Hu Rongbo,Yang Yu,Shi Yu,Xiang You,Tian Lijuan

(School of Business Administration,Shenyang Pharmaceutical University,Shenyang 110016,China)

Abstract Objective To briefly introduce the construction and operation of the National Sentinel Alliance for Adverse Drug Reaction (ADR) Monitoring,and provide reference for strengthening the safety monitoring of drugs after listing in China.Methods The literature research method was used to analyze the establishment and promotion measures of the National Sentinel Alliance for ADR Monitoring,and then some countermeasures and suggestions were put forward to enhance the construction of the alliance.Results and Conclusion The alliance based on Chinese hospital pharmacovigilance system (CHPS) has played an important role in ADR monitoring and reporting.Promoting the construction of the alliance can provide a new method for improving the scientific evaluation system and active supervision system of drug safety after listing.Therefore,the construction of alliances at the national and provincial levels should be strengthened.Besides,relevant laws and regulations must be improved to accelerate the research and development of information systems,which will deepen the active monitoring of the alliance continuously.

Keywords:Chinese hospital pharmacovigilance system;alliance for monitoring;adverse drug reaction monitoring

Sentinel hospitals are medical institutions that have been approved by the National Center for Adverse Drug Reaction (ADR) Monitoring(hereinafter referred to as the National Center).They have a strong capability of monitoring ADRs/adverse drug events (ADEs) and they can carry out key drug monitoring and re-evaluation with the help of Chinese hospital pharmacovigilance system (CHPS)[1].CHPS is deployed in various sentinel hospitals so that it can access their information systems and medical data to realize online generation,review,reporting,feedback and analysis of ADR information in these hospitals.Therefore,it can effectively solve the current reporting problems such as high omission rate,strong randomness and incomplete information,and then provide technical support for the establishment and operation of monitoring alliances.

The alliance reports ADRs to the National Center through CHPS.Then the National Center analyzes and summarizes the ADRs,issues notices and provides early warning of adverse reactions.This will further improve China’s ADR monitoring network and management system and promote the progress of ADR monitoring in medical institutions.

1 The development of sentinel hospitals and the alliance

Because of many deficiencies in the ADR passive monitoring system,combining the actual situation in China,and drawing on the experience of the US Food and Drug Administration (FDA) sentinel initiative,the former China Food and Drug Administration (CFDA)started the pilot work for the construction of ADR monitoring sentinel hospitals in September 2016.Therefore,the National Sentinel Alliance for ADR Monitoring was established.First,hospitals voluntarily sign up,and then they should be recommended by the provincial center for ADR monitoring (hereinafter referred to as the provincial center).Finally,after the review from National Center they can sign the alliance cooperation agreement.The CHPS should be deployed in each sentinel hospital management system to realize the online generation,review,reporting,feedback and analysis of ADR information.

Nine hospitals,including Xiyuan Hospital of the Chinese Academy of Traditional Chinese Medicine,First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine,Shanghai General Hospital,Renmin Hospital of Wuhan University,Jiangxi Provincial Hospital of Traditional Chinese Medicine,Nanfang Hospital of Southern Medical University,the Ninth People’s Hospital of Chongqing,Maternal and Child Health Hospital of Guiyang Province,First Affiliated Hospital of Xi’an Jiaotong University,joined the National Sentinel Alliance for ADR Monitoring in September 2016[2].They became the first national pilot units,marking the official launch of the work.This laid the foundation for the follow-up construction of monitoring alliance.

As of June 25,2019,there had been 179 medical institutions that officially joined the National Sentinel Alliance for ADR Monitoring[3],as shown in Fig.1.By the end of the Thirteenth Five-Year Plan,the National Center will have to establish a monitoring alliance with 300 sentinel hospitals,which will further strengthen the sentinel construction of the ADR monitoring in China.

Fig.1 Development process of sentinel hospitals in China

2 Overview of pharmacovigilance system in sentinel hospitals based on hospital information system (HIS)

China’s pharmacovigilance system started late.At the first pharmacovigilance seminar in 2007,Chinese government decided to establish a pharmacovigilance system based on an ADR monitoring system[4].Generally,ADR monitoring will be conducted after the drug is marketed,but pharmacovigilance runs through the entire life cycle of the drug.Therefore,strengthening ADR monitoring will lay a solid foundation for the good development of pharmacovigilance.

With the application of HIS in medical institutions,it not only provides hospitals with the collection,storage,processing,extraction and data exchange of patient’s diagnosis and treatment information and other information[5],but also forms an electronic platform to carry out pharmacovigilance for medical institutions.At present,China’s ADR monitoring is mainly based on spontaneous reporting.Primary medical institutions are required to report ADR information in the national ADR monitoring system,but the HIS cannot be connected with the national ADR monitoring system.Therefore,the National Center established a sentinel hospital pharmacovigilance system on the basis of HIS to improve the ADR monitoring system and promote the development of national pharmacovigilance system.

