Study on the Connotation and Application of Real World Evidence

Ding Wei,Yang Yue,

(1.School of Business Administration,Shenyang Pharmaceutical University,Shenyang 110016,China;2.International Food & Drug Policy and Law Research Center,Shenyang 110016,China)

Abstract Objective To define the concepts and characteristics of real world data (RWD),real world research,real world evidence (RWE) and other related terms so as to better apply RWE to serve the whole life cycle monitoring of pharmaceutical products.Besides,some reference can be provided for drug supervision and medical services to further standardize the clinical application of drugs.Methods Through literature retrieval at home and abroad,the development process of exploring RWE in Europe and America was briefly introduced,and its development status in China was compared and analyzed as well.The application fields of RWE were explored based on the whole life cycle of drugs.Results and Conclusion RWE can provide proof for drug life cycle regulatory evaluation.Some European countries and the United States gradually apply RWE to regulatory decision-making and related policy research.Due to its bright prospect,China is also strengthening the expansion of RWE application fields and exploring its use in-depth.

Keywords:real world evidence; connotation; application

On January 7,2020,the first document,“Guidelines for Real World Evidence (RWE)to Support Drug Research and Development and Evaluation (Trial) ”was issued by National Medical Products Administration.This milestone event has received considerable attention from the pharmaceutical industry and academia.The application of RWE to regulatory decisions is a profound change in the field of drug regulation in China.In the developed countries,using real-world evidence to evaluate the effectiveness and safety of drugs in drug research and regulatory has become a hot issue.This is based on an industry status quo,namely,although randomized controlled trials (RCT)have always been the best standard for evaluating the effectiveness and safety of drugs,it will be challenging to extrapolate its research conclusions to clinical applications,and the implementation of RCT requires high costs,including time.Therefore,the research of RWE arises at this historic moment.RWE is based on real world data (RWD).Through scientific research methods,RWD are processed in depth to obtain RWE that possesses guiding function for drug research and development and regulatory decisions.Although many institutions and scholars in our country have started some real world research projects,the application of RWE in medical and health fields,especially in drug regulatory decisions,is still limited.The purpose of this study is to promote RWE to support drug research and regulatory decisions in various forms,including pre-market clinical research and development,and post-market re-evaluation.

This article focuses on the following three questions step by step.The first is how to obtain effective RWD.The second question is how to transform RWD into RWE through scientific and rigorous methods.And the third is how to apply RWE to supervision.It means to use RWE to support drug research and development and regulatory decisions.In answering how to obtain the effective real world research data,this paper introduces block chain technology through analysis in the data collection,and builds a drug traceability system based on block chain technology.Through the establishment of a dual block chain traceability system,drug marketing license holders,production and business enterprises and users can cross-verify the data to provide authenticity guarantee for the traceability of drug life cycle data,making the RWD of drugs more reliable,transparent and traceable,which has good application value.In data processing,this paper explores real world research methods starting with actual effect RCT and observational research methods.

Besides,this paper also explores the construction of a scientific decision-making system for medical products and health policies based on RWE.On the one hand,RWE can promote pre-market drug clinical evaluation and regulatory decisions.This includes exploring new drug research and development needs,assisting in clinical trial design,approving new indications for listed products,and obtaining drugs for rare diseases.For example,PD-1 inhibitors are the case.On the other hand,RWE,as the key evidence for post-marketing drug monitoring,evaluation and decision-making,can put forward the research model of RWE in post-marketing drug research,evaluation and decision-making.Starting with the key drug monitoring and other measures,the practical application of RWE in drug life cycle monitoring is expounded,and the post-marketing evaluation of andrographolide injection is taken as an example for empirical research.

Real world study (RWS) also has many problems in data processing and research design,such as high development cost of trusted database and validity of evidence.The universality and rationality of the application of RWE,especially the rationality of drug effectiveness decision,still need further study.At present,the framework of global RWS is not uniform,and its application methods and acceptance degree are also different.Drug regulatory authorities still have a lot of room to explore the way to promote the use of RWE in drug decision-making and improve regulatory and decision-making efficiency.

