Real-World Evidence Supporting New Drug Review and Approval in European Union and Its Enlightenment to China

Lan Yipeng,Huang Zhe,2＊

(1.School of Business Administration,Shenyang Pharmaceutical University,Shenyang110016,China;2.Research Institute of Drug Regulatory Science,Shenyang Pharmaceutical University,Shenyang110016,China)

Abstract Objective To analyze the application of real-world evidence (RWE) in the field of medicine in European Union,and provide suggestions for RWE supporting the review and approval of new drugs in China.Methods The European Medicines Agency (EMA) and other databases were used to search relevant documents for analyzing the European Union’s new drug review and approval process with the support of RWE.Results and Conclusion The European Union carrying out new drug review and approval with the support of RWE has just begun.The decision-making process includes three stages such as new drug research and development,review,and approval.However,there are some challenges in data quality,research methods,evidence sufficiency,and research process of RWE supporting the European Union in reviewing and approving new drugs.At present,RWE can accurately grasp the clinical effects of drugs and improve the safety and effectiveness in the process of assisting the review and approval of new drugs.At the same time,RWE also can promote the development and application of Traditional Chinese Medicine (TCM) and help find out the potential value of TCM such as new indications.

Keywords:real-world evidence;new drug review and approval;European Union;enlightenment

1 Introduction

Real-world evidence (RWE) refers to the collection of various data around related scientific issues from the real medical environment,such as family and community hospitals.RWE is used in clinical medicine,evidence-based medicine,pharmacy,and other fields.The aim of using RWE is to evaluate the impact of a certain intervention on the health of the subjects[1].As early as 1960,two researchers of United States,Botts and Edlavitch,discovered that the research design under the real environment might be different from the research design under the clinical trial.Since then,the research on the real world has started[2].After half a century of development,in 2016,the US Congress promulgated the “21st Century Cure Act”,allowing the U.S.Food and Drug Administration (FDA) to use RWE to replace clinical trials and conduct drug researches.As a result,RWE made a major breakthrough in research.The European Union’s research on RWE has also made significant progress in recent years.For example,researchers used RWE to find that troglitazone,rofecoxib and other drugs had other adverse reactions after they were on the market,thus withdrawing these drugs from the market.Compared with traditional clinical trials,the research design using RWE is more in line with the actual clinical environment,which has a wide range of selected subjects and broad intervention measures.It can better meet the clinical needs of subjects,and has higher clinical practical value.At present,the scientific review system with indication evaluation mode as the core and true clinical value as the guidance has been gradually established in the new drug review and approval process,which just can introduce RWE into the new drug review and approval process.Therefore,the research on the application of RWE in the review and approval of new drugs not only has important theoretical significance,but also a good practical application value.

At present,there is no research on RWE in drug review and approval in China,but there are some RWE research in other medical fields.In terms of drug clinical trials,Ren Qian,et al.[3]collected clinical data from cardiology and endocrinology departments from more than 40 centers through real-world study (RWS),evaluating the prevalence of proteinuria in patients with diabetes and hypertension and comparing their risk factors.Giovanni Corrao[4]used RWE to provide the balance information between the benefits of statins on cardiovascular (CV) and their harm on diabetes in clinical practice.In terms of drug research and development (R&D),the FDA has launched the RWE program to support research on new indications for drugs or biological products that have been approved for marketing[5].Kern,et al.[6]adopted a selfcontrol research design,using real-world observation information and new analysis techniques to analyze a large amount of data,and found that RWE could be used to provide a way to help drug discovery for dementia.In terms of drug regulation,the FDA has indicated its willingness to use RWE to support the approval of regulated drugs,thereby accelerating the acquisition of new cancer drugs[7].Pitts,et al.[8]proposed that in the context of the dynamic development of regulatory science,the lessons learned from RWE and RWS could help advance patient care,which could also help researchers obtain benefit-risk data and the level of uncertainty found in clinical calculations.Sun Xin et al.[9]discussed the role of RWE from different data sources in the pre-market evaluation and post-marketing monitoring of medical devices.They analyzed the value of RWE in drug device regulatory decision-making,and provided reference for the correct use of RWE in the future to promote drug device regulatory decision-making.In terms of medical insurance,Royalty,et al.[10]used RWE to investigate the influence of out-ofpocket premiums on the decision to join employer health insurance and other benefit plans.She found that the RWS could effectively solve the problem of information bias.In terms of new drug registration,the European Medicines Agency (EMA) briefly introduced how RWE could support drug registration approval decisions.Sun Xianze,et al.[11]analyzed the development of RWS on the drug review and approval system in European Union and its enlightenment to China’s drug regulatory.

