The Enlightenment of FDA’s “Real-World Evidence Program Framework” to China

Yu Xiuna,Li Wanying,Dong Li

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

Abstract Objective To provide a reference for China to use real-world evidence (RWE) in drug approval and regulatory decision-making system.Methods The main content of “Real-World Evidence Program Framework” issued by the FDA was summarized by literature research method,and the related system construction in China was analyzed.Results and Conclusion To promote the use of real-world study (RWS) for drug regulatory decisions,China should issue guidelines on RWS.Besides,the construction of data standards and the shared database should be strengthened.Then,the demonstration projects should be introduced extensively and the guidance for RWS of enterprises must be enhanced.Meanwhile,close attention should be paid to dealing with the relationship between stakeholders.

Keywords:FDA;real-world data;real-world evidence;enlightenment

“Real-world evidence (RWE) Program” issued by the FDA on December 6,2018 has attracted extensive attention from various countries and regions in the world.This program not only promotes the use of real-world study (RWS) for drug regulatory decision-making,but also provides a clear roadmap for achieving this goal.

1 Background of “Real-World Evidence Program Framework”

FDA’s “Real-World Evidence Program Framework” was mandated based on “21st Century Cures Act”.“21st Century Cures Act” made a huge change on section of the FDA’s drug regulatory decision,stating that under certain circumstances,data summary and RWE other than completed clinical trial data are supportable for drug approval.Sources of these data summary and RWE include observational studies,medical claims databases,patient registry,and even in-house use settings[1].Based on this,FDA released “Real-World Evidence Program Framework”to provide a clear roadmap of using RWE to support regulatory decision-making[2].

2 Main elements of “Real-World Evidence Program Framework”

2.1 Defining the terms of real-world data (RWD)and RWE and clarifying the “Real-World Evidence Program Framework”

RWD is data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources.

RWE is the clinical evidence regarding the usage and potential benefits or risks of a medical product derived from analysis of RWD.

This program standardizes the scope of RWS and clarifies how to avoid the quality defects of RWD,while ensuring the accuracy,integrity,and relevance of the input data.

2.2 Specifying the scope and protocol of the “Real-World Evidence Program Framework”

It clearly states that this framework applies to drugs and biological products.It also outlines FDA’s plan to implement its RWE program,which includes internal process,guideline development,stakeholder engagement and demonstration projects.This program also includes the use of RWE to help support agency regulatory decisions.RWE can be the prospective studies in the early stage to facilitate the development of traditional clinical trials,and thus indirectly promote the approval of drugs.In addition to such indirect influence,RWE can also directly affect FDA regulatory decision-making process,which is mainly reflected in the following two aspects.

Safety evaluation:FDA considers the possibility of conducting RWS with the “sentinel initiative”system which was launched in 2018 with hundreds of millions of patients’ information,thus providing drug safety decision-making before drugs are approved for marketing.

Effectiveness evaluation:FDA currently only uses RWE to promote decision-making on drug effectiveness in a few areas such as oncology and rare diseases.FDA can accelerate the drug approval based on the RWE generated by RWS.But at the same time,the traditional randomized controlled trial (RCT) is still required to demonstrate the effectiveness of the drugs.

2.3 The requirement for RWE quality evaluation

In the process of using RWE to promote the approval of drug efficacy,FDA will mainly evaluate the quality of evidence from three aspects:data quality,study design and implementation.

Based on the case study principle for different types of cases,FDA will focus on evaluating the accuracy,integrity,and relevance of RWD.In terms of data relevance evaluation,in addition to assessing whether the data is related to the research,consideration should also be given to whether the collected data is comprehensive,and whether the existing tools can be used for statistical analysis.

2.4 Listing the types of study design that support decision-making

In the program,FDA provides three types of study design to support effective decision-making,including pragmatic RCT (pRCT),non-randomized single-arm/one-arm trial and observational study.In the framework,the wide potential uses of RWD and RWE are also analyzed,as shown in Table 1.

Table 1 The potential uses of RWD/RWE in clinical trials

2.5 Listing the factors while using RWD to generate RWE

The main factors considered by FDA include:(1)Whether the RWD is fit for use;(2) Whether the trial or study design used to generate RWE can provide adequate scientific evidence to answer or help answer the regulatory question;(3) Whether the study conduct meets FDA’s regulatory requirements.

2.6 Explaining the regulatory considerations and problems of implementation of FDA’s “Real-World Evidence Program Framework”

In RCTs and observational studies (including informed consent and oversight),it specifies in detail the identification on potential questions regarding the applicability of regulatory requirements to use of RWD for regulatory decision-making,evaluation of the adequacy of current guidelines on the use of electronic sources,and the main elements of relevant data standards and implementation strategies.At the same time,the importance of engagement of stakeholders is particularly emphasized.

2.7 Listing some of demonstration projects

In this part,FDA lists several demonstration projects,which clearly explain the methods and processes of using RWE,including data requirements,RWE tools and RWE study design.It helps guide the use of RWD and RWE.

