Research on Real-World Evidence and Application in EU and Its Enlightment to China

Wang Chao,Lian Guiyu

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

Abstract Objective To analyze the research and application status of real-world evidence (RWE) in the European Union(EU) and provide a reference for China’s government.Methods By consulting the policy guidelines issued by EU EMA and the documents of European countries at home and abroad,the basic principles and case notes of EU RWE implementation were comprehensively analyzed.Results and Conclusion Research on RWE in EU is mainly carried out from four aspects:R&D decision,application of expanded trial certificate,medical insurance decision,and supervision decision,which plays an important role in the progress of European clinical medicine.Therefore,researchers in China should draw lessons from these four perspectives and design reasonable research directions and programs.

Keywords:EU;real-world evidence;R&D decision;health care decision;regulatory decision

The research of real-world evidence (RWE)focuses on related scientific issues,and comprehensively uses pharmacoepidemiology,biostatistics,evidencebased medicine,pharmacoeconomics,and other approaches to deal with real-world data (RWD),thus obtaining evidence that is more in line with clinical practice[1].RWE is defined as data collected outside the usual grouping of randomized clinical trials[2].It is generally accepted in the research community today that drug safety information obtained from premarketing clinical trials is incomplete and needs to be supplemented by longer,larger-scale,and more heterogeneous studies.For example,rofecoxib,triglitazone,and pentecoxib were proved to be safe based on pre-marketing clinical trials in the European Union,but they were withdrawn from the market due to adverse reactions during use,causing huge losses.Therefore,how to learn from the experience of the European Union and carry out the application of RWE in China has both theoretical and practical value.

At present,most scholars at home and abroad believe that it is of great significance to carry out research related to RWE[3-9],and the main research directions are as follows.The first is the research on the definition of RWE.Domestic scholars defined RWE as the risk and benefit of products in real clinical practice[10],while some scholars from European Medicines Agency (EMA) in EU defined RWE as the data collected outside the group of conventional randomized clinical trials[2].The second is about the role of RWE research.For example,Yao Chen studied how to use good RWD to produce high-quality RWE to support pharmacy regulation[11].Some scholars in the US FDA believed that the research hypothesis based on RWE could provide a reference for the further clinical trials or serve as a prior historical comparison in the design of Bayesian clinical trials,providing a prior information for medical device clinical trials[12].The third is on RWE research methods.Peng Xiaoxia,et al.proposed the research norms[13].EMA scholars in EU pointed out that the research methods should start from genetic data and then combine big data with the real world[14].

Nowadays,although there has been a wide range of studies,few research documents are on RWE in EU,and there is a lack of comprehensive research on the application of RWE in EU.In particular,there is no in-depth study on how we can learn from the research results of RWE in EU.Therefore,this paper discusses the research and application status of RWE in EU from four perspectives,namely,decision making of RWE in R&D,application for expanding trial certificate,the decision of medical insurance,and the regulatory decision,which are the reference for the application of RWE in China.

1 RWE supports EU’s new drug research and development (R&D) decision

Real-world clinical practice gives RWE absolute practical value.It overcomes the limitation of highly controlled variables in the process of randomized controlled trials (RCTs),which is expected to greatly improve the effectiveness and efficiency of the whole life cycle of drugs[15].This provides an opportunity for RWE to support drug development decisions.

At a seminar for COVID-19 hosted both by the International Drug Regulatory Association and the Association of European Drug Authorities,international regulatory authorities raised the question of how data generated in clinical practice can be used as supplementary evidence for vaccine R&D of COVID-19[16].Experts from more than 25 countries and organizations believed that RWE,based on observational studies of RWD,had a significant clinical role in the development,authorization and monitoring of COVID-19 vaccines.

2 RWE supports EU’s application for expanding medicines

Drugs approved on the basis of RCT evidence,due to the small number of cases,short research time,strict conditions for subjects selection to enter into the study group,and mandatory criteria for the degree of intervention can lead to low safety of test results and infeasibility of promotion.Besides,the difficulty of determining the best medication scheme and the lack of corresponding economic benefits have greatly limited the safety of the results.RWE can supplement key RCT data to address the above issues and facilitate the application for a certificate of appropriateness.Additionally,RWE is able to further verify the applicability of a new drug after obtaining an approval,and support the expansion of the applicability.

