n recent years, real-world evidence (RWE) developed from real-world data (RWD) has become one of the hottest topics worldwide in the practice of drug and medical device registration and supervision. China’s regulatory authorities have also shown positive attitudes toward the role of RWE in drug R&D and registration review.

RWE Policy Development in China

In 2015 and 2016, the State Council of China issued the Action Plan for Promoting the Development of Big Data, which requires promoting the development and sharing of public resource data, including big data for medical and health services, and promoting the development and application of big data through top-level design. In 2016, the introduction of Guiding Opinions of the General Office of the State Council on Promoting and Regulating the Application and Development of Big Data in Health Care put forward a series of guiding principles to promote and standardize the development of health and medical big data applications, providing the basis for carrying out real-world studies (RWS) in terms of data resources and technical support establishment.

In 2018, the Wu Jieping Medical Foundation and China Chest Cancer Research Cooperation Group released the China Real-World Research Guide, which is the first RWS-related guide in China. In July 2019, the China REal world-data and studies ALliance (ChinaREAL) published a series of articles in the Chinese Journal of Evidence-Based Medicine explaining the application of RWD regarding technical specifications, research design, data management, and statistical analysis. In October 2019, the real-world research professional committee of China’s traditional Chinese Medicine Association released the draft of the technical guidelines for real-world research of Chinese patent medicine at the first academic seminar on real-world research of traditional Chinese medicine.

In this same timeframe, the National Medical Products Administration (NMPA) also issued corresponding guiding principles. From May 2019 to December 2023, NMPA and its Center for Drug Evaluation (CDE) successively issued the below and officially initiated construction of the RWE framework system by China’s regulators.

May 2019: The Basic Considerations of Real-World Evidence Supporting Drug Research and Development: This guideline aims to provide clarity on the definition of real-world research, outline the use and scope of real-world evidence in drug R&D, explore the basic principles for the evaluation of RWE, and consequently provide scientific and practical guidance for industry to consider when utilizing RWE to support drug development.

January 2020: Guiding Principles of Real-World Evidence Supporting Drug R&D and Evaluation (Trial Implementation): This guideline aims to provide clarity on the definition of RWE; guide the collection and suitability assessment of RWD; specify the status and applicable scope of RWE in drug regulatory decision-making; explore principles for the evaluation of RWE; and consequently provide reference for industry and regulatory agencies in utilizing RWE to support drug regulatory decision-making. This Guideline represents current thinking and knowledge and will be constantly revised and improved by deepening of research and knowledge.

August 2020: CDE released Technical Guiding Principles of Real World Evidence Supporting Drug R&D and Evaluation for Children (Trial Implementation): This guideline is formulated to address the actual research and development and registration needs for pediatric drugs, and to communicate considerations for drug regulatory agencies in response to new research methods, in China. It is designed to echo implementation of the ICH E11 (R1) Guideline in China, and to help drug developers and clinical researchers better understand the application of Guiding Principles of Real World Evidence Supporting Drug R&D and Evaluation (Trial Implementation) in research and development of pediatric drugs.

April 2021: CDE released The Guiding Principles for Real-World Data Used to Generate Real World Evidence (Trial Implementation): As a supplement to the above Guidelines for Real-World Evidence to Support Drug Development and Evaluation (Trial implementation), this guideline provides specific requirements and guiding suggestions for the definition, source, evaluation, curation, standards, safety compliance, quality assurance, applicability, and other aspects of RWD, to help sponsors evaluate the applicability of RWD, better curate RWD, and adequately prepare to generate reliable RWE.

February 2023: CDE released Guidelines for Design and Protocol Framework of the Real-World Studies of Drugs (Trial implementation): To guide sponsors in scientifically and rationally designing real-world studies and specify technical requirements for writing real-world study protocols, these guidelines illustrate the basic considerations of real-world study design and establishing the study protocol in drug research and development and evaluation, and provides other guidance on conducting real-world studies in drug research and development.

February 2023: Guidelines for the Communication of Real-World Evidence Supporting Drug Registration Applications (Trial implementation): Based on the Drug Registration Regulation released by the State Administration for Market Regulation (SAMR) and Measures for Administration of Communication for Drug R&D Activities and Technical Review released by CDE, this CDE guideline identifies core issues to discuss in communication, requirements of data to be used in meetings, and other aspects of using RWE to support registration applications, and provides recommendations for applicant communication at critical junctures to improve the efficiency of clinical drug research and development.

