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 Ministry of Science and Technology (MOST).

National Medical Products Administration (NMPA)

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, the SAMR-Org, and CHN-21, 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 drug clinical trial institutions; 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.

Ministry of Science and Technology

The Bioscrty-Law, the MgmtHumanGen, and the Rules-MgmtHGR delineate that MOST is responsible for China's management of human genetic resources (HGR). The MgmtHumanGen and the Rules-MgmtHGR stipulate that MOST’s 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 supports 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 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 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, 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, MOST entrusted the China Biotechnology Development Center 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

See the Scope of Assessment section for more details and see the HGR-Licenses, HGR-Procedures, and the HGR-LicenseSummary, for additional information on HGR licenses and procedures.

The Rules-MgmtHGR also state that applications must pass a security review organized by MOST 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 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 (MOST), and foreign affairs, as well as relevant military agencies, to analyze national biosecurity issues, and organize, coordinate, and drive national biosecurity work. MOST 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, 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 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 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 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). Please note that the NMPA refers to ICH guidelines as foreign reference guidance and provides Chinese translations, when available, at CHN-49.

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 CHN-5, 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

Ministry of Science and Technology

Per HGR-WorkUpdt and CHN-4, the following is the MOST Biotechnology Development Center’s contact information for the management of human genetic resources:

Ministry of Science and Technology
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: Xu Penghui
Phone number: 010-58881479
Contact: Zhu Min
Phone number: 010-88225151 or 010-88225168
Information system support: 17610386080

This profile covers the role of the Department of Health & Human Services (HHS)’s Food & Drug Administration (FDA) in reviewing and authorizing investigational new drug applications (INDs) to conduct clinical trials using investigational drug or biological products in humans in accordance with the FDCAct, 21CFR50, and 21CFR312. Regulatory requirements for federally funded or sponsored human subjects research, known as the Common Rule (Pre2018-ComRule and RevComRule), which the HHS and its Office for Human Research Protections (OHRP) implements in subpart A of 45CFR46, are also examined. Lastly, additional HHS requirements included in subparts B through E of 45CFR46 are described in this profile, where applicable, using the acronym 45CFR46-B-E. (Please note: ClinRegs does not provide information on state level requirements pertaining to clinical trials.)

Food & Drug Administration

As per the FDCAct, 21CFR50, and 21CFR312, the FDA is the regulatory authority that regulates clinical investigations of medical products in the United States (US). According to USA-92, the FDA is responsible for protecting public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices.

An overview of the FDA structure is available in USA-33. Several centers are responsible for pharmaceutical and biological product regulation, including the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). Additionally, per USA-88, the Office of Clinical Policy (OCLiP) develops good clinical practice and human subject protection policies, regulation, and guidance.

See USA-47 for a list of FDA clinical trials related guidance documents.

Office for Human Research Protections and Common Rule Agencies

Per USA-93, the OHRP provides leadership in the protection of the rights, welfare, and well-being of human research subjects for studies conducted or supported by the HHS. The OHRP helps ensure this by providing clarification and guidance, developing educational programs and materials, maintaining regulatory oversight, and providing advice on ethical and regulatory issues in biomedical and social-behavioral research.

USA-65 states that the Common Rule (Pre2018-ComRule and RevComRule) outlines the basic provisions for institutional ethics committees (ECs) (referred to as institutional review boards (IRBs) in the US), informed consent, and Assurances of Compliance. See USA-65 for a list of US departments and agencies that follow the Common Rule, which are referred to as Common Rule departments/agencies throughout the profile.

The RevComRule applies to all human subjects research that is federally funded or sponsored by a Common Rule department/agency (as identified in USA-65), and: 1) was initially approved by an EC on or after January 21, 2019; 2) had EC review waived on or after January 21, 2019; or 3) was determined to be exempt on or after January 21, 2019. (Per USA-55 and USA-74, the RevComRule is also known as the “2018 Requirements.”) For 2018 Requirements decision charts consistent with the RevComRule, including how to determine if research is exempt, see USA-74. For more information about the RevComRule, see USA-66.