Some current studies analyzed and demonstrated the application of RWE in the field of medicine from multiple angles.However,few of them analyzed and demonstrated the application of RWE in drug registration,and few researches were carried out to assist RWE in the review and approval of new drugs.Therefore,based on the analysis of the application of RWE in the medical field of European Union and the current status of China’s drug registration review and approval process,this article briefly illustrates the process of European Union’s new drug review and approval with the support of RWE and its enlightenment to China.

2 Analysis of RWE supporting the decision of European Union’s new drug review and approval

The EMA participated in the “GetReal Initiative” project in 2013.Its purpose is to develop new methods for collecting and synthesizing RWE,which can be used earlier in the development and registration of drugs,as well as in the health care decision-making.The “2017 Global Drug Regulatory Authority Summit” listed RWE supporting drug R&D and registration as one of the three main topics.From then on,some multinational pharmaceutical companies have set up dedicated teams to conduct research on RWE.At present,the EMA has no cases of drug approval based on real-world data (RWD),but it allows RWE to assist the analysis process of drug review and approval.

2.1 RWE helping analyze the drug review and approval process

In the past process of drug registration,the drug review department evaluated the safety and effectiveness of new drugs based on the results of randomized controlled trial (RCT).However,for some diseases with large market,patients can benefit from new drugs as soon as possible.Therefore,for sympathy,the Center for Drug Evaluation may approve some drugs with unclear effects on the market and start post-market research quickly.As the research further deepens,some problems will often arise.For example,some patients will not benefit from the new drugs.These minor problems may endanger patients’ lives[12].Therefore,the drug regulatory authorities of European Union and pharmaceutical enterprises have explored the use of RWE to assist drug review and approval.It means clinical trial protocols are rejected,and on the basis of consulting relevant subject knowledge and following the practice guidelines of drug epidemiology and evidence-based medicine,specific treatment strategies are adopted in the current medical environment,and the effects of medical interventions in the real world environment on the health of the subjects are observed.Finally,the drug is approved according to the results.All the data come from the health information system,medical insurance system,disease registration system,national adverse drug reaction monitoring sentinel alliance database,natural population cohort and special disease cohort database,mobile-related database,death registration database,patient report outcome data,and other special databases.The above databases contain the information of doctor’s diagnosis,patient demographics,prescription,drugs and other information.Compared with traditional RCT data,the RWE filtered from RWD can truly reflect the scope and distribution of patients,and it can better evaluate patient compliance,drug safety and effectiveness in the real drug administration process.Therefore,it provides a reference for the drug review department to make decisions on new drug review and approval[13,14].

The process of RWE supporting European Union drug review and approval is as follows:

(1) As to drug R&D stage,it mainly conducts RWS on the clinical effects of drugs,including data based on disease frequency of population and distribution,patients to be treated,medical needs to be met,disease prevalence and current standards of care,and clinical trial recruitment.Pharmaceutical enterprises should make full use of RWE to conduct pre-approval drug research in accordance with the evaluation criteria of new drug review and approval,including the characteristics of the disease,the availability of treatment methods,the target population,the treatment effect,and the safety and effectiveness of the drug and other factors related to clinical research.

(2) As to drug evaluation stage,the drug review department evaluates the application materials.The drug review department requires the new drug application unit to describe the nature of the disease according to the review and approval standards.So it can determine the clinical effects of medical products or services,measure drug safety,harm,and the quality of care.RWE is used to reflect drug safety,effectiveness,and side effects.At this stage,RWE can be used to solve many problems.For example,in addition to the scarcity of cases and difficulty in recruiting,the biggest challenge in clinical trials of drugs for rare disease is the selection of controls.Due to the small number of rare disease patients,it is hard to recruit enough subjects to carry out randomized controlled trial.Therefore,one-arm experiments are often designed for external control.This external control can be a group of patients treated earlier or a group of patients treated in different environments at the same time.The research data and information of the disease can be used as an external control group and compared with the treatment group in the clinical trial.The final research data obtained can be transformed into RWE to assist the review and approval of rare disease drugs.

(3) As to drug approval stage,drug review department will decide whether a new drug can be registered based on the previous assessment.After approval,post-market research of the drug can be conducted,including target populations,patient follow-up surveys.Meanwhile,those who failed will continue to improve the safety and effectiveness of the drug,pharmacological and toxicological research data,and clinical trials based on feedback documents and other application materials.

2.2 Challenges in drug review and approval with the support of RWE

Due to the wide range of patients,the large sample size,the wide coverage of the population,and the existence of differences in combined medications,the real clinical data are different from the traditional RCT in the process of transforming them into RWE.Therefore,pharmaceutical enterprises may face the following four challenges in the process of using RWE for new drug declaration[13-16].

