Research On The Current Status And Countermeasures Of Off-Label Drug Use

Background:As an essential complementary form of clinical diagnosis and treatment,off-label drug use（OLDU）has two sides.On the one hand,it has special significance for diagnosing and treating the specific population,such as children and patients with rare diseases.On the other hand,unreasonable and unnecessary OLDU has also caused a certain degree of impact on patient medication safety.Therefore,understanding and mastering the current situation of OLDU and implementing targeted interventions have important roles and values in standardizing clinical diagnosis and treatment behavior and ensuring medication safety.Objectives:（1）To systematically review the domestic and foreign literature on OLDU in recent years,grasp its global status and change trend,and provide a reference for further analysis of OLDU behavior in China.（2）To investigate and analyze the current situation of OLDU for children’s respiratory system diseases in outpatient（emergency）clinics in Gansu Province,comprehensively understand its distribution and change trend in the population,region,and time period,and provide a basis for further guiding clinical standardization and rational medication.（3）To deeply explore the relevant influencing factors of OLDU behavior,sort out the opinions and suggestions of various stakeholders on OLDU issues,and provide a reference for further improving the situation of OLDU and improving health care services.Methods:（1）Systematically searched CNKI,Wan Fang Data,CBM,MEDLINE（via Pub Med）,Web of Science,and Embase databases to collect descriptive studies related to OLDU.After conducting bias risk assessment and data extraction on the included studies,comprehensively grasped the prevalence and trend of OLDU at home and abroad through meta-analysis;（2）Screening prescriptions for respiratory system diseases in children from the outpatient（emergency）clinics’medical prescription data of 244 medical institutions in Gansu Province from March 2-8 and September 1-7,2020,and conducting judgment on OLDU based on the instructions of corresponding drugs in the prescriptions.The current status of OLDU for children’s respiratory system diseases in outpatient（emergency）clinics in Gansu Province was indicated by descriptive statistical methods.Exploring the distribution differences of OLDU among different types,regions,hospital levels,physician titles,and patients with different ages or gender by the Chi-Squared Test method,and analyzing the possible influencing factors of OLDU through binary logistic regression analysis;（3）Based on systematic analysis of relevant literature related to attitudes and behaviors regarding OLDU,we figured out the current management status of OLDU in China and comprehensively analyzed the views and suggestions of the respondents through in-depth interviews with relevant stakeholders.Laws,regulations,and policy documents at home and abroad were also considered to explore feasible countermeasures for improving the problem of OLDU.Results:（1）Among the retrieved 3,624 articles,158 studies that mentioned the prevalence of OLDU were finally included.There were 137 studies published in Chinese and 21 in English,involving 226,764 patients,116,481,478 prescriptions,and774,223 medication records.Meta-analysis showed that in the past three years,the prevalence of OLDU in prescriptions was 21.3%（95%CI[20.4%,22.3%]）,in medical records was 29.6%（95%CI[24.7%,34.5%]）,and in patients was 62.0%（95%CI[48.5%,75.5%]）.Subgroup analysis pointed out that the prevalence of over-indication drug use in prescriptions,medication records,and patients was 3.6%（95%CI[3.4%,3.8%]）,9.3%（95%CI[8.3%,10.2%]）,and 53.0%（95%CI[16.0%,89.9%]）respectively.The prevalence of OLDU in prescriptions,medication records,and patients in the 0～18 years age group was 30.7%（95%CI[29.7%,31.8%]）,37.5%（95%CI[30.5%,44.4%]）,and 89.8%（95%CI[71.2%,99.9%]）.In China,the prevalence of OLDU among prescription,medication records,and patients was 20.8%（95%CI[19.7%,21.8%]）,28.8%（95%CI[23.9%,33.8%]）,and 68.6%（95%CI[52.3%,84.9%]）respectively.（2）In the data of outpatient and emergency Western medicine prescriptions in Gansu Province in the first week of March and September 2020,a total of 46,614 medical records for children with respiratory system diseases were included,involving 15,700 patients and 21,831 prescriptions.The investigation results showed that the prevalence of OLDU in prescriptions and medication records was 36.18%and20.84%respectively,with 42.33%of patients who experienced OLDU.The most common type of OLDU was over-indication drug use,with a prevalence of 24.31%in the prescription.The prevalence of OLDU in tertiary A and tertiary B hospitals was relatively low,with 20.66%and 20.41%respectively.Prescription physicians with senior professional titles have a higher frequency of using OLDU,which is 42.04%and23.39%in prescriptions and medication records.There was no significant difference in the prevalence of OLDU among children of different ages and sexes.Binary logistic regression analysis showed that regions with higher gross domestic product were more likely to have OLDU behavior than regions with lower gross domestic product（OR=1.190,95%CI[1.118,1.266]）.Prescription physicians with senior professional titles are more likely to prescribe drugs beyond the instructions（OR=1.513,95%CI[1.380,1.659]）.Compared to tertiary hospitals,secondary hospitals are more prone to present OLDU behaviors(OR_3B=0.568,95%CI[0.352,0.917];OR_3A=0.476,95%CI[0.446,0.509]).