Per the RevComRule, the Pre2018-ComRule requirements apply to research funded by a Common Rule department/agency (as identified in USA-65) that, prior to January 21, 2019, was either approved by an EC, had EC review waived, or was determined to be exempt from the Pre2018-ComRule. Institutions conducting research approved prior to January 21, 2019 may choose to transition to the RevComRule requirements. The institution or EC must document and date the institution's determination to transition a study on the date the determination to transition was made. The research must comply with the RevComRule beginning on that date. For pre-2018 Requirements decision charts consistent with the Pre2018-ComRule, including how to determine if research is exempt, see USA-74.

See USA-54 for additional information regarding compliance with the Pre2018-ComRule and the RevComRule.

USA-65 indicates that the FDA, despite being a part of the HHS, is not a Common Rule agency. Rather, the FDA is governed by its own regulations, including the FDCAct and 21CFR50. However, the FDA is required to harmonize with the Pre2018-ComRule and the RevComRule whenever permitted by law.

If a study is funded or sponsored by HHS, and involves an FDA-regulated product, then both sets of regulations will apply. See G-RevComRule-FDA for additional information.

Other Considerations

Per USA-16, the US is a founding regulatory member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The US has adopted several ICH guidance documents, including the E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population (US-ICH-E11), E17 General Principles for Planning and Design of Multiregional Clinical Trials (US-ICH-E17), and E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) (US-ICH-GCPs), which are cited throughout this profile.

Contact Information

Food & Drug Administration

As per USA-81, USA-91, and USA-90, the contact information for the FDA is as follows:

Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993
Telephone (general inquiries): (888) 463-6332

CDER Telephone (drug information): (301) 796-3400
CDER Email: druginfo@fda.hhs.gov

CBER Telephone: (800) 835-4709 or (240) 402-8010
CBER Email (manufacturers assistance): Industry.Biologics@fda.hhs.gov
CBER Email (imports): CBERimportinquiry@fda.hhs.gov
CBER Email (exports): CBERExportCert@fda.hhs.gov

Office for Human Research Protections

Per USA-82, the contact information for the OHRP is as follows:

Office for Human Research Protections
1101 Wootton Parkway, Suite 200
Rockville, MD 20852
Telephone: (866) 447-4777 or (240) 453-6900
Email (general inquiries): OHRP@hhs.gov

Department of Health & Human Services

According to USA-83, the contact information for the HHS is as follows:

US Department of Health & Human Services
Hubert H. Humphrey Building
200 Independence Avenue, S.W.
Washington, D.C. 20201
Call Center: (877) 696-6775

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).

Ministry of Science and Technology

Per the Bioscrty-Law and the MgmtHumanGen, Ministry of Science and Technology (MOST)’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 ethical principles and ethical 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

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

As delineated in the Rules-MgmtHGR, MOST 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 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 ethical 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. Following those submissions, the international cooperative clinical research can be carried out.

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. Per the NMPA-No50-2018 and the NMPA-No48-2020, with regard to chemical drugs and biological products, the applicant should 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. 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.)

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 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. The drug registration inspection of overseas-produced drugs must be implemented by the port drug inspection agency.

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. 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 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 will achieve innovations and expedited 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.

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 in the past decade. 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.

The NMPA-No34-2022 and Prcdrs-Changes indicate that if there are protocol changes that have a significant impact on trial safety, scientific validity, or data reliability the sponsor should submit a new clinical trial application to the NMPA. See Prcdrs-Changes for working procedures for other changes during the review of the clinical trial application.

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. CHN-19 and NMPA-No52-2018-Interp describe 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 adjust 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 further guidance on the NMPA’s drug regulatory requirements, please refer to CHN-60.

Ministry of Science and Technology

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, and the research must pass ethical 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 on its online platform, which will generate a record number. (Note that HGR-WorkUpdt indicates that MOST has initiated operation of a new online platform for HGR at CHN-6. Per HGR-InfoSys, the original online platform is available at CHN-23. For help with the two systems, contact Xu Penghui, Department of Social Development and Science and Technology, MOST at 010-58881479; Zhu Min, China Biotechnology Development Center, at 010-88225151 or 010-88225168; or the information system support at 17610386080.) For additional HGR guidance and procedures, see CHN-76.