2.1 Mutual promotion and information sharing between CHPS and HIS

At present,most hospitals in China still report ADR reports manually.Only a few hospitals adopt a semi-automatic way to realize information sharing and online reporting by developing an in-hospital ADR reporting system.However,the ADR reporting system in these hospitals lacks the data interaction with the national ADR monitoring system.Besides,this system has not been widely applied.Since most systems have general effect with complicated reporting process,the reporting information is incomplete,arbitrary with high omission rate.Therefore,the quantity or quality of ADR reports has not been effectively improved in these hospitals .

In response to the above problems,CHPS is rooted in the information system and medical data of each medical institution through the connection between the national ADR monitoring database and HIS,reaching into the frontline of clinical medicine.When medical staffs discover cases of ADRs,relevant information is automatically extracted through HIS to assist reporters to fill in and shorten the reporting time.Medical cases of ADRs can be obtained through searching electronic medical records with keywords to provide reference for timely detection of ADRs.Thereby the efficiency and quality of reports from medical institutions will be improved.

The CHPS of sentinel hospitals has been trial-launched in Guangdong Province since 2014.Currently,CHPS has been embedded in HIS of the People’s Hospital of Qiannan.Using its ADR knowledge base and searching engine technology,the ADRs or abnormal medication signals of patients in HIS can be automatically captured and uploaded.Finally,the information will be reviewed by a fulltime pharmacist and uploaded to the national ADR monitoring system.After the application of the system,the effect is remarkable.The new model of ADR monitoring,which changes from“passive monitoring”to“combination of active and passive monitoring”,not only increases the number and quality of ADR reports significantly,but also improves the working methods and efficiency of the reporting staffs.In addition,by using the ADR active monitoring function,hospitals can monitor the key drugs to discover the missed or potential ADRs/ ADEs,timely.This will avoid the possibility of a large number of ADEs.

2.2 Structure of pharmacovigilance system based on HIS in sentinel hospitals

The structure of pharmacovigilance system in sentinel hospitals based on HIS is mainly composed of three parts:hospital information management platform,data center and CHPS.

2.2.1 Hospital information management platform

The plat form is the data source of pharmacovigilance system in sentinel hospitals.The main data includes:(1) Basic information of patients,doctors’ advice/prescription information,patient hospitalization information and drug information in HIS.(2) Test items and test report information of patients in laboratory information management system(LIS).(3) Diagnosis information,admission records and discharge records in the electronic medical record(EMR) system.

2.2.2 Data center

The data center is responsible for data collection.It obtains data from the hospital information management platform,and then it processes the information in three steps:extract,transform and load.It is called ETL in abbreviation.Then the data processed through ETL will be loaded into the intermediate library,a unified data standard interface,which can convert different data structures in HIS,LIS,and EMR into a unified data structure.Pharmacovigilance systems in the sentinel hospitals can directly transfer the data in the intermediate library.

2.2.3 CHPS

CHPS is a user application platform.Users can access the system through front-end tools to implement functions such as drug data regularization,ADR auxiliary reporting and active monitoring,pharmacovigilance information,early warning and statistical analysis[6].

3 Measures to promote the construction of national sentinel alliance

3.1 National level

To promote the alliance,the National Center held a meeting on the construction of sentinel hospitals in September 2016,highlighting the current status of ADR monitoring in medical institutions in China,the demonstration of CHPS in the sentinel hospitals and the experience of applying CHPS.In November of the same year,a seminar on monitoring was organized to conduct in-depth exchanges and discussions on specific technical issues,current tasks and development direction.The convening of the above meetings has greatly promoted the construction of the alliance.

For the construction of sentinel alliance,the National Center has carried out six work exchanges so far.For example,at the 2018 National ADR Monitoring Working Conference,the direction of expanding the sentinel alliance for ADR monitoring was clearly defined.In 2018,the National Sentinel Work Exchange emphasized the establishment of an alliance to explore an active monitoring model for post-market research.Through the above work exchanges,the National Center further clarified the overall conception of the sentinel alliance.It means the sentinel alliance platform and its innovate cooperation methods should be used to strengthen the data analysis capabilities,and provide technical support for in-depth ADR monitoring.

Regarding the promotion of CHPS,the National Center held a Training Meeting on the Construction of the Sentinel Alliance and the Promotion of CHPS in Guangzhou on March 31,2017.The heads of ADR Monitoring Centers in various provinces (regions and cities) across the country participated.The work training not only implemented the CHPS deployment experience throughout the country,but also gradually spread the CHPS to all the medical institutions,strengthening its information monitoring system,and helping upgrade the hospital hardware and software equipment.

