Clinical research in China is regulated and overseen by the National Medical Products Administration (NMPA) (the Chinese name translates as “State Drug Administration”) and the National Health Commission (NHC).

National Medical Products Administration

As per the DRR, the NMPA-Org, the DAL, the RegImplemDAL, the RegImplemDAL-Amndt, the SC-Opinions-No44, the NMPA-No50-2018, and the NMPA-No230-2015, the NMPA is the regulatory authority responsible for national drug registration management, which includes regulation of clinical trials. Per the DRR, NMPA’s Center for Drug Evaluation (CDE) is responsible for the evaluation of drug clinical trial applications, drug marketing authorization applications, supplementary applications, and overseas drug production registration applications. The NMPA grants permission for clinical trials to be conducted in China in accordance with the provisions of the DAL, the VaccineLaw, the DRR, the SC-Opinions-No44, the NMPA-No50-2018, and the NMPA-No230-2015. The drug category in which an applicant chooses to register determines the clinical trial application review and approval or filing process.

Per the SC-IRP and the SAMR-Org, China established the State Administration for Market Regulation (SAMR). The SAMR is a full ministry agency reporting directly to the State Council of the People's Republic of China. Under the SAMR is the NMPA, which regulates clinical trials.

As delineated in the NMPA-Org and CHN-78, the NMPA implements China’s guidelines, policies, and decision-making for the supervision and administration of drugs, medical devices, and cosmetics. It is responsible for safety supervision; standards management; drug registration; quality management; risk management; pharmacist licensing; inspection systems; international cooperation; guiding provincial and municipal drug administration; and other tasks assigned by the State Council and Party Central Committee. The NMPA is charged with accelerating the examination and approval of innovative drugs, establishing a system of listing license holders, promoting electronic review and approval, and improving efficiencies.

Per CHN-77, the following NMPA departments are involved with clinical trial application and drug registration:

• Drug Registration Management Department – formulates, supervises, and implements drug standards (including clinical trial quality management), technical guidelines, and registration
• Drug Administration Department – formulates and supervises the implementation of pharmaceutical production quality management standards for drugs, Chinese medicines, biological products, and special drugs (e.g., radioactive and toxic), and formulates and implements a drug adverse reaction monitoring and alert system

Per the DRR, the NMPA-No50-2018, and CHN-81, the NMPA includes the National Institutes for Food and Drug Control (NIFDC) and the CDE, which are directly involved in the clinical trial application and drug registration approval process. Other relevant institutes and organizations include the National Pharmacopoeia Commission, the Food and Drug Inspection Center, the Medical Device Technology Evaluation Center, the Administration Service Center, the Information Center, the Licensed Pharmacist Certification Center, the News and Publicity Center, and the International Exchange Center.

Further, the DRR delineates the responsibilities of the drug regulatory departments of provinces, autonomous regions, and municipalities directly under the Central Government. With respect to clinical trials, they are responsible for organizing the daily supervision and investigation of institutions conducting drug clinical trials; participating in drug registration verification and inspection organized by the NMPA; and other matters entrusted by the NMPA.

The roles of the CDE and the NIFDC in the clinical trial application review and approval process are discussed further in the Scope of Assessment section.

National Health Commission

Per the NHC-HGRmgt, the State Council’s NHC is responsible for China’s management of human genetic resources (HGR). (Note that per SC-Order777 and NHC-HGRmgt, management of HGR was transferred from the Ministry of Science and Technology (MOST) to NHC, effective May 1, 2024). The NHC-HGRmgt states that the original application process and online platform (CHN-6) remain unchanged. As indicated in CHN-24, the NHC is responsible for formulating health policies and systems in China, including health services, hospitals, special populations, drugs, traditional Chinese medicines, and disease control and prevention. See CHN-24 for a comprehensive list of NHC responsibilities and functions. (Please note that the MgmtHumanGen was amended by SC-Order777 to reflect the transfer of HGR management from MOST to the NHC, but the Rules-MgmtHGR has not been amended yet to show the transfer.)

The MgmtHumanGen and the Rules-MgmtHGR stipulate that MOST’s (now the NHC’s) HGR responsibilities include employing experts in the fields of biotechnology, medicine, health, ethics, law, etc. to form an expert review committee to review and approve international cooperative research. The Rules-MgmtHGR indicates that MOST (now the NHC) should support the rational use of HGR to carry out scientific research, develop the biomedical industry, improve diagnosis and treatment techniques, strengthen management and oversight of HGR, improve approval services and efficiency, and advance the standardization of approvals and information disclosure. MOST (now the NHC) is responsible for national efforts such as the investigation, administrative licensing, supervision and inspection, and administrative punishments of HGR. Regarding administrative licensing, licenses must be obtained for the collection and preservation of Chinese HGR and for international collaborations in certain situations. As needed, MOST (now the NHC) entrusts relevant organizations to carry out formal reviews and technical reviews of application materials for administrative licensing of HGR, as well as efforts such as filing, prior reporting, supervision and inspection, and administrative punishments. The science and technology departments (committees and bureaus) of provinces, autonomous regions, and municipalities directly under the Central Government, and the Science and Technology Bureau of the Xinjiang Production and Construction Corps, are responsible for the management of the following HGR in their regions:

• Oversight and inspection and routine management of HGR
• Investigation and handling of illegal cases of HGR within the scope of their authority
• As entrusted by MOST (now the NHC), carry out other efforts such as administrative licensing of HGR in their region

See Rules-MgmtHGR-Interp for a policy interpretation of the Rules-MgmtHGR.

Per HGR-WorkUpdt, the NHC’s China Biotechnology Development Center was entrusted to implement technical work related to the management of HGR. As described in CHN-4, the functions of the Center are:

• Coordinate and supervise the implementation of the management of HGR
• Examine and approve international cooperation projects involving HGR
• Accept applications for the export of HGR, and handle exports and export certificates
• Register and manage important genetic lineages and genetic resources in specific regions
• Manage other work related to HGR

The Rules-MgmtHGR also state that applications must pass a security review organized by MOST (now the NHC) if the study’s provision or opening of HGR information to foreign entities may impact China’s public health, national security, or the social public interest. In addition, per the Bioscrty-Law, MOST (now the NHC) regulates biotechnology safety under the National Security Commission pursuant to a Coordination Mechanism for National Biosecurity (CMNB). The CMNB consists of the competent State Council departments for health, agriculture and rural affairs, science and technology, and foreign affairs, as well as relevant military agencies, to analyze national biosecurity issues, and organize, coordinate, and drive national biosecurity work. MOST (now the NHC) and the other agencies under CMNB establish safety monitoring/reporting requirements, an early warning system, and implementing regulations.

Regarding monitoring and protecting HGR, as delineated in MgmtHumanGen, NHC (formerly the MOST) is also authorized to strengthen the protection of HGR in China, which involves conducting surveys and implementing a declaration and registration system for important genetic families and human genetic resources in specific regions. MOST (now the NHC) will enforce the regulations and levy fines for illegal HGR activities which include:

• Collecting HGR from important genetic families and specific regions in China without approval, or collecting HGR of the types and quantities specified by MOST (now the NHC) through special regulation
• Preserving Chinese HGR without approval
• Conducting international cooperative scientific research using Chinese HGR without approval
• Failing to pass the security review that may affect China's public health, national security, and social public interest to foreign organizations, individuals, and institutions that they establish or actually control, and
• Failing to file with MOST (now the NHC) the type, quantity, and use of the HGR in China before an international cooperative clinical trial begins

Other Considerations

Per CHN-59, China is a regulatory member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). CHN-49 summarizes the ICH guiding principles and provides Chinese translations, when available.

Please note: China is party to the Nagoya Protocol on Access and Benefit-sharing (CHN-30), which may have implications for studies of investigational products developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see CHN-55.

Contact Information

National Medical Products Administration (NMPA)

Per CHN-31, the following is the NMPA’s contact information:

National Medical Products Administration
No. 1 Beiluyuan Zhanlan Road
Xicheng District
Beijing 100037
P.R. China

Per CDE-Reloctn, the following is CDE’s contact information:

National Medical Products Administration
Center for Drug Evaluation
Building 1-5
District 2, No. 22 Guangde Street
Beijing Economic and Technological Development Zone
Beijing, 100076
P.R. China

Phone number: 010-68585566

National Health Commission

Per HGR-WorkUpdt, HGR-AppGuide, and CHN-4, following is the contact information for NHC’s HGR consultation:

National Health Commission
China Biotechnology Development Center
Rooms 1022 and 1001, Building 4
No. 16 West Fourth Ring Middle Road
Haidian District
Beijing, 100036
P.R. China

Contact: Zhu Min
Phone number: 010-88225151 or 010-88225168
Information system support: 17610386080
Email: ycb@cncbd.org.cn

Medicines and Healthcare Products Regulatory Agency

As per the MHCTR and the MHCTR2006, the Medicines and Healthcare Products Regulatory Agency (MHRA) is the regulatory authority responsible for clinical trial approvals, oversight, and inspections in the United Kingdom (UK). The MHRA grants permission for clinical trials to be conducted in the UK in accordance with the MHCTR and the MHCTR2006.

According to GBR-57, the MHRA is an executive agency within the Department of Health and Social Care (DHSC). MHRA’s responsibilities are to:

• Ensure that medicines, medical devices, and blood components for transfusion meet applicable standards of safety, quality, and efficacy
• Ensure that the supply chain for medicines, medical devices, and blood components is safe and secure
• Promote international standardization and harmonization to assure the effectiveness and safety of biological medicines
• Help to educate the public and healthcare professionals about the risks and benefits of medicines, medical devices, and blood components
• Support innovation and research and development that is beneficial to public health
• Influence UK and international regulatory frameworks so that they are risk-proportionate and effective at protecting public health

Per the G-CTAuth-GBR, the agency’s Clinical Trials Unit (CTU) focuses specifically on reviewing applications to conduct clinical trials of medicinal products. For a listing of MHRA services and information, see GBR-36.

G-ATMP states that MHRA is also the competent authority for advanced therapy medicinal products (ATMPs) and for UK manufacturers or importers of ATMPs. An ATMP is a medicinal product which is either a gene therapy medicinal product, a somatic cell therapy medicinal product, or a tissue engineered product.

Pursuant to the MMDAct, the Secretary of State for DHSC is authorized to make clinical trials regulations and amend or supplement the law relating to human medicines, taking into consideration the safety of human medicines, the availability of human medicines, and the likelihood of the UK being seen as a favorable place to carry out research relating to human medicines, conduct clinical trials, or manufacture or supply human medicines.

Please note: The UK is party to the Nagoya Protocol on Access and Benefit-sharing (GBR-5), which may have implications for studies of investigational products developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see GBR-48.

Contact Information

Per GBR-58, the following is the MHRA’s contact information:

Medicines and Healthcare Products Regulatory Agency
10 South Colonnade
Canary Wharf
LONDON
E14 4PU
UK

Main Phone: +44 020 3080 6000
Fax: +44 0203 118 9803
General Email: info@mhra.gov.uk
Data Protection Email: DataProtection@mhra.gov.uk
Importing Investigational Medical Products from Approval Countries Email: for queries, complete this contact form and email to gmpinspectorate@mhra.gov.uk

Clinical Trials of Medicines:
Email: clintrialhelpline@mhra.gov.uk
Phone: +44 020 3080 6456

In addition, the G-CTAuth-GBR includes other email addresses for specific purposes related to submissions.

Overview

National Medical Products Administration

In accordance with the DRR, the DAL, the NMPA-No50-2018, the SC-Opinions-No44, and the NMPA-No230-2015, the National Medical Products Administration (NMPA) is responsible for reviewing and approving clinical trial applications for drugs to be registered in China, as required. The DRR clarifies that the NMPA regulates clinical trials for drugs in development that are ultimately seeking market approvals in China. Per the DAL and the DRR, and as explained in CHN-7, CHN-18, and CHN-1, China adopted a drug marketing authorization holders (MAHs) system across China. All entities or drug research institutions holding drug marketing authorizations must take responsibility for drug safety, effectiveness, and quality controllability in the whole process of drug research and development, production, distribution, and use. Based on this system, the MAHs are also named as applicants or sponsors during clinical trials. The scope of the NMPA’s assessment includes Phase I through Phase IV clinical trials and bioequivalence studies. As stated in the DRR, clinical trials of drugs must be reviewed and approved by an ethics committee (EC). The DRR indicates that EC review may be submitted in parallel to NMPA’s review, but the study cannot be initiated until after review and approval by the EC. The DRR emphasizes a risk-based approach to drug registration and clinical trial approvals, following the principles of openness, fairness, and justice. This is guided by demonstrating clinical value, encouraging research and creation of new drugs, and promoting the development of generic drugs.

As delineated in the DRR, the SC-Opinions-No44, and the NMPA-No51-2016, the drug classification in which an applicant chooses to register determines the clinical trial application review and approval process. Per the DRR, the registration of drugs must be classified and managed in accordance with three (3) broad categories of Chinese medicines, chemical medicines, and biological products. The NMPA-No44-2020 and CHN-1 delineate the classifications within the chemical medicine category as follows:

• Class 1: Innovative drugs that have not been marketed in China or overseas (i.e., drugs that contain new compounds with clear structures and pharmacological effects, and have clinical values)
• Class 2: Modified new drugs that have not been marketed in China or overseas (i.e., drugs that have their structure, dosage form, formulation, process, route of administration, and indications optimized on the basis of known active ingredients and have significant clinical advantages)
• Class 3: Drugs manufactured by domestic applicants by imitating the original drugs that have been marketed overseas but not yet in China; such drugs must have the quality and efficacy consistent with the reference listed drug
• Class 4: Drugs manufactured by domestic applicants by imitating the original drugs that have been marketed in China; such drugs must have the quality and efficacy consistent with the reference formulations
• Class 5: Drugs that have been marketed overseas and are under application for being marketed in China

As per NMPA-No21-2021, the NMPA provides additional technical support to expedite the review and approval process of domestically unlisted drugs that have been listed overseas in the above Classes 3 and 5.

Per the DRR, the registration of biological products is classified according to innovative biological products, new medicines of improved biological products, and already listed biological products (including biological similar drugs). As delineated in the NMPA-No43-2020, biological products refer to preparations that use microorganisms, cells, animal or human-derived tissues, and bodily fluids as starting materials, and are made with biological technology for the prevention, treatment, and diagnosis of human diseases. In order to standardize the registration and management of biological products, biological products are divided into preventive biological products, therapeutic biological products, and in vitro diagnostic reagents managed by biological products. Preventive biological products refer to vaccine-like biological products used for human immunization to prevent and control the occurrence and prevalence of diseases, including immunization program vaccines and non-immunization program vaccines. Therapeutic biological products refer to biological products used in the treatment of human diseases, such as proteins, polypeptides and their derivatives prepared from engineered cells (such as bacteria, yeast, insect, plant, and mammalian cells) with different expression systems; cell therapy and gene therapy products; allergen products; microecological products; biologically active products extracted from human or animal tissues or bodily fluids or prepared by fermentation, etc. The following are descriptions of biological product classifications for both preventive and therapeutic uses:

• Class 1: Innovative vaccines that have not been marketed at home or abroad
• Class 2: Improved vaccines that improve the safety, effectiveness, and quality controllability of new products by improving the domestic or overseas marketed vaccine products, and have obvious advantages
• Class 3: Vaccines that have been marketed at home or abroad

Per the VaccineLaw, the NMPA must approve vaccine clinical trials. The NMPA-No32-2019 explains that the VaccineLaw strengthens the supervision and enforcement of vaccines and deepens the reform of the drug review and approval system. This includes strengthening the management of vaccine clinical trial institutions and investigating and punishing illegal activities related to applying for vaccine clinical trials (e.g., false data).

National Health Commission

Per the NHC-HGRmgt, the National Health Commission (NHC) is responsible for China’s management of human genetic resources (HGR). (Note that per SC-Order777 and NHC-HGRmgt, management of HGR was transferred from the Ministry of Science and Technology (MOST) to NHC, effective May 1, 2024. SC-Order777 amends the MgmtHumanGen to reflect the transfer of HGR management from MOST to NHC, but the Bioscrty-Law and the Rules-MgmtHGR have not been amended yet to show the transfer). Per the Bioscrty-Law and the MgmtHumanGen, MOST’s (now the NHC’s) scope of assessment is the collection, preservation, utilization, and external provision of HGR to ensure these activities:

• Do not endanger the public health, national security, and social public interests of China
• Are in accordance with ethics principles and reviews per relevant regulations
• Respect the privacy rights of HGR donors, obtain their prior informed consent, and protect their legitimate rights and interests, and
• Comply with the technical norms formulated by MOST (now the NHC)

See the Rules-MgmtHGR for the prescribed conditions when MOST (now the NHC) licenses must be obtained for the collection of Chinese HGR.

As delineated in the Rules-MgmtHGR, MOST (NHC) licenses must be obtained for the preservation of HGR, which involves storing HGR with legal sources under appropriate environmental conditions, ensuring their quality and safety, and using them for future scientific research, excluding temporary storage for teaching purposes. If the preservation also involves the collection of HGR, applicants only need to apply for an administrative license for the preservation of HGR, and do not need to separately apply for a collection license. Next, the Rules-MgmtHGR require administrative licenses for international scientific research cooperation that use and export HGR. If there is no export, only prior filing/notification with MOST (now the NHC) is required before initiating the international research cooperation.

Per the Rules-MgmtHGR, where multicenter clinical research is carried out, the sponsor or the primary site/unit (either the Chinese unit or a foreign party unit) may apply for administrative licensing or filing after the primary site/unit passes the ethics review. After the sponsor or primary site/unit obtains the administrative license or completes the filing, the medical and health institution(s) participating in the clinical research must submit the ethics review approval document of their site/unit, or the certification materials for the ethics review approval provided by the primary site/unit, along with the letter of commitment issued by the site/unit, to MOST (now the NHC). Following those submissions, the international cooperative clinical research can be carried out.

As delineated in the HGR-AppGuide, the scope of the administrative license for the collection of HGR applies to the following activities to be carried out within the territory of China:

• HGR collection activities for important genetic pedigrees – applies to blood-related groups with genetic diseases and/or with special hereditary physical or physiological characteristics, as well as the members of the group with genetic diseases and/or special hereditary physical or physiological characteristics involving three (3) generations or more.
• HGR collection activities in specific areas – applies to HGR from populations who have lived in isolation or special environments for a long time and have special physical characteristics or adaptive traits in physiological characteristics. Specific areas are not divided based on whether they are ethnic minority concentrated areas.
• HGR collection activities for large-scale population research with a population of more than 3,000 – includes but is not limited to cohort studies, cross-sectional studies, clinical studies, and constitutional studies.

Clinical Trial Review Process

National Medical Products Administration

As delineated in the DRR, the NMPA is the regulatory authority responsible for national drug registration management, which includes management of clinical trial applications. The NMPA’s Center for Drug Evaluation (CDE) is responsible for evaluating drug clinical trial applications, drug marketing authorization applications, supplementary applications, and re-registration applications for drugs produced overseas. The DRR states that applicants may communicate with major technical institutions including the CDE at key stages, such as before submitting a drug clinical trial application.

Communications and Pre-Application Protocol Review

Per the NMPA-No50-2018, the NMPA-No48-2020, and the NMPA-No51-2023, with regard to chemical drugs and biological products, the applicant must first request a communication meeting with the CDE to determine the integrity of the clinical trial application data and the feasibility of conducting the clinical trial. The NMPA-No51-2023 reaffirms the required communications between the applicant and the CDE and review of the clinical trial protocol before submitting the clinical trial application. The CDE conducts a preliminary review of the information provided by the applicant according to relevant requirements. The review team reviews the science, completeness, operability, and risk controllability of the clinical trial protocol, focusing on the basis for the research, safety, and whether the risk management measures of the drug support the conduct of clinical trials. In addition to clearly responding to the specific questions raised by the applicant, the submitted clinical trial protocol is reviewed to ensure participant protection. For confirmatory, or critical clinical trials, CDE must also evaluate the suitability of the target population, the science of the dosage and cycle and the primary endpoint indicators, the acceptability of statistical assumptions, the rationality of sample size estimation, the operability of the risk management plan, and the benefit/risk assessment elements. CDE’s review team communicates its findings by holding a meeting (face-to-face or online) or by giving a written reply and must provide the applicant with the minutes of the communication meeting or the written reply. See NMPA-No51-2023 for additional details on the pre-application communications and protocol review.

Clinical Trial Application Review

Per the NMPA-No50-2018, the NMPA’s Drug Registration Management Department is responsible for conducting administrative reviews of clinical trial applications, and then forwarding the submissions to the CDE for technical review. (Deviations from this general process are described further below in this section.) The DRR states that after completing the pharmacology, toxicology, and other studies supporting the clinical trials of the drug, the applicant must submit relevant research materials in accordance with the application requirements (See Submission Process and Submission Content sections for details). If the application materials meet the screening requirements, NMPA’s pharmaceutical, medical, and other technical personnel review the clinical trial applications for drugs.

Per the DRR, when reviewing the application, the CDE will conduct an associated review of the chemical raw materials, auxiliary materials, and packaging materials and containers used in direct contact with the pharmaceutical preparations. The CDE makes a risk-based decision on whether to initiate an on-site inspection based on the registered varieties, processes, facilities, and previous acceptance verification. For innovative drugs, improved new drugs, and biological products, on-site verification of drug registration manufacturing and inspection of pre-market drug manufacturing quality management must be conducted. If manufacturing verification is required, the applicant and the drug regulatory department of the province, autonomous region, or municipality directly under the Central Government where the applicant or manufacturer is located will be informed. The National Institutes for Food and Drug Control (NIFDC) (also referred to as the Procuratorate), or the drug inspection agency designated by the NMPA, will conduct the inspections and testing, as needed. The drug registration inspection of overseas-produced drugs must be implemented by the port drug inspection agency.

The NMPA-No51-2023 specifies that the CDE review team must evaluate the science, completeness, operability, and risk controllability of the clinical trial protocol in the application. If necessary, an expert consultation meeting may be held. For clinical trials that are approved after review, the technical review team’s conclusion and associated "Clinical Trial Approval Notice" must clearly state the indications, clinical trial protocol title, number, version number, version date, etc. The review team’s conclusion and notice may propose revisions or suggestions to the clinical trial protocol if necessary. For clinical trial protocols that require revisions, CDE will notify the applicant through a professional inquiry letter, clearly informing the applicant of the problems and revision opinions in the current protocol. The applicant must submit a revised clinical trial protocol within five (5) days, following the guidance in the Prcdrs-Changes. For clinical trial protocols that are deemed unfeasible, have participant safety risks, or other serious defects, and the applicant cannot revise and improve them within the time limit specified in the inquiry letter, the clinical trial application will not be approved. In the review team’s conclusion and the "Notice of Disapproval of Drug Clinical Trials", the applicant should be clearly informed of the reasons for the disapproval.

The NMPA-No51-2023 also states that before conducting subsequent phased drug exploratory clinical trials, a corresponding drug clinical trial protocol must be reviewed and approved by the EC. After completing exploratory clinical trials and before conducting confirmatory (or critical) clinical trials, an application for a communication meeting must be submitted to the CDE to evaluate the subsequent clinical trial protocol (if applicable).

With regard to vaccine clinical trials, the VaccineLaw indicates that the NMPA will review the clinical trial plan, the safety monitoring and evaluation system, the selection of participants, and whether there are effective measures according to the degree of risk to protect the legal rights of the participants. Vaccine clinical trials can only be carried out or organized by a tertiary medical institution that meets the conditions prescribed by the NMPA and the health and safety department of the State Council, or a disease prevention and control institution at or above the provincial level.

Per the DRR, the DAL, the NMPA-No50-2018, and CHN-14, a clinical trial application will be considered approved after 60 working days if the applicant does not receive a rejection or an inquiry for clarification from the NMPA. As specified in the DRR, drug clinical trials must be carried out within three (3) years after approval. If the drug clinical trial application is approved and no participant signs an informed consent form within three (3) years from the date of approval, the approval lapses. If it is still necessary to carry out the drug clinical trial, the applicant must re-apply. Upon approval/registration of the drug, the applicant receives a drug registration certificate, which is valid for five (5) years. An application for drug re-registration must be submitted six (6) months before the validity period expires.

The DRR states that to amend content in the original drug registration approval, the applicant must conduct sufficient research and verification on the change of the drug and fully evaluate the possible impact of the change on the drug. Data on the impact of safety, efficacy, and quality control must be submitted with the application for amendment. The NMPA-No51-2023 indicates that when changes to a clinical trial protocol are needed, the sponsor may first conduct a self-assessment of the changes in accordance with the relevant requirements of the DRR and the NMPA-No34-2022, and implement further work based on the results of the self-assessment. For substantial changes, the sponsor must submit materials in accordance with the relevant requirements of the NMPA-No34-2022. The CDE review team must review the supplementary application and notify the applicant of whether any/all of the proposed changes are approved. For changes that are not approved, CDE must clearly state the reasons. See NMPA-No51-2023 for definitions of substantial and non-substantial changes to a protocol. Also see Prcdrs-Changes for working procedures for other changes during the review of the clinical trial application.

Expedited Clinical Trial Review

The DRR authorizes regulatory pathways for priority review and approval (including for breakthrough therapeutic drugs), conditional approval, and special approval procedures. As per the SC-Opinions-No44, the NMPA-No230-2015, and the NMPA-No51-2016, a new drug classification system, priority review for innovative drugs and those deemed to have an urgent clinical need, and other changes help China to be more innovative and expedite reviews. With regard to priority review, per the NMPA-No230-2015 and the DRR, the NMPA may apply expedited review and approval procedures to applications for urgently needed drugs and vaccines that are intended to treat certain illnesses or patient populations (e.g., children or elderly people) that the State Council or the NMPA consider to be clinically in demand. The DRR expanded priority review to breakthrough therapeutic drugs, which are used to prevent and treat diseases with the following conditions: are seriously life threatening or seriously affect the quality of life, there are no effective prevention or treatment methods, and there is sufficient evidence to show that they have obvious clinical advantages. Applicants must apply to the CDE at the critical stage of the drug clinical trial. See CHN-69 for handling guidelines on priority review and approval.

The NMPA-No21-2024 describes NMPA’s pilot work plan for optimizing the review and approval of clinical trials for innovative drugs. This initiative aims to review and approve innovative drug clinical trial applications within 30 business days (a reduction from the 60 days as described above in the normal procedures). Pilot projects will be carried out in provinces (autonomous regions and municipalities) that meet the conditions laid out in NMPA-No21-2024. The scope of the pilot project is clinical trial applications for Class 1 innovative drugs (excluding cell and gene therapy products, vaccine products, etc.). Applicants are not subject to regional restrictions and must have at least three (3) innovative drug clinical trial applications approved at home and abroad, have extensive experience in clinical trial implementation and pharmacovigilance management, and be able to conduct a comprehensive risk assessment of clinical trial projects and develop an effective risk management plan before submitting a clinical trial application. In principle, the pilot institution must be a national medical center or national clinical medical research center in the pilot area and must have established a work system to provide clinical trial project establishment, ethics review, and contract review services before the applicant submits a new drug clinical trial application. See NMPA-No21-2024 for additional requirements on application submission and applicant and institutional eligibility. The applicant must initiate the clinical trial within 12 weeks after the approval of the clinical trial application. The pilot work will last for one (1) year and the experience of the pilot work will be summarized in July 2025. One (1) pilot project has been approved in Beijing and Shanghai as indicated in NMPA-No55-2024.

According to the NMPA-No82-2020, the NMPA establishes working procedures for the review of breakthrough therapy drugs, conditional approval of drug marketing priority review, and approval of drug marketing authorization. Sponsors can apply for expedited status for breakthrough therapeutic drugs in Phase I and II clinical trials—usually no later than before the commencement of Phase III clinical trials. Breakthrough drug procedures are designed to be used during clinical trials of drugs to prevent and treat patients with conditions that may be severely life-threatening or that may severely affect their quality of life. There are also no existing effective prevention and treatment methods nor is there sufficient evidence to show that the investigational drugs being tested have obvious clinical advantages compared with existing treatment methods. Also see CondtlAppl-Drugs for technical guidelines on the conditional approval of drugs for marketing.

Per the NMPA-No79-2018, the NMPA established a special review channel for urgently needed drugs that were already on the market in the United States, Europe, and Japan since 2008. Applicants may apply for a drug listing and proceed to conduct the clinical trials while the CDE conducts a technical review of the application materials.

The DRR also authorizes the CDE to conditionally approve breakthrough therapeutic drugs for marketing during clinical trials and vaccines that are urgently needed for major public health emergencies and the benefits outweigh the risks. The applicant must communicate to the CDE on the conditions for marketing with conditional approval and the research work to be completed after marketing, and submit an application for drug marketing approval after communication and confirmation. For the conditionally approved drugs and vaccines, risk management measures must be implemented after the drug is marketed, and the drug clinical trial must be completed within the prescribed time limit. Finally, the DRR authorizes the NMPA to implement special approval procedures for drugs required for public health emergencies. The circumstances, procedures, time limits, and requirements for special approval, will be subject to the NMPA’s procedures for specific approval of drugs.

For background on China’s reformation of the review and approval system to encourage innovation of drugs, see the SC-Opinions-No42. China’s regulatory pathways for expedited approvals and other reforms to the clinical trial submission and review process are described in the Submission Process and Submission Content sections. NMPA-No52-2018-Interp describes the requirements for clinical trial and drug registration applications using trial data generated entirely overseas, as well as data generated from simultaneous research occurring in China and abroad. CHN-11 also provides useful information on the NMPA’s overall clinical trial application review and approval process.