Per HGR-Procedures, for applications on collection, preservation, and international cooperation research with export of Chinese HGR, MOST will screen the electronic application to ensure it is complete within one (1) working day of submission to CHN-6 or CHN-23. Upon acceptance, MOST issues an acceptance slip and initiates the technical review. MOST organizes experts to conduct technical reviews of accepted applications and form opinions. MOST decides whether to approve or disapprove an application and announces the results and reasons on the MOST website (CHN-76). If the approval is not granted, the reasons will be explained. If the approval is granted, MOST will send the approval decision letter to the provincial science and technology administrative department by mail within 10 working days and publish the mailing details on its website (CHN-76). The applicant should then go to the provincial science and technology administrative department to receive the approval decision letter with the acceptance form.

Per HGR-Procedures, regarding clinical trials of international cooperation research where there is no export, the Chinese legal entity can directly file the clinical trial to CHN-6 or CHN-23. After the filing materials are successfully submitted and the filing number is obtained, international cooperative clinical trials can be carried out. Where multicenter clinical trials are involved, the team leader can conduct the filing procedures. After the other participating medical institutions obtain the filing number of the team leader unit, they can upload their ethical approval documents and the required documentation to the online platform to carry out international cooperative clinical trials.

See CHN-76, for additional HGR processes and policies, and see HGR-FAQs for frequently asked questions on HGR applications. See Submission Process and Submission Content sections and the Specimens topic for additional information on HGR regulatory management.

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 (MOST), 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.

Overview

In accordance with the FDCAct, 21CFR50, and 21CFR312, the Food & Drug Administration (FDA) has authority over clinical investigations for drug and biological products regulated by the agency. 21CFR312 specifies that the scope of the FDA’s assessment for investigational new drug applications (INDs) includes all clinical trials (Phases 1-4). Based on 21CFR56 and 21CFR312, institutional ethics committee (EC) review of the proposed clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the United States (US)).

As delineated in 21CFR312 and USA-42, sponsors are required to submit an IND to the FDA to obtain an agency exemption to ship investigational drug(s) across state lines to conduct drug or biologic clinical trial(s). An IND specifically exempts an investigational drug or biologic from FDA premarketing approval requirements that would otherwise be applicable. 21CFR312 states that “‘IND’ is synonymous with ‘Notice of Claimed Investigational Exemption for a New Drug.’"

According to USA-42, the FDA categorizes INDs as either commercial or non-commercial (research) and classifies them into the following types:

• Investigator INDs - Submitted by physicians who both initiate and conduct the investigation, and who are directly responsible for administering or dispensing the investigational drug.

• Emergency Use INDs - Enable the FDA to authorize experimental drugs in an emergency situation where normal IND submission timelines cannot be met. Also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.

• Treatment INDs - Submitted for experimental drugs showing potential to address serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.

Per the G-PharmeCTD, non-commercial products refer to products not intended to be distributed commercially and include the above listed IND types.

As indicated in the G-IND-Determination, in general, human research studies must be conducted under an IND if all of the following research conditions apply:

• A drug is involved as defined in the FDCAct

• A clinical investigation is being conducted as defined in 21CFR312

• The clinical investigation is not otherwise exempt from 21CFR312

The G-IND-Determination states that biological products may also be considered drugs within the meaning of the FDCAct.

Further, per 21CFR312 and the G-IND-Determination, whether an IND is required to conduct an investigation of a marketed drug primarily depends on the intent of the investigation and the degree of risk associated with the use of the drug in the investigation. See 21CFR312 and the G-IND-Determination for detailed exemption conditions for marketed drugs.

Clinical Trial Review Process

As delineated in 21CFR312, the FDA's primary objectives in reviewing an IND are to ensure human participant safety and rights in all phases of the investigation. Phase 1 submission reviews focus on assessing investigation safety, and Phase 2 and 3 submission reviews also include an assessment of the investigation’s scientific quality and ability to yield data capable of meeting marketing approval statutory requirements. An IND may be submitted for one (1) or more phases of an investigation.

As per USA-41 and USA-94, the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) receive IND submissions for drugs, therapeutic biological products, and other biologicals. Per the FDCAct and 21CFR312, an IND automatically goes into effect 30 calendar days from receipt, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. A clinical hold is an order the FDA issues to delay or suspend a clinical investigation. If the FDA determines there may be grounds for imposing a clinical hold, an attempt will be made to discuss and resolve any issues with the sponsor prior to issuing the clinical hold order. See 21CFR312 for more information on clinical holds.

