The Latest Advance of the FDA Sentinel Initiative and Its Enlightenment to China

Xie Xuerong,Tian Lijuan

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

Abstract Objective To study the useful experience of the FDA’s Sentinel initiative and provide a reference for the smooth implementation of China’s active drug safety surveillance after marketing.Methods By searching the official website of the FDA and relevant literature at home and abroad,the development history,framework,organizational system,data source and protection,monitoring tools and application of the FDA Sentinel initiative were sorted out.Results and Conclusion Sentinel initiative is an active surveillance method adopted by the US FDA to evaluate approved drugs and other medical products by using electronic health care data from various sources,which has formed a relatively mature management system in terms of data protection monitoring tools and other aspects.Drawing on the experience of FDA,China should integrate and utilize the existing health care database and expand the source of sentinel alliance database.Besides,the government should explore distributed database management mode to protect patients privacy effectively.Meanwhile,a public-private partnership platform can be established by formulating relevant regulations and policies to encourage academic institutions and pharmaceutical companies to make full use of sentinel data for mining data security signals and developing new monitoring tools.

Keywords:FDA;Sentinel initiative;active surveillance

Sentinel initiative is a monitoring system established by the FDA,the public,academia,and the business community in the United States in 2008,which enables the FDA to actively collect information about the safety and performance of its regulated products after marketing.The FDA can quickly and safely obtain information in a large amount of electronic medical data (such as electronic health records,insurance claim data,and registration forms) from multiple data partners through sentinels for security assessment.The sentinel is currently transitioning from mining safety information to developing monitoring functions.The capabilities,tools,data infrastructure and innovative methods of sentinel will continue to expand.This article introduces the development history,framework structure,organizational system,data sources and protection,monitoring tools,and application status of the US FDA’s sentinel operations to provide a reference for China to improve its post-marketing monitoring system of drugs.

1 The development history of Sentinel initiative

At the beginning of the 21st century,with the increasing awareness of public safety in the United States,patients and caregivers demand more information about the benefits and potential risks of the medical products.Besides,the application of information technology in the US healthcare system is also increasing.In September 2005,Health and Human Services (HHS) requested the FDA to expand its current medical product safety risk monitoring system and establish multiple data systems to enhance its data screening capabilities.

In response to the above requirements,in September 2007,the US Congress passed the“FDA Amendments Act (FDAAA)”,requiring the FDA to establish an active risk identification and analysis (ARIA) system.FDAAA requires the FDA to cooperate with the public,academia,and private entities to jointly find methods for obtaining access to different data sources.Therefore,a post-marketing risk identification and analysis system that can link and analyze medical data from multiple sources can be established.By 2012,this system should have contained data for at least 100 million people.According to the requirements of the FDAAA,in May 2008,FDA launched a project called Sentinel initiative.This action aims to supplement the deficiencies of the existing monitoring system by using the automated medical health data system to help the FDA conduct active surveillance of medical products after marketing[1].

In September 2009,FDA signed a four-year contract with Harvard Pilgrim Health Care for a total of 72 million US dollars.According to the requirements of the agreement,Harvard Pilgram Health Care established a Mini-Sentinel Coordination Center (MSCC),which was a small version of the sentinel system.Therefore,it created a common data model and distributed data method to enable the FDA to track medical care.The performance of the product and the protection of patient privacy have laid the foundation for the full implementation of sentinel operations.In 2011,sentinel distributed database(SDD) reached the FDAAA’s target of 100 million people.In 2012,in order to quickly solve security issues,Mini-Sentinel created a new programming tool for daily queries.In September 2014,FDA began the transition from the Mini-Sentinel stage to a full sentinel system.In February 2016,FDA officially launched a full sentinel system and incorporated it into the regulatory plan.