Overseas Data and Waiving Local Clinical Trials

The NMPA-No35-2017 and interpretations in NMPA-No52-2018-Interp describe requirements for clinical trial and drug registration applications to the NMPA using trial data generated entirely overseas, as well as data generated from simultaneous research occurring in China and abroad. With regard to the latter, researchers can conduct Phase I of multi-regional clinical trials (MRCT) of imported investigational new drugs and therapeutic biological products (excluding vaccines) simultaneously in China.

As per NMPA-No52-2018, clinical trial and drug registration applications for imported new drugs or therapeutic biological products using trial data generated entirely overseas do not need to be registered first in their own country in order to enter China. Overseas clinical trial data is acceptable for direct China registration provided that:

• The data is reliable, authenticated, and complies with the requirements of the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CHN-37)
• The data can assess the efficacy and safety for the target indication
• There are no ethnic sensitivities to Chinese local populations influencing efficacy and safety
• The data meets China’s drug registration requirements

See the NMPA-No52-2018 for additional details on the review and approval of overseas clinical trial data. For overseas clinical trial data completed before the enactment of NMPA-No35-2017, the NMPA will consider exemption from conducting local clinical trials, with the condition that the applications meet all other Chinese drug regulatory requirements.

For a running list (in reverse chronological order) of NMPA guidance on drug regulatory requirements, please refer to CHN-60.

National Health Commission

The MgmtHumanGen and the Bioscrty-Law prohibit foreign entities or individuals from collecting or preserving Chinese HGR in China, or providing Chinese HGR for use abroad, except under prescribed conditions to carry out scientific research activities, which must be conducted through collaboration with Chinese scientific research institutions, higher education institutions, medical institutions, or enterprises. Per the MgmtHumanGen and the Rules-MgmtHGR, the foreign entity and the Chinese entity must jointly file an application for approval to MOST (now the NHC), and the research must pass an ethics review in the countries (regions) where the partners are located. The only exception to the approval requirement is international collaborations in clinical trials that do not involve the export of Chinese HGR materials such as organs, tissues, or cells comprising the human genome, genes, or other genetic substances. Such clinical trial collaborations, however, must be filed with MOST (now the NHC) on its online platform (CHN-6), which will generate a record number. See HGR-InfoSys for background on CHN-6. Per HGR-InfoSys, for help with the online platform, contact Zhu Min with the NHC’s China Biotechnology Development Center at 010-88225151 or 010-88225168; or the information system support at 17610386080.

Per the HGR-AppGuide, following administrative screening, the NHC will confirm receipt through CHN-6 and organize a technical review. NHC must conduct its review and issue a decision within 20 working days. If the application is approved, NHC notifies the applicant of the approval through CHN-6 and a letter. If there are missing materials, NHC gives the applicant a one-time opportunity to correct the application and resubmit. If the application exceeds the scope of the license, NHC informs the applicant that the application is not approved.

The Bioscrty-Law prohibits engaging in biotechnology research, development, and application activities that endanger public health, damage biological resources, or destroy ecosystems and biodiversity. Units engaged in biotechnology clinical trials must be responsible for the safety of their biotechnology research, development, and application; adopt biosafety risk prevention and control measures; and formulate biosafety training, follow-up inspections, regular reports, etc. China is implementing a classified management system for biotechnology research and development activities into three (3) categories: high-risk, medium-risk, and low-risk. The risk classification standards are to be formulated, adjusted, and announced by the competent State Council departments for science and technology (now the NHC), health, agriculture, and rural areas. High-risk and medium-risk biotechnology research and development activities must include risk assessments and risk prevention/control and emergency plans for biosafety incidents. The Rules-MgmtHGR also states that clinical trial applications must pass a security review organized by MOST (now the NHC) if the study’s provision or opening of HGR information to foreign entities may impact China’s public health, national security, or the social public interest.

For additional details, see the HGR-FAQs for frequently asked questions on HGR applications. Also see the Submission Process and Submission Content sections and the Specimens topic for additional information on HGR regulatory management.

Overview

In accordance with the MHCTR and the MHCTR2006, the Medicines and Healthcare Products Regulatory Agency (MHRA) is responsible for reviewing, evaluating, and approving applications for clinical trials using registered or unregistered investigational products (IPs). (Note: IPs are known as investigational medicinal products (IMPs) in the United Kingdom (UK)). The G-CTApp specifies that the scope of the MHRA’s assessment includes all clinical trials (Phases 1-4). Per G-CTApp and G-IRASCombRev, all new clinical trial applications must be prepared, submitted, and reviewed via the combined review process, which offers a single application route and parallel/coordinated review from MHRA and the ethics committee (EC) leading to a single UK decision for clinical trials.

Regarding licensing of biosimilars (i.e., generic biotech medicines), see the G-Biosimilars for details on the UK’s recent regulatory changes to ease or remove clinical trial requirements for the MHRA’s review and approval of biosimilars.

Clinical Trial Review Process

Per GBR-72, under combined review, research teams make a single application using a new part (GBR-125) of the Integrated Research Application System (IRAS) (GBR-78), which goes to both the MHRA and an EC at the same time. The regulatory and ethics reviews are done in parallel and any requests for further information are raised jointly. A single response to these requests leads to a single decision from both reviews. The G-CTApp states that the initial combined review assessment will be completed within 30 days of application submission. Applications for healthy volunteer trials and sponsor-determined phase 1 trials in non-oncology participants may qualify for a shortened assessment time and the MHRA will work with the EC to expedite these applications. When applications need expert advice, the MHRA will seek advice from the Clinical Trials, Biologicals and Vaccines Expert Advisory Group (CTBV EAG) of the Commission on Human Medicines (CHM). In addition, the CHM will then discuss the trial at their meeting, which will take place later in the same week as the CTBV EAG meeting. See the G-CTApp for examples of which trials require expert advice and for detailed requirements. The MHRA also supports the conduct of trials with complex innovative designs such as umbrella, basket, platform, and master protocol plus submodules. These trial designs are characterized by the presence of prospective major adaptations, such as the addition of new IPs or introducing new trial populations. Before submitting a clinical trial application with a complex innovative design and/or an amendment requesting approval of major adaptations, sponsors are recommended to establish a dialogue with the MHRA and seek advice.

The G-CTApp states that under the combined review process, the MHRA will inform applicants of the outcome of the submission along with the EC’s review and decision. The outcomes could be one (1) of the following:

• Acceptance of the request for a clinical trial authorization
• Acceptance of the request for a clinical trial authorization subject to conditions
• Grounds for non-acceptance of the request for a clinical trial authorization

As indicated in the G-CTApp, with respect to grounds for non-acceptance, applicants will have the opportunity to respond, usually within 14 days; however, this may be extended on request. A communication informing the applicant of the combined MHRA and EC decision will usually be sent within 60 days of receiving the original valid application. If an extension to the response date has been agreed to, then this will impact the final decision timeline. Notification of a decision relating to a gene therapy product, somatic cell therapy (including xenogenic cell therapy) product, tissue engineered product, or products containing genetically modified organisms will be sent within 90 days of receiving the original application, unless otherwise advised. Communications will be sent electronically via email from MHRA_CT_Ecomms@mhra.gov.uk. The MHRA will only send official correspondence to the named applicant email address. According to the MHCTR, if the sponsor or the designated representative does not receive a request for additional information from the MHRA within 30 days, the application is considered authorized. (See the Timeline of Review section for additional details.)

Per GBR-9, the EC’s ethical opinion applies for the duration of the study, which was stated in the clinical trial application and protocol. An extension of the study period is not in itself a substantial amendment, except where it is related to other amendments that would be substantial, such as an increase in target recruitment, addition of new procedures or sub-studies, or extension of follow-up. Where the duration of the study is to be extended beyond the period specified in the application form, the EC should be notified.

IRAS (GBR-78) is a single system for applying for the permissions and approvals for health and social care/community care research in the UK. It generates the IRAS ID and uses filters to ensure that the data collected and collated is appropriate to the type of study, and consequently the permissions and approvals required. The system helps applicants meet the regulatory and governance requirements. As described in GBR-67, approval from the Health Research Authority (HRA) is required for all National Health Service (NHS) project-based research led from England or Wales. HRA and Health and Care Research Wales (HCRW) approval brings together the assessment of governance and legal compliance. For any new studies led from Scotland or Northern Ireland but have English and/or Welsh NHS sites, the national research and development coordinating function of the lead nation will share information with the HRA and HCRW assessment teams, who can issue HRA and HCRW approval for English and Welsh sites and thereby retain existing compatibility arrangements. Studies led from England or Wales with sites in Northern Ireland or Scotland will be supported through existing UK-wide compatibility systems, by which each country accepts the centralized assurances, as far as they apply, from national coordinating functions without unnecessary duplication. For details on HRA’s assessment criteria and standards for approval, see GBR-29.

UK-wide Research

The UKwide-Rsrch specifies that the four (4) UK nations take a consistent approach to study-wide reviews with one (1) application for all relevant UK sites. Each UK nation will take assurances from the study-wide review conducted by the lead nation (the nation conducting the initial review). The following outlines key differences in approvals from UK nations:

• England and Wales – For any research taking place in England and/or Wales, the sponsor will receive an HRA and HCRW approval letter, which will detail any further requirements before beginning the research
• Northern Ireland – Each participating Northern Ireland Health and Social Care body will confirm their capacity and capability after the relevant study-wide reviews and participating site assessments and arrangements are complete
• Scotland – For any research taking place in Scotland, the sponsor will receive Research & Development permission after the relevant study-wide reviews and site assessments and arrangements are complete

Notification Scheme

Per the G-CTApp, MHRA’s notification scheme enables a more streamlined and risk-proportionate approach to processing clinical trial authorization for “initial” applications. The scheme only applies to clinical trial applications for Phase 4 and certain Phase 3 clinical trials deemed to be of lower risk. Interest in the notification scheme should be registered via the combined review process described above (GBR-125). MHRA acceptance of an application under the notification scheme will be confirmed within 14 calendar days from the application received effective date and authorization by the MHRA will be granted unless any criterion is not suitably met. If the MHRA determines the application does not meet the notification scheme criteria, an objection decision will be communicated within 14 calendar days from the application received effective date, and the application will continue under full clinical trial assessment with a decision communicated within the 30-day statutory timeframe.

As indicated in the G-CTApp, the notification scheme acceptance criteria are as follows:

Phase 4 trials must meet both of the following criteria:

• All IPs are licensed and used according to the relevant UK, United States of America (USA), or European Union (EU) marketing authorization (except for placebo)
• There are no ongoing safety concerns with the IP(s) that the sponsor is aware of, for example other trials on temporary halt/clinical hold, other trials with unresolved urgent safety measures or post-marketing regulatory restrictions

Phase 3 trials must meet at least one (1) of the following criteria:

• The trial is already approved in the USA or EU based on the same protocol and Investigator’s Brochure (IB) versions submitted to MHRA, and for EU approvals, the same version of the IP dossier. For trials approved in the USA only, the IP dossier submitted to the MHRA must document the same IP manufacturing process
• The MHRA has approved in the last two (2) years a previous Phase 3 clinical trial of the IP(s) at the same dose (or a higher dose), dosing frequency (or a higher frequency) and route of administration, and for the same indication (even if the trial was with a different sponsor) and utilizing the same manufacturing process
• IPs are licensed and used according to the relevant UK, USA, or EU marketing authorization (except for placebo)

In addition, the G-CTApp states that to be eligible for the scheme, a Phase 3 trial must not include any of the following:

• Complex, innovative trial design (e.g., basket, umbrella, and platform) that allows for prospective major adaptations such as the addition of indications or IPs via future amendments
• Includes pediatric participants
• Includes pregnant or breastfeeding participants
• IP is first in class
• IP is an advanced therapy medicinal product (ATMP)

Brexit Background

Per the G-MHRASubmiss, Brexit, the EUCouncil-Brexit, the WithdrlAgrmt, and the G-AfterTransition, the UK withdrew from the EU on January 31, 2020. The MHRA updated and published clinical trials guidance that became effective on January 1, 2021. G-AfterTransition summarizes the guidance to sponsors and researchers. Furthermore, the G-MHRASubmiss describes how to make certain regulatory submissions to the MHRA (substantial amendments, end-of-trial notifications, and developmental safety update reports (DSURs)). Per the MHCTR-EUExit and as explained in GBR-115, the new guidance went into force via the MHCTR-EUExit (also known as the “Exit Regulations”). The Exit Regulations also update existing UK legislation by, for example, replacing references to EU databases with newly established UK databases. The G-IPsNIreland delineates that the supply and use of IPs in Northern Ireland must follow EU laws as per the Northern Ireland Protocol. For policy papers and details on the Northern Ireland Protocol, see GBR-119. For broader information and a comprehensive Brexit “checker” of new rules in the UK, see GBR-60.

To help ensure the continuity of supply of IPs for clinical trials the BrexitLtr-IPs indicates that the UK will unilaterally recognize certain EU regulatory processes for a time-limited period. This recognition is known as “standstill.”

GBR-115 indicates that the UK is committed to being as aligned as possible with the EU Clinical Trials Regulation (GBR-21). The MMDAct grants authority for regulations to be made that correspond or are similar to GBR-21. For more information about GBR-21, see GBR-54.

National Medical Products Administration

In accordance with the DRR, the applicant is required to pay a fee after the drug registration is approved by the National Medical Products Administration (NMPA). As per the NMPA-No75-2020 and CHN-14, the NMPA charges the following drug registration fees to review and approve clinical trials as part of the drug registration process (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• New drugs made in China: 192,000 Yuan
• New drugs made outside China: 376,000 Yuan
• Generic drugs made in China: 318,000 Yuan
• Generic drugs made outside China: 502,000 Yuan
• One-time import of drugs: 2,000 Yuan

As specified in NMPA-No75-2020 and CHN-14, the fees are based on one (1) active pharmaceutical ingredient or one (1) preparation as one (1) variety. If another specification is added, the registration fee will be increased by 20% according to the corresponding category.

For further guidance on fees associated with submitting supplementary applications and registering renewals for imported drugs and more, please refer to NMPA-No75-2020.

Payment Instructions

NMPA-No37-2022 indicates that to register a drug, the applicant should submit the drug registration application to NMPA’s Government Service Portal (CHN-71). The relevant center will conduct an administrative review. Next, the non-tax income collection management system of the Ministry of Finance will send an electronic payment code to the applicant in the form of a text message. The applicant can pay through the counter payment, self-service terminal, online payment, self-service POS card, bank exchange, or transfer and payment. The applicant will receive confirmation of electronic payment via email within 10 working days. Electronic payment documents have the same legal effect as paper instruments.

National Health Commission

Per HGR-AppGuide, the National Health Commission (NHC) does not charge a fee for an application for a human genetic resources (HGR) license in China.

Medicines and Healthcare Products Regulatory Agency

As per the MHCTR, the MHCTR2006, and the G-CTApp, the sponsor or the designated representative is responsible for paying a fee to the Medicines and Healthcare Products Regulatory Agency (MHRA) to submit a clinical trial application for authorization. According to the G-MHRAPaymt, applicants will receive an invoice to make a payment for the outstanding amount after validation of the application. Applicants must pay invoices upon receipt or they will incur penalty fees. Non-payment may also result in suspension of any license or authorization, followed by legal proceedings for any unpaid amounts.

As delineated in the G-MHRAFees, the MHRA levies the following clinical trial processing fees:

• 3,366 British Pounds – Applications with an Investigational Medicinal Product (IMP) dossier (higher fee for phase 1, full and simplified IMP dossier)
• 248 British Pounds – Applications without an IMP dossier (lower fee for phase IV, cross referral, additional protocol)
• 248 British Pounds – Clinical trial variation/amendment
• No cost – Phase 4 notification
• 248 British Pounds – Assessment of annual safety reports

Note per the G-MHRAFees, there is no annual clinical trials fee and no fee for Phase IV notifications. For a cross-referral or additional protocol submission, no new IMP dossier or investigators brochure data should be provided; however, copies of the relevant manufacturer’s authorization(s) and qualified person declaration (if applicable) should be provided since these are study specific.

Per the G-CTAuth-GBR, the fees for the annual safety reports are applicable to annual progress reports and Development Safety Update Reports (DSURs). From June 1, 2024, MHRA will only accept online payment of this fee via MHRA’s payments service (GBR-26) prior to submission of an annual safety report. Receipts generated will be sent by email and must be included in the report submission as proof of payment. Failure to provide evidence of payment will result in the submission being made invalid.

The G-CTApp further indicates that no fees are required for applications submitted and authorized under the Notification Scheme.

Payment Instructions

According to the G-MHRAPaymt, the MHRA does not accept checks. Payments can be made electronically by bank transfer, credit card, or debit card. The relevant invoice and customer number should be quoted when making payments. Bank transfers should be sent to:

Account Name: MHRA
Account Number: 10004386
Sort code: 60-70-80
Swift code: NWBKGB2L
IBAN: GB68NWBK60708010004386
Bank: National Westminster Bank

Bank address:
National Westminster Bank RBS
London Corporate Service Centre, 2^nd Floor
280 Bishopsgate
London
EC2M 4RB
UK

As per G-MHRAPaymt, credit or debit card payments may be made securely online using GBR-26. Remittance advice notices can be sent to sales.invoices@mhra.gov.uk and should include the relevant invoice number on the remittance advice. MHRA cannot accept any documentation sent by postal mail service. Further information can be obtained by emailing sales.invoices@mhra.gov.uk. G-MHRAPaymt further provides that clinical trial application invoice disputes/queries should be emailed to ctdhelpline@mhra.gov.uk and cc: sales.invoices@mhra.gov.uk.

The G-CTApp indicates that invoices for clinical trial authorization applications and substantial amendment applications are sent directly to the applicant shortly after a valid submission has been established. The applicant’s cover letter should clearly highlight the purchase order (PO) number where available. It is the responsibility of the applicant to ensure timely payment of invoices for their submissions. Invoices must be settled on receipt of invoice. For additional information, applicants may contact the MHRA Finance Department at 020 3080 6533 or sales.invoices@mhra.gov.uk.

Overview

As per the Measures-Ethics, the RegEthics, the EC-Guide, the NMPA-GCP-No57-2020, the DRR, and the DAL, an ethics committee (EC) must approve a clinical trial application prior to a sponsor initiating a clinical trial. Per the NMPA-NHC-No101-2019, each institution that conducts biomedical research is required to have an EC that is responsible for reviewing the scientific and ethical rationality of drug clinical trial programs, reviewing and supervising the qualifications of drug clinical trial researchers, supervising the development of drug clinical trials, and ensuring the ethics review process is independent, objective, and fair. Per the Measures-Ethics, institutions conducting life sciences and medical research involving people must establish ECs to carry out ethics reviews of such research. When the institution does not establish an EC, or the EC is unable to meet the needs of the review, the institution may entrust another institutional EC or a regional EC and implement extended supervision through follow-up reviews.

As described in the EC-Guide, China’s ethics review landscape comprises ethics expert committees and institutional ECs. Ethics expert committees are divided into the National Medical Ethics Expert Committee and provincial medical ethics expert committees. They are mainly responsible for guidance, consultation, and training, and generally do not undertake specific ethics review tasks. Institutional ECs are established by medical and health institutions in accordance with relevant requirements, and are mainly responsible for ethics review, training, and consultation in their institutions. Per the Measures-Ethics, provincial-level health departments establish and manage regional ECs. The EC-Guide states that the regional ECs and institutional ECs have the same status and are subject to the same requirements. ECs at different levels and in different institutions should strictly perform their respective duties, carry out effective communication and collaboration, adhere to the independence, impartiality, and objectivity of ethics review, and ensure that all medical research complies with ethical standards and requirements to fully protect the safety and rights of research participants. Following are brief overviews of each type of EC:

• The National Medical Ethics Expert Committee formulates standards for the construction of institutional ECs and ethics review guidelines, including review content, review procedures, additional protection for special groups, and review time limits; publishes ethics review requirements for high-risk activities in scientific and technological ethics; and formulates standard requirements for ethics review application materials.
• The provincial medical ethics expert committees promote the implementation of the above-mentioned ethics review standards and operating guidelines within the administrative region, promotes the construction and operation of the institutional ECs in the region, and standardizes the work of ethics review. The provincial medical ethics expert committees can make supplementary adjustments to the above-mentioned ethics review standards and operating guidelines in light of the cultural customs of the region.
• The institutional EC establishes and improves the ethics review work system and operating procedures in accordance with the guidance of the national and the provincial medical ethics expert committees, improves the conflict of interest management and quality control mechanisms, and ensures that the ethics review process is independent, objective, and fair. ECs at different levels and in different institutions should strictly perform their respective duties, which includes conducting and ensuring ethics reviews that protect the safety and rights of research participants.

Note that per the Measures-Ethics-Interp, the main framework and provisions of the Measures-Ethics and the RegEthics are generally consistent and both regulations should be followed. Some provisions in the newer Measures-Ethics have been refined and improved in combination with the requirements of new laws and regulations and the actual conditions of colleges, universities, and research institutes. The RegEthics will be reviewed and revised to closely align with the Measures-Ethics. (ClinRegs will monitor and update the China profile, as needed.)

Ethics Committee Composition

Pursuant to the NMPA-GCP-No57-2020, the EC composition must meet health authority requirements, and include members of various categories with different gender compositions. The EC members must be trained in ethics review and be able to review ethical and scientific issues related to clinical trials.

Per the Measures-Ethics, the EC-Guide, and the RegEthics, ECs should have at least seven (7) members. The EC-Guide and the RegEthics state that the ECs should be composed of multidisciplinary specialists in biomedicine, management, ethics, law, sociology, statistics, and other areas that collectively represent the qualifications and experience to provide a fair scientific and ethics review. The RegEthics states that in areas where minority ethnic groups reside, the institution should consider including members of those groups on the EC. The EC-Guide indicates that there should be one (1) member who does not belong to the institution and has no close relationship with the project researchers (the same member can meet both requirements). As delineated in the Measures-Ethics, EC members must be selected from experts in the fields of life sciences, medicine, bioethics, law, and people from outside the institution, and there must be members of different sexes. Ethnic minority members must be considered in ethnic minority areas. EC members must have the corresponding ethics review capabilities, and regularly receive training on ethical knowledge of life sciences and medical research and knowledge of relevant laws and regulations.

The Measures-Ethics, the EC-Guide, and the RegEthics provide that the EC can hire an independent consultant if necessary. The Measures-Ethics and the RegEthics state that the independent consultant advises on specific project issues under review and does not participate in the voting. The EC-Guide further indicates that there should be clear institutional regulations on the qualifications, hiring procedures, and job responsibilities of independent consultants, and the hiring process of independent consultants should be recorded and filed.

The EC-Guide and the RegEthics provide that the EC composition should include a chairperson and vice chairpersons, who are elected by committee members. The number of vice chairpersons is not specified in the guidelines. When the chairperson is absent, the deputy chair performs the chairperson’s duties. ECs should not accept any research project applications that do not comply with national laws and regulations. In addition, the EC should refuse to review any projects in which they have a conflict of interest. See the EC-Guide for additional guidance on managing ECs.

Terms of Reference, Review Procedures, and Meeting Schedule

As per the Measures-Ethics, the RegEthics, the EC-Guide, and the NMPA-GCP-No57-2020, each institution must have written SOPs, including a process to be followed for conducting reviews. To ensure the independence, objectivity, and impartiality of the ethics review process, the Measures-Ethics stipulates that the SOPs must include conflict of interest management and quality control mechanisms. Further, the EC must formulate an ethics review system in emergency situations (e.g., epidemic outbreaks) and clarify the time limit for review.

Per the Measures-Ethics, scientific research managers and other relevant personnel must conduct bioethics education and training. The EC-Guide specifies that all committee members should undergo basic professional training in scientific research ethics before starting their EC service at a provincial or above-level scientific research course and receive an ethics training certificate. Participation in continuing education should be on a continuous basis to ensure improvement.

As delineated in the Measures-Ethics, the term of office for members of ECs that review life sciences and medical research involving people must not exceed one (1) year, and they may be re-elected. The EC must have one (1) chairman and several vice chairmen, who must be elected by EC members through consultation and then appointed by the institution. EC members, independent consultants, and their staff must sign confidentiality agreements on sensitive information learned during ethics review work. The EC must accept the supervision of the institution's management. The EC may decide to approve, disapprove, approve after revision, re-examine after revision, continue research, suspend, or terminate the research under review, and must explain its reasons. The decision must be approved by more than one-half of all members of the EC. Members must vote after full discussion of the ethical issues involved in the study, and opinions inconsistent with the review decision must be recorded in detail.

The RegEthics states that EC members should agree to disclose their names, occupations, and affiliations, and to sign the reviews, confidentiality agreements, and a conflict of interest declaration. Each EC member term is five (5) years, after which they can be reappointed. Each institution that establishes an EC should also provide financial compensation to its committee members. EC review and approval decisions must take place during formal meetings. The majority of the total EC membership should be present to conduct reviews.

In addition, the NMPA-GCP-No57-2020 requires the EC to establish and implement the following written documents:

• Provisions on the composition, establishment, and filing of the EC
• The meeting schedule, meeting notice, and meeting review process sequence
• The initial review and follow-up review procedures of the EC
• A rapid review and approval procedure for minor amendments to the experimental protocol agreed to by the EC
• Procedures for promptly notifying researchers of review opinions
• Procedures for appealing ethics review opinions

The RegEthics and the NMPA-GCP-No57-2020 state that written records of all meetings and resolutions should be preserved for five (5) years following the completion of a clinical trial.

Overview

As set forth in GAfREC, the United Kingdom (UK) has a centralized recognition process for ethics committees (ECs), known as research ethics committees (RECs) in the UK. ECs are part of an accountable and independent Research Ethics Service (RES) (GBR-62).

As described in GBR-51 and GBR-62, the RES has a dual mission to protect the rights, safety, dignity, and well-being of research participants and to facilitate and promote ethical research that is of potential benefit to participants, science, and society. To achieve this, GBR-62 states that the RES works with the devolved administrations to conduct the following activities:

• Provide robust, proportionate, and responsive ethical review of research through ECs
• Provide ethical guidance to ECs
• Provide and deliver a managed structure to support ECs
• Deliver a quality assurance (QA) framework
• Deliver a training program
• Work with colleagues across the UK to maintain a UK-wide framework for ethical review
• Work with colleagues in the wider regulatory environment to streamline the processes for approving research
• Promote and support transparency in research

As stated in GAfREC, the RES encompasses England’s Department of Health and Social Care (DHSC), Northern Ireland’s Department of Health, the Scottish Government Health and Social Care, Finance, Digital and Governance Directorates, the Welsh Government’s Department of Health and Social Care as well as the ECs that are collectively recognized or established by these authorizing bodies. The UK Health Departments have authorized the head office of the RES in England, within the Health Research Authority (HRA), to perform some UK-wide functions on behalf of the other head offices, including performing some of the functions of the UK Ethics Committee Authority (UKECA), which is the statutory body that recognizes ECs for the review of clinical trials of investigational medicinal products (CTIMPs). (See Oversight of Ethics Committees section for more details on RES and UKECA functions.) In accordance with the MHCTR and the MHCTR2006, ECs recognized to conduct reviews of clinical trials for CTIMPs are authorized by the UKECA. The UKwide-Rsrch reaffirms that GAfREC is the UK policy document governing the RES function and EC reviews in each country.

All recognized RES ECs are required to comply with the provisions delineated in GAfREC, the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), and GBR-9. However, specific ECs within the RES are recognized, or otherwise designated, to review certain types of research proposals. A list of recognized ECs within the RES is available through GBR-111. Also see GBR-64 for EC definitions.

Ethics Committee Composition

As delineated in the MHCTR and GAfREC, a RES-recognized EC, which includes those recognized by UKECA, may consist of up to 18 members. Collectively, members must encompass the qualifications and experience required to review and evaluate the scientific, medical, and ethical aspects of a proposed clinical trial. The ECs should include a diverse mixture of members in terms of age, disability, gender, race, religion, and sexual orientation. One third of the committee must also be lay members, and half of the lay members must be persons who are not and never have been health care professionals, clinical researchers, or managers of clinical research (also known as lay members). Additionally, GAfREC states that a quorate meeting must be attended by at least seven (7) members and include the chair, at least one (1) expert member, and one (1) lay member. GBR-9 mirrors this requirement, but adds that when investigational products are reviewed, a lay member must be present. See GBR-113 for additional recommendations for composition.

Per GBR-9, in order to accommodate the United States’ (US) quorum definition pursuant to regulations for the protection of human subjects in research (45 CFR 46) and the Common Rule (45 CFR 46 Subpart A), the RES also makes special arrangements to review UK-based research funded by US Federal Government departments and their agencies. In such cases, the quorum is a majority of the EC. See the ClinRegs United States page, Ethics Committee topic for more information on ethics review requirements in the US.

As indicated in GAfREC, committee member appointments are valid for up to five (5) years. Appointments may be renewed; however, members should not normally serve more than two (2) consecutive terms of five (5) years on the same EC, and members may resign at any time. Members must maintain confidentiality regarding all ethical review related matters and refuse any projects in which they have a conflict of interest. See the MHCTR and GAfREC for additional EC composition requirements.

Terms of Reference, Review Procedures, and Meeting Schedule

In addition to complying with composition requirements, GAfREC, GBR-113, and GBR-9 state that an EC must also adopt written standard operating procedures (SOPs). The SOPs should cover the entire review process from application submission to opinion and notification, amendments, and annual reporting.