Draft released in November 2023: Guidelines for Application of Real-World Data Based on Disease Registry (Draft for Comment): The CDE issued this as a draft to guide sponsors in how to establish a disease registry and how to assess and utilize existing disease registry data to generate RWE sufficient to support administration of regulatory decision-making.

The definition of real-world research in NMPA’s Guiding Principles of Real-World Evidence to Support Drug R&D and Evaluation (Trial Implementation) refers to the research process of collecting data related to the health of the research object or summary data derived from these data in the real-world environment to address predefined clinical problems and obtain clinical evidence of drug use and potential benefit-risk through analysis. Real-world data (RWD) is data related to patients’ health status and medical behavior obtained through various channels. Real-world evidence (RWE) is clinical evidence about the use and potential benefits or risks of medical products obtained through the analysis of real-world data. These definitions are aligned with US FDA’s.

Key RWE Use Cases in China

Real-world research has long existed in clinical practice, and RWD has supported the registration and oversight of medical devices or drugs to a certain extent. Examples of Real-World Evidence Used in Medical Device Registration Decision-Making released by FDA in 2021 lists 90 examples of real-world evidence supporting registration decision-making from 2012 to 2019, even though there were no pertinent regulations or policies in the US until 2016.

In China, there is a similar situation across drug and medical device approvals. Here are examples of RWE-supported products approved in China before CDE issued RWE guidelines:

• In 2018, the CDE approved bevacizumab to expand the treatment regimen to a combined platinum-based chemotherapy regimen. Bevacizumab was initially approved in combination with 5-fluorouracil-based chemotherapy for the treatment of patients with metastatic colorectal cancer. It was then extended to the combination of carboplatin and paclitaxel for the first-line treatment of patients with unresectable advanced, metastatic, or recurrent nonsquamous non-small cell lung cancer (NSCLC). In 2018, the results of three real-world studies showed, on the basis of platinum-containing doublet chemotherapy, that the combination of bevacizumab significantly prolonged PFS (progression-free survival) and OS (overall survival) compared with chemotherapy alone, which was consistent with global population data, with no new safety issues. CDE approved bevacizumab in combination with platinum-based chemotherapy for the first-line treatment of patients with unresectable advanced, metastatic, or recurrent NSCLC. The three real-world studies (RWS) results provide strong supporting evidence for this decision.
• In 2019, the NMPA approved denosumab for treatment of giant cell tumor of the bone that is unresectable or that may lead to severe dysfunction after surgical resection. Afterward, the applicant obtained evidence from multiple global multicenter clinical studies and real-world evidence generated from the National Health Insurance Research Database (NHIRD) in Taiwan and the Clinical Data Analysis and Reporting System (CDARS) in Hong Kong to evaluate the efficacy and safety of denosumab in reducing the incidence of clinical osteoporotic fractures in treated Chinese postmenopausal women with osteoporosis in clinical practice in the Taiwan and Hong Kong populations. In June 2020, the NMPA approved the application of this new indication in mainland China.

Most of the remaining examples were approved through Boao Lecheng Pilot Zone (please see full explanation later in the article) and are mainly based on existing overseas data from products that have already been approved abroad, supplemented by data from Chinese people in Boao Lecheng.

• In March 2021, pralsetinib was approved as the first medicine under Boao Lecheng Pilot Zone (see Government-Driven RWE Projects below) which will be introduced later in this article. Relevant real-world research results, as a supplement to the clinical trial results, assisted in the efficacy evaluation and safety evaluation in the advanced non-small cell lung cancer (NSCLC) population in China.
• In November 2021, trilaciclib for injection was approved by NMPA to be used prophylactically in patients with extensive-stage small-cell lung cancer (ES-SCLC) receiving platinum-containing drugs combined with etoposide, to reduce the incidence of bone marrow suppression caused by chemotherapy.
• In April 2021, the NMPA accepted the NDA for fluocinolone acetonide intravitreal implant. In June 2022, it was officially approved by NMPA for the treatment of chronic noninfectious uveitis involving the posterior segment of the eye (chronic NIU-PS). This is the first new drug approved in China mainly based on RWD from Boao Lecheng.
• In July 2023, NMPA approved the long-acting lipid-lowering small interfering ribonucleic acid (siRNA) cholesterol-lowering drug inclisiran injection for the treatment of adult patients with primary hypercholesterolemia or mixed dyslipidemia.