In 2015,EMA applied RWE to expand the applicability of a new drug,and approved Alexion’s application for expanding the applicability of Eculizumab by using RWE.It conducted an adaptive licensing pilot project from 2014 to 2016 to explore the possibility of RWE to assist in expanding drug licenses.In addition,EMA and the European Health Technology Assessment (HTA) are working closely together on basis of European drug epidemiology and drug alert system to explore how to use RWE to expand the applicability of drugs,and strive to establish a RWE research framework within the HTA[17].

3 RWE supports EU’s health care decisions

It is difficult to recruit volunteers or clinical trials of some rare diseases because there are few such cases.Due to the lack of effective treatments for some life-threatening rare diseases,RCTs on patients often have some ethical problems,making it difficult for RCTs to be implemented in the rare disease groups.Moreover,the cost of treating rare diseases is so high that most patients cannot be covered by the national health insurance.At present,RWE in EU mainly provides relevant supplementary materials for HTA to support the decision on the inclusion of drugs for rare diseases in national medical insurance[18].

The UK’s National Institute for Health and Clinical Excellence (NICE) makes it clear in its Guidelines for Health Technology Assessment that RCT evidence is a priority,but RWE can supplement rare diseases[19].According to research from EU,the number of documents containing RWE in reports from NICE to HTA increased year by year from 2012 to 2017.Among them,about 5% used RWE as supplementary material,and 13% of drug studies were for rare diseases.In addition to the UK,France,the Netherlands and other countries also used RWE in the study of drugs for rare diseases.Therefore,it is necessary to use RWE as an important supplementary material to include rare disease drugs in the medical insurance category[20].

4 RWE supports EU’s drug regulatory decisions

RWE applied to drug regulatory decisionmaking,first of all,can form part of the evidence in real clinical practice to obtain patient data.These data can become the first choice of evidence for drug regulatory agencies to determine the safety and efficacy of drugs,which compensate for the current role of drug regulatory decision-making,and improve drug regulatory work capacity.It can also improve the speed of supervision based on RWE research.In addition,according to drug research,RWE discussions should be carried out to give specific recommendations for regulatory and restrain regulators.

Some EU’s regulatory procedures involve uncertainty in the implementation process,which requires RWE to conduct an initial assessment.To meet the practical requirements,regulators have established a number of special drug approval procedures,such as breakthrough therapy designation(BTD),fast track,accelerated approval,and adaptive pathway.A pilot project was launched in 2014 to explore the feasibility of using RWE to support drug regulatory decisions.In 2017,the Head of the Medical Agency (HMA) and EMA set up a large task force to collect the RWD.Regulatory agencies will increasingly use the conclusions from these data to evaluate drug benefits-risk throughout the life cycle,and give acceptable suggestions on drug decision making[21].

5 Enlightment and suggestions

Although research on RWE is still a new thing,it has received great attention in the field of national policy and global academic research.More and more countries attach importance to the application of RWE.The FDA of US and the EMA of EU are the leading figures in RWE research.China should follow the footsteps of these organizations in RWE research,learning their good experience to increase our innovation for clinical medical activities.

5.1 Promoting drug R&D through RWE

The effectiveness and safety of the drug R&D are of great importance.RWE can provide guarantees for the effectiveness and safety of drugs in a real clinical environment to promote drug R&D.RWE obtained through real world study during drug development includes randomized clinical trials using real world results or safety data,and PCT design.RWE can only be used as an external control of the drug development process in single-arm clinical trial for rare diseases and major diseases that are life threatening and cannot be tested due to ethical issues.China can learn from the experience of the European Union and combine with the actual situation of drug R&D to give full play to the advantages and characteristics of RWE and promote the development of relevant drugs[22].

