the position and education level of clinicians and hospital level. The position was positively associated with the urgency and difficulty of guideline implementation. In contrast, the education level is positively associated with the degree of urgency and negatively associated with the degree of difficulty of guideline implementation. Compared with secondary hospitals, for recommendations 2.5, 4.2, 6.1, 6.2, and 7.1, tertiary hospitals perceived a higher degree of urgency in guideline implementation than secondary hospitals (see Appendix 1 for the guideline recommendations). However, tertiary hospitals had lower difficulty scores of guideline implementation for recommendations 2.1, 2.2, 2.4, 2.5, 3.1, 3.2, 4.1, 5.1,7.1, and 7.3. Table 3 details the statistically significant factors influencing the urgency and difficulty of guideline implementation.

The comments on guideline implementation

One hundred twenty-eight questionnaire respondents provided feedback or commented on implementing the Guideline. Thirty-eight respondents (29.69%) commented that the Guideline could address an important clinical issue in the current healthcare system and was eager to implement it. Twenty-five (19.53%) respondents identified barriers to the implementation of the recommendations, including the medical staff’s busy schedules, the absence of off-label drugs from the medical insurance list, the national health administration’s lack of leadership, and the primary medical staff’s ignorance of evidence-based medicine (Table S4).

Discussion

According to this study, the recommendations in the guideline for the management of pediatric off-label use of drugs in China were implemented more in tertiary hospitals than in secondary hospitals and more in children’s hospitals than in non-children’s hospitals. The implementation rates of 21 recommendations ranged from 41.1% to 65.5%. The recommendations were considered less difficult for those which had put them into practice. Factors impacting the urgency and difficulty of guideline implementation were different, but the common influencing factors included the position and education level of clinicians and hospital level. The most difficult recommendation to implement was 2.3, which stated that the experts’ team for the pediatric off-label use of drugs should include professors who are majored in evidence-based medicine, health economics, epidemiology, ethics, and the law.

This study showed a low percentage of hospitals that had implemented the recommendations for the guideline, similar to the results of the national implementation study for the “Expert Consensus on Pediatric Off-Label Use of Drugs” (i.e., the Consensus) in 2017 (12,20). This result shows that pediatric off-label drug use management in China has been promoted slowly in the last 5 years. The consensus is yet to be well-implemented and applied after it has been produced. Similarly, healthcare professionals still need to comply more with the guidelines in Europe and the United States, where guidelines have been developed for pediatric off-label drug use (1,21,22). Numerous studies have explored barriers to implementing pediatric off-label drug use, such as financial reimbursement obstacles, a lack of familiarity with the concept of off-label drug use, and ethical and legal issues (20,21,23-26). However, more research must be done on the corresponding implementation strategies (6). Thus, it is suggested that guideline developers should design further tailored implementation strategies based on the contextual factors influencing pediatric off-label drug use.

We found that the position of healthcare professionals was the main factor impacting the degree of difficulty and urgency of the Guideline implementation. Similar to previous studies, Clinicians’ position influences the implementation of guidelines (27,28). The difficulty of implementing guidelines increases with the position because pediatricians with higher position are more inclined to prescribe off-label medications (12,29-32). Based on their extensive clinical experience, amount of literature, etc., doctors with higher position are more confident in prescribing drugs off-label (31). Hence, doctors with higher position utilize off-label drugs more frequently, making handling these common clinical practices harder. Also, the healthcare professionals with high positions believe that all recommendations should be implemented as soon as possible because healthcare professionals with high positions may be more dedicated and professional than others (33).

Common barriers to guideline implementation in health system included deficiency in staff continuous education, insufficient support from institutions, limitations of infrastructure (34). The most common barriers of healthcare professionals’ failure to adhere to clinical practice guidelines aligned with the Theoretical Domains Framework (TDF) domain of environmental context and resource (35). Our study similarly found that the hospital environment impacted guidelines implementation—the hospital level and the type of hospital impacted the guideline implementation, and showed that the lower the hospital grade, the more difficult it was to implement. Presumably the low-level hospitals in China frequently need more organizational expertise and resources to follow recommendations and control off-label drug use in children (36-38). Thus, implementing the Guidelines in facilities with low-level hospitals may be more challenging than in high-level hospitals. In China, different levels of hospitals have different responsibilities, and the higher the level, the stronger the treatment capacity. Compared with higher-level hospitals, lower-level hospitals have more pressing medical resources, for example, clinicians may be less experienced in off-label drug use, hospitals may have less sophisticated management, and pharmacy departments are not equipped with rational medication use systems. Also, compared to other hospital types, healthcare professionals from children’s hospitals perceived implementing guidelines as more urgent. Children’s hospitals are better equipped, more refined, and better managed in pediatrics than other hospital types (39,40). Consequently, healthcare professionals from children’s hospitals may feel the more urgent need for management of off-label use of drugs in children’s hospitals.