（3）Among the retrieved 3,266 articles,27 related studies（five in Chinese and 22 in English）were included.On this basis,four interview outlines were formed for various stakeholders（two general persons with medical and medication experience,one clinician,two pharmacists,and one relevant researcher in university）of OLDU,covering six to ten main questions,and the interview duration ranged from30 to 60 minutes.The analysis of the interview content shows that the cognition,attitude,and behavior of medical workers such as clinicians and pharmacists on the use of OLDU have improved under the promotion of academic research,laws and regulations.However,patients or the public still lack a scientific understanding of OLDU,and their awareness of safe and standardized drug use still needs to be strengthened.Researchers’exploration of OLDU issues still needs to be further deepened.At the same time,there are many problems in the management of OLDU,such as low enthusiasm in the application and filing of OLDU,weak legal risk awareness,a vague sense of value identity,untimely approval and catalog updates,and insufficient motivation and ability to update drug instructions.In response to these problems,summarizing the views of the interviewees and combining relevant documents at home and abroad,this study proposed the following suggestions to improve the behavior and current situation of OLDU:1)conducting health education on relevant knowledge of OLDU to the public,popularizing and continuously strengthening the knowledge and awareness of standardized and safe drug use,to improve their awareness of using drugs according to the specification or doctor’s instructions;2)Providing training for medical workers on knowledge and ability of using OLDU,and effectively improving their relevant professional competence and skills;3)Establishing and optimizing the management procedures for OLDU in medical institutions,steadily improving the approval efficiency of OLDU,establishing an emergency management mechanism,and enhancing the quality and capacity of health services in institutions from multiple dimensions,paths,and directions;4)Clarifying the responsibilities and obligations of various stakeholders in the use of OLDU,playing the advantages and functions of different roles,and promoting the joint participation of all sectors of society in improving the use of OLDU;5)Opening a multi-channel information sharing mechanism for OLDU,assisting drug manufacturers in updating iterative instructions,while providing decision-makers with multiple aspects of information and data,and providing reference for further standardizing clinical rational drug use diagnosis and treatment behavior.Conclusions:In recent years,the behavior of OLDU has been widespread at home and abroad,and it is still necessary to pay close attention to the changing trend of this behavior in the future.At the same time,there are few studies related to OLDU in the western region of China,and it is recommended to strengthen high-quality research in this region.Preliminary exploration has found that the prevalence of OLDU for children’s respiratory system diseases in outpatient（emergency）clinics in Gansu Province is high,and it is related to the level of medical institutions,the economic level of the region where they are located,and the professional title of prescription physicians.It is recommended to carry out large-scale,multicenter research to explore the priority issues of OLDU in Gansu Province and implement targeted interventions.With the promulgation and implementation of the"The Law on Doctors of the People’s Republic of China",China has entered a new stage in the issue of OLDU.Education and management of OLDU in China still need to be continuously promoted,from improving public awareness,enhancing their consciousness of standardized drug use,strengthening the service quality and capabilities of medical workers and medical institutions,and increasing the initiative of drug manufacturers to update and revise their drug instructions,promoting the further improvement of laws and regulations on the use of OLDU through multiple dimensions,and work together with all sectors of society to enhance rational medication and protect the health of the entire population.