According to USA-41, with respect to sponsor-investigators, once the FDA receives the IND, an IND number will be assigned and the application will be forwarded to the appropriate reviewing division. A letter will be sent to the sponsor-investigator providing notification of the assigned IND number, date of receipt of the original application, address where future submissions to the IND should be sent, and the name and telephone number of the FDA person to whom questions about the application should be directed.

As indicated in 21CFR312, the FDA may at any time during the course of the investigation communicate with the sponsor orally or in writing about deficiencies in the IND or about the FDA's need for more data or information. Furthermore, on the sponsor's request, the FDA will provide advice on specific matters relating to an IND.

21CFR312 indicates that once an IND is in effect, a sponsor must submit a protocol amendment if intending to conduct a study that is not covered by a protocol already contained in the IND, there is any change to the protocol that significantly affects the safety of subjects, or a new investigator is added to carry out a previously submitted protocol. A sponsor must submit a protocol amendment for a new protocol or a change in protocol before its implementation, while protocol amendments to add a new investigator or to provide additional information about investigators may be grouped and submitted at 30-day intervals. See 21CFR312 for more information on protocol amendments.

As per 21CFR312, if no subjects are entered into a clinical study two (2) years or more under an IND, or if all investigations under an IND remain on clinical hold for one (1) year or more, the IND may be placed by the FDA on inactive status. An IND that remains on inactive status for five (5) years or more may be terminated. See 21CFR312 for more information on inactive status.

21CFR312 indicates that the FDA may propose to terminate an IND based on deficiencies in the IND or in the conduct of an investigation under an IND. If the FDA proposes to terminate an IND, the agency will notify the sponsor in writing, and invite correction or explanation within a period of 30 days. If at any time the FDA concludes that continuation of the investigation presents an immediate and substantial danger to the health of individuals, the FDA will immediately, by written notice to the sponsor, terminate the IND. See 21CFR312 for more information on FDA termination.

For more information on CDER and CBER internal policies and procedures for accepting and reviewing applications, see USA-96 and USA-95, respectively.

Expedited Processes

USA-84 further indicates that the FDA has several approaches to making drugs available as rapidly as possible:

• Breakthrough Therapy – expedites the development and review of drugs which may demonstrate substantial improvement over available therapy
• Accelerated Approval – allow drugs for serious conditions that fill an unmet medical need to be approved based on a surrogate endpoint
• Priority Review – a process by which the FDA’s goal is to take action on an application within six (6) months
• Fast Track – facilitates the development and expedites the review of drugs to treat serious conditions and fill an unmet medical need

See USA-84 and USA-85 for more information on each process. Additionally, see the FDCAct, as amended by the FDORA, for changes to the accelerated approval process.

Other Considerations

The G-RWDRWE-Reg, issued as part of the FDA’s Real-World Evidence (RWE) Program (see USA-17), discusses the applicability of the 21CFR312 IND regulations to various clinical study designs that utilize real-world data (RWD). See the G-RWDRWE-Reg for more information.

For information on the appropriate use of adaptive designs for clinical trials and additional information to provide the FDA to support its review, see G-AdaptiveTrials.

For research involving cellular and gene therapy, see the guidance documents at USA-80.

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: the sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each one):

• 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.

Ministry of Science and Technology

Per HGR-ExprtLicenseGuide, there is no fee for an approval from the Ministry of Science and Technology (MOST) to export human genetic resources (HGR) from China.

Food & Drug Administration

The Food & Drug Administration (FDA) does not levy a fee to review investigational new drug submissions.

However, per the FDCAct, FDARA, and USA-45, the FDA has the authority to assess and collect user fees from companies that produce certain human drug and biological products as part of the New Drug Application (NDA). Per USA-43, the NDA is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the United States. The data gathered during the animal studies and human clinical trials of an investigational new drug become part of the NDA.

Overview

As per the Measures-Ethics, the RegEthics, the EC-Guide, the NMPA-GCP-No57-2020, the DRR, and the DAL, an ethical review 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 ethical 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 ethical 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. See the Scope of Review section for more requirements regarding EC review of life sciences and medical research involving people.

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.

