EU Real-World Evidence Supports the Expansion Indications for Drugs and Its Enlightenment to China

Wang JiaoJiao,Huang Zhe,2＊

(1.School of Business Administration,Shenyang Pharmaceutical University,Shenyang 110016,China;2.Research Institute of Drug Regulatory Science,Shenyang Pharmaceutical University,Shenyang 110016,China)

Abstract Objective To analyze the value of EU real-world evidence (RWE) in supporting the expanded indications for drugs and to provide reference for the decision-making of expanding drug indications supported by RWE in China.Methods By searching relevant domestic and foreign literature and case analysis,the practice of the RWE of EU to support the expansion indications for drugs was investigated.Results and Conclusion The EU uses RWE to carry out adaptive path research,which provides a new idea for drug R&D and approval.Besides,it also provides evidence in supporting the research of expanded indications for drugs.With the increasing cognition of RWE,it will play a key role in medical and regulatory decisions in China.

Keywords:EU;real-world evidence;expanded indication;adaptive path;enlightenment

1 Introduction

Real-world evidence (RWE) refers to the clinical evidence of the use and potential benefits or risks of pharmaceutical products obtained through realworld data (RWD) analysis.RWE runs through the life cycle of pharmaceutical products to provide reliable evidence for the development and production of effective and safe pharmaceutical products[1].Globally,medical and health institutions and relevant regulatory authorities in various countries are paying more attention to the application and development of RWE to promote R&D and innovation of pharmaceutical products.In recent years,real-world study (RWS) based on RWD has been applied to new drug development and management[2-3],drug regulation[4],medical care decision-making[5]and other aspects.With the widespread application of RWE,Sherman RE,et al.proposed that the results of RWS can be used as evidence for the approval of drugs for expanded indications[6].For example,the European Medicines Agency (EMA) approved an application from Alexion pharmaceuticals in 2015,agreeing it could apply RWD/RWE to Eculizumab to expand the drug indications for safety and efficacy studies.

The “Guiding Principles for Drug R&D and Evaluation Supported by Real-World Evidence(Trial)” was issued by the National Medical Products Administration on January 7,2020,stipulating that RWE can be used as the evidence chain to support drug regulatory and clinical decision-making.Among them,exploring and proving the therapeutic value of approved drugs in other diseases,and extending or correcting indications for approved drugs are important directions for RWE to support drug development and review.Due to differences in drug R&D and healthcare decision-making in various countries,their methods of using RWE to carry out related research are also different.Therefore,this article refers to the value of European RWE in supporting the expanded indications for drugs,and provides reference for promoting RWE in the decision-making of drug expansion in China.

2 EU RWE supports the decision-making of the expansion indications for drugs

During the clinical application of drugs,it is common that some drugs are unregistered.We usually define randomized controlled trials (RCTs)as the highest level of evidence-based evidence.For drugs that have been approved for marketing,RCT is often required to increase their indications.RCTs are not feasible or non-optimal research designs.In contrast,RWE generated by non-interventional studies or practical clinical trials (PCTs) supporting the expansion or modification of drug indications is more applicable and feasible.

In March 2014,the EMA and stakeholders(including patients and health technology assessment institutions) jointly launched an adaptive licensing pilot project,which proposed adaptive pathways to meet the clinical treatment needs of patients and promote the listing of new drugs.On March 8,2016,the EMA released a report on the adaptive licensing pilot project,which mentioned that the adaptive pathway referred to a structured approach for approving experimental drugs with potential breakthrough therapeutic benefits for patients in a gradual manner[7].It was based on a progressive learning path under conditions of recognized uncertainty.The adaptive pathway involves the iterative phase of data collection and regulatory evaluation.From March 2014 to August 2016,the EMA carried out a small-scale trial plan and approved the temporary listing of six new drugs.At the same time,RWE was obtained based on the daily medical effects of patients,including the effectiveness and side effects of drugs.Adaptive path acquisition of patient data mainly relies on medical sensors,mobile phone applications,data processing tools,etc.Over time,more evidence will be collected to form the research results of real-world trials,thus licensing adjustments can be gradually made to expand or limit the previously authorized drug indications.

In particular,the research method of the EU’s adaptive path should consider the following factors and meet the corresponding requirements.First is to conduct a comprehensive evidence research.Approved indication studies need to consider the cognition of drug and all research data generated from RWD,including non-clinical and clinical data.Second is the research population.The approved indication research should be conducted in sensitive populations that can reflect potential differences.The differences in the pharmacokinetic data,biodistribution,and pharmacodynamic research of the product in the patients need to be considered.The toxicity differences in the patients under this indication,and other factors that may affect the safety and effectiveness of the product under various indications (such as comorbidities,combination drugs) should be detected.The end points of clinical trials should be fully demonstrated.Third is the Security.Safety is a separate consideration.Only when the safety information of the drug in a certain indication is confirmed,studies can be carried out based on safety data.Generally,during clinical trials,safety assessment is a short-term process that may not recognize rare events.Therefore,EU countries actively carry out pharmacovigilance to monitor the adverse reactions of drugs.

