Fu Min ,Huang Zhe, ,Xu Fengxiang

(1.School of Business Administration,Shenyang Pharmaceutical University,Shenyang 110016,China;2.Research Institute of Drug Regulatory Science,Shenyang Pharmaceutical University,Shenyang 110016,China)

Abstract Objective To provide references and suggestions for the application of real-world evidence in the decision-making of drug regulation in China.Methods The application of EU real-world evidence in drug regulatory decision support was analyzed through literature research and other methods,and the specific operation of its application was demonstrated by case studies.Results and Conclusion The application of EU real-world evidence in drug regulatory decision-making has achieved certain results and is in a stable development stage.The application of real-world evidence in China’s drug regulation is feasible.The successful application of EU real-world evidence can provide reference for China.

Keywords:EU;real-world evidence;drug regulatory decisions;enlightenment

1 Introduction

1.1 Research background

Real-world evidence refers to the full analysis of applicable data in the real world,including clinical evidence about drug use and its potential risk and benefit obtained through retrospective,prospective,observational studies,or actual clinical studies[1-4].

At present,the EU and the United States are vigorously promoting the research on the real-world evidence,and enhancing its application in drug review,approval and post marketing supervision,which have achieved certain results.Among them,the U.S.Congress encourages FDA to carry out realworld research and use real-world evidence to support new indication approval and post marketing research of drugs and other medical products.The EU focuses on the combination of real-world evidence and big data technology.Research on real-world evidence based on big data has better compliance and economy.The development of big data technology also provides technical support for the application of real-world evidence.

The European Medicines Administration(EMA) participated in the GetReal initiative in 2013,which aimed to develop new methods for collecting real-world evidence for early use in drug R&D and healthcare decision-making.In 2014,the EMA launched the adaptive licensing pilot project to explore the feasibility of drug evaluation using realworld evidence.At the beginning of the project,the EMA believed that real-world evidence mainly played the role of supplementary evidence for clinical trials in drug approval,which was used to support drug safety decision-making.With the wide application of real-world evidence,the EMA began to consider using real-world evidence to support the effectiveness of drugs.At present,the EU has carried out many realworld evidence for drug regulatory research.

For example,in 2015,the EMA approved Alexion’s application for extended indications of Eculizumab by using real-world evidence.At the same time,the Headquarters of the European Drug Administration and the European Drug Administration jointly set up a big data working group to use big data to improve regulatory decision-making and evidence standards.The EMA has also launched an adaptive licensing pilot project to explore the feasibility of realworld evidence to support drug regulatory decisions.These studies have achieved good results.It can be seen that in the field of medicine,the application of real-world evidence in the EU has been in the lead,especially its combination with advanced technologies such as big data.

At present,the common challenge in the field of medicine is how to obtain high-quality data,and China is also facing the same challenge.Although China’s attention to real-world evidence is increasing year by year,the application of real-world evidence requires much data analysis,statistical methods,research,and design,and the current application situation is not mature.However,based on the above analysis,the EU’s research in this field is at the international leading position.Therefore,this paper analyzes the relevant research and application of EU’s real-world evidence based on big data technology in drug regulatory decision-making and its enlightenment to China,which has theoretical value and practical significance.

1.2 Research status at home and abroad

At present,there are some research results on the real-world evidence in China[5-6].On the one hand,scholars have studied the application prospect and promotion of real-world evidence.For example,Yuan Ni,et al.[7]analyzed the bottlenecks encountered in the current process of drug review and approval for the treatment of rare and life-threatening diseases according to the“Principle of Knowing that Real-World Evidence Supports Drug R&D and Review(Trial)”promulgated by National Medical Products Administration.And they explored the application of real-world evidence in rare disease drugs.Shi Shuyuan,et al.[8]introduced the project of Harvard University research team using real world data to carry out non-randomized research,thus promoting the application of real-world evidence.They focused on the bias in the process of real-world data research and its coping strategies to provide evidence support for medical regulatory agencies.On the other hand,scholars have studied the challenges faced by the application of real-world evidence and the corresponding methods.For example,Sun Xin,et al.[9]explored the real-world data and research technical specification system,and advocated promoting China’s medical and health decision-making level through continuous improvement of production technical specifications.Liao Yingfen,et al.[10]proposed that transforming real-world data into real-world evidence through scientific and rigorous methods is a common challenge for drug R&D and supervision,and displayed the positive role of realworld evidence in drug supervision.The research results at present not only provide us important information to understand the development and application of domestic Real-World Evidence but a variety of research ideas as well.Compared with EU and the USA,the research and application of realworld evidence in China started late,and there are still some defects in the key technologies and core steps.Therefore,it is important to explore the application mode of real-world evidence combined with big data technology in Europe and America,especially the European Union,learning from its advanced methods in pharmaceutical supervision.Based on this,we can develop the application mode of real-world evidence suitable for China’s condition.

Most foreign scholars focus on developing new tools to improve the role of real-world evidence in decision support.For example,J Langham,et al.[11]comprehensively analyzed the website data of health technology assessment and reimbursement agencies published in France,Germany,Italy,the Netherlands,Spain,Sweden,and the United Kingdom,and explored the role of real-world evidence in distinguishing new products and their most suitable target groups of patients.In view of the challenges faced by real-world evidence research,AD,Xia et al.[12]developed a real-world evidence framework,which is a concise,intuitive,and interactive tool to align multi-disciplinary stakeholders with common goals,and it encourages the use of systematic methods for real-world data research planning.D Floyd,et al.[13]analyzed the specific requirements of European countries for real-world evidence to support the continuous market access of new drugs for the treatment of non-small cell lung cancer (NSCLC).The results show that real-world evidence is expected to play an important role in distinguishing between new products and their most suitable target groups of patients.

