How Real-World Evidence Supports Healthcare Decisions in EU and Its Enlightment to China

Li Longxiao,Lian Guiyu

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

Abstract Objective To summarize the concept,background,application value of real-world evidence (RWE) and its enlightenment to China based on the analysis of the information about the RWE supporting health decision in the European Union,and to provide a reference for Chinese health departments.Methods Through literature research and data collection,the requirements of EU countries,especially some typical countries,for clinical evidence in health decision were obtained,and the application of RWE in supporting health decision in EU was analyzed with specific cases.Results and Conclusion RWE plays an increasingly important role in supplementing the evidence base of clinical trials,verifying the safety and effectiveness of medical devices,and accelerating the market access of new drugs.With the improvement of RWE quality,RWE will not only be used in the evaluation of biological agents and chemical drugs,but also play an important role in the evaluation of traditional Chinese medicine and the post-marketing evaluation of medical devices.

Keywords:real-world evidence;EU;health decision;enlightment

Real-world evidence (RWE) refers to the integration of data resources through real-world study(RWS) and the application of various methods and technologies to transform real-world data (RWD) into evidence for clinical and medical decision-making[1].RWE is used to identify drug safety risks,such as risk management plans and pharmacovigilance plans.When medical products such as new drugs or medical devices are approved for marketing,their safety and effectiveness will be judged through an extensive collection of medical products data.The whole life cycle of medical products is supervised.In addition,RWD can be used for economic evaluation,such as evaluating the outcomes of pharmaceutical products used in the real world to better support health care decisions.

With the development of medical technology,people’s demand for health care decision-making is increasing,and more attention is paid to RWS in the field of health care.Therefore,RWE has become a common concern of health care decision-makers,researchers,and pharmaceutical enterprises[2].

At present,medical reform is vigorously carried out in China,so the construction of medical system needs to be improved,especially in the formulation of essential drug lists and determination of clinical treatment plans[3].In the process of health care decision-making,the evaluation of clinical evidence is important.Therefore,the purpose of this study is to summarize the concept,background,application value,and its enlightenment of RWE to China by analyzing the relevant information of the EU using RWE to support health care decision.

1 The use of various kinds of evidence in health decision making by the National Institute for Health and Care Excellence(NICE) in UK

The NICE,established in 1999,is an executive non-departmental public body in UK.Its main responsibility is to provide standards and guidelines for national health care services based on the best available evidence,so as to provide some suggestions for improving health care decision-making[4].NICE published a unified guideline and methodology manual in 2014,which recommended that available randomized controlled trial (RCT) evidence should be considered first when evaluating the effectiveness of health care programs.At the same time,although RWE may be biased,we should pay more attention to RWE when evaluating the long-term effect of a project[5].Besides,when conducting clinical trials,it is difficult to randomize the group subjects at this time,and ethical requirements are often not met.Therefore,RWS may be more appropriate to assess causality and relevance.

When clinical technical evaluation is carried out,the number of the deviation of RCT data is small,which is the best evidence to evaluate the relative therapeutic effect.However,the manual also points out that the extrapolation of RCT evidence is poor and sometimes it cannot provide sufficient evidence to quantify the effect.Therefore,we need to supplement the data from RWS.However,we still need to pay attention to the potential bias of observational studies[4].

In order to prove the safety and effectiveness of interventional therapy,priority should be given to RCT evidence when evaluating it.Meanwhile,relevant RWD (such as case series or registry) can also be used for evaluation under certain conditions.

There are two kinds of evidence that need quantitative analysis in medical technology assessment,one is published research,and the other is unpublished research (such as observational study).Because there are many uncertain factors (such as doctor’s operation) that will affect the implementation effect of medical technology.The evaluation of medical technology should be based on more RWE than RCT evidence.The best evidence to prove validity is system evaluation,followed by RCT evidence.Although RWS (such as cohort studies) may also be used as evidence,there are large deviations.Accuracy is to compare test results between healthy people and patients,so the best evidence is usually the prospective cohort study or retrospective case-control study.For the evaluation of side effects,the guidelines recommend that RCTs and other comparative studies should be used,but better evidence could be obtained from case studies,cross-sectional studies,and adverse reaction data of patient registration.

RCT evidence was explicitly recommended for all project evaluations,except for medical technology assessments.At the same time,the guidelines also pointed out that evidence from RWS should be considered when conducting systematic evaluations.