3.2 Provincial level

For laws and regulations,Shandong Provincial Drug Administration and National Health Commission of the people’s Republic of China jointly issued a document,promulgating the“Administrative Measures on Drug and Cosmetic Adverse Reaction Monitoring”on November 12,2019,which was officially implemented on January 1,2020.It started a precedent for the management of sentinel alliance for ADR monitoring in provincial drug regulatory departments,laying the foundation for the in-depth development of sentinel construction[7].

For the development and construction of CHPS,on June 7,2016,Guangdong Provincial Center held a seminar on the project Research and Establishment of CHPS commissioned by the National Center,and it completed the research and development (R&D)of CHPS with Guangdong University of Technology and the former Center for Drug Evaluation,CFDA.Guangdong Provincial Center and its research team have accumulated rich experience in active monitoring of ADR and post-marketing safety research,which played an exemplary role for other provinces.

For promoting the deployment of CHPS,the centers for ADR monitoring of all provinces have held promotion meetings to join the sentinel alliance.For instance,on April 25,2018,the leaders of ADR monitoring system and sentinel alliance declaration units in some cities of Xinjiang attended the meeting.On August 16,2018,the directors of many tertiary hospitals in Henan Province,the heads of ADR monitoring departments,some directors of municipal ADR centers and the provincial municipal bureaus attended the meeting.On November 30,2018,persons in charge of the city center and some medical institutions that declared sentinels attended the meeting in Fujian Province.The application of CHPS were introduced in these meetings,and the experience of some sentinel hospitals was shared as well.By convening the promotion meetings of CHPS in the provincial centers,all the medical institutions understood the convenience and system safety of CHPS.Meanwhile,their enthusiasm for applying for CHPS could further promote the construction and orderly operation of CHPS in every province.

For the promotion of sentinel alliance,Shandong Provincial Center formulated a three-step strategy.First,it made the annual work plan and released“Measures for the Management of Drug and Cosmetic Adverse Reaction Monitoring”.Second,the overall arrangements and detailed interpretation of the alliance work was made to clarify its direction.Lastly,sentinel units were organized to declare research topics and financial support was given.A four-level linkage mechanism of national-provincial-city-medical institutions was established by Guangxi Provincial Food and Drug Administration,which formulated annual drug monitoring plans and evaluation plans.This could actively promote sentinel research projects and fully implement all the tasks of sentinel construction.

3.3 Medical institution level

Medical institutions in various provinces,autonomous regions,and municipalities can voluntarily declare first,then they will be recommended by the provincial centers for ADR monitoring in their area.After being approved by the National Center,they can finally sign an alliance agreement to conduct alliance unit selection and construction.At present,more than 300 medical institutions nationwide have applied for registration as monitoring sentinels,of which more than 100 have already deployed and implemented CHPS[8].After CHPS goes online,all alliance units report ADR to the National Center through the system,and the number of reports shows a substantial increase.Through the application of CHPS system,the reporting efficiency of ADR in medical institutions is improved greatly as well as the initiative and standardization of medical personnel’s reporting on ADRs.In addition,some medical institutions have actively promoted the construction of sentinel alliances and in-hospital ADR monitoring by participating in scientific research projects related with CHPS organized by provincial centers.

4 Suggestions on promoting the construction of National Sentinel Alliance for ADR Monitoring

4.1 Balanced the distribution of National Sentinel Alliance for ADR Monitoring to drive monitoring in different regions

In 2018,the average number of case reports per million people in China was 1 119.The coverage rate at the county level was 97.9%.From the above data,it can be seen that the level of ADR monitoring is still high,and the case report of districts and counties exceeds the requirement of reporting ratio (more than 90%) of counties (cities and districts) in the 13th Five-Year Plan.However,there are still differences in the promotion of monitoring in various regions.Guangdong,Jiangsu,Shandong and other regions have actively promoted the deployment of sentinel alliances,while it is difficult to promote the alliances in Northeast,Guangxi and other regions.Since the construction progress of sentinel alliances varies from place to place,it is necessary to establish a balanced distribution of sentinel alliances to drive the ADR monitoring in these regions.

For areas with densely distributed sentinel hospitals,experts on ADR monitoring are invited to conduct in-hospital training on CHPS to improve the professional competence of staff in these hospitals.Besides,sentinel units should be actively organized to apply for research topics and accumulate experience in ADR monitoring systems and drug re-evaluation after marketing.The provincial center can work with the Provincial Health Committee to formulate“Measures for the Management of Provincial Monitoring Sentinel”,which will promote the standardization of the management of monitoring sentinel.