These studies indicate the current application of EU real-world evidence and provide ideas and theoretical guidance for us to support drug regulatory decision-making in China.However,most of the current studies only objectively analyze the application and exploration of EU real-world evidence,which do not put forward targeted suggestions based on EU characteristics and domestic drug regulatory conditions.Based on the combination of real-world evidence and big data in EU,this paper illustrates the positive role of real-world evidence in the decision-making of drug regulation and puts forward corresponding suggestions according to the development of drug regulation in China.

2 The role of real-world evidence in decision support

Research shows that in recent years,the cost of large-scale clinical trials is increasing,but the quality of evidence supporting health decision-making has not improved.Under this context,researchers and pharmaceutical companies began to expand the scope of research to a more complex real-world background,collecting data from electronic medical records,medical insurance databases,mobile applications and other channels to improve research efficiency,save time and cost,and obtain evidence from more patients.In developed countries,with the improvement of regulatory awareness and pharmaceutical enterprises’attention to the whole life cycle of products,the concept,legislation,and practice of Real-World Evidence have made great progress in the past decade.

At present,the EU’s drug regulatory model is constantly reforming and innovating,gradually transforming from the traditional passive supervision to a more proactive and forward-looking supervision.According to the existing research,the support of real-world evidence for drug regulatory decisionmaking is mainly reflected in the accurate description of drug use risk.The European Drug Administration closely combines real-world evidence with big data,providing a more active data support for drug regulatory decisions[14].To meet the data requirements of this active regulatory model,European drug regulatory agencies had actively collected relevant data in the early stage of decision-making,instead of waiting for enterprises to carry out relevant trials and report data,which was the traditional regulatory model.Through the research on the application of real-world evidence in drug regulatory decisionmaking in EU,it is found that real-world evidence has great practical significance in supporting drug safety decision-making in China,but its role in effective drug regulatory decision-making needs to be further strengthened[15].Based on this,EMA held a seminar on the application of real-world evidence in drug efficacy research,which focused on the analysis of the advantages and disadvantages of real-world evidence and observational research,practical clinical trials,and registration studies to measure drug efficacy[16].It provided guidance for the real-world evidence in the formulation of regulatory decisions on drug effectiveness.

In general,combined with big data technology,real-world evidence can provide data support for drug regulatory decision-making from the following aspects.First,for newly marketed drugs,real-world research can obtain the effect and safety information of drugs according to the symptoms of the disease,treatment methods,target population and other factors related to clinical research,which can provide supporting evidence for their registration and listing.Second,for the drugs sold on the market,more reasonable and feasible real-world evidence is used to support the evaluation of new indications.Third,real world data can re-evaluate the drugs being used,the feedback from patients and drug economic benefits[17],providing evidence for the requirements or reevaluation of drugs after marketing.

3 The enlightenment of the application EU real-world evidence to China

Through the above analysis,we can get that the application of real-world evidence can obtain drugrelated information more accurately that is in line with the actual situation.Therefore,it can provide a higher quality reference for drug regulatory departments.Real-world evidence can more objectively evaluate the safety of drugs,especially with the support of big data technology,and the reliable data sources greatly increase the credibility of evidence.

Since clinical trials are infeasible or difficult to implement in the process of drug research and development,using real-world evidence as a supplement to evaluate the effectiveness and safety of drugs has become a critical path,which will provide new evidence for drug regulatory decision-making in China.Due to China’s huge pharmaceutical market and drug demand,this high efficiency,easy to carry out evaluation method has more practical value.As a new research index,with its continuous development and improvement in various countries,real-world evidence is gradually recognized and accepted,and is actively used in decision-making in the field of medicine[18].Combined with the application of EU’s real-world evidence in drug regulation and the development status of drug regulation in China,the following enlightenments are summarized.

(1) China’s government should further create a policy environment for real-world research.The successful application of European real-world evidence in drug regulation benefits from the favorable development environment provided by the EU and its favorable policies.Although China has introduced some relevant policies,the incentive effect needs to be improved.

(2) The research process should be standardized to ensure the collection efficiency and application quality of real-world evidence.Regulatory agencies have strict requirements on data quality.The traditional paper-based data collection or electronic transcribed data collection mode will greatly increase human costs,but the data quality is still not guaranteed[19].Therefore,it is necessary to innovate information collection methods and develop basic tools matching real-world data to promote the development of realworld data in drug supervision.

(3) The real-world evidence in China should be combined with the current information technology.It can be seen from the above analysis that the European Drug Administration advocates the combination of real-world data and big data technology,which provides more active data support for drug regulatory decisions[20-21].China can also try to combine the realworld data research with the developed information technology,which can not only make the data collection more comprehensive,but also help the popularization of real-world research.

(4) There is an urgent need to develop a research community that promotes cooperation between research institutions and stakeholders.Only by creating a scientific research environment with common goals,mutual understanding,and joint efforts,can we promote the in-depth development of the real-world evidence in drug supervision.

4 Conclusion

Real-world evidence is scientific research data oriented by clinical needs,which can provide scientific reference for drug regulatory decision-making.Besides,it can make important contributions to improving the quality of drug service and maximizing patients’ rights and interests.At present,the research and practice of EU on the application of real-world evidence in drug regulation provide scientific reference and guidance for China’s drug regulation decision-making.It will be an inevitable trend to carry out real-world research and use real-world evidence in the future.