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 ethical review. In areas where minority ethnic groups reside, the institution should consider including members of those groups on the EC. 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 ethical 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 independent consultant advises on specific project issues under review and does not participate in the voting.

The EC-Guide and the RegEthics provide that the EC composition should include a chairperson and several vice chairpersons, all of whom 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 ethical 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 ethical 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. This training should be renewed every two (2) years in a continuing education program. In addition, they should have experience participating in drug clinical trials and obtain the good clinical practice (GCP) training certificate recognized by the National Medical Products Administration (NMPA).

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 ethical 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 indicated in 21CFR50, 21CFR56, and 21CFR312, the United States (US) has a decentralized process for the ethics review of clinical investigations. The sponsor must obtain institutional level ethics committee (EC) approval for each study. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the US.)

As set forth in 21CFR50, 21CFR56, and 21CFR312, all clinical investigations for drug and biological products regulated by the Food & Drug Administration (FDA) require institutional EC approval.

The Pre2018-ComRule and the RevComRule also require that human subjects research receive institutional EC approval. However, note that these regulations’ definition of “human subject” does not include the use of non-identifiable biospecimens. Therefore, the use of non-identifiable biospecimens in research does not, on its own, mandate the application of the Pre2018-ComRule to such research. However, the RevComRule does require federal departments or agencies implementing the policy to work with data experts to reexamine the meaning of “identifiable private information” and “identifiable specimen” within one (1) year of the effective date and at least every four (4) years thereafter. In particular, these agencies will collaboratively assess whether there are analytic technologies or techniques that could be used to generate identifiable private information or identifiable specimens.

(See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

Per the RevComRule, for non-exempt research (or exempt research that requires limited EC review) reviewed by an EC not operated by the institution doing the research, the institution and the EC must document the institution's reliance on the EC for research oversight and the responsibilities that each entity will undertake to ensure compliance with the RevComRule. Compliance can be achieved in a variety of ways, such as a written agreement between the institution and a specific EC, through the research protocol, or by implementing an institution-wide policy directive that allocates responsibilities between the institution and all ECs not operated by the institution. Such documentation must be part of the EC’s records. The G-HHS-Inst-Engagemt can help an institution to determine if a research study can be classified as non-exempt.

Ethics Committee Composition

As stated in 21CFR56, the Pre2018-ComRule, and the RevComRule, an EC must be composed of at least five (5) members with varying backgrounds to promote complete and adequate research proposal review. The EC must be sufficiently qualified through member experience, expertise, and diversity, in terms of race, gender, cultural backgrounds, and sensitivity to issues such as community attitudes, to promote respect for its advice and counsel in safeguarding human participants’ rights and welfare. EC members must possess the professional competence to review research activities and be able to ascertain the acceptability of proposed research based on institutional commitments and regulations, applicable laws, and standards. In addition, if an EC regularly reviews research involving vulnerable populations, the committee must consider including one (1) or more individuals knowledgeable about and experienced in working with those participants. See the Vulnerable Populations section for details on vulnerable populations.

At a minimum, each EC must also include the following members:

• One (1) primarily focused on scientific issues
• One (1) focused on nonscientific issues
• One (1) unaffiliated with the institution, and not part of the immediate family of a person affiliated with the institution

No EC member may participate in the initial or continuing review of any project in which the member has a conflicting interest, except to provide EC requested information.

Terms of Reference, Review Procedures, and Meeting Schedule

As delineated in 21CFR56, ECs must follow written procedures for the following:

• Conducting initial and continuing reviews, and reporting findings and actions
• Determining which projects require review more often than annually, and which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review
• Ensuring that changes in approved research are not initiated without EC review and approval except where necessary to eliminate apparent immediate hazards to participants
• Ensuring prompt reporting to the EC, institution, and FDA of changes in research activity; unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination

Per the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, ECs must establish and follow written procedures for the following:

• Conducting initial and continuing reviews, and reporting findings and actions to the investigator and the institution
• Determining which projects require review more often than annually, and which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review
• Ensuring prompt reporting to the EC of proposed changes in research and ensuring that investigators conduct the research in accordance with the terms of the EC approval until any proposed changes have received EC review and approval, except where necessary to eliminate apparent immediate hazards to participants
• Ensuring prompt reporting to the EC, the institution, the FDA, and the Department of Health & Human Services (HHS)’ Office for Human Research Protections (OHRP) of any unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination.