Per GBR-9, applications that have been submitted via the CTIMP combined review service will be validated by the MHRA, and EC staff do not need to undertake a formal validation check. ECs should check the application against the validation checklist and request any missing information or clarifications from the applicant if required. All validated clinical trial applications for an ethical opinion should be reviewed at a full meeting of an EC. An EC should normally hold at least 10 scheduled full meetings in each year for the purpose of ethical review of applications. Additional meetings may be held where necessary to ensure that an ethical opinion on an application is given within the relevant time limit (or to discuss matters relating to the establishment or operating procedures of the EC or for training purposes). Meetings to review applications should normally be held at intervals of one (1) month unless there are holidays. The schedule of EC meetings for the financial year commencing on April 1^st should be agreed to by December 1^st in the previous financial year. The schedule should set out the dates, times, and venues of meetings, and the closing date for applications for each meeting. All members and deputy members of the EC should receive details of the schedule. The closing dates for full applications should normally be 14 calendar days prior to each EC meeting. In the case of applications for Phase 1 clinical trials in healthy volunteers, Type 1 ECs may adopt a later closing date for applications not less than seven (7) calendar days prior to the meeting and may accept applications booked in advance of the closing date which are submitted up to seven (7) days before the date of the meeting.

According to GBR-9, the EC Chair is responsible for ensuring that the EC reaches clearly agreed to decisions on all matters. If the Chair is unavailable, then the meeting should normally be chaired by the vice-Chair or, if the vice Chair is also unavailable, by the alternate vice-Chair. The EC meeting should reach unanimous decisions by consensus wherever possible. Where a consensus is not achievable, a formal vote should be taken by a counting of hands. The decision of the EC should be determined by a simple majority of those members present and entitled to vote. A record should be kept of the number of votes, including abstentions, in the minutes. Where the vote is tied, the Chair may give a casting vote, but should first consider any other options to arrive at a more consensual decision. Where any member wishes to record a formal dissent from the decision of the committee, this should be recorded in the minutes but should not be included in the opinion letter. An agenda should be prepared for an EC meeting and EC staff must prepare minutes of the EC meetings. See GBR-9 for additional requirements on the agenda, meeting conduct/decisions, and minutes during full EC meetings.

As per GBR-9, documents for EC meetings should be distributed as soon as possible after the agenda is finalized and applications have been validated, and in any case no later than 10 calendar days prior to the meeting (with the exception of expedited, proportionate review, and Phase 1 applications where there has been prior agreement). Under no circumstances should full applications be tabled at the meeting. Applications should be made available to members via the HRA Assessment and Review Portal (HARP) as soon as the application is validated, and an email sent to the EC members to inform them the application is now viewable.

GBR-9 requires ECs to retain all the documentation relating to a CTIMP on which it gives an opinion:

• Where the trial proceeds, for at least three (3) years from the conclusion or early termination of the trial
• Where the trial does not proceed (e.g., it is given an unfavorable opinion, or does not start following a favorable opinion), for at least three (3) years from the date of the opinion

In accordance with GBR-9, documentation should be retained on all invalid applications for at least one (1) year from the date of invalidation; and for three (3) years where the application is withdrawn by the EC, the chief investigator, or the sponsor after the EC review but before a final opinion is given. Signed final copies of the minutes of full EC meetings and sub-committee business should be retained electronically for at least 20 years. Where paper records are destroyed in accordance with this policy, they should be shredded and disposed of as confidential waste. Electronic records of studies will be retained indefinitely.

For detailed EC procedures and information on other administrative processes, see GAfREC, GBR-113, and GBR-9.

Overview

According to the EC-Guide, the NMPA-GCP-No57-2020, and the NMPA-No11-2017, the primary scope of information assessed by the ethics committee (EC) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial, in accordance with the requirements set forth in the Declaration of Helsinki (CHN-84). Per the Measures-Ethics and the RegEthics, ethics reviews and relevant personnel must comply with the Constitution of the People's Republic of China and Chinese laws and regulations. The Measures-Ethics indicates that life science and medical research involving humans must respect research participants and follow the principles of beneficence, non-harm, and fairness, and protect privacy and personal information. Per the RegEthics and the EC-Guide, the EC must also pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable (See the Vulnerable Populations section for additional information about these populations). In addition, the EC is responsible for ensuring a competent review of all ethical aspects of the clinical trial protocol; evaluating the possible risks and expected benefits to participants; confirming the suitability of the investigator(s), facilities, and methods; and verifying the adequacy of confidentiality safeguards.

Per Measures-Ethics, life science and medical research involving humans is defined as research activities using biological samples and information data (including health records and behaviors) of research participants, specifically including the following:

• Activities that use methods such as physics, chemistry, biology, and traditional Chinese medicine to conduct research on human reproduction, growth, development, aging, etc.
• Activities that use methods such as physics, chemistry, biology, traditional Chinese medicine, psychology, and other methods to conduct research on human physiology, psychological behavior, pathological phenomena, disease etiology and pathogenesis, as well as disease prevention, diagnosis, treatment, and rehabilitation
• Activities using new technologies or products to conduct experimental research on the human body
• Activities that use methods such as epidemiology, sociology, and psychology to collect, record, use, report, or store biological samples, information data, and other scientific research materials (including health records, behaviors, etc.) related to life sciences and medical issues

The GeneEdit-Ethics states that human genome editing research should have important scientific and social value, and should be limited to medical interventions for treatment or prevention. Non-medical genomic changes to research participants are prohibited. Researchers and institutions should follow the GeneEdit-Ethics for principles and ethical behavior to guide human genome editing research.

Note that per the Measures-Ethics-Interp, the main framework and provisions of the Measures-Ethics and the RegEthics are generally consistent and both regulations should be followed. Some provisions in the newer Measures-Ethics have been refined and improved in combination with the requirements of new laws and regulations and the actual conditions of colleges, universities, and research institutes. The RegEthics will be reviewed and revised to closely align with the Measures-Ethics. (ClinRegs will monitor and update the China profile, as needed.)

Role in Clinical Trial Approval Process

As per the RegEthics, the NMPA-GCP-No57-2020, the DRR, the DAL, and the SC-Opinions-No42, the National Medical Products Administration (NMPA) and the EC must approve a clinical trial application prior to a sponsor initiating a clinical trial. As stated in the DRR, clinical trials of drugs must be reviewed and approved by an EC. The DRR indicates that the EC review may be submitted in parallel to the NMPA’s review, but the study cannot be initiated until after review and approval by the EC. The NMPA-GCP-No57-2020 and the RegEthics also state that the EC must review and approve any protocol amendments prior to those changes being implemented.

Per the Rules-MgmtHGR, the collection, preservation, use, and external provision of China’s human genetic resources (HGR) must comply with ethical principles and pass the ethics review of ECs that have been registered with the relevant management departments. Further, applications for administrative licenses for international scientific research cooperation on HGR must pass an ethics review in the respective countries (regions) where both parties are located. Where the foreign party is truly unable to provide the ethics review certification materials of the country (region) where it is located, it may submit the proof that the foreign party unit recognizes the ethics review opinions of the Chinese unit.

The Measures-Ethics, the EC-Guide, and the NMPA-GCP-No57-2020 provide that the EC’s scope of review must include the following (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Whether the institutions and researchers are competent; the qualifications and experience of the investigator meet clinical research requirements
• Whether the research plan meets the required scientific and ethical principles, has scientific and social value, does not violate the provisions of laws and regulations, and does not harm the public interest
• The degree of risk compared to the expected study benefit
• The informed consent process and whether the relevant information provided is complete and easy to understand, and whether the method for obtaining consent was appropriate
• Whether confidentiality measures have been taken to protect the participants’ privacy, personal information, and data
• Whether the guidelines for the selection and exclusion of participants are appropriate and fair
• Whether the participants are clearly informed of their rights in the research, including the right to equal treatment and that they can withdraw from the research at any time without reason and not be treated unfairly because of this
• Whether the participant received reasonable compensation for participating in the research, and in case of damage or death, whether the treatment and compensation measures are appropriate; participants must not be charged research-related fees for participating in the research
• Whether there is a designated contact for handling and obtaining informed consent and answering questions related to participant safety
• Whether appropriate measures are taken to minimize participant risks
• Potential conflicts of interest
• When conducting non-therapeutic clinical trials, if the participants’ informed consent is implemented by their guardians instead, whether the trial protocol gives full consideration to the corresponding ethical issues, laws, and regulations
• Whether the corresponding ethical issues, laws, and regulations are fully considered in the trial plan if the trial protocol clearly states that the participants or their guardians cannot sign an informed consent form (ICF) before the trial in an emergency
• Whether participants are forced or induced to participate in clinical trials due to improper influence, including whether the ICF has content that waives legal rights or exempts researchers, institutions, or sponsors from being responsible
• Whether the method, content, and timing of the release of research results are reasonable

Per the Measures-Ethics and the EC-Guide, the EC will make one (1) of the following decisions (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Approval: The EC unconditionally approves an initial review of the research protocol and will conduct follow-up reviews. The research can start immediately after approval.
• Approval after modification: The EC conditionally approves a research protocol if the research leader accepts the EC’s proposed amendments.
• Review after modification: If the EC needs more substantive information about the research project under review, it will decide to suspend the deliberation until the committee receives new information.
• Approve continuation of research.
• Not approved: The EC votes against a research proposal. The reasons for disapproval must be communicated to the research leader, who is given an opportunity to defend the research.
• Suspension or termination of research: The EC suspends or terminates a research project.

The Measures-Ethics specifies that the EC must conduct the review and issue its opinion within 30 days of acceptance of the materials.

The Measures-Ethics states that before the implementation of research approved by the EC, researchers, ECs, and institutions must truthfully, completely, and accurately upload information to the registration platform (CHN-53), including research, ethics review opinions, and institutional review opinions in accordance with the requirements of the national medical research registration and filing information system, and promptly update the information according to the progress of the research. Researchers, ECs, and institutions are encouraged to upload information in real time during the study management process.

The NMPA-GCP-No57-2020 specifies that the EC must pay attention to and clearly require investigators to report in a timely manner the following: deviations or modifications to the trial protocol to eliminate emergency hazards to participants; changes that increase the risk to participants or significantly affect the implementation of clinical trials; all suspicious and unexpected serious adverse reactions; and new information that may adversely affect the safety of participants or the implementation of clinical trials. The EC has the right to suspend or terminate clinical trials, as needed. Finally, the EC must accept and properly handle requests from participants. Per the EC-Guide, if there are accidental injuries or violations during the research project, the EC has the right to request the suspension or termination of an approved research project. Further, the EC reviews amendments to the protocol and informed consent form, and reviews serious adverse events and violations of the protocol. The Measures-Ethics states that when a serious adverse event is reported, the EC must conduct a timely review to determine whether the measures taken by researchers to protect the personal safety and health rights and interests of research participants are adequate, reassess the risk-benefit ratio of the research, and issue review opinions.

As delineated in the NMPA-No34-2022, protocol changes that result in updating the investigator’s brochure, ICF, or other relevant documents should be reported to the EC by the sponsor. The Measures-Ethics indicates that if approved research requires revision of the research plan, informed consent, recruitment materials, or other materials provided to research participants, the researcher must submit the revised documents to the EC for review. Further, the EC must conduct follow-up reviews at least annually in accordance with relevant reports submitted by the investigators. The follow-up review must include the following considerations:

• Whether the research is conducted in accordance with the approved research plan and reported in a timely manner
• Whether the research content was changed without authorization during the research process
• Whether changes or new information increase the risk to research participants or significantly affect the implementation of the research
• Whether it is necessary to suspend or terminate the research early
• Other content that needs to be reviewed

Per the EC-Guide, the EC has the right to request regular follow-up reviews of approved research projects based on the possibility and degree of research risks. The RegEthics provides that the EC must designate members to conduct follow-up examinations of approved research projects. The number of members for follow-up review must not be less than two (2), and the review is required to be reported to the EC. Further, the EC may apply to the provincial medical ethics expert committees to provide advice on the ethics review of research that involves a relatively high-risk or special population.

Expedited Review

As delineated in the Measures-Ethics, the EC may conduct expedited review of research in the following circumstances:

• Research whose risk is not greater than the minimum risk
• Research in which the approved research protocol is slightly modified and does not affect the risk-benefit ratio of the research
• Follow-up review of approved research
• Research conducted by multiple institutions, when the EC of the participating institution confirms the ethics review opinion issued by the lead institution, etc.

Where the situation is urgent, an ethics review must be promptly carried out. In the case of emergencies such as outbreaks, ethics reviews and review opinions are generally carried out within 72 hours, but the requirements and quality of ethics reviews must not be reduced. For expedited review, the EC chairman designates two (2) or more members to conduct the ethics review and issue review opinions. The review opinions must be reported at the EC meeting. If it is discovered during this review that there is a change in the risk-benefit ratio of the research, there is a disagreement among the review members, or the review members propose that a meeting review is required, etc., then a full review procedure must be held.

During an outbreak of an epidemic, the EC-Guide advises ECs to adhere to the highest scientific and ethical standards for independent review of the research project to ensure balancing of quality and timeliness. The materials provided by the researcher can be simplified according to the situation. The EC should pay special attention to the informed consent process as participants may be improperly exploited due to their obvious vulnerability, especially when it involves high-risk and risk-uncertain research. It should be ensured that participants choose to participate voluntarily and independently after being fully informed and fully understanding the possible risks of research. Research participants or the legal representative/guardian must be allowed to withdraw from research unconditionally at any stage. See the EC-Guide for additional guidance on the EC review when there is a major epidemic risk.

Multicenter Studies

Per the Measures-Ethics, research carried out in multiple institutions may establish collaborative mechanisms for ethics review, ensuring that all institutions follow the principles of consistency and timeliness. Both the lead institution and the participating institution must organize an ethics review. The EC of the participating institution must conduct a follow-up review of the research in which the institution participates. Where establishments cooperate with enterprises and other institutions to carry out life science and medical research involving humans, the institutions must fully understand the overall situation of the research, clarify the scope of use and handling methods of biological samples and information data through agreements subject to ethics review and follow-up review, and supervise their proper disposal after the research is completed.

Per the EC-Guide, the review of international cooperative research projects requires ethics review by the lead unit. For cooperative research projects conducted in China, the trial protocols should be submitted to the EC for a single-review process and should be consistent, though the EC will accept that informed consent may vary slightly in different institutions. The RegEthics also provides that multicenter research may establish a collaborative review mechanism to ensure that the research institutions of each project follow the principles of consistency and timeliness. The lead agency EC is responsible for project review and confirmation of the ethics review results of participating institutions. ECs of the participating institutions must conduct an ethics review of the research in which the institution participates in a timely manner and provide feedback to the lead agency for review.

Exemption from Ethics Review

The Measures-Ethics states that ethics review may be exempted where human information data or biological samples are used to carry out life science and medical research involving humans if the research does not cause harm to the human body or does not involve sensitive personal information or commercial interests. This is to reduce unnecessary burdens on scientific research personnel and promote the development of life science and medical research involving people. The exemption may apply in the following circumstances:

• Using lawfully obtained public data or conducting research through data generated by observing and not interfering with public conduct
• Using anonymized information and data to carry out research
• Using existing human biological samples to carry out research, and the source of the biological samples complies with relevant laws and regulations and ethical principles; the relevant content and purpose of the research are within the scope of the informed consent; and the research does not involve the use of human germ cells, embryos, reproductive cloning, chimerism, and heritable gene manipulation
• Carrying out research using human-derived cell lines or cell lines derived from biobanks, where the relevant content and purpose of the research are within the scope authorized by the provider, and do not involve activities such as human embryonic and reproductive cloning, chimerism, and heritable gene manipulation

Overview

According to GAfREC, the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), and GBR-9, the primary scope of information assessed by ethics committees (ECs) within the United Kingdom (UK) Health Departments’ Research Ethics Service (RES) (GBR-62) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. (Note: ECs are known as research ethics committees (RECs) in the UK). GAfREC specifies that ethical review is required for research proposals that involve investigational products (IPs), material consisting of human cells, and other situations that are described in GAfREC.

As per GAfREC, the MHCTR, the MHCTR2006, the MHCTR2006-No2, and GBR-113, ECs must pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations).

As indicated in GAfREC, the MHCTR, the MHCTR2006, GBR-113, and GBR-9, ECs are responsible for ensuring an independent, timely, and competent review of all ethical aspects of the clinical trial protocol. They must act in the interests of the potential research participants and the communities involved by evaluating the possible risks and expected benefits to participants; confirming the suitability of the investigator(s), facilities, and methods; and verifying the adequacy of confidentiality and privacy safeguards. See GAfREC, the MHCTR, the MHCTR2006, and GBR-9 for detailed ethics review guidelines.

GBR-112 indicates that certain ECs are flagged for special expertise including gene therapy or stem cell clinical trials; Phase 1 studies in healthy volunteers; Phase 1 studies in participants; research involving adults lacking capacity; research involving children; research involving prisoners or prisons; or fast-track ECs.

Role in Clinical Trial Approval Process

As described in GBR-9, GBR-66, and GBR-95, the type of EC responsible for approval (known as a “favorable opinion” in the UK) within the RES depends on the type of research being conducted. Per GAfREC and GBR-9, ECs are recognized or established by the United Kingdom Ethics Committee Authority (UKECA) to conduct reviews of clinical trials for IPs (known as clinical trials for investigational medicinal products (CTIMPs) in the UK). Per GAfREC, RES-recognized ECs established under Health Department policy within each of the four (4) UK nations (England, Northern Ireland, Scotland, and Wales) review research studies other than IP clinical trials. Also see GBR-64 for definitions of EC terminology and GBR-111 and GBR-112 to search for ECs within the RES.

As indicated in the MHCTR, the MHCTR2006, and GAfREC, IP applications require the favorable opinion of a UKECA-recognized EC, and approval by the Medicines and Healthcare Products Regulatory Agency (MHRA) prior to the sponsor or the designated legal representative initiating the trial. The G-CTApp states that all new clinical trial applications must be prepared, submitted, and reviewed via the combined review process, wherein a single application route and coordinated review by MHRA and the EC leads to a single UK decision. New clinical trial applications for combined review are prepared and electronically submitted to the new combined review section of Integrated Research Application System (IRAS) (GBR-125). Per GBR-78, IRAS does not change the requirements for review, including authorizations or signatures, of any regulatory authority or National Health Service (NHS) body. Therefore, it requires different authorizations depending on the type of study and the applicable review bodies. According to GBR-9, submissions of the electronic application must be made to IRAS on the same day that a booking is made to schedule an EC review through the NHS REC’s Online Booking Service (GBR-95).

According to the MHCTR, GAfREC, and GBR-9, for all studies, only one (1) EC review (referred to as the “main EC”) is needed for a project taking place in the UK, regardless of the number of sites. Furthermore, GBR-9 states that the Chief Investigator (CI) should be based in the UK and that the REC may agree exceptionally to an application being submitted by a CI based outside the UK, but should consider as part of the ethical review whether adequate arrangements are in place for supervision of the study in the UK. The ethical review includes an assessment of the suitability of each site or sites at which the research is to be conducted in the UK. The site assessment is not a separate ethical review, but forms part of the single ethical review of the research. Management permission is still required from the organization responsible for hosting the research before it commences at any site. In the case of international studies, an application must be made to an EC in the UK, whether or not the study has a favorable ethical opinion from a committee outside the UK, and whether or not it has started outside the UK.

Per GBR-68, unless an application is being processed under the proportionate review service, the applicant should attend the EC meeting if possible. The EC will notify the sponsor of its decision, usually within 10 working days of the EC meeting. GBR-9 indicates that the EC should reach one (1) of the following decisions on any application reviewed at a full meeting or a proportionate review sub-committee meeting:

• A final opinion, which may be either favorable with standard conditions, favorable with additional conditions, or unfavorable
• Provisional opinion with request for further information, which means the EC may decide that a final opinion cannot be issued until further information or clarification has been received from the applicant

The MHCTR, GBR-9, and GBR-68 state that the EC must give its opinion within 60 calendar days of receipt of a valid application. When an EC requires further information before confirming its opinion, it may give a provisional opinion and may make one (1) written request for further information, clarification, or changes to documentation. The time required for the EC to receive a complete response to its request does not count against the 60-day timeline. Certain studies, including gene therapy studies, will take 90 days, or 180 days if a specialist group or committee is consulted. For other exceptions, see GAfREC and the MHCTR. (See the Submission Process and Timeline of Review sections for detailed submission process requirements.)

Per GBR-116, the Health Research Authority (HRA), on behalf of the UK, offers a fast-track research ethics review. Fast-track ethics review is open to global clinical trials and Phase 1 trials, whether the sponsor is commercial or non-commercial. This includes:

• Any CTIMP led from the UK with at least one (1) other country participating
• Any CTIMP led from outside the UK which could be placed in any country and the UK is competing for participation (including any only taking place in the UK)
• Any Phase 1 or Phase 1/2 CTIMP in healthy volunteers or participants

Fast-track ethics review is not available for any CTIMP involving a gene therapy medicinal product, any CTIMP funded by the US Department of Health and Human Services, and any other type of clinical trial or research study.

Per GBR-9, the EC’s favorable ethical opinion applies for the stated duration of the study, except where action is taken to suspend or terminate the opinion. The MHCTR, GAfREC, and IRAS (GBR-78) require the applicant to identify an expected end date for the study. A change to the definition of the end of the study is a substantial amendment. Extension of the study beyond the period specified in the application form is a non-substantial amendment.

GBR-9 describes EC processes related to reviewing and approving clinical trial amendments and any related notifications. The sponsor of a CTIMP may make an amendment to a clinical trial authorization, other than a substantial amendment, at any time after the trial has started. These do not need to be notified. If the amendment is substantial, the sponsor is required to submit a valid amendment to the MHRA and/or the REC that gave the favorable opinion of the trial. Where the sponsor requests an ethical opinion on a CTIMP, the EC should provide this in all cases within 35 calendar days of receiving a valid amendment. If the opinion is unfavorable, the sponsor may then modify the proposed amendment. A written notice of the modification should be sent to the main EC at least 14 calendar days before it is due to be implemented. The EC may then give an unfavorable opinion on the modified amendment within 14 calendar days, otherwise it may be implemented. See GBR-9 and GBR-98 for guidance on what changes qualify as a substantial amendment, which requires notification to the EC and MHRA. GBR-9 states that while the EC is not responsible for proactive monitoring, it has a duty to keep the favorable ethical opinion under review in the light of progress reports and significant developments and may review the opinion at any time. If information raises concerns about the suitability of the site or investigator, the favorable opinion may be reviewed.

No applicable requirements.

As set forth in GAfREC, ethics committees (ECs) are not permitted to charge an application fee or seek any other financial contribution or donation for reviewing research proposals. Additionally, EC members receive no payment for contributing to the application review process at scheduled meetings or for attending these meetings.

Overview

Per the NMPA-NHC-No101-2019, the National Medical Products Administration (NMPA) oversees and supervises the registration and filing of clinical trial institutions. Drug clinical trials must be conducted in registered clinical trial institutions that meet the applicable requirements, which include having an ethics committee (EC).

Registration, Auditing, and Accreditation

The RegEthics states that all biomedical research institutions in China should establish their own ECs. Per SC-Opinions-No42, the NMPA adopted a registration system for institutions with qualifying conditions to be entrusted to conduct clinical trials and operate ECs. An institution is entrusted to conduct clinical trials if it has an EC and the main investigators of clinical trials have senior professional titles and have participated in more than three (3) clinical trials, among other conditions. To apply for qualification, institutions must submit an application via the online filing system (CHN-82) and fulfill the requirements pursuant to the NMPA-NHC-No101-2019. Per the Measures-Ethics, institutions must register the EC within three (3) months of its establishment and upload the information to CHN-82. Medical and healthcare institutions must register with the appropriate oversight authority. Other institutions must register with the competent department at a higher level according to their administrative affiliation. The EC must submit the previous year's work report to the appropriate institutional department before March 31^st of each year, including:

• A list of personnel and resumes of committee members' work
• The EC charter
• Work systems or relevant work procedures
• Other relevant materials required by the appropriate department

When the above information changes, the institution must promptly update the information to the appropriate institutional department.

As delineated in the RegEthics and interpreted in CHN-41, the National Health Commission (NHC) is responsible for managing ECs nationwide, organizing the inspection and management of the national ethics review of biomedical research involving human beings, establishing the National Medical Ethics Expert Committee, and for developing policies relating to ethics review. The National Medical Ethics Expert Committee conducts research on major ethical issues in research involving humans and provides policy advice and guides the provincial ECs. Per CHN-3, China established a National Science and Technology Ethics Committee to strengthen the ethics governance system. Further, the SC-EthicalGov establishes principles and guides the committee in its responsibility to develop and coordinate the ethics governance system.

The EC-Guide describes the inspection and oversight mechanisms among the ECs in China. The National Medical Ethics Expert Committee formulates an inspection and evaluation indicator system for institutional ECs, including review quality, review efficiency, committee member capabilities, conflict of interest management, etc., to guide provincial medical ethics expert committees in carrying out ethics inspections within the region. The National Medical Ethics Expert Committee also inspects, evaluates, and supervises the work of provincial medical ethics expert committees. The provincial medical ethics expert committees are responsible for conducting regular inspections and evaluations of the ethics review work of medical institutions and regional ECs within the administrative area at the same level, making recommendations on how to manage non-standard ethics review work, and may establish an information disclosure mechanism based on actual conditions. Institutional ECs should check and evaluate the indicator system, continuously improve their operations, and actively cooperate in completing various inspections and evaluations. Regular self-evaluation is encouraged to improve work quality and review efficiency.

As delineated in the RegEthics, the provincial, autonomous regional, and municipal health authorities also have ECs set up under their own administration. The provincial medical ethics expert committees assists in promoting the institutionalization and standardization of the ethics review work of human biomedical research in its administrative region, and guides, inspects, and evaluates the work of the institutional ECs in the administrative region. It also performs training and consulting work. The local health administrative department at or above the county level supervises and manages the ethics review work of biomedical research involving people in its administrative region. Per the Measures-Ethics, provincial-level health departments, in conjunction with relevant departments, must formulate measures for the establishment and management of regional ECs. The regional EC must file with the provincial health department and upload information in CHN-82.

For additional information about oversight of ECs, including inspections, see the RegEthics.

Overview

As stated in GAfREC and GBR-9, the United Kingdom (UK)-wide Research Ethics Service (RES) (GBR-62) provides proportionate and responsive ethical review of research through its “recognized” ethics committees (ECs), known as research ethics committees (RECs) in the UK. Per the MHCTR, the MHCTR2006, and GAfREC, the UK Ethics Committee Authority (UKECA) is the statutory body that recognizes ECs for the review of clinical trials of investigational products (CTIMPs). The UK Health Departments have authorized England’s Health Research Authority (HRA) to perform some of the RES functions (more details below).

As indicated in the MHCTR and GBR-9, the UKECA recognizes two (2) types of ECs for new CTIMPs:

• Type 1: Reviews Phase 1 clinical trials of investigational products (IPs) taking place at any site in the UK, where the sponsor has no knowledge of any evidence that the product has effects likely to be beneficial to the participants of the trial, and the participants are healthy and not suffering from the disease or condition to which the trial relates.
• Type 3: Reviews clinical trials of IPs taking place at any site in the UK, including first-in-person studies involving people with the target disease or condition to which the trial relates.

As stated in GAfREC, the HRA performs the following EC oversight activities on behalf of the UKECA:

• Develops and manages a national training program for ECs
• Develops, implements, and maintains standard operating procedures (SOPs) for ECs and provides advice and support to ECs on procedural issues
• Develops a quality assurance program, including accreditation of ECs, based on regular monitoring and audit of their operation and performance
• Provides guidance and advice to assist ECs in their work and encourage consistency of approach to common issues in research ethics
• Acts for UKECA to provide a national mechanism for operational advice and assistance to ECs recognized to review and approve clinical trials
• Acts for UKECA to handle appeals against the unfavorable opinions of ECs in respect of CTIMPs
• Acts for UKECA to transfer to a successor EC the functions of an EC that has ceased to operate or that has been varied, abolished, or had its recognition revoked
• Acts for UKECA to reallocate to ECs applications made to the Gene Therapy Advisory Committee which do not require its review

Further, per GAfREC, the following oversight functions are the responsibility of UKECA for the purposes of clinical trials:

• Establishes or recognizes ECs
• Establishes or recognizes ECs to act in relation to such descriptions or classes of research as it considers appropriate
• Abolishes or revokes the recognition of ECs that it has established or recognized
• Monitors the extent to which ECs adequately perform their functions, including through annual reports from ECs it has recognized
• Approves standing orders and SOPs for EC business and operations, as well as variations and revocations to these orders and procedures

Registration, Auditing, and Accreditation

Per GAfREC, HRA, acting for UKECA, develops a quality assurance program to encourage a consistently high level of service to applicants, including accreditation of ECs, based on regular monitoring and audit of their operation and performance.

GBR-123 indicates that HRA implements a rolling accreditation program to audit UK ECs against standards as detailed in GAfREC and GBR-9. ECs are issued with an audit decision: full accreditation, accreditation with conditions (low-risk non-compliance identified requiring an action plan), or provisional accreditation (high- and low-risk issues requiring an action plan). Published bi-annually, HRA’s latest accreditation report is at GBR-124. In addition, quality control checks are undertaken, and results are shared with management teams. For example, operational managers observe EC meetings and provide a check against agreed-upon standards relating to meeting conduct and minute taking. Findings from the meeting observations are shared with the EC chair and staff and collated to identify common themes to inform improvements. For more information about quality assurance, contact quality.assurance@hra.nhs.uk.

Overview

As per the DRR, the National Medical Products Administration (NMPA) grants permission for clinical trials to be conducted in China pursuant to the drug registration process, in accordance with the DAL, the VaccineLaw, and other laws and regulations. The NMPA-GCP-No57-2020, the DRR, the DAL, and the SC-Opinions-No44 require the sponsor to obtain NMPA and ethics committee (EC) approvals of a clinical trial application. As stated in the DRR, EC review may be submitted in parallel to the NMPA’s review, but the study cannot be initiated until after review and approval by the EC.

