Yu Zhongyi,Xu Fengxiang

(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 study the use of real-world evidence by EU and its member states for establishing a strategy for rare diseases and provide references for the inclusion of orphan drugs in China’s medical insurance.Methods A case analysis method was used to introduce the EU’s decision to include rare disease drugs in medical insurance by using real-world evidence because clinical data of rare diseases were difficult to obtain.Results and Conclusion China can use real-world evidence to make medical insurance decisions based on the experience of the EU and continue to invest more in rare diseases,which can solve the problem of few drugs for patients with rare disease.

Keywords:EU;real-world evidence;rare disease;medical insurance

Real-world evidence (RWE) refers to the use of analysis of real-world data (RWD) to obtain clinical evidence about the usage and potential benefits or risks of a medical product[1].RWD refers to data relating to patient health status.The sources of these data mainly include electronic health records (EHR)[2],product and disease registries,insurance claims databases,medical equipment used by patients,and other tools (such as mobile devices) that can obtain health status.Nowadays,RWD has become an important part of medical big data,providing pharmaceutical companies,medical staff,and medical insurance institutions with a larger and more accurate RWE.

1 Introduction

RWE has the potential to supplement traditional clinical practice information in the experiment(evidence that has been submitted to the regulatory agency).Therefore,it can provide marketable data at a lower cost in a short time[3,4].With the establishment of a variety of electronic databases or systems,and the popularity of more electronic equipment and application of software for recording physical health,scholars have more opportunities or channels to obtain RWE.Data scientists are optimizing technologies such as artificial intelligence (AI),machine learning(ML),and natural language processing (NLP) to better extract and utilize RWD.Meanwhile,regulators are formulating rules on RWD access,use,storage,and privacy policy.All these provide strong technical and policy support for future real-world research.Through building a high-quality clinical medical database,high-value and effective information can be dug out in multiple dimensions.The information can form reports through reasonable analysis.The results can not only bring more cost-effective medical services to patients,but also provide evidence-based guidance for medical workers.At the same time,it can provide hospital managers with decision-making and guidance for hospital operation.It also can provide pharmaceutical companies with information for research and development,marketing promotion.In addition,it offers support for medical and health department to make medical insurance decisions[5].A major application of RWE is to provide convincing evidence to medical insurance regulators and payers,which supports prescription pricing,promotes the inclusion of drugs in medical insurance,and provides reimbursement basis for new therapies.Its aim is to speed up drugs approval process,to improve medical standards,reduce medical costs and enhance the quality of patients’ life.

As early as 2013,the European Medicines Agency (EMA) started a research project which aimed at developing a new method for collecting RWE[6].With the widespread application of RWE,the EMA began to study the use of RWE to support the inclusion of drugs in medical insurance decisionmaking.Due to the characteristics of rare diseases,patients with rare diseases have been neglected for a long time,and their medical security rights are easily overlooked[7].Therefore,many pharmaceutical companies with marketed rare disease drugs have invested a lot of resources in RWD mining for many years,aiming to better submit real case information to the medical insurance center.

2 EU real-world evidence supports the inclusion of rare disease drugs in medical insurance decision

Due to the small number of patients with rare diseases[8],high drug prices,urgent demand,and randomized controlled trials (RCT) that are difficult to implement in the rare disease group,rare disease drugs cannot be quickly included in the medical insurance coverage.Therefore,RWE is used to support rare disease drugs inclusion of medical insurance decisionmaking.It has become a research direction with important practical significance.Inclusion of medical insurance decisions requires relevant clinical data to obtain marketing authorization.However,the number of patients in phase III studies of rare diseases is small because the traditional clinical trial process requires an experimental group and a control group.Due to the small number of rare patients,it is unreasonable to arrange half of the patients in the control group.If the real-world data in the single-arm study can be used to show the true characteristics of the disease[9],the data in the experimental group can be compared,which not only reduces the time investment,but also the cost.For patients,they can access systematic treatment faster.