3 The Enlightenment to China

3.1 Issuing guidelines for research based on RWE that is generated to support drug effectiveness

FDA believes that the use of new technologies,such as electronical medical record systems,mobile health technology,and electronic data capture can effectively improve the efficiency of clinical research.But at the same time,the quality,authenticity,and reliability of the data sources must be guaranteed.FDA released three guidelines of “Use of Electronic Informed Consent Questions and Answers”,“Use of Electronic Records and Electronic Signatures in Clinical Investigations Under 21 CFR Part 11–Questions and Answers”,and “Use of Electronic Health Records in Clinical Investigations”in December 2016,June 2017,and July 2018,respectively[3-5],to guide researchers to generate reliable and transparent RWD with electronic data platform.

Along with the gradual development of RWS,China has successively released a series of related guidelines,as shown in Table 2.

Table 2 Guidelines related to RWS released by China agency

China still needs further advancement in this regard.It is suggested to draft,seek opinions,and release relative guidelines and documents timely from a practical point of view.

3.2 Identifying and assessing data standards and implementation strategies required to use of RWD/RWE

In RCTs and observational studies (including informed consent and oversight),it specifies in detail of identification on potential questions regarding the applicability of regulatory requirements to use of RWD for regulatory decision-making.The potential risk of RWE includes:(1) The quality and traceability of data sets are difficult to be guaranteed;(2) Error of the analysis tool used by the data scientist;(3)Few experts with both medical knowledge and RWE analysis knowledge lead to incorrect or unreliable analysis results.

Therefore,based on foreign experience,China should publish standards for using electronic source data.With scientific electronic source data standards,combined with the operating characteristics of China’s hospital information system (HIS),a relevant database can be established to accurately collect RWD.Meanwhile,a deep investigation should be performed to identify the gaps between RWD/RWE data standards and existing drug approval and regulatory,to provide a guidance for enterprises with typical cases,a clear process and implementation framework.

3.3 Building database to generate more extensive and rich information

For a long time,FDA has monitored and evaluated drug safety by conducting post-marketing studies.In 2007,“FDA Amendment” required FDA to set up a post-marketing risk identification and analysis database.Based on this,FDA officially launched the “sentinel initiative” in 2008 and established a nationwide electronic system for drug safety monitoring.

China should proceed with the database construction and collect more extensive information by building up a large-scale data platform,which is beneficial for obtaining RWD and help generate qualified RWE to support drug approval and later oversight[6].Fluticasone propionate inhaled aerosol is an inhaled glucocorticoids developed by GlaxoSmithKline (GSK),which has been used in China for more than ten years for pediatric and adults with asthma.This variety uses clinical trial data for children ≥ 1 year old abroad to apply to expand the scope of the applicable population in China,from the“children ≥ 4 years old” to “children ≥ 1 year old”[7],consistent with overseas approvals.

3.4 Strengthening the cooperation with stakeholders

The importance of stakeholder engagement is mentioned in the program,which is critical for the implementation of FDA’s “Real-World Evidence Program Framework”.The cooperation between RWE stakeholders,such as clinicians,medical systems,related patients,pharmaceutical companies,and policy makers,is a critical part of “Real-World Evidence Program Framework”.FDA’s approach is to strengthen the cooperation from two perspectives.

As we all know,the implementation of RWS is by no means a unilateral act.Chinese government should integrate all stakeholders to participate in this program.For the development of new drugs and the subsequent use of RWD and RWE for marketing approval,all stakeholders need to fully understand RWS.The openness and transparency of information can promote and popularize the use of RWS,and provide guarantee of the wide use of RWE in the future.There are many ways to attract academic institutions,representatives of patients,pharmaceutical companies,and other stakeholders to actively participate in the discussion.The discussion should also be extensive,which can include data acquisition,study design,statistical methods,and others.

3.5 Introducing the demonstration projects and strengthening the guidance for RWS of enterprises

Several typical demonstration projects are shared in this “Real-World Evidence Program Framework” to provide guidance and reference for enterprises,including introduction to the potential and challenges faced by using electronic health record(eHR),demonstration of creating a multi-purpose design of high-quality clinical/research records,a large randomized and non-interventional clinical trial on factors which impact atrial fibrillation,as well as the evaluation of non-interventional design.Therefore,China should also provide introduction and guidance of the demonstration projects.This is the exploration and practice of RWD and RWE,which needs continuous accumulation of experience and gradual improvement.Enterprises can learn from these demonstration projects and conduct RWS afterwards.

On March 26,2020,the approval of Allergan’s“Glaucoma Drainage Tube” was published on the National Medical Products Administration (NMPA)website.This is the first medical device approved in China by using domestic RWD.The promotion of such case will provide guidance for enterprises to conduct RWS[8].

4 Conclusion

The “Real-World Evidence Program Framework”can serve as a roadmap for incorporating RWD and RWE into the regulatory paradigm comprehensively.Besides,it provides a reference for other countries and regions in the world to explore RWE.Its enlightenment to China is significate.China should continuously explore the potential value of RWE and apply it to regulatory decision-making flexibly.Meanwhile,China should also provide certain guidance to enterprises to better use RWE for their research.It will play a greater potential role in drug evaluation and oversight on the traditional Chinses medicine.