The above were approved through the Boao Lecheng Pilot as of October 2023. Other medical products are being reviewed and approved under the ongoing Boao Lecheng pilot program.

Government-Driven RWE Projects

Advancing RWE in drug research and development has become a hot topic globally. The Chinese government has also made great efforts to promote the development of RWE in China, both on the country level and province level.

NMPA RWE Project 2019

The NMPA RWE Research Project is a joint initiative conducted by government (the China Center for Food and Drug International Exchange, or CCFDIE), academia (Peking University Health Science Center, or PKU HSC), and industry (domestic and multinational companies from the pharmaceutical and medical device sectors). The research project was initiated in 2018 and focused on RWE-related policy landscape research and case studies to assist in further policy development. The NMPA RWE Research Project is an important part of China’s strategy to promote innovation in the pharmaceutical industry, reduce the time and cost of drug research and development, and improve patient outcomes. In December 2023, NMPA teamed with the People’s Government of Hainan to co-sponsor the Boao International Conference on Real World Studies of Medical Products, which was hosted by CCFDIE, the Hainan Medical Product Administration (HNMPA), the Hainan Health Commission, and the Boao Lecheng Pilot Zone.

Boao Lecheng Pilot Zone

Usually referred to as Lecheng, the Boao Lecheng International Tourism Pilot Zone was approved and launched by the State Council in 2013. The goal of this pilot zone is to accelerate the introduction of global innovative drugs, medical devices, and technologies from developed countries and to give Chinese patients access to the most advanced medical treatments previously approved by major overseas regulatory agencies. As of November 2023, 13 pharmaceutical and medical device products have been approved for market launch with RWE generated from Lecheng’s RWD in supporting clinical evaluation.

In June 2019, the NMPA and the People’s Government of Hainan jointly announced the start of the Clinical RWD Application Pilot Project in Boao. According to its implementation plan: “Clinical data for the non-China registered products used in Boao would be regarded as real-world data and could be used to support product registration.” Beginning in June 2021, companies could submit their RWD plan and other relevant documents to support registration of their pharmaceutical products through HN MPA (Hainan Medical Products Administration) to CDE/NMPA.

In March 2023, the People’s Government of Hainan Province released the Provisional Regulation on Management of Drugs and Medical Devices with Urgent Clinical Needs in Hainan Free Trade Port Boao Lecheng International Medical Tourism Pilot Zone to strengthen supervision and management of imported drugs and medical devices with clinical urgency and ensure the safe use of drugs and medical devices.

Greater Bay Area

The Guangdong-Hong Kong-Macao Greater Bay Area, usually referred to as the Greater Bay Area (GBA), consists of Hong Kong, Macao, and nine cities in Guangdong Province.

In August 2021, the Guangdong Medical Products Administration released its Provisional Regulation on Management of Drugs and Medical Devices with Urgent Clinical Needs in GBA. This allowed designated hospitals operating in nine GBA mainland cities to use HK-registered drugs for urgent medical needs, subject to the approval of Guangdong Province. RWE from administration of these drugs is to be collected as reference for subsequent product registration in mainland China. Regulatory policy RWE related to the GBA will be further developed.

Conclusion and Future Prospects

China’s regulatory authorities have shown positive attitudes toward the role of RWE in drug R&D and registration review. NMPA has recognized the importance of accelerating the release of relevant guidelines and frameworks to translate these attitudes into practice. Over the past two years, several relevant guidelines have been developed and issued, providing a rich policy reserve for carrying out real-world drug R&D in China. Through implementing multiple CDE guiding principles and establishing the Boao Lecheng Pilot Zone, which provides a practical platform for real-world research, industry and regulators are utilizing RWD/E in drug registration.

NMPA and CDE continue to encourage use of RWE through their emphasis on data mining of historical real-world data, direction on how to efficiently collect and translate RWD into high-quality RWE suitable for regulatory purposes, and support of pilots and other initiatives that introduce more therapies to Chinese patients. They also actively participate in harmonization of ICH guidelines on RWE/RWD-related topics. With continued research and collaboration between industry, regulators, and healthcare stakeholders, it is likely that RWE will become an increasingly important component of drug research and development and registration in China.