The National Institute of Health and Clinical Excellence (NICE) in the United Kingdom clearly stated in its official guidelines for Health Technology Assessment (HTA) that when considering the inclusion of rare disease drugs in health insurance decisions,RWE can be taken as an important supplementary material.This enables medical insurance decisionmakers to judge whether the drug should be included in medical insurance based on RWD.The factors include the price of the drug,the type of patients in medical insurance,and the time to start and stop treatment etc.Expanding the use of RWE in pharmacoeconomic evaluation can realize the risk control of medical insurance cost[10].For example,Eculizumab can be used to treat paroxysmal nocturnal hemoglobinuria (PNH),which is not only rare,but also has a complicated cause.Later,RWE was used to prove a major discovery of the drug,which can treat atypical hemolytic-uremi csyndrome (aHUS).In 2015,Alexion’s application for the use of RWE to expand the indications of Eculizumab was approved by the EMA.In the same year,NICE also supported it for aHUS patients of all ages to be included in the NHS medical insurance,which greatly increased its market share[11].The medical care of the EU member states are relatively sound.The reimbursement policies for orphan drugs are mainly formulated by each member state,and there are some differences in the restrictions and proportions in the reimbursement[12].France and the Netherlands adopt social medical insurance,so the reimbursement of orphan drugs is mainly determined by the budget[13].Italy and the United Kingdom adopt a national medical insurance model.Although drug regulatory authorities have approved applications for rare disease indications based on single-arm studies,HTAs in other EU regions such as the United Kingdom,France,Germany,Italy,and Spain still hope to use other evidence to support medical insurance reimbursement decisions[14].Data show that in the HTA reports of NICE from 2012 to 2017,5% used RWE,and 13% of them were rare disease drugs.Meanwhile there have been more and more HTA reports using RWE[15].In 2017,NICE released the assessment of Asfotase alfa (for the treatment of paroxysmal hypophosphatemia in children with rare diseases) and accepted the natural history model of the disease based on RWD.The HTA guidelines clearly stated that historical data can be used as the control data of the single-arm trial.At the same time,NICE also accepted the quality of life and biological activity data of Asfotasealfa patients obtained from investigative research and observational research.It provided economic evidence for drugs for rare disease to be included in medical insurance[16].

3 The inclusion of drugs for the treatment of rare diseases in China’s medical insurance

Since the establishment of China’s basic medical insurance system,the medical insurance department has attached great importance to the treatment of rare diseases.To reduce the burden of drugs for patients with rare diseases,the governments at all levels have successively introduced different measures,and some rare disease drugs are included in National Basic Medical Insurance[17].In 2017,the national medical insurance negotiations included 2 rare disease drugs.In the 2019 update of the medical insurance catalog,5 rare disease drugs were included through medical insurance access,and 7 drugs were included through medical insurance negotiations.In 2020,the drug protection mechanism for rare diseases was proposed[18].Despite this,some expensive drugs for rare diseases have not been included in medical insurance yet.The individual patients and families are bearing a huge burden of drug costs.

At present,China has not set up an independent orphan drug qualification certification process[19].In making medical insurance decisions,it is necessary to focus on the affordability of drugs.Drug price,reimbursement,and the specific method of reimbursement will directly affect the availability of medications for patients.To truly use RWE to improve the status of rare diseases in China and solve the problems,Chinese government still needs to explore new solutions continuously.Therefore,various departments will have a long way to go[20].

4 Enlightenment to China

Although RWE can save time for rare disease drug to review,approval and enter medical insurance coverage,several aspects in the use of RWE should be taken into consideration.

(1) Due to the small number of rare disease patients,high treatment costs,and difficulty in obtaining disease data,it is still necessary to improve the top-level design of the rare disease medical care system.

In the process of incorporating rare disease drugs into the medical insurance,an open,complete,systematic,and transparent price negotiation system should be established.For drugs with inaccurate clinical efficacy but expensive price,we should request for further access to clinical data through drawing lessons from the EU’s rare disease drug negotiation experience.The EU uses the results of HTA as the basis for selecting the medical insurance catalog.Chinese government is also working hard to strengthen the position of HTA in selecting medical insurance catalogs,medical insurance access,and drug price negotiations.However,the current work is not enough.It is necessary for the government to provide further support for the development of HTA by making laws and regulations.Thus,the RWE can be used as a decision-making method and standard to have a better development in China.

(2) To obtain a true and comprehensive RWE,China needs to further improve the construction of the HIS database.

Whether RWE is scientific and reasonable depends on the quality of the data.Through searching the medical records information in the HIS database,a complete and comprehensive electronic medical records will be formed to ensure that the obtained RWE is effective.The management of medical record can not only reduce the cost of collecting medical data in hospitals,but also improve the efficiency of medical work.Therefore,it can improve the quality of medical care.

(3) To better analyze RWD,it is necessary to increase the training of RWE-related researchers.

The efforts to cultivate RWE-related research talents in China are insufficient now.To better prove the true value of the drug and provide data proof for inclusion in medical insurance,relevant professionals should be required to learn to use insurance data,electronic medical records,registration data,and other survey data for statistical analysis and research analysis.The results of the analysis can be used for clinical trials,products positioning,and market access.

5 Conclusions and prospects

In the decision-making process of medical insurance departments,drug economics has gradually taken an increasingly important position.Meantime,RWD can play an important supporting role in the process of submitting HTA applications by pharmaceutical companies.As HTA continues to increase familiarity with RWD,it can be seen that the acceptance of RWE by all parties will increase.The use of RWE can promote the inclusion of more rare disease drugs into medical insurance,which can help rare disease patients get out of the dilemma of longterm medication and high drug costs.They will have a promising future.