1 Definition of RWE

1.1 RWD and their sources

RWD is data related to the health status of patients or health care services collected regularly from various sources.RWD has a wide range of sources,including electronic medical record,electronic health record (EHR),claims data,product and disease registry,information collected by personal health equipment,public health monitoring data,and regional data,etc[1]. The amount of data is very large.However,because the data collection is not designed for a specific research purpose,the data are scattered and highly heterogeneous.At the same time,the integrity and accuracy of the data also have some problems.In addition,some data,such as claims data,which are related to privacy and infringement,are less accessible.

1.2 RWS and classification

RWS refers to the research based on RWD and conducted by evidence-based medicine,clinical drug epidemiology and other methods. Different organizations in the world have different opinions on what the RWD should include,but the essence is to require the data to come from real medical institutions and reflect the medication information of patients in the actual diagnosis and treatment process.RWS is different from traditional clinical trial.The design of traditional clinical trial is usually random,controlled and double blind.In other words,the subjects are randomly assigned to the test group and the control group to avoid the influence of individual differences on the test,and neither the investigators nor the subjects know what kind of test intervention is given[2].Because of this characteristic,traditional clinical trials are also called randomized controlled trial (RCT).Traditional clinical trials usually have strict criteria for the selection of subjects,and data are collected by specialized researchers according to standard procedures,including the use of case report form,followed by statistical analysis.Traditional clinical trials are carried out in an ideal environment different from clinical practice,emphasizing control of confounding factors and optimization of data quality,and they do not belong to RWS[3].

There are two types of RWS:intervention research and observation research.Observation research is more universal.Interventional research generally has practical characteristics that are close to clinical reality on the basis of traditional clinical trial design.For example,real clinical medical data are collected through EHR and claims data,which belong to RWS category.Observational research is designed for non-intervention clinical research and is not considered as a clinical trial[4].Observation research includes retrospective or prospective research.The retrospective observational study is based on historical data to identify the population and determine exposure/treatment.The study design has determined variables and expected results.Prospective observational studies have no historical data.At the beginning of the study,people of interest are identified,and exposure/treatment and generated data are collected along with the study to find the results.

A typical case,such as the study of ADAPTABLE(NCT02697916),which began in April 2016,is a randomized trial of effectiveness that can produce RWE.This test compares the benefits and longterm effectiveness of two commonly used aspirin doses (81 mg and 325 mg).Twenty thousand patients with myocardial infarction or known history of atherosclerosis and cardiovascular disease were randomly assigned one of the doses.This experiment used electronic algorithms to identify potential participants from the National Patient-Centered Clinical Research Network (PCORnet) health system partners.The test was integrated into daily clinical care with the lowest admission/discharge standard,and there was no additional treatment plan except one dose of aspirin.The trial used EHR and claims data obtained from PCORnet to capture the main endpoints,such as death,hospitalization due to non-fatal myocardial infarction or non-fatal stroke.At the same time,secondary endpoints,such as coronary artery revascularization,hospitalization due to severe bleeding,and other patients’ information were also recorded.RWS data come from medical institutions,families,communities,etc[5].From the above analysis,RWS and RCT can be complementary and not antagonistic.Both of them need scientific and reasonable research design,test schemes and statistical methods.The criteria for distinguishing RWS from RCT are the scenarios for research and implementation.

1.3 Understanding RWE correctly world study and classification

RWE refers to clinical evidence related to the use of medical products and potential benefits or risks generated by analyzing RWD.The difference with traditional clinical research evidence lies in the source of data,not research methods or experimental design.RWE has different values in clinical and regulatory decisions.Some people think that RWE comes from the real clinical medical practice,and the obtained results have good extrapolation,which can best explain the problems under the real conditions.Therefore,they are more reliable than the traditional clinical trials,and have high research efficiency.Other people think that RWD lack mature and strict methodological guidance and the research results will be biased.So,the RWE is not effective.However,in recent years,with the rapid development of information technology and evidence-based medicine,RWS has attracted more and more attention.Its significance is not only to provide evidence for drug listing license,but also to support drug life cycle regulatory evaluation and decisionmaking in a variety of forms,covering many links such as clinical research and development before drug listing and re-evaluation after drug listing.