Per the NHC-HGRmgt, the National Health Commission (NHC) is responsible for China’s management of human genetic resources (HGR). (Note that per SC-Order777 and NHC-HGRmgt, management of HGR was transferred from the Ministry of Science and Technology (MOST) to NHC, effective May 1, 2024). The NHC-HGRmgt states that the original application process and platform (CHN-6) remain unchanged. Per the Rules-MgmtHGR, the collection, preservation, use, and external provision of China’s HGR must comply with ethical principles and pass the ethics review of ECs that have been registered with the relevant management departments. Further, with applications for administrative licenses for international scientific research cooperation, the HGR project must pass an ethics review in the respective countries (regions). As part of the application filing for international cooperative clinical trials, NMPA approvals, notices, and/or filing registration must be obtained in advance, along with the EC approvals. Therefore, EC and MOST (now the NHC) review cannot occur in parallel. (Please note that SC-Order777 amends the MgmtHumanGen to reflect the transfer of HGR management from MOST to the NHC, but the Rules-MgmtHGR has not yet been amended to show the transfer.)

Regulatory Submission

National Medical Products Administration

The NMPA-No50-2018 establishes the broad submission procedures for clinical trials, which are detailed below through implementing regulations and guidance. The DRR states that a Chinese legal entity must submit the drug registration application. Clinical trial applications are also considered drug registration applications. Overseas drug manufacturers without legal representation in China must apply for drug registration through Chinese legal persons to handle relevant drug registration matters.

The applicant should prepare materials and apply for a communication meeting with the NMPA’s Center for Drug Evaluation (CDE) in accordance with the requirements of the NMPA-No48-2020, which includes requirements for different categories of meetings involving applications for new drugs. The NMPA-No48-2020 includes the application form (Appendix 1) and communication meeting materials (Appendix 2). The meeting’s purpose is to determine the integrity of the clinical trial application data and the sponsor’s ability to ensure the participant’s safety. If existing or supplemental data can support the clinical trial, then the applicant can submit a clinical trial application after the meeting or after supplementing the data. The NMPA-No51-2023 reaffirms the required pre-trial meeting and states that the applicant must submit a communication application to the CDE before 1) applying for the first clinical trial of a new drug and 2) before completing the exploratory clinical trial and conducting the confirmatory (or critical) clinical trial. The NMPA-No23-2023 provides guidance on common issues and general requirements for the Phase III pre-clinical trial meeting with the CDE in regards to innovative drugs.

Per the NMPA-No50-2018, the applicant may directly submit a clinical trial application without requesting a communication meeting with the CDE in the following cases: they clearly understand the technical guidance; have sufficient experience in drug clinical trials; can ensure the quality of data in the application; or the application is for a multicentered international clinical trial being conducted in parallel that has permission to conduct the clinical trials in countries or regions with an established and functional regulatory and monitoring infrastructure. In addition, the NMPA-No48-2020 stipulates that the application for conditional approval and/or the application for priority review and approval procedures must be communicated and confirmed with the CDE before submittal. (See below for procedures on priority review and approval.)

CHN-14 states that Chinese legal entities must submit application materials to the NMPA/CDE for a formal process review (including checking the electronic materials as described below). NMPA will process clinical trial applications within five (5) working days if the study falls within the scope of its authority; the application materials are complete and comply with the prescribed format; and if all required supplementary materials are submitted. If accepted, the CDE then organizes and conducts its review of the clinical trial application on behalf of the NMPA. As required in the ElectronicApps-Rqts and the NMPA-No110-2022, all documents for drug registration applications (including clinical trial applications, letters of commitment, declarations, and supplemental material) must be submitted electronically on CD-ROM to the CDE, in accordance with the current regulations, technical requirements for electronic CD-ROMs of application materials, and electronic file structure of drug registration applications. The ElectronicApps-Rqts clarifies that the CDE no longer accepts paper documents for administrative licensing by mail, except for applications that were accepted before January 1, 2023 and must continue to submit supplementary material in paper format. The applicant or registered agent is required to electronically sign the electronic declaration materials; the application and electronic seal can be found in the CDE’s Applicant Window (CHN-58). For details on the cover requirements for CD-ROM cases and the cover of the file bag, refer to Annex 1 in ElectronicApps-Rqts.

As indicated in CDE-Reloctn, the applicant should fill in and submit the relevant information in the "Online Appointment for Submission of Materials" module under the "Online Appointment" item in the "Applicant's Window" column of CDE’s Applicant Window (CHN-58). To mail CDs and other application materials in electronic format, applicants should use the following mailing address:

Business Management Office of the Center for Drug Evaluation
State Drug Administration
Room 102, Building 2
District 2, No. 22 Guangde Street
Beijing Economic and Technological Development Zone
Beijing, 100076
P.R. China

Per the ElectronicApps-Rqts, after receiving the disc submitted by the applicant, the CDE will determine if the disc can be read normally, passes the electronic signature verification, and has no computer viruses. If the disc does not pass these reviews, the CDE will notify the applicant and request resubmittal; the original disc will be disposed of in accordance with the CDE’s destruction procedures. If accepted, the CDE will push the electronic documents to the "Drug Business Application System" and "Drug eCTD Registration System" and the applicant is notified by SMS.

The ElectronicApps-Rqts provides additional requirements on the arrangement of discs:

• Submit one (1) complete set of electronic application materials on CD-ROM (including clinical trial database, if applicable) for review
• Submit one (1) complete set of electronic declaration materials on CD-ROM (including clinical trial database, if applicable) for verification at the same time.
• For clinical trial database data, the relevant materials must be prepared in a separate set of CD-ROMs.

Additionally, the ElectronicApps-Rqts states that within five (5) working days after the acceptance of the drug registration application, the applicant must upload a Microsoft Word file of the application materials (e.g., pharmacy, non-clinical, and clinical reviews) through the CDE’s Applicant Window (CHN-58). The documents related to pharmaceutical materials (active pharmaceutical ingredients (APIs), pharmaceutical excipients, and pharmaceutical packaging materials) should be uploaded as PDF files. Further, per the DRR, supplementary materials (e.g., clinical trial research materials, consultations, and data submittals) are handled via the CDE’s Applicant’s Window (CHN-58).

Note that per CHN-14, all application materials must be in Chinese with the original language attached, and materials in other languages can be attached as reference. Chinese translations should be consistent with the original text.

The NMPA-No44-2020, the NMPA-No43-2020, and the NMPA-No10-2018 require applicants to apply the International Council for Harmonisation (ICH)’s M4: Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD) (CHN-38) to the registration applications for drugs, therapeutic biological products, and vaccines. See the NMPA-No16-2018 for guidance on Phase I clinical trial applications. To standardize the submission of drug clinical trial data, meet the newly revised drug registration application data requirements, and improve the efficiency of drug review, the NMPA-No16-2020 provides guidance on the content and format of clinical trial data. The guidance is based on the data submission requirements of international regulatory agencies, including the Clinical Data Interchange Standards Consortium (CDISC).

For administrative support, applicants can request a meeting and/or consult the NMPA’s Government Service Portal (CHN-71).

Bioequivalent Studies

Per the NMPA-No230-2015, for generic drugs, a bioequivalence study will only need to be filed with the NMPA. The applicant should submit record filing materials to the NMPA 30 days before submitting the bioequivalence studies. For the generic drug filing, the applicant must obtain EC approval and sign a clinical study agreement with the clinical site prior to filing the bioequivalent study. See CHN-70 for handling guidelines for bioequivalent drugs.

Priority and Special Procedures

In addition, the DRR authorizes regulatory pathways for priority review and approval (including for breakthrough therapeutic drugs), conditional approval and special approval procedures. Per CHN-69, after the registration application is transferred to the CDE, applicants can apply for accelerated review directly to the CDE at CHN-58. CHN-69 contains the application and additional procedures for submitting applications for priority review and approval. As per the SC-Opinions-No44, the NMPA-No230-2015, and the NMPA-No51-2016, a new drug classification system, priority review for innovative drugs and those deemed to have an urgent clinical need, and other changes help China to be more innovative and expedite reviews. As delineated in the NMPA-No23-2018, for drugs listed overseas and that treat seriously life-threatening conditions, if there is no ethnic difference in the study, they can submit the clinical trial data obtained overseas and directly apply for the drug listing registration.

Protocol Changes

As delineated in the NMPA-No34-2022, when there is a protocol change during a clinical trial, the sponsor should follow these submission guidelines:

• For substantial changes that may significantly increase the risk to participant safety, the sponsor must submit a clinical trial application as per the instructions above
• For substantial changes that do not significantly increase participant safety risk, but may significantly affect the scientific validity and the reliability of the data, the sponsor should submit a communication meeting application to the CDE (see above)
• Non-substantive changes can be implemented after being approved by the EC and filed with the NMPA
• After the protocol is changed, the sponsor must update the drug clinical trial registration (See the Initiation, Agreements & Registration section) and submit the relevant updates in progress reports

National Health Commission

Per the MgmtHumanGen and the Rules-MgmtHGR, the foreign entity and the Chinese entity must jointly file an application for approval to MOST (now the NHC) and pass an ethics review in the partners’ countries. The only exception to the MOST (now the NHC) approval requirement is international collaboration in clinical trials that do not involve the export of Chinese HGR materials such as organs, tissues, or cells comprising the human genome, genes, or other genetic substances—these must be filed with MOST (NHC), which will generate a record number (see below for steps) and pass an ethics review in the partners’ countries.

As stated in the HGR-AppGuide, the HGR license application must be submitted to NHC via the Human Genetic Resources Service System (CHN-6), including application information and supporting materials. After verification, the system posts updates for the applicant.

See HGR-InfoSys for background on the online platform and contact information. For help with the online platform, contact Zhu Min, NHC’s China Biotechnology Development Center, at 010-88225151 or 010-88225168; or the information system support at 17610386080.

Ethics Review Submission

Each institutional and regional EC has its own required submission procedures.

Overview

In accordance with the MHCTR, the MHCTR2006, the G-CTApp, and GBR-9, the United Kingdom (UK) requires the sponsor or the designated legal representative to obtain clinical trial authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA) prior to initiating the trial. Per G-CTApp and G-IRASCombRev, the UK’s combined review process offers a single application route and coordinated/parallel review from MHRA and the ethics committee (EC) leading to a single UK decision for clinical trials.

Note: G-CTApprovedCountries and the MHCTR-EUExit list the countries where a clinical trial sponsor or their legal representative may be established; these countries are initially European Union (EU) and European Economic Area (EEA) countries.

Combined Review Submission

Per G-CTApp and G-IRASCombRev, all new clinical trials applications of investigational products (CTIMPs) must be prepared, submitted, and reviewed via the combined review process using the Integrated Research Application System (IRAS) (GBR-125). For support and getting started, users should review GBR-72 and contact the combined review team at cwow@hra.nhs.uk. Step-by-step instructions are provided in G-IRASCombRev. As delineated in GBR-9, applications submitted via the combined review service are submitted jointly by the chief investigator and the sponsor. Per GBR-116, applicants seeking fast-track review of clinical trial applications must also apply via combined review on GBR-125. Per the G-CTApp, MHRA’s notification scheme enables a more streamlined and risk-proportionate approach to processing clinical trial authorization for “initial” applications. The scheme only applies to clinical trial applications for Phase 4 and certain Phase 3 clinical trials deemed to be of lower risk. Interest in the notification scheme should be registered via the combined review process (GBR-125). Per G-ATMP, all advanced therapy medicinal products must submit clinical trial applications using the same processes as all other medicines. See Scope of Review section for fast-track eligibility criteria.

Per GBR-122, for studies that were submitted before combined review, these applicants should continue to submit amendments and reports for these studies at IRAS via GBR-78’s log-in. HRA will update sponsors and applicants with full instructions and plenty of notice for any planned changes in the future, such as the migration of existing, ongoing studies. See GBR-122, for additional details on the migration of existing materials in IRAS. GBR-72 includes learning resources and a video on the combined review process.

G-IRASCombRev contains a step-by-step guide to combined review submission. The following is an overview of the steps:

• Finalize protocol and supporting documents
• New users create IRAS account and create a new project and allocate roles
• Complete project details, study information, and clinical trial dataset in IRAS and upload supporting documentation
• Send application to the sponsor to review and authorize
• Book an EC online and submit application

G-IRASCombRev indicates that when selecting an EC meeting that is not the first available meeting, the 60-day regulatory clock for both the EC and the MHRA will start on the cutoff date for the meeting that is chosen, which is 14 days before the meeting date. Once booked, the EC booking page will update to show the confirmed booking details. The applicant will then be able to scroll down the page to select the option to “submit to the regulators.” See G-IRASCombRev for detailed step-by-step instructions.

For overall help during the submission process, see the CTapp-Issues which identifies common issues with validation and assessment of clinical trial applications and how to avoid them.

Other regulatory information aside from new clinical trial applications are to be submitted pursuant to the G-MHRASubmiss. These submittals include substantial amendments for existing clinical trials, end-of-trial notifications, and developmental safety update reports (DSURs). The G-CTAuth-GBR also states that clinical trials not approved or yet transitioned over to the combined review process should continue to use the online MHRA Submissions portal (GBR-13). The steps for gaining access to GBR-13 are contained in the G-MHRASubmiss and GBR-11.

For overviews of submittals to MHRA, see GBR-18. Also see the Initiation, Agreements & Registration section for information on obtaining a trial identification number during trial registration.

The UKwide-Rsrch provides guidance and requirements for research in more than one (1) United Kingdom (UK) nation, and specifies that the four (4) nations of the UK take a consistent approach to study-wide reviews so that sponsors only need to submit one (1) application on GBR-125 in most circumstances. Each UK nation will take assurances from the site-wide review conducted by the lead nation (the nation conducting the initial review).

As described in GBR-78, other relevant approvals can be sought on the IRAS site. For example, applicants can request inclusion in the National Institute for Health and Care Research Clinical Research Network (NIHR CRN) Portfolio, which comprises high-quality clinical research studies that receive support services from the Clinical Research Network in England.

Per G-CTApp, MHRA supports the conduct of trials with complex innovative designs such as umbrella, basket, platform, and master protocol plus submodules. When submitting a clinical trial application for a trial with innovative designs that involve prospective major adaptations, the sponsor must justify the choice of a complex trial design, ensure that each adaptation as well as the entire trial are safe and scientifically sound, and describe how the integrity of trial results will be maintained throughout the conduct of the trial. See G-CTApp for example scenarios of when it is appropriate to propose major adaptations via submission of a substantial amendment request. Before submitting an application for authorization of a trial with a complex innovative design and/or an amendment requesting approval of major adaptations, sponsors are recommended to establish a dialogue with the MHRA and seek advice.

As delineated in the MHCTR, the clinical trial application and accompanying material must be provided in English.

Regulatory Authority Requirements

National Medical Products Administration

As delineated in the NMPA-No51-2023, the applicant must submit the following materials to the National Medical Products Administration’s (NMPA) Center for Drug Evaluation (CDE) to have a communication meeting prior to submitting a clinical trial application for an exploratory clinical trial:

• The overall clinical development plan
• A complete first clinical trial protocol
• A risk management plan
• A subsequent clinical trial protocol, if applicable
• Non-clinical research review
• Pharmaceutical research review, etc.
• A clear statement of the issues to be communicated

Next, the NMPA-No51-2023 states that prior to completing the exploratory clinical trial, the applicant must submit the following to CDE for another meeting to discuss conducting the confirmatory (or critical) clinical trial and the subsequent clinical trial protocol:

• A preliminary analysis of the results of the early clinical trials that have been conducted
• A scientific, reasonable, complete, and feasible confirmatory (or critical) clinical trial protocol based on the existing clinical trial data
• A risk management plan
• A review of non-clinical studies
• A review of pharmaceutical studies, etc.

Per the DRR, after completing the pharmacology, toxicology, and other studies supporting the clinical trials of the drug, the applicant must submit relevant research materials to the NMPA. When applying for drug registration, the applicant must provide true, sufficient, and reliable data, materials, and samples to prove the safety, effectiveness, and quality controllability of the drug. In cases where overseas research materials and data are used to support drug registration, its source, research institution, or laboratory conditions, quality system requirements, and other management conditions should conform to prevailing international principles and applicable Chinese drug registration management requirements. CHN-14, CHN-70, and CHN-69 contain application materials and handling guidelines covering domestic drug and biological product clinical trial applications; imported drug and biological product clinical trial applications; priority review application procedures; and bioequivalence filing procedures. In general, the applications require information about the drug (e.g., names, formulation and ingredients, indications, and packaging), patents, the applicant, and the institution(s). In addition, the applications require a declaration attesting that the application and associated materials comply with the DAL, the DRR, and other applicable laws and regulations. The application and submitted data and samples must be true and legal, and they should not infringe on the rights and interests of others. The content of the electronic file submitted must be the same as the printed file. If any data is found to be false, the applicant bears the legal consequences caused by it.

The NMPA-No51-2023 requires the applicant to submit the following materials with the clinical trial application, in accordance with the NMPA-No44-2020 and the NMPA-No43-2020:

• A complete clinical research and development protocol
• A complete plan for the proposed clinical trial
• A risk management plan
• A framework for the subsequent clinical trial plan (if applicable)

The NMPA-No16-2018 provides guidance on technical information to be included in the application dossier for Phase I clinical trials:

• Introductory description and overall research plan
• Researcher’s manual (Investigator’s Brochure (IB))
• Clinical trial plan
• Pharmacy research information
• Pharmacology and toxicology information
• Description of previous clinical use experience
• Overseas research material

Per the SC-Opinions-No42, the NMPA-No10-2018, and CHN-14, that applicants should apply the International Council for Harmonisation (ICH)’s M4: Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD) (CHN-38) to the registration applications for drugs, therapeutic biological products, and vaccines.

See CHN-20 for additional analyses and overview of the China clinical trial application submission content.

National Health Commission

Per the NHC-HGRmgt, the National Health Commission (NHC) is responsible for China’s management of human genetic resources (HGR). (Note that per SC-Order777 and NHC-HGRmgt, management of HGR was transferred from the Ministry of Science and Technology (MOST) to NHC, effective May 1, 2024. Please note that SC-Order777 amends the MgmtHumanGen to reflect the transfer of HGR management from MOST to the NHC)). The NHC-HGRmgt states that the original application process and platform (CHN-6) remain unchanged.

The MgmtHumanGen requires that applications for a license to collect or preserve HGR meet the following conditions:

• Applicants prove legal person status
• The purpose of collection and/or preservation is clear and legal
• The collection and/or plan is reasonable
• In the case of preservation, the premises where the HGR will be deposited is legal
• Proof of passing ethics review
• Having a department and management system responsible for the management of collecting and/or preserving the HGR
• Having premises, facilities, equipment, and personnel suitable for collection and/or preservation activities

As delineated in the MgmtHumanGen, the application for international collaborative scientific research using China’s HGR must demonstrate:

• The research is not harmful to the public health, national security, or social public interests of China
• The two (2) parties to the cooperation are a Chinese entity and a foreign entity with legal person status and have the basis and ability to carry out relevant work
• The purpose and content of the cooperative research are clear and legal, and the duration is reasonable
• The cooperative research plan is reasonable
• The HGR to be used are of legal origin, and their types and quantities are consistent with the research content
• The research passed an ethics review of the respective countries (regions) of the cooperation parties
• The ownership of the research results is clear, and there is a reasonable and clear profit distribution plan

Information on the submission content for the HGR export license is summarized in the Specimen Import & Export section.

Ethics Committee Requirements

Each ethics committee (EC) has its own application form and clearance requirements that can differ significantly regarding the number of copies to be supplied and application format requirements.

The following list was compiled from the Measures-Ethics and the RegEthics to exemplify the common elements shared by the various application forms (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Application for Human Research Ethics Review (See CHN-27 for a sample institutional application)
• Application Protocol for Results of Research or Related Technologies
• Protocol
• Sample ICF (See Children/Minors section for additional information)
• Case Report Form
• Principal investigator(s) CV(s)
• NMPA approval letter
• Certificate of Analysis for the drug issued by the National Institutes for Food and Drug Control (NIFDC) or corresponding provincial, autonomous region, or municipal institutes
• IB
• Any additional feedback from other ECs participating on the protocol
• Statement of planned tasks
• Letter of intention for cooperation
• Letter of commitment on the reliability of research materials
• Scientific opinions
• Statement of no conflict of interest
• Proof of the source of biological samples and information data
• Site list
• Site profile(s)
• Product literature
• Insurance policy (if any)
• Materials provided to participants
• Information on the lead research investigator; the legal qualification certificate of the institution; and the source of research funding
• Recruitment advertisements and their release forms
• An explanation of the form of publication of research results
• Other relevant materials that the EC believes need to be submitted

Clinical Protocol

As delineated in the NMPA-GCP-No57-2020 and the ICH’s Guideline for Good Clinical Practice E6(R2) (CHN-37), the clinical protocol should include the following elements (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• General information
• Background information
• Trial topic, purpose(s), and objective(s)
• Sponsor name and address
• Trial site location
• Principal investigator(s) name(s), qualification(s), and address(es)
• Trial design, random selection method, and blinding level
• Inclusion criteria; participant treatment, inclusion, exclusion, and release procedures; and method of grouping participants
• Form, dosage, route, method, and frequency of administration; treatment period; usage order of concomitant medicines; and packaging and labeling description
• Investigational product registration, usage record, delivery, handling and storage conditions (See Investigational Products topic for detailed coverage of this subject)
• Efficacy assessment
• Safety assessment
• Statistics
• Direct access to source data/documents
• Quality control/quality assurance
• Ethics
• Data handling/recordkeeping
• Financing/insurance
• Clinical observations, on-site visits, and measures to ensure the participant’s compliance with trial procedures
• Rules regarding clinical trial termination and completion
• Adverse event recording requirements, and serious adverse event reporting methods (See Safety Reporting section for additional information)
• Proposed trial schedule and completion date
• Publication policy

For complete protocol requirements, please refer to Chapter 6 of the NMPA-GCP-No57-2020 and Section 6 of CHN-37.

Regulatory Authority Requirements

As specified in the G-CTApp, a clinical trial submission package to the Medicines and Healthcare Products Regulatory Agency (MHRA) should contain the following documents:

• Cover letter (when applicable, the subject line should state that the submission is for a Phase 1 trial and is eligible for a shortened assessment time, or if it is submitted as part of the notification scheme); this letter should clearly highlight the Purchase Order (PO) number to help the MHRA invoice and allocate payments promptly and efficiently
• Clinical trial application form in PDF and XML versions
• Protocol document
• Investigator’s brochure (IB)
• Investigational medical product dossier (IMPD) or a simplified IMPD
• Summary of scientific advice obtained from the MHRA or any other regulatory authority, if available
• Manufacturer’s authorization, including the importer’s authorization and Qualified Person declaration on good manufacturing practice for each manufacturing site if the product is manufactured outside the European Union (EU) (See G-ImportIMPs and the Manufacturing & Import section for more information)
• Copy of the United Kingdom (UK) or the European Medicines Agency’s decision on the pediatric investigation plan and the opinion of the pediatric committee, if applicable
• Content of the labelling of the investigational product (IP) (known as investigational medicinal product (IMP) in the UK) (or justification for its absence)

Ethics Committee Requirements

As per the MHCTR, the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), ECs require the chief investigator (CI) to submit the following documentation for ethics approval:

• Application for an EC opinion
• A summary of the trial, including justification, relevance, and methodology to be used
• Research hypothesis
• Statistical analysis and justification for the numbers of participants to be recruited
• Protocol
• IB
• Peer review process details
• Sponsor name and contact information
• Financial arrangements for the trial (e.g., funding sources, participant reimbursement, compensation provisions in the event of trial-related injury or death, and insurance or indemnity coverage for sponsor and investigator(s)) (See the Insurance & Compensation section for additional information)
• Terms of agreement between sponsor and participating institution(s)
• Material to be used (including advertisements) to recruit potential research participants (See the Initiation, Agreements & Registration section for additional information on participant recruitment)
• Informed consent form and copies of materials to be provided to participants (See the Required Elements section for additional information)
• Participant treatment plans
• Benefit/risk assessment for participants
• Investigator(s) Curriculum Vitaes (CVs)
• Trial design and suitability of facilities

Further, to help with planning before seeking EC approval, GBR-18 provides a checklist for CIs.

Clinical Protocol

Per GBR-9, the protocol describes the objectives, design, methodology, statistical considerations and organization of a clinical trial. According to GBR-113, the clinical protocol should contain the following elements:

• Protocol summary
• Sponsor or designated representative name and contact information
• Investigator(s) CV(s) and contact information
• IP description (See the Investigational Products topic for detailed coverage of this subject)
• Form, dosage, route, method, and frequency of administration; treatment period
• Trial objectives and purpose
• Trial design, random selection method, and blinding level
• Participant selection/withdrawal
• Participant treatment
• Summary of potential risks and known benefits to research participants
• Safety and efficacy assessments
• Adverse event reporting requirements (See the Safety Reporting section for additional information)
• Statistics and methods to track trial data
• Sponsor specifications for direct access to source data/documents
• Quality control/quality assurance procedures and practices
• Ethical considerations
• Data management and recordkeeping
• Financing and insurance details
• Publication policy

For complete protocol requirements, refer to GBR-113.

Overview

As stated in the DRR, ethics committee (EC) review may be submitted parallel to the National Medical Products Administration (NMPA) review, but the study cannot be initiated until after review and approval by the EC.

Per the NHC-HGRmgt, the National Health Commission (NHC) is responsible for China’s management of human genetic resources (HGR). (Note that per SC-Order777 and NHC-HGRmgt, management of HGR was transferred from the Ministry of Science and Technology (MOST) to NHC, effective May 1, 2024). The Bioscrty-Law, the MgmtHumanGen, and the Rules-MgmtHGR, delineate that MOST (now the NHC) is responsible for China's management of HGR, which includes reviewing and approving research. Per the Rules-MgmtHGR, the collection, preservation, use, and external provision of China’s HGR must comply with ethical principles and pass the ethics review of ECs that have been registered with the relevant management departments. As part of the application filing for international cooperative clinical trials, NMPA approvals, notices, and/or filing registration must be obtained in advance. In addition, EC approvals must be submitted with the filing, so therefore cannot occur in parallel. (Please note that SC-Order777 amends the MgmtHumanGen to reflect the transfer of HGR management from MOST to the NHC, but the Bioscrty-Law and the Rules-MgmtHGR have not been amended to show the transfer.)

Regulatory Authority Approval

National Medical Products Administration

Per the DRR, upon application submittal, the NMPA will complete the administrative examination for completeness within five (5) days of receiving the application, and issue a notice of acceptance. If the application does not meet the technical requirements for review, the NMPA will notify the applicant, who must submit the additional information within five (5) days of the notice. According to CHN-14, the NMPA will process clinical trial applications within five (5) working days if the study falls within the scope of its authority; the application materials are complete and comply with the legally-prescribed format; and the applicant submits all supplementary application materials in accordance with the NMPA’s requirements. Per the DRR, the NMPA-No50-2018, and CHN-14, a clinical trial application will be considered approved after 60 working days if the applicant does not receive a rejection or an inquiry for clarification from the NMPA. These procedures do not apply in every situation and additional reforms are provided below.

The DRR indicates that the following is not included in the above time limits:

• Time taken by the applicant for supplementary information, rectification after verification, and verification of production processes, quality standards, and instructions as required
• Delays in the time of verification, inspection, and expert consultation meetings
• If the review and approval procedure is suspended, the time occupied during the period of suspension of the review and approval procedure
• Time taken by the initiation of overseas verification

The application review by the Center for Drug Evaluation (CDE) and inspections and testing by National Institutes for Food and Drug Control (NIFDC) can affect the timeline beyond 60 days, as needed. The CDE conducts technical reviews and the NIFDC tests drug samples. The NMPA-No51-2023 specifies that if necessary, an expert consultation meeting may be held. For clinical trials that are approved after review, the technical review team’s conclusion and associated "Clinical Trial Approval Notice" must clearly state the indications, clinical trial protocol title, number, version number, version date, etc. The review team’s conclusion and notice may propose revisions or suggestions to the clinical trial protocol if necessary. For clinical trial protocols that require revisions, CDE will notify the applicant through a professional inquiry letter, clearly informing the applicant of the problems and revision opinions in the current protocol. The applicant must submit a revised clinical trial protocol within five (5) days, following the guidance in the Prcdrs-Changes.

According to the NMPA-No82-2020, the NMPA timelines for review and decisions for expedited applications are as follows: The CDE will review the application for breakthrough drug procedures submitted by the applicant and, if necessary, organize an expert advisory committee for demonstration. The CDE must report the review results to the applicant within 45 days after receiving the application. If it is necessary to extend the review time limit, the extended time limit must not exceed one-half of the original review time limit. The CDE must publicize the specific information and reasons for the types of drugs to be included in the breakthrough therapy program, including the name of the drug, the applicant, the proposed indication (or functional indication), the application date, and the reason for the proposed inclusion. If there is no objection within five (5) days of the public announcement, it will be included in the breakthrough treatment drug program; if an objection is raised against the publicly announced product, a written opinion must be submitted to the CDE within five (5) days; the CDE must organize another review and make a decision within 15 days and notify all relevant parties.

Per the NMPA-No79-2018, for applications to conduct clinical trials with drugs treating rare diseases with urgently needed drugs already on the market in the United States, Europe, and Japan in the past decade, the CDE completes the technical review within three (3) months after acceptance; for other overseas new drugs, the technical review is completed within six (6) months after acceptance.

The NMPA-No21-2024 describes NMPA’s pilot work plan for optimizing the review and approval of clinical trials for innovative drugs. This initiative aims to review and approve innovative drug clinical trial applications within 30 business days (a reduction from the 60 days as described above in the normal procedures). The applicant must initiate the clinical trial within 12 weeks after the approval of the clinical trial application. The pilot work will last for one (1) year and the experience of the pilot work will be summarized in July 2025. For application and eligibility details see NMPA-No21-2024 and Scope of Assessment section.