21CFR56, the Pre2018-ComRule, and the RevComRule further require that an institution, or where appropriate an EC, prepare and maintain adequate documentation of EC activities, including copies of all research proposals reviewed. The applicable records must be retained for at least three (3) years after completion of the research. For more details on the EC records included in this requirement, see the Pre2018-ComRule, the RevComRule, and 21CFR56.

See G-IRBProcs for detailed FDA guidance on EC written procedures to enhance human participant protection and reduce regulatory burden. The guidance includes a Written Procedures Checklist that incorporates regulatory requirements as well as recommendations on operational details to support the requirements.

Per 21CFR56, the Pre2018-ComRule, and the RevComRule, proposed research must be reviewed during convened meetings at which a majority of the EC members are present, including at least one (1) member whose primary concerns are nonscientific, except when an expedited review procedure is used. Research is only considered approved if it receives the majority approval of attending members.

Refer to the Pre2018-ComRule, the RevComRule, 21CFR56, the G-IRBProcs, and the G-IRBFAQs for detailed EC procedural requirements.

In addition, per the Pre2018-ComRule, the RevComRule, and the G-HHS-Inst-Engagemt, any institution engaged in non-exempt human subjects research conducted or supported by a Common Rule department/agency (as identified in USA-65) must also submit a written assurance of compliance to OHRP. According to USA-59, the Federalwide Assurance (FWA) is the only type of assurance of compliance accepted and approved by OHRP for HHS-funded research. See USA-57 for more information on FWAs.

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, ethical 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

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 ethical 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 ethical review in the respective countries (regions) where both parties are located. Where the foreign party is truly unable to provide the ethical review certification materials of the country (region) where it is located, it may submit the proof that the foreign party unit recognizes the ethical 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: the sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• 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: the sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• 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 the EC must conduct the review and issue its opinion within 30 days of acceptance of the materials.

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. The Measures-Ethics state 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.

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, ethical 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.

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

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 Committee of Medical Ethics Experts to provide advice on the ethical 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 ethical review opinion issued by the lead institution, etc.

Where the situation is urgent, an ethical review must be promptly carried out. In the case of emergencies such as outbreaks, ethical reviews and review opinions are generally carried out within 72 hours, but the requirements and quality of ethical reviews must not be reduced. For expedited review, the EC chairman designates two (2) or more members to conduct the ethical 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.

Multicenter Studies

Per the Measures-Ethics, research carried out in multiple institutions may establish collaborative mechanisms for ethical review, ensuring that all institutions follow the principles of consistency and timeliness. Both the lead institution and the participating institution must organize an ethical 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 ethical 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 ethical 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 ethical review results of participating institutions. ECs of the participating institutions must conduct an ethical review of the research in which the institution participates in a timely manner and provide feedback to the lead agency for review.

Exemption from Ethical Review

The Measures-Ethics states that ethical 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

21CFR56, 21CFR312, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs state that the primary scope of information assessed by the institutional ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. As delineated in 21CFR56, the Pre2018-ComRule, and the RevComRule, 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; Children/Minors; Pregnant Women, Fetuses, & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations). The EC is also responsible for ensuring a competent review of the research protocol, evaluating the possible risks and expected benefits to participants, and verifying the adequacy of confidentiality safeguards.

See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

Role in Clinical Trial Approval Process

In accordance with 21CFR56 and 21CFR312, the Food & Drug Administration (FDA) must review an investigational new drug application (IND) and an EC must review and approve the proposed study prior to a sponsor initiating a clinical trial. The institutional EC review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. According to 21CFR56, the Pre2018-ComRule, and the RevComRule, the EC may approve, require modifications in (to secure approval), or disapprove the research.

Refer to the G-RevComRule-FDA for information on the impact of the RevComRule on studies conducted or supported by the Department of Health & Human Services (HHS) that must also comply with FDA regulations.

Per 21CFR56, the Pre2018-ComRule, the RevComRule, and the G-IRBContRev, an EC has the authority to suspend or terminate approval of research that is not being conducted in accordance with the EC’s requirements or that has been associated with unexpected serious harm to participants. Any suspension or termination of approval will include a statement of the reasons for the EC’s action and will be reported promptly to the investigator, appropriate institutional officials, and the department or agency head (e.g., the FDA). See the G-IRBContRev for additional information and FDA recommendations on suspension or termination of EC approval.