2 Application of RWE

2.1 RWE supports regulatory agencies in making decisions on drug review and approval

In order to meet the needs of clinical medication,regulatory agencies need to continuously improve the efficiency of drug review and approval,and accordingly establish some special approval channels for new drugs.For example,adaptive pathway is one of them,which means that drugs are initially approved for a small group of patients who may benefit the most.And then,the data obtained through clinical practice are further expanded to a wider group of patients[6].These approval channels need RWE obtained after the drugs are listed to verify the initial evaluation.RWE can obtain patient data in daily clinical practice,making it the preferred evidence for regulatory agencies to determine the safety and effectiveness of drugs.The final report of the European Medicines Agency,adaptive pathway pilot project emphasizes that all of the 18 proposals accepted in the second phase of the pilot include plans to supplement randomized clinical trials with RWE[7].For a long time,FDA has been monitoring and evaluating drug safety by conducting postmarketing research.The main source of FDA’s drug epidemiological inquiry and research is electronic health data in sentinel system,including claims data and pharmacy dispensing data[8].FDA currently uses RWE to support drug effectiveness decisions mainly in the areas of tumors and rare diseases.

2.2 RWE provides evidence for determining the efficacy of drugs and guidelines for optimal use

The application of RWE is expanded into early communication with heath technology assessment,institutions and payers.In the initial declaration submitted to the National Institute for Health and Clinical Excellence,RWE accounted for 9% in 2015,22% in 2016 and 37% in 2017 respectively.Most European HTA agencies have made recommendations on the sources of RWD and issued practical guidelines[9].At the same time,RWE has important value in eliminating the uncertainty of new therapies and reducing costs.

RWE is a clinical practice from the real world,overcoming the limitations of highly controlled RCT in representing the real world patients and treatment programs.RWE is rooted in real clinical practice and has the advantages of high efficiency,no need for strict setting and easy research[10]. Medical and health institutions can formulate clinical guidelines through RWE.For example,RWE is referred to in the European Respiratory Society’s guidelines for the treatment of idiopathic pulmonary fibrosis,colitis tissue and Crohn’s disease in Europe.

2.3 RWE helps to evaluate the safety and effectiveness of drugs in the whole life cycle

RWE is gradually being applied in the postmarketing evaluation of drugs.It includes adding or modifying instructions,changing dosage,dosage scheme or route of administration for new population,adding more effective information,such as safety information and other label changes[11].Based on RCT evidence,new drugs are usually tested in a relatively small number of cases and subject to strict screening,unified intervention,and completed in a short period of time.Therefore,its safety information is relatively limited,and the medication plan may not be optimized.It is necessary to use RWD to make a more comprehensive evaluation of the effectiveness,safety and medication plan of drugs in general population,including economic benefits,and constantly make adjustments and optimizations of products according to the latest evaluation.Research generally includes the role of post-marketing research based on RWD in the evaluation of old varieties of drugs and the re-development of listed drugs based on RWD[12].The contents covered include confirming the safety of drugs (unexpected,drug interaction,safety of complex population,etc.),evaluating the actual use effect,evaluating the comparative effect among varieties (more widely applicable population,special population,treatment compliance,etc.),and revalidating the drug efficacy,etc.

Nowadays,big data is changing our lives.With the development of image,text,speech recognition and other technologies,many RWD can be rapidly structured.Through big data analysis methods,cloud storage,cloud computing and other technologies,dispersed massive RWD can be quickly integrated and analyzed,thus generating RWE.RWE can not only help regulatory agencies to make decisions on drug review,approval and supervision,but also help medical and health institutions to formulate and optimize clinical practice guidelines.More importantly,it can help drug marketing license holders to better strengthen the management of drug life cycle.It is believed that under the promotion of new ideas and technologies,RWE will certainly be applied more widely in the future.