For additional details on other expedited review pathways, see the Scope of Assessment section.

National Health Commission

Per the HGR-AppGuide, for HGR license applications, the NHC will pre-screen the electronic application to ensure it is complete. If the application does not pass, then the applicant will have one (1) opportunity to correct the submission. Per Rules-MgmtHGR, MOST (now the NHC) must make an administrative licensing decision on HGR license applications within 20 working days of acceptance. HGR-AppGuide reiterates the 20 working-day deadline by NHC, the agency currently authorized to approve HGC licenses. The Rules-MgmtHGR states that where an administrative licensing decision cannot be made within 20 working days, it may be extended by 10 working days with the approval of MOST (now the NHC), and the reason for the extension must be notified to the applicant. If it is necessary to conduct hearings, inspections, testing, quarantine, appraisals, and technical reviews, this additional time required must not be counted within the time limit, and the applicant must be notified in writing of the required time.

Ethics Committee Approval

In accordance with the Measures-Ethics, the EC must carry out an ethics review and issue its opinion within 30 days of acceptance. In urgent situations, an ethics review must be promptly carried out. In the case of emergencies such as outbreaks, ethics reviews and review opinions are generally carried out within 72 hours, and the requirements and quality of ethics reviews must not be reduced. Per the NMPA-GCP-No57-2020 and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CHN-37), the institutional EC should review a proposed clinical trial within a reasonable time. The EC’s recommendations should be issued in writing and should indicate an approval; an approval after necessary modifications have been made; a disapproval; or a decision to terminate or suspend an already approved trial.

Overview

Per G-CTApp and G-IRASCombRev, all new clinical trials applications for investigational products (CTIMPs) must be prepared, submitted, and reviewed via the combined review process. Combined review offers a single application route and coordinated/parallel review from the Medicines and Healthcare Products Regulatory Agency (MHRA) and the ethics committee (EC) leading to a single United Kingdom (UK) decision for clinical trials.

Combined Review

Per the G-CTApp and GBR-72, the initial combined review assessment will be completed within 30 days of being submitted. The G-CTApp indicates that applications for healthy volunteer trials and sponsor-determined phase 1 trials in non-oncology participants may qualify for a shortened assessment time and MHRA will work with the EC to expedite these applications. The MHRA and the EC will inform applicants of the outcome of a submission. If there are grounds for non-acceptance of the application, the applicant will have the opportunity to respond, usually within 14 days, though this may be extended on request. Communication informing the applicant of the MHRA and EC decisions following receipt of the responses will usually be sent within 60 days of receiving the original valid application. If an extension to the response date has been agreed to, then this will impact the final decision timeline. Notification of the decision relating to a gene therapy, somatic cell therapy (including xenogenic cell therapy) product, tissue engineered product, or products containing genetically modified organisms will be sent within 90 days of receiving the original application unless otherwise advised.

The G-CTApp states that the MHRA uses automated electronic communication. To ensure receipt of MHRA correspondence, applicants should add MHRA_CT_Ecomms@mhra.gov.uk to their safe sender email list. MHRA will only send official correspondence to the named applicant email address. According to the MHCTR, if the sponsor or the designated representative does not receive a request for additional information from the MHRA within 30 days, the clinical trial application is treated as authorized.

Regarding the new notification scheme, the G-CTApp states that this pathway enables a more streamlined and risk-proportionate approach to processing clinical trial authorization for “initial” applications for Phase 4 and certain Phase 3 clinical trials deemed to be of lower risk. Applications submitted under this scheme will be processed by the MHRA within 14 calendar days from the application received effective date, provided the sponsor can demonstrate the trial meets the inclusion criteria. Authorization by the MHRA will be granted unless any criterion is not suitably met. If the MHRA determines the application does not meet the criteria, an objection decision will be communicated within 14 calendar days from the application received effective date, and the application will continue under the full authorization assessment with a decision communicated within the 30-day statutory timeframe.

In addition, as stated in the G-CTApp, certain first-in-human (Phase 1) trials of investigational products with higher risk or greater elements of uncertainty require the MHRA to seek advice from the Clinical Trials, Biologicals, and Vaccines Expert Advisory Group (CTBV EAG) of the Commission on Human Medicines (CHM) before approval for the trial can be given. See the G-CTApp for detailed requirements.

Overview

Per the DRR, clinical trials must be conducted in institutions conducting drug clinical trials that comply with relevant regulations, and abide by the NMPA-GCP-No57-2020, including written approval from the ethics committee (EC) to the researcher before clinical trial implementation. Further, clinical trials of vaccines must be implemented or organized by China’s designated three-level medical institutions or disease prevention and control institutions at or above the provincial level that meet the prescribed conditions.

Per the NHC-HGRmgt, the National Health Commission (NHC) is responsible for China’s management of human genetic resources (HGR). (Note that per SC-Order777 and NHC-HGRmgt, management of HGR was transferred from the Ministry of Science and Technology (MOST) to NHC, effective May 1, 2024). The Bioscrty-Law, the MgmtHumanGen, and the Rules-MgmtHGR delineate that MOST (now the NHC) is responsible for China's management of HGR, which includes reviewing and approving research before initiation. Per the Rules-MgmtHGR, clinical trials involving the collection, preservation, use, and export of China’s HGR must be approved by ECs in the relevant institutions. Further, applications for administrative licenses for international cooperation clinical trials (without exports) using HGR must pass an ethics review in the partner countries and be filed with MOST (now the NHC) before initiating the study. The Rules-MgmtHGR also state that clinical trial applications must pass a security review organized by MOST (now the NHC) if the study’s provision or opening of HGR information to foreign entities may impact China’s public health, national security, or the social public interest.

Clinical Trial Agreement

As delineated in the NMPA-GCP-No57-2020 and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CHN-37), the sponsor must sign an agreement or contract with the participating institution(s). The NMPA-GCP-No57-2020 also states that before the trial begins, the sponsor and the investigator must sign a written agreement regarding the trial protocol, monitoring, auditing, and standard operating procedures, as well as each party’s responsibilities during the trial.

Per the NMPA-GCP-No57-2020, the agreement must include the following elements:

• Compliance with this specification and relevant clinical trial laws and regulations during the implementation of clinical trials
• Implementation of the trial protocol agreed to by the sponsor and investigator, and approved by the EC
• Compliance with data recording and reporting procedures
• Consent to supervision and inspection
• Retention period of necessary documents related to clinical trials
• The agreement on publishing articles and intellectual property rights

Clinical Trial Registration

Per the DRR, the sponsor must register the drug clinical trial plan and other information on the drug clinical trial registration and information disclosure platform before launching the drug clinical trial. The NMPA-No9-2020 requires the National Medical Products Administration (NMPA)'s Center for Drug Evaluation (CDE) to establish and maintain this registry (CHN-53). Before starting a clinical trial, the clinical trial information must be registered in any of these situations:

• The clinical trial has been approved by the NMPA
• The clinical trial of a chemical drug bioequivalence test was recorded and the record number obtained
• Phase IV clinical trials and post-marketing studies were conducted in accordance with the requirements of the drug registration certificate or NMPA notice
• Other situations required for registration according to the NMPA

Also see the handling guideline for clinical trial registration (CHN-13) for more information and frequently asked questions.

Governance

Pursuant to the NHC-ClinProjMgmt, medical institutions must develop internal rules and standard operating procedures (SOPs) for administering clinical studies; centralize financial management of clinical study projects; and maintain a project-based approval system and supervision throughout the study process. In addition to having an EC, medical institutions must also establish a Clinical Study Administration Committee and a subordinate body, and a Clinical Study Administration Division to handle daily project administration. For detailed requirements, see the NHC-ClinProjMgmt.

Overview

In accordance with the MHCTR, the MHCTR2006, and GAfREC, a clinical trial can only commence after the sponsor or the designated representative receives authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA) and the chief investigator (CI) receives an approval from a recognized ethics committee (EC). In addition, GBR-9 clarifies that a favorable EC opinion does not imply that research activity at sites can begin. Confirmation of management permission or approval from relevant care organization(s) to proceed with the research also needs to be in place. In addition, if the EC issued a favorable opinion with additional conditions, the clinical trial cannot start until these conditions are met. GBR-18 indicates that once all the relevant approvals are in place, all documentation has been finalized, and all participating sites have the information they need, the trial can begin. This process is often achieved by holding a start-up meeting at each site so that the CI ensures all technical aspects of a trial and protocol requirements are fully understood by relevant site staff. Trial-specific training (protocol and procedures) and review of trial conduct (e.g., safety reporting) is often undertaken at this stage. For clinical trials of an investigational product (IP), this communication should also include pharmacy staff, if applicable, so that they can confirm all requirements are in place before dispensing IPs to participants.

See GBR-40 for information about DigiTrials, which supports clinical trials in England to provide safe, authorized access to patient data to help set up trials. DigiTrials includes recruitment and feasibility services to identify whether there are enough suitable participants, as well as participant communication and outcomes services.

Per the MHCTR and GBR-18, specific documentation, including MHRA licensing, must be in place before an IP can be released for a clinical trial.

As stated in the MHCTR, clinical trials should be conducted in compliance with the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), and laboratory practices for IPs must comply with the UK-GLPs. Per the CTIMP-Condtns, MHRA assumes that the trial will commence within 12 months of the date of the favorable ethical opinion. The EC must be notified of the trial start date with evidence of the authorization. Further, the trial should not commence at any site until management permission has been obtained from the organization responsible for the care of the participants at the site. If the trial does not commence within 12 months of the favorable opinion being issued, the sponsor should send the EC a written explanation for the delay. A further written explanation should be sent after 24 months if the research has still not commenced. If the trial does not commence within 24 months of the favorable opinion being issued, the EC may recommend to the MHRA that the clinical trial authorization should be suspended or terminated. See CTIMP-Condtns for additional information on standard conditions for clinical trials.

Per GBR-78, all project-based research must also have governance and legal compliance approvals from the appropriate lead United Kingdom (UK) Health Department. The Integrated Research Application System (IRAS) (GBR-78) facilitates this process. As described in GBR-67, approval from the Health Research Authority (HRA) is required for all National Health Service (NHS) project-based research led from England or Wales. HRA and Health and Care Research Wales (HCRW) approval brings together the assessment of governance and legal compliance. For any new studies that are led from Scotland or Northern Ireland but have English and/or Welsh NHS sites, the national research and development coordinating function of the lead nation will share information with the HRA and HCRW assessment teams, who can issue HRA and HCRW approval for English and Welsh sites and thereby retain existing compatibility arrangements. Studies led from England or Wales with sites in Northern Ireland or Scotland will be supported through existing UK-wide compatibility systems, by which each country accepts the centralized assurances, as far as they apply, from national coordinating functions without unnecessary duplication. For more information on HRA’s assessment criteria and standards for approval, see GBR-29.

Clinical Trial Agreement

According to GBR-107 and GBR-70, contracts and agreements should be in place prior to the initiation of a trial. GBR-107 provides model templates for industry-sponsored clinical trials with the NHS/Department of Health and Social Care (DHSC) participants in hospitals throughout the UK Health Services, which encompasses England, Northern Ireland, Scotland, and Wales. Applicants are advised to use the templates without modification. Any proposed modifications will not be accepted unless first agreed to by the UK Contracting Leads. Proposing modifications to the templates is likely to result in significant delay.

GBR-107 also provides the model non-commercial agreement (mNCA) template to meet the requirements of non-commercial sponsors and the NHS/DHSC bodies undertaking the research. This agreement has been developed as a single, UK-wide agreement template, meaning that it can be used irrespective of where the sponsor and research site are established. It is designed to be used without modification or negotiation. The mNCA has been developed for a range of interventional research scenarios, including clinical trials, medical device studies, research using participant data, and research using human tissue. The terms and conditions are suitable for all such scenarios and only the completion of highlighted sections, including the schedules of the agreement, will differ depending on the study involved.

The UKwide-Rsrch reiterates that national model contracts are available and, as such, contracting expectations and arrangements across the four (4) UK nations are broadly similar. For all four (4) nations:

• In commercially sponsored research, it is mandatory to use the unmodified contract templates appropriate to the study type
• In non-commercially sponsored research, it is expected that the unmodified contract appropriate to the study type is used; use of bespoke or modified agreements, where an appropriate template exists, is likely to result in significant delay and costly review; any modifications must be highlighted in the application

The UKwide-Rsrch also highlights national differences relating to the way contractual agreements are reviewed and agreed. In England and Wales, sponsors must obtain a waiver from HRA and HCRW to use a modified or bespoke agreement (an agreement that differs from a published UK-wide model agreement template). This waiver allows NHS sites to freely negotiate all the contractual terms of the agreement; in Wales, this negotiation is carried out with a central team. In Northern Ireland, to modify the UK-wide model agreement template, a waiver is needed from the Health and Social Care R&D Approvals Service, which allows sites to freely negotiate all the contractual terms of the agreement. In Scotland, sponsors can expect to carry out a single contract negotiation for all Scottish sites, which will be negotiated with a nominated lead site or central team. If the study is single center, it will be negotiated at the relevant site.

Additional details and templates are available in GBR-107 and GBR-70.

Clinical Trial Registration

As per the GBR-102 and the G-CTApp, the sponsor or investigator is required to register the clinical trial in a publicly accessible database as a condition of a favorable ethical opinion. Registration should occur before the first participant is recruited and no later than six (6) weeks after recruitment of the first participant. To help researchers meet the UK’s transparency requirements, GBR-102 indicates that the HRA will automatically register approved clinical trials with the International Standard Randomised Controlled Trial Number (ISRCTN) Registry (GBR-47) to ensure that information is publicly available. ISRCTN is the UK’s preferred clinical trials registry. HRA’s commitment to register clinical trials on behalf of sponsors and researchers is in line with the “Make It Public” research transparency strategy (see GBR-55).

Per GBR-18, each clinical trial must have a unique trial number. Clinical trials with sites in the European Union (EU), the European Economic Area (EEA), or Northern Ireland should also apply for a European number. Per GBR-87, as of January 31, 2023, all new clinical trials with sites in Europe should register on the new Clinical Trials Information System (CTIS) (GBR-39). GBR-39 specifies that by January 31, 2025, any ongoing trials must be transitioned from EudraCT (GBR-87) to GBR-39. For more information, see the EudraCT transition fact sheet (GBR-16). CTIMP-Condtns indicates that for clinical trials involving sites in both the UK and the EU, a record in EU’s GBR-39 does not satisfy the public registry condition because the UK component of the trial will not be visible in CTIS (GBR-39). Failure to register is a breach of the clinical trial conditions unless a deferral has been agreed to.

Per GBR-102, HRA also recognizes any registry covered by the World Health Organization (WHO) or the International Committee of Medical Journal Editors (ICMJE), such as clinicaltrials.gov (GBR-49). For any submissions prior to December 31, 2021, the applicant should have registered their clinical trial on an established international register.

Safety Reporting Definitions

In accordance with the NMPA-GCP-No57-2020, the following definitions provide a basis for a common understanding of China’s safety reporting requirements:

• Adverse Event (AE) – All adverse medical events that occur after participants receive the experimental drugs. They can be manifested as symptoms and signs, diseases, or abnormal laboratory tests, but they may not be causally related to the experimental drugs
• Serious Adverse Event (SAE) – Any untoward medical occurrence that at any dose: results in death, is life threatening, requires hospitalization, results in persistent or significant disability or incapacity, or causes a congenital anomaly/birth defect after the participant receives the experimental drug during a clinical trial
• Adverse Drug Reaction (ADR) – Any adverse or undesired reactions that may be related to the experimental drugs that occur during clinical trials. There is at least a reasonable possibility of the causal relationship between the experimental drug and the adverse event (i.e., the correlation cannot be ruled out)
• Suspicious and Unexpected Serious Adverse Reactions (SUSAR) – Suspicious and unexpected serious clinical manifestations that exceed the existing information, such as the Investigator's Brochure (IB) of the trial drug, the instructions of the marketed drug, or the summary of product characteristics

In addition, the G-SftyRptStds includes “Serious Adverse Drug Reactions” (SADRs) as well as other important medical events, which require medical judgement to determine if measures are needed to prevent the occurrence of one (1) of the preceding.

See the NMPA-No31-2024 for NMPA’s guidance on evaluating the correlation between AEs and drugs used in clinical trials.

Safety Reporting Requirements

Investigator Responsibilities

Per the NMPA-GCP-No57-2020, the investigator should immediately report all SAEs in writing to the sponsor, and then provide a detailed and written follow-up report in a timely manner. However, this does not include SAEs that do not need to be reported immediately per the trial protocol or other documents (such as the investigator’s brochure). SAE reports and follow-up reports should indicate the participant’s identification code in the clinical trial, not the participant’s real name, citizenship number, and residential address. AEs and abnormal laboratory values that are important for the safety evaluation specified in the test plan must be reported to the sponsor in accordance with the requirements and time limit of the test plan. For reports involving deaths, the investigator should provide the sponsor and the ethics committee (EC) with other required information, such as autopsy reports and final medical reports.

The Measures-Ethics state that for research that has been approved for implementation, researchers must immediately report SAEs that occur during the research process to the EC. The EC must conduct a timely review to determine whether the measures taken by researchers to protect the personal safety and health rights and interests of research participants are adequate, reassess the risk-benefit ratio of the research, and issue review opinions.

Sponsor Responsibilities

Per the DRR, the sponsor must regularly submit a safety update report to the National Medical Products Administration (NMPA)'s Center for Drug Evaluation (CDE) via the Applicant’s Window (CHN-58). The safety update report during the research and development period should be submitted once a year, and within two (2) months after the full year following approval of the drug clinical trial. The CDE may require the sponsor to adjust the reporting cycle based on the review situation. Additional guidance on the safety update report is provided in the NMPA-No7-2020 and the NMPA-No65-2021. For international multicenter clinical trials, NMPA-No2-2015 states that sponsors should unify the collection and evaluation methods of AEs, use a unified glossary to code AEs, and establish a unified safety database for the collection and evaluation of SAEs. AE or SAE reports should comply with the relevant national and regional requirements.

The DRR requires the sponsor to report SUSARs and other potentially serious safety risks to the CDE in a timely manner in accordance with relevant requirements. The NMPA-GCP-No57-2020 and the G-SftyRptStds specify that the sponsor is responsible for the safety assessment of the drugs during the trial period. The G-SftyRptStds and the NMPA-No65-2021 state that during the clinical trial, the sponsor judges whether SUSARs are related to the drug. When the sponsor and the investigator cannot agree on the causal relationship between the AE and the drug, the experimental drug should not be ruled out and it must be reported. Also see NMPA-No102-2019 for guidelines on classifying AEs in clinical trials of investigational vaccines.

The NMPA-No16-2023 and the NMPA-No5-2020 state that a sound pharmacovigilance system should be established to monitor safety risks during drug clinical trials, which should include comprehensive drug data collection and risk monitoring, identification, assessment, and control. In addition, safety problems and risks should be discovered in a timely manner, and necessary risk management measures should be taken proactively, such as adjusting clinical trial plans, and suspending or terminating clinical trials, etc. The NMPA-No5-2020 provides guidance on evaluating and managing safety issues and requires sponsors to actively cooperate with clinical trial institutions and other relevant parties to strictly implement the main responsibility of safety risk management.

The NMPA-GCP-No57-2020 requires the sponsor to promptly notify the investigator, the clinical trial institution, and the drug regulatory authority of issues discovered in the clinical trial that may affect the safety of participants, the implementation of the clinical trial, and the consent of the ECs. Further, the sponsor must promptly report SUSARs to all participating investigators, clinical trial institutions, and ECs; sponsors must also report SUSARs to drug regulatory and health authorities. The NMPA-GCP-No57-2020 states that after receiving safety information from the sponsor, the investigator should sign the documentation and consider whether to treat the participant and make corresponding adjustments to the protocol.

The NMPA-No65-2021 and the G-SftyRptStds specify reporting timelines for unexpected death or serious life-threatening adverse reactions. The sponsor must submit the report as soon as possible after first learned, but not more than seven (7) days; and detailed follow-up information should be submitted within the next eight (8) days. For SUSARs, the report should be submitted as soon as possible after the first notification, but not more than 15 days. In addition to individual SUSAR reports, other potentially serious safety risk information should be reported to the CDE as soon as possible, and medical treatments should be decided upon for each situation. Generally, information that significantly affects the evaluation of the drug’s risks and benefits, changes in drug usage, or information that affects the overall drug development process, falls into this category. Domestic and foreign safety reports should be reported in Chinese. Further, the DAL states that if there is a safety problem or risk during the clinical trial, the sponsor must adjust the clinical trial plan, suspend or terminate the clinical trial, and report the issue to the NMPA.

See NMPA-No60-2021 for guidance on writing safety reference information in the investigator’s manual.

Form Completion & Delivery Requirements

As per the NMPA-No50-2018, the NMPA-No10-2018, and the G-SftyRptStds, investigators must comply with the rapid reporting requirements in the International Council for Harmonisation (ICH)’s E2A Guideline, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (CHN-39), and ICH E2B(R3), Electronic Transmission of Individual Case Safety Reports (CHN-40). As indicated in the G-SftyRptStds, all SUSARs from clinical trials should be reported in compliance with E2A and E2B(R3). To comply with these requirements, the project’s electronic safety database must meet the E2B(R3)’s XML format and be submitted to the CDE in Chinese (CHN-58). Potentially serious security risks can be sent as a “Quick Report” through e-mail to: lcqjywjj@cde.org.cn. See NMPA-No17-2023 for frequently asked questions and answers related to rapid safety reporting. Additional questions pertaining to rapid reporting can be sent to ywjjxtwt@cde.org.cn.

According to the NMPA-No230-2015, in clinical trials of new drugs, which now only require a one-time approval, after the completion of Phase I and Phase II trials, the applicant should submit all test results and demonstrate that no safety problems were found before beginning the next phase of the trial. Furthermore, NMPA-No230-2015 states that the applicant must submit all adverse event data on time.

Safety Reporting Definitions

According to GBR-1 and GBR-64, the following definitions provide a basis for a common understanding of the United Kingdom’s (UK’s) safety reporting requirements:

• Adverse Event or Adverse Experience (AE) – Any untoward medical occurrence in a participant, including occurrences which are not necessarily caused by or related to that product
• Adverse Drug Reaction (ADR) – Any untoward and unintended response in a participant to an investigational medicinal product which is related to any dose administered to that participant
• Serious Adverse Event (SAE), Serious Adverse Drug Reaction (SADR), or Unexpected SADR – Any AE, ADR, or unexpected ADR that results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or a congenital anomaly/birth defect
• Unexpected Adverse Drug Reaction (ADR) – An adverse reaction where the nature or severity is inconsistent with the applicable product information
• Suspected Unexpected Serious Adverse Reaction (SUSAR) – A suspected serious adverse reaction, which is also “unexpected,” meaning that its nature and severity are not consistent with the information about the medicinal product in question

Per the G-CTAuth-GBR, the Medicines and Healthcare Products Regulatory Agency (MHRA) advises that the guidance on reference safety information (RSI) contained in GBR-30 (developed by the Clinical Trials Facilitation Group of the Heads of Medicines Agencies (HMA)) remains applicable. For clinical trials that are being conducted in the UK, an RSI cannot be used for expectedness until the RSI has been approved by the MHRA. Additional SUSARs that occur before the new RSI is approved should be reported in the usual expedited manner. If sponsors wish to harmonize the implementation date of an RSI in a trial that includes European Union (EU) and UK sites, then they can use the date when approval is granted in all member states and the UK. In the interest of efficiency and harmonization for multinational trials, the MHRA recommends that amendments including changes to the RSI are submitted to the UK and EU at the same time. The RSI in place at the time the SUSAR occurred should be used to assess expectedness for follow-up reports.

Safety Reporting Requirements

Per GBR-99, a sponsor or investigator may take appropriate urgent safety measures (USMs) to protect research participants against any immediate hazard to their health or safety, without prior authorization from a regulatory body. The main ethics committee (EC), and the MHRA for clinical trials for investigational medicinal products (CTIMPs), must be notified immediately (no later than three (3) days) in the form of a substantial amendment that such measures have been taken and the reasons why. GBR-9 states that for trials which have been submitted via the combined review service, one USM notification is made via the combined review part of the Integrated Research Application System (IRAS) (GBR-125) and received by the MHRA. No additional notification is required directly to the EC. GBR-32 reaffirms this stating that SUSARs and safety reports for CTIMPs that were approved by combined review should be submitted to the MHRA only. If the safety report requires action, the MHRA will instruct the study team to submit a substantial amendment. Any other SUSARs or annual safety report submitted UK wide will be acknowledged by email by the EC. The submitted cover report for the SUSAR or annual safety report will not be signed and returned, and the email will act as the formal acknowledgement.

In addition, the G-CTAuth-GBR states that the sponsor should call the MHRA’s Clinical Trials Unit at 020 3080 6456 to discuss the issue with a safety scientist, ideally within 24 hours of measures being taken, but no later than three (3) days. If key details are not available during the initial call, then the sponsor should inform the MHRA no later than three (3) days from the date the measures are taken by email to clintrialhelpline@mhra.gov.uk. Written notification in the form of a substantial amendment is also required. The substantial amendment covering the changes made as part of the USM is anticipated within approximately two (2) weeks of notification to the MHRA. Any potential reason for delay of substantial amendment submission should be discussed and agreed upon with the MHRA at the time of initial notification or through a follow-up call. Submission of the substantial amendment must not be delayed by additional changes outside of those taken and required as an urgent safety measure. Unrelated and unacceptable changes may result in rejection. For more details on how submissions should be made using MHRA Submissions, see G-CTAuth-GBR.

Investigator Responsibilities

As specified in the MHCTR, GBR-1, and GBR-30, the investigator is responsible for reporting all SAEs/SADRs immediately to the sponsor. The report may be made orally or in writing and followed by a detailed report no later than 24 hours after the event. When the reported event results in a participant’s death, the investigator must provide the sponsor with any requested information. According to the MHCTR, in cases where reporting is not immediately required according to the protocol or the Investigator’s Brochure (IB), the investigator should report an SAE/SADR within the appropriate timeframe based on the trial requirements, the seriousness of the SAE/SADR, and protocol or IB guidelines. Per GBR-1, the investigator and the sponsor share responsibility for the assessment and evaluation of adverse events with regard to seriousness, causality, and expectedness.

See GBR-18 for a safety reporting flowchart that gives an overview of the investigator’s expedited safety reporting requirements to the sponsor for a clinical trial in the UK.

Sponsor Responsibilities

According to the MHCTR, the G-CTAuth-GBR, and the MHCTR-EUExit, the sponsor is required to record and report all relevant information about fatal or life-threatening SUSARs as soon as possible, but no later than seven (7) calendar days to the MHRA, to the institution in which the trial is being conducted, and to the EC. Any additional relevant information should be sent within eight (8) days of the initial report. The sponsor must also report any non-fatal or non-life threatening SUSARs no later than 15 calendar days following first awareness of the event. Per GBR-1, the investigator and the sponsor share responsibility for the assessment and evaluation of adverse events with regard to seriousness, causality, and expectedness. Per the G-CTAuth-GBR, sponsors must report all UK-relevant SUSARs to the MHRA. The agency’s definition of ‘UK-relevant’ includes:

• SUSARs originating in the UK for a trial
• SUSARs originating outside the UK for a trial
• If the sponsor is serving as a sponsor of another ongoing trial outside the UK involving the same medicinal product
• SUSARs involving the same medicinal product if the sponsor of the trial outside the UK is either part of the same mother company or develops the medicinal product jointly, on the basis of a formal agreement, with the UK sponsor

Per GBR-18, sponsors should develop formal, written processes for the management of adverse events and safety reports, including the handling of both expedited reports and annual safety reporting.

Other Safety Reports

Per the G-CTAuth-GBR, sponsors must submit Development Safety Update Reports (DSURs) to the MHRA. The DSUR should consider all new available safety information received during the reporting period. The DSUR should include:

• A cover letter listing all relevant clinical trial numbers of trials covered by the DSUR and an email address for correspondence (Note: per GBR-18, every clinical trial with a European site must include a European number. GBR-87 indicates that as of January 31, 2023, all new clinical trials with sites in Europe should use the Clinical Trials Information System (CTIS) (GBR-39)
• An analysis of the participant’s safety in the concerned clinical trial(s) with an appraisal of its ongoing risk/benefit
• A listing of all suspected serious adverse reactions (including all SUSARs) that occurred in the trial(s)
• An aggregate summary tabulation of SUSARs that occurred in the concerned trial(s)

As stated in the G-CTAuth-GBR, at the end of the DSUR reporting period, the sponsor may assess the new safety information that has been generated and submit any proposed safety changes to the IB as a substantial amendment. This amendment must be supported by the DSUR and approved before the RSI is changed. A shortened DSUR is available for approved trials under MHRA’s notification scheme that are not part of a multi-study development program. Phase 4 national (UK only) trials of licensed products, which commanded a low fee from the MHRA, and where all participants have completed treatment and are only in the follow-up stage will also be suitable for submission of a short format DSUR. As an alternative to producing a full DSUR for these trials, the Health Research Authority Annual Progress Report (GBR-27) may be used.

The MHRA and Health Canada jointly released DSUR-UK_Canada to strengthen participant safety in clinical trials by improving the quality of DSURs. To increase the transparency of the data included in DSURs, the MHRA and Health Canada are requiring that the region-specific section of the DSUR explain how safety data were reviewed during the reporting period. Specifically, the region-specific section of the DSUR should include a summary description of the processes used by the sponsor to review the worldwide safety data of the investigational product (IP) (e.g., regular analyses of accumulating data, in-house safety review meetings, proposal of specific pharmacovigilance activities, or substantial modifications of the protocol). In addition, the region-specific section must describe how each safety signal (i.e., an event with an unknown causal relationship to the IP) identified during the reporting period was evaluated, as well as how a decision was made regarding the signal itself.