2 Case analysis and research

2.1 RWE supporting the case of BEGIN® market access in EU

The new generation of ultra-long-acting insulin analogue BEGIN®,with its unique polyhexamer long-chain structure,can form an insulin reservoir at the injection site,and slowly release the effective ingredients into the blood circulation,thus realizing the ultra-long-term action time of 42 hours.The action curve of the drug is like the physiological insulin secretion curve,and its super long-term and stable hypoglycemic characteristics can make patients get a convenient experience of injection at a flexible time when necessary[6].

According to a report in European Medicines Agency’s “EBI Open Day” 2016 held in London,in a large phase Ⅲ clinical trial in Europe,the safety and efficacy of BEGIN® on adults with type I and type Ⅱdiabetes were evaluated by using RWS method.The results of RWS show that BEGIN® can further reduce the level of glycated hemoglobin,cutting the incidence of hypoglycemia events and the dose of insulin injection.Therefore,it is an effective,economical and high-quality clinical treatment plan to improve the quality of patients’ life and reduce the cost of treatment[7].

In fact,in the initial clinical trial,no unique effect of BEGIN® on hypoglycemia patients was found.However,RWE complemented the evidence based on phase III clinical trials and helped to prove the other value of this product.

2.2 RWE for a safety study of continuous glucose monitoring (CGM) system in multiple-use cycles

In March 2018,the FDA approved the Eversense CGM system of sensors for patients over 18 years old.This is the first fully implanted 90-day continuous blood glucose monitoring system approved by the FDA.The safety and efficacy of Eversense CGM system in type 1 and type 2 diabetes mellitus have been confirmed in the first three clinical trials,but the long-term safety and performance of the sensor in the insertion and removal cycle need to be further verified.Therefore,the long-term safety and performance of Eversense CGM system in multiple sensor insertionpull cycles in adult patients with type I and type Ⅱdiabetes were further evaluated by the post market clinical follow-up (PMCF) registry.

The study collected records of all patients who had subcutaneous placement of sensors at 534 participating centers in Europe and South Africa from June 2016 to August 2018.Adverse events (AEs) were recorded for all patients at each visit.The adverse events were related to the equipment,procedure,or drug (dexamethasone acetate).The primary safety endpoint was the incidence of severe adverse events(SAE) associated with four sensor insertion-removal cycles[8].

A total of 3 023 patients were enrolled in this study,5 417 sensors were implanted,and 1 260 patients were followed up.Among them,969 patients used the system for more than 6 months,and 173 patients used the system for more than 1 year.The results showed that 91% of the sensors were completely used for 90 days and 75% for 180 days.The incidence of serious adverse events was zero.The most frequently reported adverse events were infection of sensor location (0.96%),failure to remove the sensor at the first attempt (0.76%) and irritation of patch location (0.66%)[8].Therefore,PMCF registry further proved the long-term security and performance of the Eversense CGM system in multiple-service cycles through RWE.

3 Inspiration to China

With the development of modern medicine and the increasing demand for medical evidencebased decision-making,the quality of RWD has been constantly improved,and the transformation from RWD to RWE becomes better.RWE will play an increasingly important role in health care decision-making.RWS can break many limitations of RCT,reflecting the efficacy of drugs or treatment programs under real conditions,and providing a scientific basis for medical decision-makers to choose new drugs or new treatment schemes in clinical treatment.RWE can not only be used in the evaluation of biological agents and chemical drugs,but also plays an increasingly important role in the evaluation of both traditional Chinese medicine and the post-marketing of medical devices.For example,RWE can be used in the treatment of coronary heart disease,chronic obstructive pulmonary disease and other diseases[9].

At present,most medical decision makers are concerned about the safety and effectiveness of medical devices in the real environment.For most treatment methods,although RWE trials cannot replace phase I-III clinical trials,they will play an increasingly important role in supplementing the evidence base of clinical trials,verifying the safety and effectiveness of medical devices,and accelerating the market access of new drugs[10].

4 Conclusions

With the rapid development of science and technology,new technologies such as natural language processing (NLP) are rapidly maturing,accelerating the review of information such as case reports,literature and social media.RWE can measure the intervention effect of all patients under real clinical conditions,and the cost of obtaining RWE is less than that of RCT.Therefore,pharmaceutical industry may prefer to replace many types of post-market RCT safety studies with RWE studies.

Although RWE has many advantages over RCT,it has risks such as data quality,consistency of methods and disregard of confounding factors[11].Both RCT and RWS have their specific weaknesses and advantages,and the combination of data from the two trials can complement each other.Previous studies have shown that RWE seems to complement approval evidence more and more.RWE cannot replace RCT evidence,but with the standardization and improvement of RWS test criteria,and more reliable databases and better methods to eliminate bias will emerge.RWE can play an important role in the fields of pharmaceutical regulation,clinical diagnosis and treatment,and pharmacoeconomics.