In the clinical trial for COVID-19 drug R&D,based on its unique data advantages,RWE will provide relatively reliable clinical evidence.China should give full play to its technical advantages in data collection and analysis,integrate data from various sources according to the information provided by patients’ hospitals,so as to accelerate the drug R&D for COVID-19.

5.2 Using RWE to support the registration of traditional Chinese medicine (TCM) and expand its applicability for certificate

RWE can test the clinical effects of drugs after marketing,and obtain more comprehensive safety and efficacy information.At the same time,on the premise of ensuring the safety and efficacy of drugs,it can test the clinical application value of drugs,which can be used to expand the applicability of drug licenses[23].

According to EU’s research on RWE,RWE is an effective method to solve the difficulty in listing TCM and defining its applicable scope[24].RWE can be used as a research method for personalized diagnosis and treatment and an overall curative effect evaluation of TCM.It can fundamentally change the traditional clinical trials of TCM as a way of review and approval,Besides,it changes the problem that TCM cannot be modernized and promoted to the world due to the rigid standards.Therefore,it greatly facilitates the registration and listing of TCM.

In addition,TCM syndrome testing in clinical practice can further determine and optimize the original clinical dosage and treatment process.It can discover new disease syndromes applicable to TCM and eliminate inapplicable disease.While discovering new interactions between drugs,including compatibility and drug combinations,we can obtain new information on the effectiveness of TCM in specific populations.Based on the above functions,RWE study is conducive to the expansion of the applicability of TCM certificate.Therefore,China should make full use of RWE in the registration of TCM and the expansion of its applicability.Learning from the experience of the European Union will promote the development of TCM to the greatest extent.

5.3 RWE supports the inclusion of rare diseases in healthcare decisions

More and more countries around the world attach importance to the application of RWE,and including rare diseases in medical insurance is also increasing.Even Germany,the country most dependent on the RCT,uses RWE as a guideline to drug reimbursement.China should also pay attention to RWE research on the inclusion of rare diseases in medical insurance.

Due to the small number of patients and the difficulty of treatment,rare diseases can cause huge physical and mental stress on patients.Because drugs for treating rare diseases are urgently needed,and it is difficult to obtain data on the economic burden of patients with rare diseases,RCT is often not implemented in rare disease groups.Relying solely on the past methods cannot solve the problem.It will make the patients dissatisfied or the public doubt the medical level and medical insurance policy in China.Therefore,the government should learn from the experience of the European Union to carry out RWE research on rare diseases.Then,RWE can be used to support medical insurance decision-making,and include rare diseases in medical insurance[25].

5.4 Establishing a drug regulatory system based on RWE

RWE has been proven by the European Union to assist regulators in drug regulatory decisions.The role of RWE for regulators in EU covers clinical R&D before listing,reevaluation of applicable certificates after listing,expansion of applicability for applying certificates,and the support for regulatory decisions after listing[26].

In order to give full play to the role of RWE in the drug regulatory system,we should draw on the good experience of the European Union to build a drug regulatory system based on RWE.At the same time,relevant supporting policies are issued to ensure the rationality of norms.A data resource database should be established from the drug regulatory platform.In addition,an intelligent analysis network linked to the regulatory platform must be set up to provide scientific regulatory advice with big data technology.It also cooperates closely with other regulatory authorities to timely adjust the deficiencies[27].By exploring the establishment of a scientific drug supervision and decision-making system based on RWE,the concept of drug supervision department and pharmaceutical industry can be changed to improve the regulatory capacity and level.

6 Conclusion

The application of RWE runs through the whole life cycle of drugs,which will be added to the traditional evidence from randomized clinical trials.It is expected to greatly improve the effectiveness and the efficiency of the drug R&D and usage in all processes.It can play a very important role for all stakeholders in the drug development and use,from patients and health care professionals to regulators,health technology assessment agencies,payer,academic researchers,and pharmaceutical industry.

With the rapid development of new treatment technologies such as precision medicine,cell and gene therapy,tumor immunity and rare diseases,RWE is becoming increasingly important.We firmly believe that with the in-depth development of big data and artificial intelligence technology,RWE will gradually become perfect,and its application will be extensive in the future.