The adaptive pathway method makes more effective use of existing legislation and regulatory tools[8],which constitutes a new approval way for drugs.It provides a scientific,effective method for the use of non-random RWE in the approval of new indications and the evaluation of post-authorization medical products[9].In this process,the adaptive path uses RWE to solve problems that cannot be solved by traditional clinical trials.Such as the therapeutic effect of drugs on different target populations,the availability of treatment methods,and so on.However,further evidence support is needed in the process of adaptive permission,especially non-random RWE.

3 Case

The Committee for Human Medicinal Products(CHMP) evaluates the authorization of drugs.Multiple myeloma is a common blood disease,and there are no effective drugs for the treatment of multiple myeloma before.On May 20,2016,based on the data of two open clinical studies,CHMP finally adopted a positive opinion and passed the scientific review of Daratumumab,authorizing Daratumumab as a monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma with conditional marketing[9].The data of the first clinical study showed that in 106 patients with multiple myeloma,the response rate of Daratumumab monotherapy was 29.2% (95%,confidence interval:20.8-38.9),and the tumor was completely or partially shrunk for 7.4 months.In the second clinical study data,42 patients with multiple myeloma had response rate of 36% with Daratumumab monotherapy.Previously,these patients had received at least three treatments (including PI and IMID) or on PI and IMID double invalidation (MMY2002 study).Darzalex is a new monoclonal antibody against CD38.Based on response rate data from two single-drug studies,Darzalex had demonstrated a durable response rate in a limited treatment regimen in a large pretreatment population.On April 28,2017,the EMA expanded the indications for Daratumab,which included the combination with lenalidomide and dexamethasone,or bortezomib and dexamethasone,for adult patients with multiple myeloma who received at least one treatment.The expansion of daratumab to lenalidomide and dexamethasone (MMY3003 study) or bortezomib and dexamethasone (MMY3004 study) has shown positive results for at least one progression-free survival treatment program for patients with multiple myeloma.After submitting the control data of the MMY3003 and MMY3004 studies,the effectiveness and safety of daratumab were confirmed.Finally,the conditional approval of daratumab was converted into a standard approval.

4 Implications to China

4.1 Supporting the rational use of unregistered drugs and improving the standardization of clinical use of drugs

The phenomenon of unregistered use of drugs is widespread in the process of clinical practice.Due to the lag in information correction of drug instructions,it cannot meet the clinical needs,which makes doctors often use unregistered drugs during clinical practice.At present,in view of the phenomenon of unregistered drug usage,the “Detailed Rules for Evaluation Standards for Tertiary General Hospitals”clearly stipulates medical institutions must establish a corresponding off-label drug management system,and the clinical use of unregistered drugs needs to be carried out in accordance with regulations[10].Since the clinical use of unregistered drugs is often decided by physicians,these drugs may easily lead to medical accidents and cause harm to patients[11].The RWE provides a scientific and effective way to standardize the use of unregistered drugs,thereby further standardizing clinical rational drug use[12].

4.2 Supporting the expansion indications for traditional Chinese medicines (TCMs) and providing diversified evidence for the evaluation of the efficacy of TCM

For TCM,most products have been on the market for a long time.Therefore,pharmaceutical companies have more demand for RWS,hoping that they can gain more effective evidence through RWS to further prove the effectiveness and indications of their medicines.At the same time,since the effect of TCM is relatively slow,it is difficult to quickly detect the improvement of the condition through hospitalization indicators.Therefore,it is necessary to pay attention to the subjective feelings of the patient and the situation of longer-term follow-up.And RWS has the feature of large amount of data and long cycle,which can be used to explore and expand the application of TCM indications and provide diversified evidence for the evaluation of TCM efficacy[13].In addition,the current TCM attaches great importance to the scientific nature of RCT scheme design,but it has the difficulty in generating baseline data that can support parameter settings.RWS can generate many valuable RWEs,which can be used in clinical trial programs to clearly locate the basic parameters of the included population(P),intervention methods (I),control settings (C),and outcome indicators (O).Therefore,it can make up for the shortcomings of TCM in the RCT program and generate scientific and operable clinical treatment evidence[14].

5 Conclusion

In this paper,we study the RWE of EU to support the decision-making in expansion indications for drugs.The adaptive path is proposed to provide a new drug approval method for new indications of drugs with non-random RWE,which provides patients with better drugs.At present,RWE related research is still in its infancy in China.Therefore,we should pay attention to the following issues.First,we should correctly understand the status of RWE in drug development and review.Although traditional RCT has limitations,it is still the highest evidencebased evidence in clinical drug research.Therefore,drug registration applications should still use RCT as the gold standard and RWE as the supplement.Second,we should formulate uniform standards for RWD.Since RWE comes from RWD,it puts forward higher requirements on the data quality of RWD.When collecting RWD,the accuracy and reliability of the RWD should be ensured to obtain real and reliable RWE.Thirdly,we should clarify the application scope of RWE.The goal of conducting RWE-related research is to better support relevant drug regulatory decisions.Therefore,we must clarify the application scope of RWE,and then medical institutions,enterprises,and relevant government departments can carry out research.In the future,RWE will play an increasingly important role in medical health and regulatory decision-making in China.