In 2017,FDA successfully developed and tested a marketable mobile application “My Studies”,which could safely store patient data in clinical studies,laying the foundation for the development of the FDA-Catalyst Project.In 2019,FDA established a new Sentinel Innovation Center (SIC),and Community Building and Outreach Center (CBOC)[2].The innovation center develops innovative methods to further advance sentinel,including finding ways to extract and structure information from electronic health records.Its goal is to create an analysis system for electronic health records with more than 10 million lives.The CBOC focuses on communication and collaboration as well as deepening the participation of stakeholders,and broadening the awareness,access and use of Sentinel tools and data infrastructure.In addition,FDA has also recruited a wide range of scientific collaborators to provide valuable technical support for the evaluation of electronic health data.Fig.1 shows the development process of the sentinel operation of the US FDA.

Fig.1 The history of FDA Sentinel initiative

Prior to 2016,the focus of the Mini-Sentinel pilot was to develop an infrastructure and methodology that would enable FDA to make full use of sentinel distributed databases for obtaining information.After 2016,the focus of FDA’s research is to use the sentinel system to evaluate safety signals and develop new monitoring tools in accordance with the legal requirements for the creation of the sentinel system.As the signal recognition function in the sentinel system matures,sentinel will play a greater role in discovering drug safety issues to complement the FDA’s increasingly powerful identification of drug safety.

2 The framework of Sentinel initiative

The sentinel operations include sentinel infrastructure and the biologics effectiveness and safety (BEST) system of the FDA Center for Biologics Evaluation and Research (CBER) (Fig.2).The sentinel infrastructure includes the sentinel system and the FDA-Catalyst project.The BEST system is part of sentinel operations to ensure the safety and effectiveness of biological products,but it operates outside the sentinel infrastructure[2].

Fig.2 The framework of Sentinel initiative

The sentinel system includes three subcomponents:active risk identification and analysis(ARIA),post-licensure rapid immunization safety monitoring (PRISM),and blood safety continuous active monitoring network (BloodSCAN) (Fig.2).ARIA is the most widely used monitoring tool for sentinel system,which is the basis of data application.Besides,it is a supplement to the FDA’s monitoring function,and it can continuously monitor the safety and effectiveness of FDA-regulated drugs.In addition,>the sentinel system supports key monitoring of vaccine safety through the PRISM system as well as supporting the regulatory review of blood and blood products through BloodSCAN.

The FDA-Catalyst project is an important supplement to the surveillance and research of the listed medical products in the sentinel system.By using sentinel infrastructure and other functions of the sentinel system,it expands the capability of collecting medical product safety information[3].FDACatalyst supplements data mainly through routine inquiries,interventions,and exchanges with health plan members and/or suppliers.In addition,this data is combined with the data contained in the sentinel infrastructure to supplement existing post-marketing monitoring system.

3 Organizational system of Sentinel initiative

The management organization involved in the sentinel operation mainly includes four parts:the US FDA,the sentinel coordination center,the sentinel data partners and cooperative agencies,and the Reagan-Udall Foundation and its innovation in medical evidence development and surveillance(IMEDS)[4](Fig.3).FDA is the supervisor and leader of Sentinel initiative,coordinating all the work of Sentinel initiative.The coordination center is the core link and bridge for data analysis and research between FDA and data partners.Data partners and cooperative agencies have data resources and they can cooperate with FDA to carry out drug safety analysis and research based on data.The Reagan-Udall Foundation and IMEDS are platforms for cooperation and interaction between FDA and academic institutions,pharmaceutical companies,and consumers.

Fig.3 The organizational system of Sentinel initiative

3.1 US FDA

FDA is responsible for Sentinel initiative,mainly maintaining decision-making and managing sentinel system contracts,determining strategic priorities,issuing project requirements,and reviewing all work.The sentinel management committee is the highestlevel organization composed of the director of the medical product center and a representative of the commissioner’s office,responsible for formulating long-term strategic directions for the sentinel.The sentinel executive committee is the main body composed of representatives of CBER,Center for Drug Evaluation and Research (CDER) and Center for Devices and Radiological Health (CDRH),focusing on formulating strategies for sentinels,supervising the implementation of projects,and submitting issues to the management committee as needed.CBER and CDER strategy and operation working groups are composed of central representatives,responsible for managing the daily operations of sentinels (including all administrative aspects),releasing the assessment results of safety issues made by the executive committee or management committee,so that the public can understand the safety issues of the medical product in time[5].