For areas with few sentinel hospitals,drug monitoring in them should start from the source.The provincial center should increase the contact and communication with the National Health Committee,and promote the ADR active monitoring in medical institutions.Besides,provincial centers should strengthen collaboration and cooperation with municipal centers to balance the distribution of sentinel hospitals.Meanwhile,training models should be enriched and more funds must be given to these hospitals for strengthening the information system hardware equipment as well the construction of technical teams.

4.2 Improving the legal system related to active monitoring and sentinel construction

Perfect laws and regulations are the guarantee for drug safety supervision,while China’s pharmacovigilance system and active monitoring model are both in their infancy with imperfect laws and regulations.The current version of“Measures for the Management of ADR Reporting and Monitoring”doesn’t contain much for active monitoring and sentinel alliance.Therefore,it should be amended in time.It should put the active monitoring into the ADR monitoring system as an effective measure for risk monitoring and early warning.In addition,it should clearly define the concept and connotation of active monitoring,subjects and responsibilities,procedures and requirements,violations and penalties.In order to help the marketing authorization holder (MAH)/pharmaceutical manufacturers establish a normalized risk management system,the specific implementation methods in the“Key Drug Monitoring and Management Standards (Trial)”should be improved constantly.The implementation of the re-assessment system will enable it to carry out safety monitoring to achieve an effective link between the pre-market and post-market risk assessment.

4.3 Establishing a long-term win-win mechanism for sentinel alliance members

The construction of the sentinel alliance plays an important role in the active monitoring of drug safety,risk control,post-marketing and re-evaluation research of drug regulatory departments,hospitals,MAH and pharmaceutical companies in China.It can help to create a win-win situation for multiple parties.

Since the sentinel alliance conducts safety research by establishing a cooperation mechanism among data sources,there is a risk that the information data may be leaked.All alliance members should abide by the relevant regulations when participating in research on key topics.In addition,they should share the data required for national drug safety monitoring research in a timely and safe manner.The effective operation of monitoring system depends on the data partners’ cooperation and needs more interests support.For example,the alliance can provide more research topics for medical personnel in the sentinel hospitals to enhance their research capabilities.It also can reduce the ADRs and risks for sentinel hospitals.By increasing the level of ADR supervision and monitoring agencies to carry out drug safety monitoring and evaluation services,the alliance will establish a win-win situation for supervision,monitoring and hospital.The specific measures taken include the following such as editing professional journals and related publications,conducting research,training,consulting and other services.In accordance with the principle of complementary advantages and resource sharing,labors and resources should be divided effectively.Alliance members should be encouraged to achieve bilateral and multilateral cooperation,which will promote information exchange and win-win cooperation between the members.

4.4 Focusing on the R&D of information systems to provide technical support for post-market reevaluation

The new system that has been put into operation online is based on the original CHPS,with functions such as collection,reporting,analysis and management of drug evaluation data[8].This drug evaluation system can quickly acquire the cases required by the project through intelligent search tools to realize the development of the drug evaluation project and the collection and management of the evaluation report data.Since the technology of new CHPS is not mature yet,in the process of collecting drug evaluation data,there is a lack of unified standards and specifications for related information on drugs and projects involved.It is difficult to retrieve target information from clinical data in different sentinel hospitals.Therefore,a standard database should be built to standardize the data output by the hospital to provide support for future medical data cleaning and application.Besides,a thesaurus should be built to provide synonyms corresponding to hospitals for the required evaluation.In this way,It can ensure that target content can be retrieved from clinical data of different hospitals when using a unified standard for searching.

In addition,information systems that use electronic healthcare data to enhance post-market drug safety monitoring are widely used.Therefore,the National Center should pay attention to the R&D of information systems by exploring advanced data processing methods and improving the R&D technical staffs.This will ensure that the information system can perform intelligent analysis and statistics on ADR case report data and better provide technical support for drug post-marketing monitoring in National Center,provincial centers and medical institutions.

5 Summary

At present,great progress has been made in National Sentinel Alliance for ADR Monitoring.However,during the construction process,there are still some problems such as unbalanced distribution of sentinel hospitals,the imperfect regulations for ADR active monitoring system,and the immature technology of CHPS.It is recommended that the national drug regulatory department improve the relevant laws and regulations on active drug monitoring as soon as possible.Besides,national and provincial ADR centers should strengthen the promotion of alliances and technical guidance for the monitoring of sentinel hospitals.Lastly,relevant departments and agencies should work together to deepen the active monitoring of China’s alliance,gradually improving the ADR monitoring system to provide technical support for the collection and monitoring of drug safety information based on real world medical big data.