As a result, we propose that several implementation strategies should be developed per various healthcare professionals position, levels of hospitals, and hospital types. Alternatively, follow the lead of China’s regional medical alliances and align with children’s hospitals that have already successfully implemented the recommendations, such as checking prescription system (41), prescription evaluation (41), pharmacological monitoring (42,43), and clinical pharmacy interventions (44). Resources are exchanged to enable the execution of the Guideline by sharing information across different levels of hospitals and radiating high levels of care to the grassroots, such as through medical consortia (45,46).

The investigators found that the most difficult recommendation to implement was 2.3, which stated that the experts’ team for the pediatric off-label use of drugs should include professors who majored in evidence-based medicine, health economics, epidemiology, ethics, and the law. Scientific evidence is the foundation for off-label drug use, and experts in evidence-based medicine methodology can accurately assess and judge the evidence’s reliability, which is indispensable in managing pediatric off-label drug use (8). Health economists can monitor and evaluate the cost of off-label use of drugs for children and optimize the use of health resources (47). Legal and ethical issues can be addressed and have long been essential factors to consider for the off-label use of drugs (48,49), especially for children (50). However, there is a large gap between clinical practice and expectations in China because Chinese hospitals usually need more experts. In China, however, there is a wide disparity between actual practice and expectations, as Chinese hospitals typically require more specialists (51-55).

Accordingly, it is suggested that national or professional organizations gather experts to develop evidence-based decision systems to respond to demands for evidence for pediatric off-label drug use, such as the German network’s Pediatric Drug Information System (PDIS) (56). Additionally, to enhance the management of pediatric off-label drug use, Chinese hospital administrators are encouraged to modify the professional organization of hospitals, including the healthcare major in evidence-based medicine, health economics, epidemiology, ethics, and the law.

The questionnaire was validated by expert scale and pre-test, with questions well-designed to effectively respond to our research objectives. Our questionnaire has a good applicability and although it is not extrapolated, it can provide a reference for related studies in other countries. There are some limitations in this questionnaire. Firstly, restricted by realistic situations, the questionnaire was not distributed to primary hospitals, nor covered all the relevant professionals in the country, only sampling research was done, with limited representativeness. Secondly, there is no international common questionnaire for this research, nor could other questionnaires be adapted, this questionnaire is a self-initiated design with some limitations in question.

This study examined the current state of pediatric off-label drug use management. It demonstrated China’s unsatisfactory implementation, which is part of the early-stage implementation research by the Guideline Development Working Group. The study indicates that there is a need to identify the influencing factors of the recommendations first and then tailor implementation strategies to facilitate the management of pediatric off-label use of drugs. There are some limitations in this study. Convenience sampling may lead to an unbalanced sample and affect the extrapolation of results. Our questionnaire was distributed widely and the study population is representative of China.

Conclusions

The recommendations in the Guideline for the Management of Pediatric Off-Label Use of Drugs have high urgency for implementation in China. However, the implementation of 21 recommendations was challenging in clinical practice. The key factors influencing implementation were the position, education, experience, and hospital level of healthcare professionals. We suggest implementing the recommendations by sharing experience across various hospital levels and radiating from high-level hospitals to the grassroots. Additionally, the professional structure of health care in hospitals needs to be adjusted to improve the management of off-label drug use in children.

Acknowledgments

We would like to thank Janne Estill, MD, PhD (University of Geneva) for his help in polishing our paper.

Funding: This research was funded by the Chevidence Lab Child & Adolescent Health of Chongqing Medical University’s Children’s Hospital’s Key Project in 2022.

Footnote

Reporting Checklist: The authors have completed the SURGE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-24-198/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-198/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-198/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-198/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Only healthcare professionals were involved in this study without direct participation/data from children. The study was approved by the Ethics Committee of Gansu Provincial Hospital (No. 2022-152). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). All participants provided informed consent to participate in the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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