See the G-CTAuth-GBR, the MHCTR, GBR-1, GBR-18, GBR-30, and GBR-99 for detailed reporting requirements for the investigator and sponsor.

Form Completion & Delivery Requirements

Per the G-CTAuth-GBR, SUSARs during clinical trials should be reported to the MHRA in one (1) of the following ways:

• Individual Case Safety Reports (ICSR) Submissions (GBR-126) (which replaces the EudraVigilance website (EVWEB)) – The ICSR Submissions route is used to submit single reports. (Note that per GBR-127, MHRA also decommissioned the eSUSAR reporting platform.)
• MHRA Gateway (which replaces the EudraVigilance Gateway) – To gain access to the MHRA Gateway, which is used to submit bulk reports, users must first register via MHRA Submissions (GBR-13). The steps for gaining access to MHRA Submissions are contained within the G-MHRASubmiss and GBR-11.

See the Regulatory Fees section for information on fees for annual safety reporting and DSURs. See the G-CTAuth-GBR and GBR-99 for more details on submittal and delivery requirements.

Interim and Annual Progress Reports

The NMPA-GCP-No57-2020 and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CHN-37) require the investigator to submit an annual report on the clinical trial to the ethics committee (EC). In addition, the investigator must provide a progress report in accordance with requirements established by the EC. When there is a situation that significantly affects the implementation of clinical trials or increases the risks to participants, the investigator should report it in writing to the sponsor, the EC, and the clinical trial institution as soon as possible. The Measures-Ethics reiterates that the researcher must submit progress reports. The NMPA-No2-2015 requires sponsors and researchers to submit the progress of international multicenter clinical trials to the EC, including but not limited to enrollment, important decisions of the independent data supervision committee (if applicable), and safety information in their own countries and other countries/regions, so as to facilitate the EC’s understanding of the overall situation of the trial, conduct follow-up reviews, and protect the safety and rights of participants.

According to the NMPA-No230-2015, in clinical trials of new drugs, which now only require a one-time approval, after the completion of Phase I and Phase II trials, the applicant should submit all test results and demonstrate that no safety problems were found before beginning the next phase of the trial. Furthermore, NMPA-No230-2015 states that the applicant must submit an annual report on time.

CHN-37 states that the investigator should promptly provide written reports to the sponsor and the institutional EC on any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants. In addition, the investigator should submit written summaries of the trial status to the institutional EC annually, or more frequently, if requested by the institutional EC. Per the Measures-Ethics researchers must promptly submit reports on suspension, termination, and completion to the EC.

Final Report

Per the NMPA-GCP-No57-2020, after the clinical trial is completed, the investigator must report to the clinical trial institution. The investigator must provide the EC with a summary of the clinical trial results and provide the sponsor with the clinical trial related reports required by the drug regulatory authority. Per the DRR, the sponsor must register clinical trial results on the Applicant’s Window (CHN-58).

Interim and Annual Progress Reports

As indicated in the G-CTAuth-GBR and GBR-9, the investigator and the sponsor share responsibility for submitting progress reports to the ethics committee (EC), as required, on the status of a clinical trial and for submitting a final study report upon the trial’s completion. These requirements comply with the progress and final reporting requirements delineated in the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113).

In accordance with GBR-32 and GBR-65, it is no longer a requirement to submit annual progress reports to the EC. However, GBR-65 states that depending on the type of approval, a progress report may be requested to track progress.

In addition, GBR-65 states that if the study was reviewed by an EC in Scotland or Northern Ireland, an annual progress report should be submitted 12 months after the date on which the favorable ethics opinion was given, except in the following instances:

• If the study is expected to run for less than two (2) years in duration
• If the study received a proportionate review
• If the study received a favorable ethics opinion from an EC in England or Wales

Furthermore, GBR-65, states that if a study was given a favorable ethics opinion by an EC in Scotland or Northern Ireland, there are separate forms for submitting progress reports, depending on the type of research. The form for clinical trials of investigational medicinal products (GBR-27) should be completed in typescript and authorized by the Chief Investigator (CI) or the sponsor/sponsor representative. An electronic copy should be emailed to the EC within 30 days of the end of the reporting period.

See the Regulatory Fees section for information on fees for annual progress reports.

Final Report

As per the MHCTR and the G-CTAuth-GBR, the sponsor must notify the Medicines and Healthcare Products Regulatory Agency (MHRA) and the EC in writing that a clinical trial has ended within 90 days of the conclusion of the trial. As indicated in GBR-128, all project-based research (not research tissue banks or research databases) that has been reviewed by an EC needs to submit a final report within 12 months of the end of the study. The final report should be completed and submitted in the combined review part of Integrated Research Application System (IRAS) (GBR-125). When completing the final report form, IRAS guides the user with instructions next to each question.

The G-CTAuth-GBR further specifies that a declaration of the end of a clinical trial should be sent to the MHRA within 90 days of the global end of the trial and within 15 days of the global premature end of the trial. The submission must include an end of trial form (GBR-133) and a cover letter. Note that only the global end-of-trial notification is required to be submitted. However, a facility may inform the MHRA of the local (UK) end of trial via the end-of-trial notification form, but these local notifications will not be officially acknowledged and the MHRA Submissions automatic email confirmation should be considered as evidence of submission. If a local end of trial is submitted, the MHRA would still expect to receive relevant safety updates and substantial amendments for the ongoing trial until the global end of trial notification is received. An exemption to this requirement must be requested via a substantial amendment for approval. The amendment must clearly state to what documents the proposal relates and provide a robust rationale for the request. All safety documentation must be submitted unless there are no other trials ongoing with the same product in the UK. Any trial activities (such as follow-ups, visits) must be completed before the submission of the global end-of-trial declaration form. It is not possible to submit amendments to the trial or the Development Safety Update Report (DSUR) once the global end-of-trial declaration form has been received by the MHRA. If the end-of-trial declaration has been received within a reporting period, or within 60 days following the data lock point, the corresponding DSUR will not be required.

Per the G-CTAuth-GBR, the timeframe for publishing the summary of results is within one (1) year of the end of trial. Sponsors should publish summary results within this timeframe in the public register(s) where they registered the clinical trial. While it is not required to submit this clinical trial summary report to the MHRA, sponsors must send a short confirmation email to CT.Submission@mhra.gov.uk once the results-related information has been uploaded to the public register and provide the relevant link.

As per GBR-9, the investigator is also required to submit a summary of the final study report to the main EC within one (1) year of the trial’s conclusion. GBR-20 clarifies that the form in GBR-20 should be used for this submittal, which includes submitting a lay summary of results. This is a UK-wide final report for all project-based research studies that have been reviewed by an EC within the UK Health Departments’ Research Ethics Service (GBR-62). The information contained in this final report helps the Research Ethics Service to monitor whether the research was conducted in accordance with the EC’s favorable opinion and applicable transparency requirements. Per the GBR-120, sponsors should include a plain language summary of their findings in the final report, which will be published on HRA’s website alongside the study research summaries. See GBR-120 for guidance on writing a good plain language summary for a general audience.

Per the G-PIPs, UK marketing authorization holders who sponsor a study that involves the use of the authorized medicinal product in the pediatric population, must submit to the MHRA results of the study within six (6) months after the trial ended. Additional requirements and submittal details are in the G-PIPs and the G-PIPsProcess.

As per the DRR, the NMPA-GCP-No57-2020, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CHN-37), a sponsor is defined as a company, institution, or organization that initiates a clinical trial, and is responsible for managing, financing, and monitoring the trial. The DRR further specifies that the enterprise or institution applicant must be able to bear corresponding legal responsibilities. Per the DRR, applicants who are approved to carry out clinical trials of drugs are referred to as “sponsors” of clinical trials. If the sponsor changes, the changed sponsor must bear the relevant responsibilities and obligations of the drug clinical trial.

Per the NMPA-GCP-No57-2020 and CHN-37, a sponsor can authorize a contract research organization (CRO) to carry out certain work and obligations regarding the clinical trial. The sponsor can entrust part or all of the work and tasks of its clinical trial to the CRO, but the sponsor is still the ultimate person responsible for the quality and reliability of the clinical trial data and should supervise the various tasks undertaken by the CRO. The CRO must implement quality assurance and quality control measures. Any work entrusted by the sponsor to the CRO must be documented in a signed agreement. The sponsor is still responsible for work and tasks that are not clearly entrusted to the CRO. The requirements for sponsors in this specification apply to CROs that undertake the work and tasks related to sponsors.

A sponsor may be domestic or foreign; however, per the DRR and CHN-11, a Chinese legal entity must submit the clinical trial application.

Per the DAL, the sponsor is also referred to as the “holder” of the drug registration certificate, which is an entity that has obtained a drug registration certificate and includes institutions that are responsible for clinical trials. The legal representative and principal person holding the drug registration certificate is fully responsible for the quality of the drug used in a clinical trial. When the holder of the certificate is an overseas entity, their designated legal person in China must fulfill the same obligations as the holder of the drug registration certificate and bear joint and several liability with the holder of the drug registration certificate.

Definition of Foreign Entities in Regard to Collecting or Preserving Human Genetic Resources

For purposes of obtaining a human genetic resources (HGR) license, the HGR-AppGuide defines foreign entities as institutions established or actually controlled by overseas organizations or individuals including the following:

• A foreign organization or individual that holds or indirectly holds more than 50% of the shares, equity, voting rights, property shares, or other similar interests of an institution
• A foreign organization or individual that holds or indirectly holds less than 50% of the shares, equity, voting rights, property shares, or other similar rights and interests of the institution, but the voting rights or other rights and interests they enjoy are sufficient to control or exert significant influence on the decision-making, management, and other behaviors of the institution
• Foreign organizations or individuals, through investment relationships, agreements, or other arrangements, are able to control or exert significant influence on the decision-making, management, and other behaviors of the institution
• Other circumstances prescribed by laws, administrative regulations, and rules.

The HGR-AppGuide indicates that domestically-invested actual controlling institutions located in Hong Kong and Macao are regarded as Chinese units.

As per the MHCTR, the MHCTR2006, the G-CTApp, GBR-103, GBR-9, GBR-2, and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), the sponsor is defined as an individual, company, institution, or organization who takes ultimate responsibility for the initiation, management, and financing (or arranging the financing) of a trial. The sponsor must ensure that the trial design meets appropriate standards and arrange for the trial to be properly conducted and reported. In addition, per GBR-101, the sponsor is the individual, organization, or partnership that takes on overall responsibility for proportionate, effective arrangements being in place to set up, run, and report a research project.

In accordance with GBR-113, the United Kingdom (UK) also permits a sponsor to transfer any or all of its trial-related duties and functions to a contract research organization (CRO) and/or institutional site(s). However, the ultimate responsibility for the trial data’s quality and integrity always resides with the sponsor. Any trial-related responsibilities transferred to a CRO should be specified in a written agreement. The CRO should implement quality assurance and quality control. Per the G-CTApp, G-SubtlAmndmt, and the GBR-103, the clinical trial sponsor or legal representative needs to be established in the UK or a country on an approved country list which initially includes the European Union (EU)/European Economic Area (EEA) countries per G-CTApprovedCountries. A change in sponsor or legal representative for a UK trial is a substantial amendment requiring submission to both the MHRA and the ethics committee. GBR-103 specifies that the legal representative:

• May be an individual person or a representative of a corporate entity
• Does not have to be a legally qualified person
• Should be willing to act as the agent of the sponsor in the event of any legal proceedings instituted (e.g., for service of legal documents)
• Should be established at an address in the UK or a country on the approved country list
• Does not assume any of the legal liabilities of the sponsor(s) for the trial by virtue of the role of legal representative and does not therefore require insurance or indemnity to meet such liabilities; but may, in some cases, enter into specific contractual arrangements to undertake some or all of the statutory duties of the sponsor in relation to the trial, in which case the legal representative would also be regarded as a co-sponsor and would then require insurance or indemnity cover

The MHCTR also permits two (2) or more parties to take responsibility for the sponsor’s functions. When this applies, the MHCTR requires one (1) of the parties to submit the clinical trial application for authorization to the Medicines and Healthcare Products Regulatory Agency (MHRA), and to specify who is responsible for carrying out the following functions:

• Communications relating to substantial amendments, modified amendments, and trial conclusion
• Communications relating to urgent safety measures
• Pharmacovigilance reporting

Overview

Per the DRR, drug clinical trials must be conducted in institutions conducting drug clinical trials that comply with relevant regulations and abide by the clinical trial quality management standards. As set forth in the NMPA-GCP-No57-2020 and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37), the sponsor is responsible for selecting the investigator(s) and institution(s) for the clinical trial, taking into account the appropriateness and availability of the study site and facilities. The sponsor must also ensure that the investigator(s) are qualified by training and experience. Prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure (IB). Additionally, the sponsor must define and allocate all study related duties and responsibilities to the relevant parties participating in the study. Furthermore, the sponsor must sign an agreement or contract with the participating institution(s). The NMPA-GCP-No57-2020 indicates that for clinical trials involving multiple institutions, the sponsor must be responsible for selecting the team leader unit. (See the Submission Content section for additional information on clinical trial application requirements). See the NMPA-GCP-No57-2020 for additional details on investigator and clinical trial institution requirements.

The NMPA-GCP-No57-2020 states that investigators and clinical trial institutions must possess the appropriate qualifications, training, and experience to assume responsibility for the trial. Further, they must be familiar with the trial protocol, IB, and related materials and information provided by the sponsor. They must be familiar with and abide by clinical trial regulations and laws and keep an authorization form for the division of responsibilities signed by the investigator. Researchers and clinical trial institutions must accept the supervision and inspection organized by the sponsor as well as by the National Medical Products Administration (NMPA). In addition, with the sponsor’s consent, investigators and clinical trial institutions can authorize qualified individuals or units to undertake clinical trial-related responsibilities and functions.

With regard to institutions, the DRR further delineates that drug clinical trials must be conducted in institutions that have the corresponding required conditions and are registered. For example, vaccine clinical trials must be implemented or organized by China’s designated three-level medical institutions or disease prevention and control institutions at or above the provincial level that meet the required conditions.

Institutional Registration

Per the SC-Opinions-No42 and the NMPA-NHC-No101-2019, the NMPA adopted a registration system for institutions with qualifying conditions to be entrusted to conduct clinical trials and operate ethics committees (ECs). This reform eases institutional burdens by removing the pre-approval accreditation requirements. Among other conditions, the NMPA-NHC-No101-2019 specifies that an institution is entrusted to conduct clinical trials if the main investigators of clinical trials have senior professional titles and have participated in more than three (3) clinical trials. The main investigator must supervise the implementation of drug clinical trials and the performance of each researcher in the performance of their work duties and take measures to implement the quality management of drug clinical trials to ensure the reliability and accuracy of the data. Institutions conducting drug clinical trials must submit a work summary report of clinical trials in the previous year before January 31 of each year. NMPA-No1-2024 provides guidance and templates to institutions conducting drug clinical trials on filling out this annual work summary report. NMPA-NHC-No101-2019 indicates that the NMPA is establishing a record management information platform for the registration and operation management of institutions conducting drug clinical trials, as well as the supervision and inspection by drug regulatory agencies.

For additional details on the registration conditions, operations management, supervision, and inspection of institutions, see the NMPA-NHC-No101-2019. Also see CHN-12 for additional details on registering institutions to carry out clinical trials in China.

Foreign Sponsor Responsibilities

The DRR requires foreign applicants/sponsors to designate Chinese legal entities to handle relevant drug registration matters.

Per the NHC-HGRmgt, the National Health Commission (NHC) is responsible for China’s management of human genetic resources (HGR). (Note that per SC-Order777 and NHC-HGRmgt, management of HGR was transferred from the Ministry of Science and Technology (MOST) to NHC, effective May 1, 2024).

Per the Rules-MgmtHGR, when data or information on human genetic resources (HGR) is provided or made available for use by foreign organizations, individuals, and institutions, the Chinese entity must notify MOST (now the NHC) in advance and may be required to pass a security review. The notification must report on the following:

• The purpose and use of providing or opening up the use of China’s HGR information to foreign entities
• The HGR data and backup copy of the information
• The basic circumstances of the foreign entities receiving the HGR information
• Risk assessments for the protection of Chinese HGR to foreign entities

This notification is not required during international scientific research that is licensed/recorded, where the Chinese unit provides the foreign party with information on HGR generated by the cooperation, and if the international cooperation agreement has stipulated that it will be used by the two (2) partners.

Note, that the Rules-MgmtHGR adopts a broad definition of “foreign units” that includes foreign organizations and institutions, as well as entities established or under “actual control” by foreign entities or individuals. See the Rules-MgmtHGR and Rules-MgmtHGR-Interp for specific guidelines for determining actual control.

Data and Safety Monitoring Board

The NMPA-GCP-No57-2020, CHN-37, and the NMPA-No65-2021 recommend establishing a Data and Safety Monitoring Board (DSMB) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. The EC-Guide indicates that any DSMB reports should be submitted to the EC during follow-up reviews, if applicable.

As delineated in G-SftyRptStds and the NMPA-No65-2021, the sponsor should appoint fulltime staff to monitor clinical trial safety information and manage serious adverse event reporting. Relevant standard operating procedures should be established, and all relevant personnel should be trained. The sponsor is also responsible to ensure staff understand the latest security information, conduct timely risk assessments, provide relevant information to inform participants and interested parties, and quickly report unexpected serious adverse reactions. Annex 3 to NMPA-No50-2018 requires that application materials for Phase I clinical trials focus on participant safety and describe the establishment of a drug safety committee and a pharmacovigilance system based on the clinical trial protocol.

NMPA-No2-2015 states that in large-scale international multicenter drug clinical trials, the establishment of independent data monitoring committees and endpoint determination committees for key indicators is usually considered. For critical clinical trials with relatively large sample sizes and relatively long research times, especially those driven by clinical events, it is necessary to establish an independent data supervision committee and establish clear working mechanisms and procedures. NMPA recommends that for studies in which Chinese patients account for more than 2%, Chinese experts be included in the global core independent data monitoring board. For situations where human factors may affect the determination of research results, such as international multicenter drug clinical trials where imaging evaluation results are the key evaluation endpoints, it is necessary to establish a unified endpoint judgment committee for the main research indicators to uniformly conduct independent evaluation and judgment of the main research indicators.

Multicenter Studies

Per NMPA-No2-2015, for international multicenter drug clinical trials, sponsors should ensure that investigators have the qualifications and ability to undertake the clinical trial. Sponsors should provide unified training for researchers, including training on clinical trial protocols, standard operating procedures, test record forms, computer use, etc. The training should clearly explain and translate various definitions; unify diagnosis, efficacy, and safety evaluation indicators; and ensure the consistency of researchers' understanding of clinical trial protocols and evaluation of relevant indicators.

In accordance with the NMPA-GCP-No57-2020 and CHN-37, to carry out multicenter clinical trials, the sponsor must ensure that all centers participating in the clinical trial comply with the trial protocol. The NMPA-GCP-No57-2020 specifies additional sponsor requirements:

• Provide the same test plan to each center; each center must comply with the same unified evaluation standards for clinical and laboratory data and instructions for filling out the case report form (CRF)
• Ensure each center uses the same CRF to record the test data obtained in clinical trials
• Indicate in the trial protocol if the investigator needs to increase the collection of experimental data, and provide the investigator with an additional CRF
• Develop a written document clarifying the responsibilities of the investigators in each center before the start of the clinical trial
• Ensure communication among researchers in each center

The NMPA-No35-2017 delineates that researchers can conduct Phase I of multi-regional clinical trials (MRCT) of imported investigational new drugs and therapeutic biological products (excluding vaccines) simultaneously in China. Upon completion of a MRCT in China, the marketing application of the imported drug can be submitted immediately and should comply with the DRR. See Submission Content section.

Overview

As set forth in the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial, taking into account the appropriateness and availability of the study site and facilities. The MHCTR2006 indicates that the sponsor must also ensure that the investigator(s) are qualified by training and experience. Additionally, the sponsor must define and allocate all study related duties and responsibilities to the relevant parties participating in the study. GBR-9 states that the chief investigator (CI) should be based in the United Kingdom (UK). In rare cases when this is not required, adequate arrangements must be in place for supervision of the study in the UK.

As delineated in the MHCTR, the MHCTR2006, and GBR-113, prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure. Per GBR-113, if a multicenter trial is going to be conducted, the sponsor must organize a coordinating committee or select coordinating investigators. Per GBR-18, for clinical trials of investigational products (CTIMPs) conducted at National Health Service (NHS) sites, the addition of a new site and/or addition or change of a principal investigator (PI) is no longer considered a substantial amendment. No changes have been made to the classification of amendments relating to new sites/change of PI at non-NHS sites. If a site is added in a nation not previously involved in a study, this should be indicated in the combined review section (GBR-125) of the Integrated Research Application System (IRAS) for CTIMPs, and made clear in a cover letter when submitting the amendment to the lead nation.

UK Local Information Pack

GBR-113 recommends establishing a Data Monitoring Committee (DMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Per GBR-63, researchers working with NHS/Health and Social Care in Northern Ireland (HSC) organizations across England, Northern Ireland, Scotland, and Wales should use the UK Local Information Pack (LIP), which provides one (1) consistent package to support study setup and delivery across the UK.

The UKwide-Rsrch explains the LIP ensures that consistent information is given to all UK research sites and indicates that there are national differences in the LIP. In England and Wales, the LIP should include the Initial Assessment Letter, which may be shared with sites. Additionally, the sponsor should send the LIP directly to the site’s Research and Development (R&D) department, delivery team, and local clinical research network (if a National Institute for Health and Care Research Clinical Research Network (NIHR CRN) Portfolio) using the England and Wales non-commercial email template or commercial email template, as appropriate. For Welsh sites, it is expected that the sponsor has a process to translate patient-facing documents into the Welsh language if requested by sites or participants. In Northern Ireland, the sponsor may send the LIP to each participating site’s R&D department and delivery team once the application has been validated and once instructed to do so by the Health and Social Care R&D Approvals Service. The LIP should be shared using the Northern Ireland non-commercial email template or commercial email template, as appropriate. In Scotland, the NHS Research Scotland Permissions Coordinating Centre makes the LIP available to participating R&D departments and the appropriate Network or Portfolio Manager. The sponsor is responsible for making the information available to the research teams using the Scotland email template, which covers both non-commercial and commercial studies.

For help with LIP packages, email templates and other requirements, see GBR-106.

Foreign Sponsor Responsibilities

GBR-103 provides that if a sponsor(s) is not established in the UK or on an approved country list (which initially includes European Union (EU)/European Economic Area (EEA) countries), it is a statutory requirement to appoint a legal representative based in the UK or a country on the approved country list for the purposes of the trial. Per the G-CTApprovedCountries, the UK published a list of countries where a sponsor of a clinical trial, or their legal representative, may be established; currently listed countries are those in the EU and EEA. The G-SubtlAmndmt delineates that a change in sponsor or legal representative for a UK trial is a substantial amendment requiring submission to both the Medicines and Healthcare Products Regulatory Agency (MHRA) and the ethics committee (EC), pursuant to the guidelines in the G-CTAuth-GBR. Where the sponsor is from the rest of the world, and the legal representative is established in the UK, and there are sites in the EU/EEA, the sponsor will need to assign an EU/EEA legal representative for these sites via a substantial amendment to the relevant EU/EEA competent authorities. No amendment submission to the MHRA is required where the sponsor or legal representative for an ongoing trial is established in the EU/EEA as the UK will continue to accept this approval. Further, no amendment will need to be submitted in the UK if the sponsor retains the UK legal representative for the UK study. Similarly, no amendment will need to be submitted in the UK if a sponsor remains in the UK and a legal representative is added to cover EU/EEA sites.

Additional foreign sponsor requirements are listed in Section 5.2 of GBR-113.

Data Safety and Monitoring Board

Per GBR-18, the chief investigator should ensure that arrangements are made for a data safety and monitoring board (known as a data monitoring committee (DMC) in the UK). GBR-113 recommends establishing a DMC to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Multicenter Studies

Per GBR-18, for multicenter trials, the careful selection and evaluation of investigator sites is critical for the successful completion of a trial within budget, timelines, and to ensure the generation of high-quality data. When undertaking site selection, the preparation of ‘reserve’ investigator sites (so that the trial may be extended to these sites if recruitment issues arise) should be considered as part of proactive trial planning. Factors that should influence investigator site selection include:

• Interest in the research question
• Experience and qualifications of the investigator
• Sufficient staff to conduct the study and their experience and qualifications
• Availability of a suitable patient population
• Adequate time to conduct and oversee the trial
• Adequate facilities
• Previous track record with similar trials
• Geographic location
• Contractual and budgetary negotiations and arrangements

Per GBR-18, for multicenter trials, the CI must ensure that each PI is provided with all relevant, version-controlled documents before commencing recruitment. Further, it is good practice to ensure the PI signs a protocol signature page to confirm receipt and their agreement to comply with the current version of the protocol. The trial master file should be held at the coordinating site and copies of relevant documents should be kept at each participating site in an investigator site file.

Further, as delineated in GBR-113, in the event of a multicenter clinical trial, the sponsor must ensure that:

• All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor
• The case report forms (CRFs) are designed to capture the required data at all multicenter trial sites
• Investigator responsibilities are documented prior to the start of the trial
• All investigators are given instructions on following the protocol, complying with a uniform set of standards to assess clinical and laboratory findings, and completing the CRFs
• Communication between investigators is facilitated

Insurance

As set forth in the NMPA-GCP-No57-2020, the sponsor is responsible for providing the investigator and clinical trial institution with legal and economic insurance or a guarantee related to the clinical trial, which must be compatible with the nature and degree of risk of the clinical trial. This insurance should not include damage caused by the investigator and the clinical trial institution itself. The International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (CHN-37) guides sponsors on providing insurance. See CHN-11 for an analysis of clinical trial insurance in China.

Per NMPA-No2-2015, for insurance provided by overseas insurance companies in international multicenter clinical trials, the sponsor should ensure that participants in China can effectively and fully claim compensation, and give priority to protecting the rights and interests of participants.

Compensation

Injury or Death

Per the Measures-Ethics, when research participants suffer research-related damages, they must receive timely and free treatment, and they must be compensated in accordance with laws and regulations and the agreement of both parties. In accordance with the NMPA-GCP-No57-2020 and the EC-Guide, the sponsor must take appropriate measures to ensure that the participants and researchers can be compensated. The sponsor must bear the costs of diagnosis and treatment for the damage or death of the participant related to the clinical trial, as well as the corresponding compensation. Further, the sponsor must provide free trial drugs to participants and pay for medical testing related to clinical trials.

In addition, CHN-37 provides guidance to sponsors on providing compensation to research participants in the event of trial-related injuries or death. The sponsor must explain to participants the compensation and/or treatment available to them in the event of trial-related injuries.

Trial Participation

Per Measures-Ethics, research participants must not be charged research-related fees, and appropriate compensation must be given to the research participants for reasonable expenses incurred in the course of the research process.

Insurance

As set forth in the MHCTR and the MHCTR2006, it is a legal requirement for an insurance and indemnity provision to be made to cover the liability of the investigator and sponsor for trial-related injuries. The MHCTR does not ascribe responsibility to the sponsor or the designated representative to obtain insurance and indemnity. However, GBR-2, GBR-103, GBR-101, and GBR-18 state that the sponsor or the designated representative is responsible for ensuring adequate insurance and indemnity arrangements are in place to cover the sponsor’s and the investigator’s potential liability, and for providing a copy of this coverage in the clinical trial application submission.

In addition, according to GBR-2, the sponsor or the designated representative must ensure that the research covered by the National Health Service (NHS)’s indemnity policy is in place for each publicly funded participating study site. See GBR-33 for detailed information on the NHS indemnity responsibilities for clinical negligence involving investigators and participants. GBR-33, specifically addresses the sponsor’s or the designated representative’s requirement to insure or indemnify the investigator participating in industry-sponsored Phase 1 clinical trials.

The International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113) also guides sponsors on providing insurance.

Compensation

Injury or Death

As specified in the MHCTR, the sponsor or the designated representative is responsible for providing compensation to research participants and/or their legal heirs in the event of Phase 1 trial-related injuries or death. According to GBR-33, the sponsor must have agreed with the research participant to provide compensation for injury whenever a causal relationship with participation is demonstrated. This undertaking can be provided directly by the sponsor through the consent process, or through authorizing the contract research organization (CRO) or investigator on behalf of the sponsor. In addition, the sponsor should follow these practices:

• If the health or wellbeing of the participant deteriorates significantly as a result of taking part in the study, the sponsor will compensate the volunteer, irrespective of the ability of the participant to prove fault on the part of the sponsor or anyone else connected with the study.
• The amount of compensation should be calculated by reference to the amount of damages that would commonly have been awarded for similar injuries by an English court had liability been proven. The amount of compensation may be reduced if the volunteer is partly responsible for the injury or if the volunteer is separately compensated under any other insurance policy.
• The sponsor and participant agree to refer any dispute about whether compensation is payable or the amount of such compensation to an arbitrator with power to consult a barrister of 10 years’ standing on any issue of law, including the amount of damages to be paid.
• Participants should be given a copy of the relevant Association of the British Pharmaceutical Industry (ABPI) guidelines and should be invited to seek clarification of any aspect of the undertaking that is not clear to them.
• Participants may make a claim through the investigator, and the sponsor should aim to respond sympathetically and promptly.

GBR-113 also provides guidance for sponsors on providing compensation to research participants in the event of trial-related injuries or death. The sponsor must explain to participants the compensation and/or treatment available to them in the event of trial-related injuries.