3.2 Sentinel Coordination Center

In September 2019,FDA announced that the sentinel had established three different coordination centers:Sentinel Operations Center (SOC),SIC,and CBOC.Each center operates independently with a leadership team and employees.The three centers execute projects related to the center’s strategic goals respectively,and they also cooperate to use sentinel systems to advance regulatory science[6](Fig.3).

The SOC is led by the Harvard Pilgrim Health Care,which continues to leverage epidemiology,clinical medicine,pharmacy,statistics,health informatics,data science (specifically,artificial intelligence,such as natural language processing,machine learning) and network operations to support post-market safety analyses.

The SIC consists of the Harvard Pilgrim Health Care,Brigham and Women’s Hospital Division of Pharmacoepidemiology and Pharmacoeconomics,Harvard School of Public Health,Duke Clinical Research Institute,Vanderbilt University Medical Center,and Kaiser Permanente Washington Health Research Institute with the University of Washington School of Public Health.The center is committed to developing innovative methods to further advance sentinel,such as exploring novel ways to extract and structure information from electronic health records.

The CBOC is responsible by Deloitte Consulting,IQVIA and Nova Research.It will focus on communication and collaboration as well as deepening stakeholder involvement and broadening access and use of sentinel tools and data infrastructure.Through modernization of sentinel websites,it enhances the user experience.

3.3 Data partners and collaborating institutions

The data partner is an important part of the sentinel system.It mainly searches and inquires relevant data in response to the safety issues raised by FDA,and provides facts for the FDA’s analysis.At present,the data partners in the sentinel system are mainly composed of 16 institutions,including private research institutions (insurance companies),medical academic institutions,and university research centers (Table 1).Cooperative institutions jointly provide health care data and scientific,technical and organizational expertise.Currently,there are 24 partner institutions,including Anthem Medicaid,Brigham and Women’s Hospital,Duke Clinical Research Institute (Table 2).

Table 1 Sentinel data partners

Table 2 Sentinel collaborating institutions

3.4 The Reagan-Udall Foundation and IMEDS

The FDA’s Reagan-Udall Foundation is an independent non-profit organization that promotes regulatory science.The foundation is managed by a board of directors,and members mainly come from academia,consumer groups,medical products and food industries,healthcare and other organizations.The foundation is an important channel between FDA and the public,providing a means for FDA to interact directly with stakeholders (including industry and consumers).

The Reagan-Udall Foundation has a publicprivate partnership called IMEDS.IMEDS provides a platform for academic institutions,and pharmaceutical companies.It allows private companies to access sentinel action systems,use data resources to monitor safety signals,conduct post-market research,and evaluate risk management measures.The IMEDS project currently consists of ten network partners,including the national and regional health systems and insurance companies in the United States.The IMEDS network has obtained medical care data of more than 116 million people since 2006,including children,pregnant women,and the population from elderly health insurance system and the medical assistance system.The data that can be used for research include demographics such as medical visits,laboratory,pharmacy experience as well as administrative claims information.The medical records from 80% of the population can be obtained[7].

4 Data source and protection of Sentinel initiative

The core data of sentinel comes from the patient information in the US healthcare system such as the national health insurance plan,large integrated delivery system,and health care organization (stored by the patient’s insurance company and supplier).The data are collected regularly during each healthcare process,which capture every medical experience,diagnosis and prescription information of patients.Then,they can be used to analyze the safety issues of FDA medical products.In addition,sentinel sites can establish links to expand the types of other supplementary data available,including registration and other databases that specifically collect information about vaccines,deaths,cancer,and other drugs or health outcomes.