The first is the challenge in data quality.Establishing scientific data collection methods and screening standards to ensure the reliability,accuracy,and completeness of selected data is the key to generating RWE.The data are mainly from different databases such as the health information system,medical insurance system,disease registration system,national adverse drug reaction monitoring sentinel alliance database,natural population cohort and special disease cohort database,mobile terminal database,death registration database,and patient report outcome data.Integrating and utilizing data from different databases effectively is also vital.

The second is the challenge in research methods.The research design of RWE generated from RWD should be scientific and reliable.In other words,the true therapeutic effect of the drug,including its safety,effectiveness,toxic and side effects,can be reflected through the analysis results of RWD.The research design that generates RWE can support the review and approval of new drugs.

The third is the challenge in the adequacy of evidence.When the RWD and research methods have quality assurance,they can ensure the safety and effectiveness of the new drug being reviewed.If the evidence is not sufficient,they cannot ensure the safety and effectiveness of the new drug.As to this problem,the RWE obtained through the later RWD can be used as supplementary evidence to help the approval of the new drug.

The fourth is the challenge in the research process.The issues such as medical ethics,informed consent of subjects,and data traceability meet the regulatory and technical requirements of the National Medical Products Administration (NMPA) can be solved with the help of RWE in the review and approval of new drugs.

3 Enlightenment

On January 7,2020,the NMPA issued the“Guiding Principles for Drug R&D and Evaluation Supported by Real-World Evidence (Trial)”.This is China’s first valuation guidance document for RWEsupported drug development and new drug review.Combined with the current status of new drug review and approval in the European Union,America and China,RWE is of great help to China’s new drug review and approval.

3.1 Accurately grasping the clinical effects of drugs and improving safety and effectiveness

RWE helps pharmaceutical enterprises to explore the true clinical utility of new drugs after they are launched on the market.Under the premise of ensuring the safety and effectiveness of the drugs,they can obtain more users’ real experience and clinical needs,so as to discover the clinical value of drugs.In addition,RWE can be used as a prospective pharmacovigilance,especially the research on some newly approved drugs with potential prescription deviations.This can help pharmaceutical enterprises discover the adverse reactions of patients after applying new drugs.RWE can not only help pharmaceutical enterprises to accurately grasp the clinical effects of new drugs and determine the market positioning of drugs,but also improve the approval rate of new drugs.

3.2 Facilitating the review and approval of drugs to promote the development of new drugs

At present,RWE is used globally to evaluate the safety and effectiveness of drugs,medical devices and other medical products,and it has accumulated a wealth of practical experience[14,15].Since the RWS in China has just begun,more researchers associate RWE with the development of Traditional Chinese Medicine(TCM).The role of TCM is getting increasingly important,especially in the COVID-19 pandemic.Some TCMs such as Lianhua Qingwen Granules have made it further recognized by the world.However,due to the lack of a standard evaluation system,many TCMs with disease treatment advantages are stuck at the clinical data gate in the process of drug registration and marketing.In addition,some hospital preparations of Chinese Medicine with good clinical effects are an extension of the prescription,they cannot pass the drug review and approval for marketing.So they can only be used in hospitals.If RWE can be used to replace routine clinical R&D in phase I or phase II clinical trials for preliminary exploration of clinical efficacy and safety,and then,the effectiveness of TCMs that have been used by humans can be confirmed through RCT,which provides supporting evidence for product registration and marketing.

3.3 Facilitating the redevelopment of drugs after they are on the market

After the new drug has passed the review and approval,it is necessary to further confirm its therapeutic value for other diseases,namely,to discover new indications[16].In addition to the discovery of new indications from early clinical trial data,the most important thing is to conduct in-depth mining of post-marketing data.For new drugs that have been approved for marketing,the discovery of new indications also requires the support of RCT data.However,when RCT is not optimal research design or RCT is not feasible,it may be more feasible to use RWE to support new indications.In addition,GRADE quality evaluation and Meta-analysis based on RWE also provide some help for the discovery of new indications.Although such methods cannot provide final evidence for the approval of new drug indications,they can give important supporting data for us to identify and apply the drug for new indications.

4 Conclusion

Although RWD has a history of half a century,its development is slow.The research of RWE in the world is currently in its infancy,especially in China.Through studying and understanding the RWS of the European Union,we can effectively offer reference for pharmaceutical industry.At present,China’s drug R&D and registration are in a transitional period.New policies and regulations are leading the pharmaceutical industry forward.These policies and regulations also bring opportunities and challenges to the review and approval of new drugs.With the indepth understanding of RWE,it will provide great help for the review and approval of new drugs.