Quality Assurance/Quality Control

Per the DRR, the management of drugs used in clinical trials must comply with the clinical trial quality management regulations specified in NMPA-GCP-No57-2020. As stated in the NMPA-GCP-No57-2020 and the NMPA-No65-2021, the sponsor must establish quality control (QC) and quality assurance (QA) systems for the clinical trial. The NMPA-GCP-No57-2020 and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37) specify that the quality management system for clinical trials should cover the entire process of clinical trials, including the design, implementation, recording, evaluation, result reports, and filing of clinical trials. NMPA-No65-2021 reiterates that sponsors must establish a quality management and pharmacovigilance system for investigational products (IPs). This system must collect safety information, monitor risk, identify and control safety problems in a timely manner, proactively take necessary risk control measures, and evaluate the effectiveness of risk control measures to protect participant safety.

Per the NMPA-GCP-No57-2020, quality management includes effective trial plan design, data collection methods and procedures, and information collection necessary for decision-making in clinical trials. The QA and QC methods for clinical trials should be consistent with the inherent risks of clinical trials and the importance of the information collected. Sponsors should ensure the operability of all aspects of clinical trials and avoid over-complication of trial procedures and data collection. The trial protocol, case report form (CRF), and other related documents should be clear, concise, and consistent. During an inspection by the National Medical Products Administration (NMPA), both the research and management teams should send personnel to participate.

The sponsor must conduct quality management based on risk. The key links and data that protect the rights and safety of participants and ensure the reliability of clinical trial results must be clearly defined when the sponsor formulates the trial plan. Risk should be considered from two (2) levels: 1) system level, such as facilities and equipment, standard operating procedures (SOPs), computerized systems, personnel, and suppliers; and 2) clinical trial level, such as trial drugs, trial design, data collection and recording, and the informed consent process. The risk assessment should consider the possibility of errors under existing risk control; the impact of the errors on the protection of participants’ rights and safety; and the extent to which the errors have been monitored. Control measures to reduce risks should be embodied in the design and implementation of the test plan, the monitoring plan, the contract with parties, SOPs, and various trainings. During clinical trials, quality management should be recorded and communicated with relevant parties in a timely manner to promote continuous improvement of risk assessment and quality. The sponsor must regularly evaluate the risk control measures based on new knowledge and experience during the clinical trial period to ensure the effectiveness and applicability of the current quality management. In addition, the sponsor’s quality management system must meet the following requirements:

• The sponsor is responsible for formulating, implementing, and updating the SOPs related to clinical trial QA and QC systems
• The entire process of clinical trials and laboratory testing must be carried out in strict accordance with the quality management SOPs, and each stage of data processing has QC to ensure that all data are reliable and the data processing process is correct
• The sponsor must sign a contract with all relevant parties, including investigators and clinical trial institutions, to clarify the responsibilities of each party
• The contract signed by the sponsor and the relevant parties must indicate that the sponsor and the NMPA can access the clinical trial site to consult the source data, source documents, and reports

To standardize the submission of drug clinical trial data, meet the drug registration application data requirements, and improve the efficiency of drug review, the NMPA-No16-2020 provides guidance on the content and format of clinical trial data. The guidance is based on the data submission requirements of international regulatory agencies, including the Clinical Data Interchange Standards Consortium (CDISC). In addition, the NMPA-No74-2020 has details on the management of records and data that must be provided to the NMPA during clinical trials in China. It indicates that data refers to the information generated during drug development, production, operation, and use, including text, values, symbols, images, audio, pictures, maps, barcodes, etc.

Per the NMPA-No2-2015, for international multicenter clinical trials when the main efficacy and important safety evaluation indicators are laboratory evaluation indicators, it is recommended to establish a central laboratory for unified testing. The laboratory should have the corresponding clinical laboratory qualifications. Where a regional central laboratory is established, the quality control consistency verification between laboratories must be carried out regularly to ensure the consistency and reliability of experimental results.

The NMPA-No48-2018 presents quality management guidelines for Phase III clinical trials using innovative drugs. The guide addresses information the sponsor should provide to the NMPA related to the active pharmaceutical ingredient and its production, considering participants’ safety, drug characteristics, dosage form and route of administration, development stage, target population, and severity of the disease.

Finally, the NMPA has issued the following quality management and technical guidelines for conduct during clinical trials. See each of these documents, for additional details:

• NMPA-No29-2024 – guidelines for pharmaceutical research and changes to biological products during clinical trials
• Risk-Prcdr – procedures for safety information assessment and risk management during clinical trials
• DctrlzCTs-Rare – technical guidelines for decentralized clinical trials using rare disease drugs
• GeneCTs-Rare – technical guidelines for clinical trials of gene therapy products for rare diseases
• PatientCtr-Risk, PatientCtr-Imp, and PatientCtr-Design – technical guidelines for patient-centered drug clinical trials, including design and risk assessment
• NMPA-No15-2023 – technical guidelines for clinical trials of chemical compound drugs
• NMPA-No34-2022 – guidelines for protocol changes during drug clinical trials
• NMPA-No32-2022 – guidelines for clinical trials of topically administered local effective drugs
• NMPA-No31-2022 – guidelines for conduct of research with in vivo gene therapy products
• NMPA-No30-2022 – guidelines for conduct of research involving immune cell therapy products
• NMPA-No29-2022 – guidelines for conduct of research with in vitro gene modification
• NMPA-No27-2022 – guidelines for conduct of research involving specific human immunoglobulins
• NMPA-No22-2021 – a research and development model to guide researchers in managing pharmaceutical changes of innovative drugs
• NMPA-No17-2022 – guidelines for clinical pharmacological research of biosimiliars
• NMPA-No4-2022 – guidelines for research of human bioavailability of bioequivalence of innovative drugs
• NMPA-No71-2021 – guidelines for research of drugs for rare diseases
• NMPA-No68-2021 – guiding principles for writing the clinical risk management plan
• NMPA-No66-2021 – guiding principles for multiplicity issues during drug clinical trials, which refers to multiple testing problems that can lead to errors and inappropriate interpretation of trial results
• NMPA-No63-2021 – guidelines for drug clinical trial data management and statistical analysis plan
• NMPA-No62-2021 – guidelines for the application of patient-reported outcomes in drug clinical development
• NMPA-No59-2021 – guidelines for analyzing the effectiveness of clinical studies of drugs
• NMPA-No50-2021 – guidelines for long-term follow-up for clinical research of gene therapy products
• NMPA-No6-2021 – guidelines for sponsors in adopting and implementing an adaptive design to improve the success and quality of the research results
• Chngs-MktChem – technical guidelines for pharmaceutical change research of listed chemicals
• Chngs-MktChemBio – technical guidelines for clinical changes in marketed chemicals and biological products
• NMPA-No21-2021 – technical requirements of pharmaceutical research and evaluation of overseas listed and domestic unlisted chemicals
• NMPA-No54-2020 – technical guidelines for clinical trials of improved chemical drugs
• Chngs-MktBio – technical guidelines for pharmaceutical change research of marketed biological products

Per the VaccineLaw, during the research and development phase for vaccines, the sponsor must establish a biosafety management system that strictly controls biosafety risks, strengthens biosafety management of pathogenic microorganisms (e.g., bacterial strains), protects the health of operators and the public, and safeguards against bacterial toxicity. The use of pathogenic microorganisms, such as strains, is legal and legitimate. The strains and cell strains used during research and development must have clear histories, biological characteristics, and generations. Detailed documentation and archives must be established to ensure that the source is legal, clear, and traceable; if the source is unknown, then it cannot be used.

As delineated in MgmtHumanGen, for international cooperative projects using human genetic resources (HGR), the sponsor must ensure the participation of the Chinese partner. During the study period, the Chinese partner and its researchers must fully participate in the research. All records and data information in the research process, and all backup documentation, must be accessible to the Chinese partner. Both the foreign and Chinese parties have the right to use the information developed with the HGR.

Monitoring Requirements

As per the NMPA-GCP-No57-2020, the purpose of monitoring is to ensure the rights and interests of participants in clinical trials, to ensure that the data in trial records and reports are accurate and complete, and to ensure that trials comply with the agreed protocol and relevant regulations. The NMPA-GCP-No57-2020 and CHN-37 require the sponsor to establish a systematic, prioritized, risk-based method to monitor clinical trials. NMPA-GCP-No57-2020 directs the sponsor to formulate audit procedures and an inspection plan with a special emphasis on protecting the rights and interests of participants, ensuring the authenticity of data, and managing risks in clinical trials. On-site supervision and centralized supervision should be conducted based on the combination of risks of clinical trials. The audit procedures must establish objectives, methods, frequency, and format content of audit reports. All problems observed and discovered by the auditors during the inspection process must be recorded in writing. The sponsor may conduct special inspections in addition to routine inspections. The sponsor selects a person independent of the clinical trial to serve as an inspector. Inspectors must have received corresponding training and inspection experience and be able to effectively perform inspection duties.

As indicated in NMPA-No2-2015, for international multicenter clinical trials, the sponsor or the contract research organization (CRO) entrusted by the sponsor must conduct supervision of each clinical trial center, the monitoring report must be archived, and the sponsor must periodically review the monitoring work. The sponsor or the CRO must formulate an audit plan and have a unified audit report template and audit result reporting system.

Further, NMPA-GCP-No57-2020 states that researchers and clinical trial institutions must agree to supervision and inspection organized by the sponsor and the NMPA. The sponsor must provide an inspection report or certificate when requested by the NMPA. In accordance with the DRR and CHN-8, NMPA’s Center for Drug Evaluation (CDE) will make a risk-based decision on whether to conduct an inspection of a clinical trial, based on the level of drug innovation and the past verification history of the clinical trial site. See NMPA-No56-2023 for NMPA’s management measures that standardize the supervision and inspection of institutions conducting drug clinical trials. In addition, NMPA-No22-2022 indicates that sponsors have the main responsibility for pharmacovigilance inspections during the conduct of a clinical trial. See NMPA-No22-2022 for key considerations during routine and causal inspections, evaluation criteria, risk factors, inspection methods, and other inspection implementation guidance.

The NMPA-No28-2020 further clarifies the link between on-site inspection of drug registration and the pre-market good manufacturing practice (GMP) compliance inspection. Based on the innovation and risk characteristics of an IP, the pre-market GMP compliance inspection will be conducted by the appropriate level regulatory authority (i.e., the CDE, province, autonomous region, or municipality). See the NMPA-No28-2020 for detailed inspection requirements.

Also, see the NMPA-GCP-No57-2020 and CHN-37 for additional guidance on audits and inspections. See NMPA-No11-2022 for guiding principles on use of risk-based statistical evaluation methods for centralized monitoring of drug clinical trials.

Premature Study Termination/Suspension

The NMPA-GCP-No57-2020 mandates that researchers, clinical trial institutions, and sponsors abide by the trial protocol, SOPs, and relevant laws and regulations. If non-compliance is found, the sponsor must take immediate measures to correct them and ensure the clinical trials are in compliance. The NMPA-GCP-No57-2020 and CHN-37 state that when an important compliance problem is discovered that may have a significant impact on the safety and rights of participants or the reliability of clinical trial data, the sponsor must conduct a root cause analysis in a timely manner and take appropriate corrective and preventive measures.

The NMPA-GCP-No57-2020 specifies that if the trial protocol is violated or there is a serious quality problem, the sponsor must hold the relevant personnel accountable and send a written report to the NMPA at CHN-58. When it is found that the investigator or clinical trial institution has serious non-compliance problems, the sponsor must terminate the investigator or clinical trial institution from continuing to participate in the clinical trial. The sponsor should also send a written report to the NMPA. At the same time, sponsors and researchers should take corresponding emergency safety measures to protect the safety and rights of participants. A sponsor who terminates or suspends clinical trials early must immediately notify the investigator, clinical trial institutions, and the NMPA, and explain the reasons.

Further, the NMPA-GCP-No57-2020 states that when a clinical trial is completed or terminated early, the sponsor must submit a clinical trial report to the NMPA. The clinical trial summary report must comprehensively, completely, and accurately reflect the clinical trial results. The safety and effectiveness data of the clinical trial summary report must be consistent with the clinical trial source data. The Measures-Ethics indicates that for research that has been approved for implementation, researchers must promptly submit reports on suspension and termination to the EC.

Quality Assurance/Quality Control

As stated in the MHCTR, the MHCTR2006, and GBR-92, the sponsor is responsible for maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, recorded, and reported in compliance with the protocol and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113). The sponsor is required to obtain agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. The sponsor must also obtain the investigator(s) and the institution(s) agreement to:

• Conduct the trial in compliance with GBR-113 and the protocol agreed to by the sponsor and approved by the ethics committee (EC)
• Comply with data recording and reporting procedures
• Permit monitoring, auditing, and inspection
• Retain essential documents until the sponsor informs them that they are no longer needed

MHCTR2006 requires the sponsor to notify the Medicines and Healthcare Products Regulatory Agency (MHRA) of serious breaches of good clinical practice (GCP) or the trial protocol. A serious breach is defined as one that is likely to affect to a significant degree: the safety or physical or mental integrity of the trial participants; or the scientific value of the trial. Per G-MHRA-SeriousBreaches, the sponsor or delegated party should notify the MHRA GCP Inspectorate within seven (7) days of becoming aware of a serious breach. Further, the sponsor should investigate and take action simultaneously after the MHRA notification. Notifications should primarily be sent to the following email address: GCP.SeriousBreaches@mhra.gov.uk.

Per the G-RiskAssmt, MHRA recommends that a risk assessment is undertaken for all clinical trials. Phase 1 trials are required to have a documented risk assessment process and to produce a risk assessment for all proposed trials. The risk assessment should be done as early as possible to help the sponsor identify whether the sponsor wishes to proceed with sponsorship and the potential category of IP for eventual marketing authorization. An early risk assessment will also identify the study management requirements, which can assist in the planning and resourcing aspects of the trial (e.g., identification of trial monitoring requirements so that these can be budgeted for in any funding application). There is no requirement to submit risk assessments to the MHRA or the ethics committee (EC). However, any safety monitoring produced because of the risk assessment must be described in the protocol. Finally, information contained in the risk assessment may prove useful in completing the application form for approvals, particularly for the EC application. See the G-RiskAssmt for details on how to conduct the risk assessment.

See GBR-10 for best practices in improving clinical trial setup to reduce timelines and increase citizens’ access to research. Also see GBR-34 for investigator training and guidance on implementing people-centered research.

Monitoring Requirements

Per GBR-18, the sponsor must develop an audit plan to assess and assure the reliability and integrity of the clinical trial systems against all relevant written standards. The following activities and checks could include the following:

• Interview staff to assess whether they are appropriately trained; understand their role(s); and are working to all relevant standards, the protocol, and SOPs.
• Tour the facility to assess if there are adequate resources and if the equipment is fit for its intended use.
• Review documents to evaluate whether data reported is verifiable from source data and that written records confirm that the trial was conducted appropriately.

Auditors must be independent of the trial team and appropriately trained for their role. Their findings and observations must be documented in a formal audit report. Any deficiencies identified during an audit must be followed up with appropriate corrective and preventive actions wherever possible.

Per GBR-18, the MHRA may conduct inspections to ensure the clinical trial is being conducted in compliance with good clinical practice (GCP) as prescribed in GBR-92 and GBR-113. The MHRA takes a risk-based approach to inspections depending on the type of trials and risk rating. Once an inspection has been completed, a formal report outlining the findings will be sent to the inspected organization. A response to this report (describing any corrective and preventive actions) must be produced. See GBR-92 for pre-inspection checklists and other resources. Per G-RiskAssmt, GCP Inspectors will review risk assessments. The risk assessment should provide the rationale behind trial management/monitoring and GCP activities applied, or not, to the trial.

Finally, the sponsor’s audits and inspections should be conducted in compliance with GBR-113, which calls for a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan). The G-Ovrsight provides additional guidance to assist sponsors and those conducting trials on implementing adequate oversight and monitoring processes for clinical trials.

Premature Study Termination/Suspension

The G-CTAuth-GBR states that the MHRA has the authority to suspend or terminate a trial. In addition, the sponsor can contact the MHRA to put a trial on temporary halt or terminate a trial. If a sponsor suspends a trial temporarily, the MHRA must be notified. Sponsors of clinical trials of investigational products (CTIMPs) must use the combined review part of the Integrated Research Application System (IRAS) (GBR-125) to submit this notification as a substantial amendment. Per GBR-122, for studies that were submitted before combined review, these applicants should continue to submit this notification at IRAS via GBR-78. The G-CTAuth-GBR indicates the notification should be made as a substantial amendment using the amendment tool, clearly explaining what has been stopped and the reasons for the suspension. To restart a trial that has been temporarily suspended, you must make the request as a substantial amendment using the notification of amendment form, providing evidence that it is safe to restart the trial.

Per the G-CTAuth-GBR and GBR-18, to terminate a CTIMP, the sponsor must notify (as a substantial amendment) the MHRA and the EC via the combined review part of IRAS (GBR-125). For studies that were submitted before combined review, the submission should be made at GBR-78, using the end-of-trial form (GBR-133). GBR-128 specifies that for CTIMPs, the declaration of end of trial must be sent to the MHRA within 15 days of the global premature end of trial. Before declaring an end of the study, sponsors should review the plans that were approved by the EC for use of tissue and data collected in the course of the study, providing information to participants, and dissemination of results. If changes need to be made to these agreed upon arrangements, the sponsor should consider whether an amendment is required before submitting the end of study notification. GBR-65 also states that if research is terminated early or is temporarily suspended, then all relevant review bodies should be notified within 15 days.

According to GBR-113, if it is discovered that noncompliance significantly affects or has the potential to significantly affect participant protection or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. Further, the sponsor should also inform the EC promptly and provide the reason(s) for the termination or suspension.

Electronic Data Processing System

Per the NMPA-GCP-No57-2020, the sponsor must meet the following requirements in electronic data processing during clinical trials:

• Select qualified personnel to supervise data processing, data verification, statistical analysis, and the writing of trial summary reports
• Use an electronic data management system that passes reliable system verification and meets the pre-set technical performance to ensure the integrity, accuracy, and reliability of the test data, and to ensure that the system is always valid for verification during the entire test process
• Have complete standard operating procedures (SOPs) that cover the setup, installation, and use of electronic data management; the SOPs must describe the verification, functional testing, data collection and processing, system maintenance, system safety, testing, change control, data backup, recovery, and system emergency plans
• Ensure the SOPs cover the responsibilities and training of sponsors, researchers, and clinical trial institutions when using computerized systems
• Prescribe in advance the method of data modification
• Ensure that the data conversion process is consistent with the original data and visibility is maintained during the process
• Ensure the security of the electronic data management system, and that unauthorized personnel cannot access it; keep a list of persons authorized to modify data; electronic data is backed up in time; clinical trials designed by blind methods are always blinded, including data entry and processing

In accordance with NMPA-GCP-No57-2020, when the information system of a clinical trial institution has the conditions for establishing a clinical trial electronic medical record, the researcher should use it first, and the corresponding computerized system should have complete authority management and audit trails, which can be traced to the creator or modifier of the record. Researchers must supervise the data collection. They must ensure that all clinical trial data are obtained from clinical trial source documents and trial records, and are accurate, complete, readable, and timely. The source data should be attributable, legible, original, accurate, complete, consistent, and durable. The modification of the source data must be explained and transparent. Relevant medical records should be included in the outpatient or inpatient medical record system. During the processing of clinical trial information, care must be taken to avoid illegal or unauthorized access, disclosure, dissemination, modification, damage, or loss of information. The record, processing, and preservation of clinical trial data must ensure the confidentiality of records and participant information. In the contract with the investigator and the clinical trial institution, the sponsor should clarify the retention time, cost, and handling of the documents.

Per the NMPA-No2-2015, international multicenter clinical trials must adopt a unified data processing center for data query, verification, storage, and analysis.

The NMPA-No74-2020 has additional guidance and requirements for the sponsor’s electronic system.

In addition, as per the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37), when using electronic trial data processing systems, the sponsor must ensure that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. Per CHN-37, the sponsor should base their approach to validate such systems on a risk assessment that takes into consideration the intended use and the potential of the system to affect participant protection and reliability of trial results. In addition, the sponsor should maintain SOPs for the systems that cover system setup, installation, and use. The responsibilities of the sponsor, investigator, and other parties should be clear, and the system users should be provided with training. Refer to CHN-37 for additional information.

Records Management

Per the NMPA-GCP-No57-2020 and CHN-37, the sponsor must retain the clinical trial data related to the sponsor and participating parties in the clinical trial. The transfer of data ownership must comply with the requirements of relevant laws and regulations. The sponsor must send written notification to the investigator and clinical trial institution about the requirements for preserving clinical trial records and when the trial-related records are no longer needed. At the beginning of a clinical trial, the investigator, clinical trial institution, and sponsor must establish archive management of the necessary documents. At the end of the clinical trial, an inspector must review and confirm the necessary documents of the investigator, clinical trial institution, and sponsor, and these documents must be properly kept in their respective clinical trial archives. Clinical trial documents must be retained for at least five (5) years after the trial drug is approved for marketing or after the termination of the clinical trial.

In addition, the NMPA-GCP-No57-2020 emphasizes that clinical trial essential documents are important to the National Medical Products Administration (NMPA)'s inspection of the clinical trial. Sponsors, investigators, and clinical trial institutions must confirm that they have appropriate storage conditions for preserving the essential documents. SOPs for document management should be formulated. The source data or its certified copy must be kept complete and readable during the retention period. In addition, the sponsor must ensure that the investigator can always consult and enter data in the case report form (CRF) reported to the sponsor during the trial. The data should not be controlled by the sponsor alone. The photocopies used as source documents should meet the requirements for certified copies. The NMPA-No37-2020 details the essential documents required for clinical trials to prove compliance with the NMPA-GCP-No57-2020. The NMPA-No74-2020 contains additional requirements on record management during a clinical trial.

Electronic Data Processing System

To safeguard personal data within electronic health record (EHR) systems, G-EHRAccess provides guidance on updating these systems to ensure access by sponsors and their representatives (e.g., monitors and investigators) is limited to only the records of clinical trial participants and that this access is auditable. See G-EHRAccess for details on system security, remote access, document sharing, consent, and other considerations.

According to GBR-113, when using electronic trial data handling processing systems, the sponsor must ensure and document that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. To validate such systems, the sponsor should use a risk assessment approach that takes into consideration the system’s intended use and potential to affect human participant protection and reliability of trial results. In addition, the sponsor must maintain standard operating procedures (SOPs) that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. With respect to the use of these computerized systems, the responsibilities of the sponsor, investigator, and other parties should be clear, and the users should receive relevant training.

Records Management

As set forth in GBR-113, sponsor-specific essential documents should be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the investigational product’s clinical development. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

However, per the MHCTR2006, the sponsor and the Chief Investigator must ensure that the documents contained in the trial master file are retained for at least five (5) years following the trial’s completion. The documents must be readily available to the Medicines and Healthcare Products Regulatory Agency (MHRA) upon request and be complete and legible. The sponsor should ensure that trial participant medical files are also retained for at least five (5) years after the trial’s conclusion.

In addition, GBR-113 states that the sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.

Responsible Parties

For requirements on personal data protection, the PIPL delineates that personal information processors are organizations or individuals who independently determine the purpose and method of processing personal information during personal information processing activities.

Data Protection

Per the PIPL, the personal information processor must ensure the safety of the personal information processed, including following principles of openness and transparency, disclosing personal information processing rules, and clearly indicating the purpose, method, and scope of processing. The PIPL applies to the processing of personal information in China for people located within the country. In addition, the PIPL and the DataSec-Regs apply to data processing activities conducted outside of China involving personal information of people located in China under the following circumstances: (1) where the processing is for the purposes of providing products or services to individuals located in China, (2) where the processing is for analyzing and evaluating the behavior of individuals located in China, or (3) other circumstances stipulated by laws and regulations.

Per the PIPL, the processing of personal information should have a clear and reasonable purpose and should be directly related to the purpose of processing with the least impact on personal rights and interests. The personal information processor must follow the principles of lawfulness, fairness, necessity, and good faith when processing personal information, and must not process personal information through misleading, fraudulent, coercive, and other methods. The collection of personal information must be limited to the minimum scope for the purpose of processing, and personal information must not be collected excessively, while following the principles of openness and transparency. The personal information processor must disclose processing rules and clearly indicate the purpose, method, and scope of processing. When handling personal information, the data quality must be guaranteed, and any inaccuracy and incompleteness of personal information must not adversely affect personal rights and interests. For additional data protection details see the DataSec-Regs, which supplements the PIPL.

The PIPL states that for sensitive personal information, which includes medical health information, the personal information processor must adopt additional protective measures, including informing participants of the necessity of processing sensitive personal information and the impact on personal rights and interests. Unless otherwise provided by laws and administrative regulations, the retention period of personal information must be the shortest time necessary to achieve the processing purpose. Also see the Id-SPI for guidance on identifying sensitive personal information.

Further, the DataSec-Regs states that where a network data processor provides or entrusts other network data processors to process personal information and important data, they must agree to the following:

• The recipient of network data must fulfill its obligation to protect network data security and process personal information and important data in accordance with the agreed purpose, method, scope, etc.
• If two (2) or more network data processors jointly decide on the purpose and method of processing personal information and important data, they must agree upon their respective rights and obligations.

Per the PIPL and the DataSec-Regs, to send personal information outside of China, the personal information processor must meet one (1) of the following conditions (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Pass the security assessment organized by the national cybersecurity and information department (See below in Data Security)
• Conduct personal information protection certification by professional institutions in accordance with the requirements of the Cyberspace Administration of China (CAC)
• Enter into a contract with the overseas recipient in accordance with the standard contract formulated by the CAC stipulating the rights and obligations of both parties
• Other conditions stipulated by laws, administrative regulations, or national cyberspace administration departments
• Where China’s international treaties and agreements permit providing personal information to foreign recipients
• It is necessary to provide personal information overseas to conclude or perform a contract to which the individual is a part
• To implement cross-border human resources management in accordance with labor rules and regulations formulated in accordance with the law and collective contracts signed in accordance with the law, and providing employees' personal information overseas is necessary
• It is necessary to provide personal information overseas to perform legal duties or obligations
• In an emergency, it is necessary to provide personal information overseas in order to protect the life, health, or property safety of a natural person

The PIPL states that the personal information processor must inform the participant of the name of the foreign recipient, contact information, processing purpose, processing method, and types of personal information. In addition, per the PIPL and the DataSec-Regs, the foreign personal information processor must appoint a representative located in China to be responsible for matters related to personal information protection and report the representative’s contact information to the data protection regulators—the CAC.

The DataScrty requires the personal information processor to manage its data processing activities to ensure data security, promote data development and utilization, protect the legitimate rights and interests of individuals and organizations, and safeguard national sovereignty, security, and development interests. CAC-No11-2022 standardizes requirements for exporting “important data” and personal information to protect the rights and interests of personal information, preserve national security and the societal public interest, and promote the cross-border security and free flow of data. Important data is defined as data that, once tampered with, destroyed, leaked, or illegally obtained or used, might endanger national security, economic operations, social stability, public health, or safety in China. Also see the DataSec-Regs for additional requirements on doing risk assessments and handling and reporting on important data. Personal information processors must conduct security assessments of personal data collected and generated in China before exporting it to overseas data processors. Data export security assessments focus on assessing risks that data export activities may bring to national security, the public interest, or the lawful rights and interests of individuals or organizations. The DataTrsfr-Regs delineates exemptions from the requirements to conduct security assessments, for example in an emergency where it is necessary to provide personal information overseas in order to protect the life, health, or property safety of a natural person. If DataTrsfr-Regs conflicts with CAC-No11-2022, the DataTrsfr-Regs supersede.

When applicable, the DataScrty states that the assessment report must be submitted to CAC through the provincial-level department where the personal information processor is located, and include the following materials:

• Declaration form
• Self-assessment report on data export risks
• Data agreements between the data processor and the overseas recipient

The CAC-No11-2022 states that data export activities that have already been conducted before the implementation of CAC-No11-2022 are noncompliant and must be rectified within six (6) months of the effective date of CAC-No11-2022 (i.e., by March 1, 2023). See the CAC-No11-2022 for additional details on conducting the data export security assessment, the provincial inspections, appeal procedures, and CAC’s review actions and timeline.

Consent for Processing Personal Data

Per the PIPL, personal consent must be made voluntarily and with the participants’ full knowledge of the processing purpose, processing methods, and types of personal information processed. In an emergency, if it is not possible to obtain consent in a timely manner to protect the life, health, property, and safety of participants, the personal information processor must promptly notify the individual after the emergency is eliminated. (Note: consent to data processing is not the same as informed consent to the research described in the Informed Consent topic.) As indicated in the DataSec-Regs, individual consent is defined as specific and unambiguous consent given by an individual for specific processing of their personal information.

The DataSec-Regs supplements the PIPL, adding detailed protection requirements when personal information processing is based on individual consent:

• The collection of personal information must not be collected beyond the scope, and personal consent must not be obtained through misleading information, fraud, coercion, etc.
• When processing sensitive personal information such as biometrics, religious beliefs, specific identities, and medical health the individual's separate consent must be obtained
• When processing the personal information of a minor under the age of 14, the consent of the minor’s parent/legal guardian must be obtained
• Personal information must not be processed beyond the purpose, method, type, or retention period of the personal information that the individual has consented to
• Processors must not frequently seek consent after an individual has clearly expressed their disagreement with the processing of their personal information
• If the purpose, method, or type of personal information processing changes, the individual’s consent must be obtained again
• If laws and administrative regulations provide that written consent must be obtained for the processing of sensitive personal information, such provisions must apply

Responsible Parties

For purposes of data protection requirements, the UK-GDPR, the UK-DPAct, and the G-GDPR delineate that the sponsor acts as the “controller” in relation to research data. This is because the sponsor determines what data is collected for the research study through the protocol, case report form, and/or structured data fields in a database. GBR-7 provides guidance on key data protection requirements to consider in the post-Brexit environment. Among other things, it describes how data can continue to flow to and from the United Kingdom (UK), as well as controller responsibilities.