Sentinel initiative covers a large amount of health data,and the application and sharing of data requires a set of procedures and policies for support.In 2002,HHS issued the newly revised “Health Insurance Portability and Accountability Act (HIPAA)”[8].The rules of HIPAA are applicable to health plans,health care institutions,and any medical service providers that transmit health information through electronic transactions.It is comprehensive and flexible to protect personal health information.In addition,data partners must comply with the state’s health information confidentiality laws,requiring informed consent before using or disclosing special types of health and health data such as HIV and genetic testing[9].The promulgation of laws and regulations not only ensures that personal health information is properly protected,but also allows necessary health information to be shared in the healthcare market to protect public health.

5 Monitoring tools for Sentinel initiative

ARIA is a special computer program for sentinel,which is the basis of data application.ARIA uses preset parameters and conventional query tools to identify and estimate risks and discover new and potential safety hazards to achieve efficient safety monitoring and analysis.FDA uses ARIA system to monitor the safety of drugs,making decisions about drug safety issues based on all the data and evidence provided by ARIA[10].

Distributed database is the data processing method of sentinel,which is a collection of unified data sets from many different data partners.The common data model is a unified data format after all data partners convert local data.The general data model consists of separate tables.Each table contains a specific type of data,which can be adapted to the needs of FDA and the conversion of other data types.The data areas contain much information such as registration,demographics,usage rates,and outpatient pharmacy dispensing.

FDA and the SOC send the question to each data partner in the form of an executable computer program.Each data partner converts its data into a common data model according to a preset standard,and performs an analysis of its data behind the firewall.Data query is distributed and returned through the secure portal,data partners only return results (not including identifiers that can directly identify patient information,such as name,phone number,etc.),which provides protection of patients privacy and their health information (Fig.4).

Fig.4 The query process of sentinel distributed database

6 Application of Sentinel initiative

The sentinel data provide a basis for regulatory decisions made by the FDA’s Drug Evaluation and Research Center.Through sentinel data analysis,FDA canceled the post-market safety studies of five products,including ustizumab,which saved a lot of manpower and financial resources.FDA also used the sentinel system to better understand the use of opioids and other medical products.For instance,whether they are used in accordance with the approved indications,how to use them during pregnancy,and how to quantify the incidence of medication errors.In addition,FDA also evaluates the effect of medical products in public health emergencies[11].

FDA uses the sentinel to create a parallel project called FDA-Catalyst.It uses a mobile app named “My Studies” to support research clinical trials,including comparative observational analysis results,and randomized controlled clinical trial results,which expands the monitoring function of sentinel system[12].“My Studies” mobile application has been applied in clinical research after being tested successfully (Table 3).

Table 3 Situation of FDA-Catalyst’s application [13]

7 Enlightenment

Sentinel operation is a project that is managed internally by the US FDA and the Sentinel Coordination Center,and it communicates with the public through the Reagan-Udall Foundation.It is a project of great significance for post-market safety monitoring of drugs.The sentinel data has a wide range of sources,including medical care data,registration and other databases that specifically collect information about vaccines,deaths,cancers,and other drugs or health results.The data management model is efficient because the distributed database and general data model are used to ensure data security effectively and improve information utilization.With the development of the FDA-Catalyst project,US sentinel operations are transitioning from mining safety information to developing monitoring functions.The sentinel monitoring capabilities,tools,data infrastructure and innovative methods will continue to expand and mature.

Drawing on the experience of FDA,China should integrate and utilize existing medical care databases[14],such as the national medical insurance information database,electronic medical database,resident electronic health record database[15]and population basic database,to expand the sources of the sentinel alliance’s database.Besides,it should explore the distributed database management model to establish a data management center for managing the data of sentinel hospitals.Then,a public-private cooperation platform should be built to enable academia and pharmaceutical companies to mine data security signals through sentinel data. Meanwhile,sentinel data retrieval signals should be strengthened to verify the true and false signals through expert evaluation,literature reference,and computer prediction.Lastly,relevant laws and regulations should be formulated to regulate data sharing and use,as well as solve problems such as privacy protection.