Data Protection

Per the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, the sponsor (known as the “controller” in data protection legislation) must comply with the following principles of the data protection legislation:

• Lawfulness, fairness, and transparency
• Purpose limitation
• Data minimization
• Accuracy
• Storage limitation
• Integrity and confidentiality (security)
• Accountability

The sponsor must show that each data processing activity has a lawful basis under this legislation, in addition to the common law basis. For health and social care research, the lawful basis is determined by the data controller’s organization type:

• For universities, National Health Service (NHS) organizations, Research Council institutes, or other public authority, the processing of personal data for research should be a “task in the public interest.”
• For commercial companies and charitable research organizations, the processing of personal data for research should be undertaken within “legitimate interests.”

As described in the G-GDPR, with regard to transparency, the sponsor should understand whether personal data is collected indirectly from a third party or directly, as these determine the actions to take to comply with data protection requirements. In most cases, the sponsor will need to provide transparency information about the legal basis and other details of processing personal data. See the table in G-GDPR, which sets out the specific transparency requirements for personal data. In addition, GBR-100 contains a series of templates by the Health Research Authority (HRA) with suggested transparency language. Further, the sponsor should take measures to ensure data is processed securely, giving consideration to security, storage, and pseudonymization/anonymization when possible. For details on complying with security and storage requirements, see GBR-100.

Per the UK-GDPR and the UK-DPAct, the data protection legislation introduces a duty requiring public authorities or bodies to appoint a data protection officer (DPO); a DPO may be required for non-public entities if they carry out certain types of processing activities. The DPO assists the sponsor with monitoring internal compliance, informs and advises on data protection obligations, provides advice regarding Data Protection Impact Assessments (DPIAs), and is a point of contact for participants and the supervisory authority. See G-GDPR for guidance related to DPIAs.

For more information on data protection requirements following the UK’s transition out of the European Union (EU), see GBR-7.

Consent for Processing Personal Data

Per the UK-GDPR, UK-DPAct, and G-GDPR, consent to participate in research is not the same as consent as the legal basis for processing personal data under the data protection legislation. Per the G-GDPR, for the purposes of the UK-GDPR, the legal basis for processing data for health and social care research should not be consent. This means that requirements in the UK-GDPR relating to consent do not apply to health and care research. Per the G-GDPR, even though consent is not the legal basis for processing personal data for research, the common law duty of confidentiality still applies, so consent is still needed for people outside the care team to access and use confidential information for research.

As delineated in the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, participants have the right to be informed about the collection and use of their personal data. This is a key transparency requirement under the data protection legislation. The UK-GDPR specifies what data individuals have the right to be informed about (i.e., privacy information). In addition, as delineated in the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, the participant has certain data rights, which are limited by a range of exemptions. These exemptions must be balanced with what is fair to participants. As indicated in the G-GDPR, exemptions to data subject rights are not automatic, but must be considered on a study-by-study basis. It is important, therefore, to take into account the relevance of data rights to a particular study in the Participant Information Sheet (PIS) when offering or limiting the rights available to research participants. If data rights have been previously offered or limited to participants that are not appropriate under UK-GDPR, then the PIS may need to be revised as a non-substantial amendment.

As indicated in the G-GDPR and GBR-100, the HRA has developed a series of templates with transparency language to help organizations comply with the data protection legislation. The requirements vary depending on the point of collection of personal data (directly or indirectly) and the timing of the study. Also see GBR-129 for guidance from the UK Information Commissioner’s Office.

The UKwide-Rsrch describes the following differences among the UK nations regarding accessing identifiable data without consent, including for potential participants:

• England and Wales – If the project involves access to identifiable patient data relating to people living or receiving care and treatment in England and Wales without consent, the sponsor may need to apply to the HRA via the Confidentiality Advisory Group (CAG) (GBR-38). The CAG provides advice to the HRA on the use of confidential patient information for research uses. See GBR-41 for details and resources on the CAG.
• Northern Ireland – There is currently no legal basis for those outside of the direct care team to process identifiable data without consent. The Health and Social Care Privacy Advisory Committee can provide advice on any options available in Northern Ireland. The Health and Social Care Honest Broker Service does not provide identifiable data for consented studies or trials but may be able to offer advice on options to access anonymized data to support research
• Scotland – If a project is multi-center, a sponsor will need to obtain permissions through the Public Benefit and Privacy Panel for Health and Social Care. For single center studies, applicants should contact the Caldicott Guardian at the research site to discuss the requirements for accessing the data

UK-US Data Bridge

As explained in GBR-22, under the “UK Extension to the EU-US Data Privacy Framework” (GBR-23), businesses in the UK can transfer personal data to certified U.S. organizations without further safeguards as defined in the GBR-23. US organizations that have been certified can opt in to receive data from the UK through the UK-US data bridge. Per GBR-19, before transferring personal data, UK organizations must verify that the receiving US organization is certified pursuant to GBR-23. Sensitive personal data must be appropriately identified as sensitive when transferred under the UK-US data bridge to ensure it receives appropriate protections under the framework. Under the UK extension, sensitive personal information includes genetic data, biometric data for the purpose of uniquely identifying a natural person, and data concerning sexual orientation. See GBR-22, GBR-23, and GBR-19 for additional information about the UK Extension to the Data Privacy Framework.

Obtaining Consent

In all Chinese clinical trials, a freely given informed consent is required to be obtained from each participant in accordance with the requirements set forth in the NMPA-GCP-No57-2020, the Measures-Ethics, the RegEthics, and the EC-Guide. In addition, China is implementing the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37) as a guidance document. As per the NMPA-GCP-No57-2020, the DAL, the EC-Guide, and CHN-37, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an ethics committee (EC) and provided to the National Medical Products Administration (NMPA) with the clinical trial application. Per the MgmtHumanGen, the ICF must also be provided to the Ministry of Science and Technology (MOST) (now National Health Commission (NHC)) as part of its application procedures for human genetic resource (HGR) licenses. In addition, per the VaccineLaw, in carrying out a vaccine clinical trial, the investigator is required to obtain a signed ICF from the participant or legal representative/guardian. (Note that per SC-Order777 and NHC-HGRmgt, management of HGR was transferred from MOST to NHC, effective May 1, 2024).

The NMPA-GCP-No57-2020, the Measures-Ethics, and CHN-37 state that the investigator, or a person designated by the investigator, must provide detailed research study information to the participant or the legal representative/guardian. As delineated in the NMPA-GCP-No57-2020, the Measures-Ethics, and the EC-Guide, the ICF content should be briefly and clearly presented orally or, in a written language, that is easy to understand, and commensurate with the comprehension level of the research participants. The participant and the legal representative/guardian should also be given adequate time to consider whether to participate. The Measures-Ethics indicates that ICFs must contain sufficient, complete, and accurate information, and be expressed in language, text, video images, and so forth that research participants can understand. Researchers must explain each item to the research participants in accordance with the content of the ICF.

As per the NMPA-GCP-No57-2020, CHN-37, and the EC-Guide, none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant or the legal representative/guardian to waive or appear to waive their legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representatives from their liabilities for any negligence. The investigator should give the participant sufficient time to understand the ICF content, and the participant should make a decision whether or not to agree to participate in the study and sign the form. In psychological research, because informed consent may affect the participant’s response to the question, thereby affecting the accuracy of the research results, the investigator can fully inform the participant and obtain informed consent following the project study’s completion.

Per DctrlzCTs-Rare, for decentralized clinical trials of rare diseases, electronic informed consent may be used. When electronic informed consent is used, the informed consent process needs to be recorded, archived, and traceable. For rare disease participants with limited mobility, researchers can use remote informed consent to more quickly and easily obtain consent and ensure that all participants have the latest version in a timely manner. To use electronic informed consent in these scenarios, researchers must conduct evaluation and verification in advance and provide the participants with instructions and training. Before adopting electronic informed consent, the participants should be fully informed of the scope of data collection, access rights, etc. generated during the electronic informed consent process. During the informed consent process, researchers should ensure data security and the privacy of the participants (including their legal representative/guardian) are protected.

Per the MgmtHumanGen, to collect Chinese HGR for a clinical trial, the participant must agree to participate in the clinical trial in writing. Information provided to the participant must be comprehensive, complete, true, accurate, and must not conceal information nor be misleading or deceiving.

For specific consent requirements for human genome editing research, see the Consent for Specimen section.

Re-Consent

The NMPA-GCP-No57-2020 and CHN-37 require investigators to use the latest version of the ICF approved by the EC and, if necessary, participants in the clinical trial process should sign an updated ICF again. If new information may affect the participant’s continued participation in the trial, the investigator must promptly notify the participant and the legal representative/guardian and make corresponding records. Per the RegEthics and the Measures-Ethics, the investigator should obtain re-consent under the following circumstances (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• The research plan, scope, and content have changed
• Research using previously collected samples that were used for diagnosis and treatment and were labeled with personal identifiable labels
• Research using human biological samples or related clinical disease history data with subject-identifiable labels from existing biological sample repositories/databases
• The risks related to the research are increased or substantially increased
• The level of civil capacity of research participants has been raised
• Other changes occur during the research

Language Requirements

The NMPA-GCP-No57-2020, the Measures-Ethics, the RegEthics, and the EC-Guide require the ICF to be presented in oral or written form in a language that the participant is able to understand.

Documenting Consent

Per the NMPA-GCP-No57-2020, the Measures-Ethics, CHN-37, and the EC-Guide, the participant and the legal representative/guardian, and researchers who perform informed consent, should sign and date the ICF. Per the Measures-Ethics, when the research participants do not have the ability to express their consent in writing, the researcher must obtain their oral informed consent and have audio and video recordings and other process records and supporting materials.

Per the NMPA-GCP-No57-2020, CHN-37, and the EC-Guide, if the ICF is not signed by the participant, the relationship should be marked on the form. If the participant and the legal representative/guardian lack the ability to read, an impartial witness must witness the entire informed consent process. The witness should sign and date the ICF after the following steps have occurred:

• The written ICF and any other written information to be provided to the participant is read and explained to the participant and the legal representative/guardian
• The participant and the legal representative/guardian, have orally consented to the participant’s involvement in the trial, and has signed and dated the ICF, if capable of doing so

Before participating in the study, the participant or the legal representative/guardian should receive a copy of the signed and dated ICF.

Waiver of Consent

The EC-Guide and the RegEthics state that the EC may grant a waiver of informed consent when the following conditions are met (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• The risk that the subject may suffer does not exceed the minimum.
• The exemption from obtaining the informed consent of the subject does not have a negative impact on the participant’s rights and interests.
• The use of human bodily materials or data that can identify the information for research has made it impossible to find the participant, and the research project does not involve personal privacy and commercial interests.
• The biological sample donor has signed an ICF agreeing that the donated sample and related information can be used for all medical research.
• The exemption requires informed consent and does not mean that it is exempt from the review of the EC.

Obtaining Consent

In all United Kingdom (UK) clinical trials, a freely given informed consent must be obtained from each participant in accordance with the requirements set forth in the MHCTR, the MHCTR2006, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113). As per the MHCTR, the MHCTR2006, and GBR-9, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an ethics committee (EC) recognized by the United Kingdom Ethics Committee Authority (UKECA) (henceforth referred to as a “recognized EC”) and operating according to standard operating procedures (GBR-9) issued by England’s Health Research Authority (HRA).) Refer to GBR-18 and GBR-69 for more on informed consent in the UK.

The MHCTR and G-ConsentPIS, state that the investigator(s) must provide detailed research study information to the participant or legal representative/guardian. The MHCTR and G-ConsentPIS also specify that the oral and written information concerning the trial, including the ICF, should be easy to understand and presented without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant and the legal representative/guardian, should also be given adequate time to consider whether to participate. Per G-ConsentPIS, the Participant Information Sheet (PIS) supports the consent process to help ensure participants have been adequately informed. In addition, the PIS forms part of the transparency information that must be provided to participants under the data protection legislation for the use and processing of personal data. (See the Personal Data Protection section for more information on data protection requirements.) For more guidance on the PIS, see the PrtInfoQty-Stds, the PrtInfo-DesignPrin, and GBR-14, which include FAQs, information principles, and standards.

Per GBR-31, the HRA guides researchers and ECs in taking a proportionate approach to seeking consent. A proportionate approach adopts procedures commensurate with the balance of risk and benefits so that potential participants are not overwhelmed by unnecessarily lengthy, complex, and inaccessible information sheets. Participants should be provided with succinct, relevant, truthful information in a user-friendly manner that promotes their autonomy. Specifically, the methods and procedures used to seek informed consent and the level of information provided should be proportionate to:

• The nature and the complexity of the research
• The risks, burdens, and potential benefits (to the participants and/or society)
• The ethical issues at stake

Per GBR-113, none of the oral and written information concerning the clinical trial, including the written ICF, should contain any language that causes the participant or legal representative/guardian to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence.

Re-Consent

According to GBR-113, the EC should approve any change in the ICF due to a protocol modification before such changes are implemented. The participant or legal representative/guardian will also be required to re-sign the revised ICF and receive a copy of any amended documentation.

Per GBR-18, during a clinical trial, researchers should periodically reaffirm the willingness of participants to continue. If significant new information becomes available, participants should be reconsented using revised (and re-approved) consent documents so that their continued consent is confirmed.

Language Requirements

As stated in the MHCTR, applications to the EC and the Medicines and Healthcare Products Regulatory Agency (MHRA) and any accompanying material, such as the ICF content, should be presented in English.

Documenting Consent

The MHCTR states that the participant or legal representative/guardian, and the investigator(s) must sign and date the ICF. Where the participant is illiterate, or the legal representative/guardian is illiterate, verbal consent should be obtained in the presence of and countersigned by an impartial witness. As provided in G-ConsentPIS, consent can be documented electronically or in writing. A physical or electronic copy of the signed consent form will still need to be provided to the participant. To record consent electronically, electronic signatures will be needed. Because there are different forms and classifications of electronic signatures, the researcher should determine what is appropriate for the particular study. GBR-6 sets out the legal and ethical requirements for seeking and documenting consent using electronic methods (also known as eConsent in the UK), as well as expectations regarding the use of electronic signatures. eConsent enables potential research participants to be provided with the information they need to make a decision via a tablet, smartphone, or digital multimedia. It also enables their informed consent to be documented using electronic signatures. This approach can supplement the traditional paper-based approach or, where appropriate, replace it.

Waiver of Consent

No information is currently available.

Based on the NMPA-GCP-No57-2020, the Measures-Ethics, the EC-Guide, the RegEthics, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37), the informed consent form (ICF) should include the following statements or descriptions, as applicable (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• The study purpose, procedures, and duration of the trial
• Any expected risks or discomforts to the participant
• Any expected benefits to the participant; if no benefit is expected, the participant should be informed of this point
• The participant’s responsibilities
• The approximate number of participants involved in the trial
• Those aspects of the trial that are experimental
• Treatment available to the participant as well as important potential risks and benefits associated with this treatment
• The alternative procedure(s) or course(s) of treatment that may be available to the participant, and their important potential benefits and risks
• The nature, form, and extent of compensation for participation
• Any expenses the participant needs to pay to participate in the trial
• The extent to which confidentiality of records identifying the participant will be maintained, and a statement that, when necessary, the sponsor, the ethics committee (EC), the National Medical Products Administration (NMPA), and drug authorities in the provinces, autonomous regions, and municipalities may be required to review participant data
• The scope and method of use of research data and research participants' personal data, and whether sharing and secondary use are carried out
• Any treatment and corresponding compensation the participant can expect to receive in the event of a trial-related injury
• The participant’s rights, including that participation is voluntary, and that the participant can withdraw from the study at any time without penalty or loss of benefits, including medical treatment, to which the participant is otherwise entitled
• Precautions and protective measures for the participant before, during, and after the research
• The foreseeable circumstances and/or reasons under which the participant's participation in the trial may be terminated
• Contact information for the sponsor and investigator in the event of participant problems or injuries related to the trial
• Basic information about the researcher and qualification of research institution
• That records identifying the participant will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the trial are published, the participant’s identity will remain confidential
• Whether the results of the study will be provided to the research participants
• That the participant or the legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the participant’s willingness to continue participation in the trial
• When appropriate, the EC may require the following additional information: whether the research may put the participant at risk but the risk is not currently foreseeable; researchers can terminate a participant’s participation in the study without their consent; new major discoveries during the research will be provided to the participant; and whether there is a potential conflict of interest
• If applicable, how biological samples will be handled

Per the MgmtHumanGen, to collect Chinese human genetic resources (HGR) for a clinical trial, the investigator must provide advance information to the participant on the purpose of collection, the possible health impact, the protection measures of personal privacy, their participation is voluntary, and they have the right to withdraw unconditionally at any time.

Based on the MHCTR, the G-ConsentPIS, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the informed consent form (ICF) should include the following statements or descriptions, as applicable (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• The study purpose, procedures, and duration
• Study title and the study Integrated Research Application System (IRAS) ID are clearly displayed
• Approximate number of participants involved in the trial
• The participant’s responsibilities in participating in the trial
• Trial treatment schedule and the probability for random assignment to each treatment
• Experimental aspects of the study
• Any foreseeable risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant
• Any benefits or prorated payment to the participant or to others that may reasonably be expected from the research; if no benefit is expected, the participant should also be made aware of this
• A disclosure of appropriate alternative procedures or treatments, and their potential benefits and risks
• Compensation and/or medical treatment available to the participant in the event of a trial-related injury
• Any additional costs to the participant that may result from participation in the research
• That participation is voluntary, the participant may withdraw at any time, and refusal to participate will not involve any penalty or loss of benefits, or reduction in the level of care to which the participant is otherwise entitled
• The extent to which confidentiality of records identifying the participant will be maintained, and the possibility of record access by the Medicines and Healthcare Products Regulatory Agency (MHRA), the ethics committees (ECs), the auditor(s), and the monitor(s)
• That the participant or legal representative/guardian will be notified if significant new findings developed during the study may affect the participant's willingness to continue
• Individuals to contact for further information regarding the trial, the rights of trial participants, and whom to contact in the event of trial-related injury
• Foreseeable circumstances under which the investigator(s) may remove the participant without consent

ICF examples and templates are provided in the G-ConsentPIS.

For more information about informed consent required elements, see GBR-18, GBR-113, GBR-100, GBR-31, and GBR-69.

Overview

In accordance with the Declaration of Helsinki (CHN-84), principles set forth in the NMPA-GCP-No57-2020, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37), China’s ethics standards safeguard the rights of research participants. Participants also have the right to receive the nationally available standard of health care, and the right to report any trial-related injuries or issues to the investigator(s) and the ethics committee (EC). The RegEthics states that the EC must protect the legitimate rights and interests of the participants, safeguarding their dignity, and promoting the development of biomedical research norms. As indicated in the NMPA-GCP-No57-2020, the EC-Guide, and the RegEthics, a participant’s rights must be clearly addressed in the informed consent form (ICF) and during the informed consent process. (See the Required Elements; Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information regarding requirements for participant rights.) See CHN-26 for an analysis of clinical trial participants’ rights in China.

The Right to Participate, Abstain, or Withdraw

As set forth in the NMPA-GCP-No57-2020, the Measures-Ethics, the EC-Guide, the RegEthics, and CHN-37, the participant or legal representative/guardian should be informed that participation is voluntary, that the participant may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As delineated in the Measures-Ethics, the EC-Guide, the NMPA-GCP-No57-2020, the RegEthics, and CHN-37, a potential research participant or the legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study. (See the Required Elements section for more detailed information regarding participant rights.)

The Right to Privacy and Confidentiality

As per the Measures-Ethics, the EC-Guide, the RegEthics, the NMPA-GCP-No57-2020, and CHN-37, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. The NMPA-GCP-No57-2020 also states that it is the responsibility of the investigator(s) to safeguard the confidentiality of research data to protect the identity and records of research participants.

The Right of Inquiry/Appeal

The Measures-Ethics, the EC-Guide, the NMPA-GCP-No57-2020, and CHN-37 state that the research participant or the legal representative/guardian should be provided with contact information for the investigator(s) and the EC to address trial-related inquiries and/or to appeal against a violation of the participant’s rights. (See the Required Elements section for more detailed information regarding participant rights.)

The Right to Safety and Welfare

The NMPA-GCP-No57-2020 and CHN-37 state that a research participant’s right to safety and the protection of health and welfare must take precedence over the interests of science and society.

Overview

In accordance with the MHCTR, the MHCTR2006, the G-ConsentPIS, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the United Kingdom’s (UK’s) ethical standards promote respect for all human beings and safeguard the rights of research participants. The MHCTR states that a participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As set forth in the MHCTR, the G-ConsentPIS, and GBR-113, the participant or legal representative/guardian should be informed that participation is voluntary, that they may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As delineated in the MHCTR, the G-ConsentPIS, and GBR-113, a potential research participant or legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.

Also see GBR-117 for an interactive web-based communications toolkit to help researchers and participants keep in touch after participation in a research study.

The Right to Privacy and Confidentiality

As per the MHCTR and GBR-113, the arrangements to protect participants’ privacy should be provided in the application to the ethics committee, and the ICF should inform potential participants of any potential risk to their confidentiality.

The Right of Inquiry/Appeal

The MHCTR and GBR-113 state that the research participant or legal representative/guardian should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries.

The Right to Safety and Welfare

The MHCTR, the MHCTR2006, and GBR-113 state that a research participant’s rights, safety, and well-being must take precedence over the interests of science and society.

The EC-Guide states that during an emergency, clinical studies on human participants must not be conducted without prior review and approval by the ethics committee (EC). Per the NMPA-GCP-No57-2020 and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37), in an emergency, if the signed informed consent form (ICF) has not been obtained from the research participant or the legal representative/guardian, or if an effective treatment is lacking, but the investigational product could save the participant’s life, recover health, or alleviate pain, the clinical trial may be conducted. However, the method used on the participant must be explained clearly in the trial protocol as well as the relevant trial documentation, and the EC must approve the protocol in advance. The participant or the legal representative/guardian should be informed about the trial as soon as possible, and consent to continue and other consent should be requested, as appropriate.

During an outbreak of an epidemic, the EC-Guide advises ECs to adhere to the highest scientific and ethical standards for independent review of the research project to ensure balancing of quality and timeliness. The materials provided by the researcher can be simplified according to the situation. The EC should pay special attention to the informed consent process as participants may be improperly exploited due to their obvious vulnerability, especially when it involves high-risk and risk-uncertain research. It should be ensured that participants choose to participate voluntarily and independently after being fully informed and fully understanding the possible risks of research. Research participants or the legal representative/guardian must be allowed to withdraw from research unconditionally at any stage.

See the EC-Guide for additional guidance on the EC review when there is a major epidemic risk.

The MHCTR, the MHCTR2006-No2, the MHCTR-BSQ, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113) make provisions to protect the rights of a research participant during the informed consent process when a clinical trial of an investigational product (IP) is complicated by medical emergencies. As delineated in the G-ConsentPIS and GBR-18, in an emergency, if the signed informed consent form (ICF) cannot be obtained from the research participant, the consent of the legal representative/guardian should be obtained. If the prior consent of the participant or legal representative/guardian cannot be obtained, the participant’s enrollment should follow measures specified in the protocol, and the ethics committee (EC) must provide documented approval in order to protect the participant’s rights, safety, and well-being. The participant or legal representative/guardian should provide consent as soon as possible.

The MHCTR-BSQ amends the MHCTR and creates an exception for minors participating in a trial where urgent treatment is required and prior consent cannot be obtained. This situation also requires the EC to issue its approval beforehand.

The MHCTR2006-No2 amends the MHCTR and creates an exception to the general rule in England, Northern Ireland, and Wales that incapacitated adults cannot be included in a clinical trial under medical emergencies. If the treatment to be provided is a matter of urgency and obtaining prior consent is not possible, incapacitated adult participants may be included in the trial once EC approval has been obtained. In Scotland, the provisions of Section 51 of the AIA2000 govern the inclusion of adults lacking capacity in research.

The G-ConsentPIS states that the United Kingdom allows adults not able to consent for themselves to be recruited into clinical trials without prior consent in emergency situations if the following conditions exist:

• Treatment needs to be given urgently
• It is also necessary to take urgent action to administer the drug (IP) for the purposes of the trial
• It is not reasonably practicable to obtain consent from a legal representative
• The procedure is approved by an EC
• Consent is sought from a legal representative as soon as possible

Overview

As per the EC-Guide, the NMPA-GCP-No57-2020, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37), in all Chinese clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. The EC-Guide and the NMPA-GCP-No57-2020 define vulnerable persons as those who are relatively (or absolutely) incapable of safeguarding their interests, and consequently, are usually incapable of giving consent or refusing to give consent due to the restriction on their capacities or freedoms. These populations include people with low socioeconomic status and low education levels. The EC-Guide also defines vulnerability to include the following areas: economic, institutional fragility, cognitive, social, medical treatment, and compliance. The NMPA-GCP-No57-2020 and CHN-37 also include members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include persons in nursing homes, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

The NMPA-GCP-No57-2020, which upholds the principles of the Declaration of Helsinki (CHN-84) and the RegEthics, both require special attention to be provided to those participants who cannot give or refuse to give consent for themselves, and for those who will not benefit personally from the research. As per RegEthics, this population includes children, pregnant women, mentally impaired persons, and people with mental disorders. Also, the Measures-Ethics requires special protection for research participants involving specific groups, such as children, pregnant women, the elderly, persons with intellectual and mental disabilities. In addition, special attention should be paid to studies involving fertilized eggs, embryos, fetuses, or those that may be affected by assisted reproductive technologies.

Note: The EC-Guide clarifies that special protections for vulnerable populations must not mean that they are excluded during the recruitment process. Vulnerable people should also benefit from research and be encouraged to participate in clinical research.

For additional information, see the Children/Minors and Mentally Impaired sections. In addition, see CHN-26 for an analysis of clinical trial participants’ rights in China.

Overview

As per the MHCTR and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), in all United Kingdom (UK) clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process.

Per GBR-131, vulnerability may be defined in different ways and may arise as a result of being in an abusive relationship, vulnerability due to age, potential marginalization, disability, and due to disadvantageous power relationships within personal and professional roles. Participants may not be conventionally vulnerable but may be in a dependent relationship that means they can feel coerced or pressured into taking part.

As stated in GBR-131, researchers must assess potential vulnerability within the context of the research, in terms of potential consequences from their participation (immediate and long-term) or lack of positive impact where this is immediately needed or expected. Further, researchers should make the participants aware of the limits to confidentiality and decide whether verbal or written consent will be more appropriate and protective of the participants’ interests. In addition, researchers should consider the following:

• Participants’ vulnerability
• Potential negative consequences or lack of personal benefits from their involvement in research where these are expected
• Providing appropriate information to elicit freely-given informed consent for participation as well as information regarding data deposit and data re-use (where deposit is possible)
• Limits to confidentiality and occasions where this may occur
• Legal requirements of working with the specific population
• Incentives and compensation for participation

In addition, GBR-131 states that when working with participants who are considered vulnerable, researchers may find themselves in a position of increased responsibilities or expectations. Researchers should endeavor to assess the likelihood of additional ethics issues and develop strategies and a framework of clear responsibilities they can refer to should such issues arise. They should also use their research ethics committee as a resource for advice and guidance. Researchers should be able to justify the approach they take in dealing with unforeseen ethics issues and maintain the integrity of the research.

As per GBR-131, in cases where research involves potentially vulnerable groups, every effort should be made to secure freely given informed consent that participants have actively provided. Every effort should be made to ensure that they have the time and opportunity to access support in their decision-making, for example by discussing their choice with a trusted adult or relative. Passive assent, including group assent (with consent given by a gatekeeper) should be avoided wherever possible, and every effort should be made to develop methods of seeking consent that are appropriate to the groups studied, using expert advice, support, and training, where necessary. Vulnerability should be considered on a case-by-case basis; many groups or individuals not traditionally considered as vulnerable could be exposed to issues from participating in research that make them vulnerable. See GBR-131 for additional resources and case studies.

See the Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired sections for additional information about these vulnerable populations.

As per MPL, minors refer to citizens who are under the age of 18.

In accordance with the NMPA-GCP-No57-2020 and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37), when the research participant is a child, the informed consent form (ICF) must be signed by the child’s parent/legal guardian. If the child can decide whether to participate, the ICF should also be approved by the child. The age of consent for children and minors is not defined in the currently available regulatory resources. See CHN-26 for an analysis of clinical trial participants’ rights in China.

Per NMPA-No11-2017, clinical trials may be conducted on children depending on existing knowledge of and extrapolation by research results in adults. Drugs that are intended for use in children should be evaluated in the appropriate age group for children and start in the high-age group followed by the low-age group. The EC-Guide stipulates the following conditions when children can participate in research:

• Only when it is shown that the research may be aimed at the prevention and mitigation of serious problems that affect the health and well-being of children
• Research that does not exceed the minimum risk
• Research that moderately exceeds the minimum risk, but is expected to directly benefit the child participants
• Research that moderately exceeds the minimum risk limit, but children may benefit from a population of participants

Per DctrlzCTs-Rare, for decentralized clinical trials of rare diseases, electronic informed consent may be used with children. Since rare diseases often occur in childhood, the use of multimedia interactive modes, such as video, audio, and charts, in the informed consent process will be more conducive to the understanding of child participants and help them to be fully informed.

Assent Requirements

No information is currently available regarding assent requirements for children or minors.

According to the MHCTR and GBR-4, a minor in the United Kingdom (UK) is an individual under 16 years of age.