Expedited Review

21CFR56, the Pre2018-ComRule, and the RevComRule indicate that the FDA and HHS maintain a list of research categories that may be reviewed by an EC through an expedited review procedure (see the G-IRBExpdtdRev for the list). An EC may use the expedited review procedure to review the following:

• Some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk
• Minor changes in previously approved research during the period (of one (1) year or less) for which approval is authorized
• Under the RevComRule, research for which limited EC review is a condition of exemption

21CFR56, the Pre2018-ComRule, and the RevComRule specify that under an expedited review procedure, the review may be carried out by the EC chairperson or by one (1) or more experienced reviewers designated by the chairperson from among the EC’s members. In reviewing the research, the reviewers may exercise all of the authorities of the EC except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the EC’s non-expedited review procedure.

Continuing Review and Re-approval

21CFR56 and the G-IRBContRev state that any clinical investigation must not be initiated unless the reviewed and approved study remains subject to continuing review at intervals appropriate to the degree of risk, but not less than once a year. The G-IRBContRev notes that when continuing review of the research does not occur prior to the end of the approval period specified by the EC, EC approval expires automatically. A lapse in EC approval of research occurs whenever an investigator has failed to provide continuing review information to the EC, or the EC has not conducted continuing review and re-approved the research by the expiration date of the EC approval. In such circumstances, all research activities involving human participants must stop. Enrollment of new participants cannot occur after the expiration of EC approval.

In addition, per the G-IRBContRev, research that qualified for expedited review at the time of initial review will generally continue to qualify for expedited continuing review. For additional information and FDA recommendations regarding continuing review, see the G-IRBContRev.

The Pre2018-ComRule similarly indicates that the EC must conduct reviews at intervals appropriate to the degree of risk, but not less than once per year. However, the RevComRule provides the following exceptions to the continuing review requirement, unless an EC determines otherwise:

• Research eligible for expedited review
• Research reviewed by the EC in accordance with the limited EC review described in Section 46.104 of the RevComRule
• Research that has progressed to the point that it involves data analysis and/or accessing follow-up clinical data from procedures that are part of clinical care

Exemptions under the Revised Common Rule

Per the RevComRule, certain categories of research are exempt from EC review, and some “exempt” activities require limited EC review or broad consent. Users should refer to Section 46.104 of the RevComRule for detailed information on research categories specifically exempt from EC review, or exempt activities requiring limited EC review or broad consent.

Per USA-54, for secondary research that does not qualify for an exemption under the RevComRule, the applicant must either apply for a waiver of the informed consent requirement from the EC, obtain study-specific informed consent, or obtain broad consent.

Further, the RevComRule modifies what constitutes research to specifically exclude the following types of research:

• Scholarly and journalistic activities
• Public health surveillance activities authorized by a public health authority to assess onsets of disease outbreaks or conditions of public health importance
• Collection and analysis of information, biospecimens, or records by or for a criminal justice agency for criminal investigative activities
• Authorized operational activities in support of intelligence, homeland security, defense, or other national security missions

See the G-IRBFAQs, the G-OHRP-IRBApprvl, and USA-54 for frequently asked questions regarding EC procedures, approval with conditions, example research, expedited review, limited review, and continuing review.

Other Considerations

Per the FDA’s G-IRBReview, an EC may review studies that are not performed on-site. When an institution has a local EC, the written procedures of that EC or of the institution should define the scope of studies subject to review by that EC. A non-local EC may not become the EC of record for studies within that defined scope unless the local EC or the administration of the institution agree. Any agreement to allow review by a non-local EC should be in writing. For more information, see G-IRBReview.

Cooperative Research Studies

In the event of multicenter clinical studies, also known as cooperative research studies, taking place at US institutions that are subject to the RevComRule, the institutions must rely on a single EC to review that study for the portion of the study conducted in the US. The reviewing EC will be identified by the Common Rule department/agency (as identified in USA-65) supporting or conducting the research or proposed by the lead institution subject to the acceptance of the department/agency. The exceptions to this requirement include: when multicenter review is required by law (including tribal law) or for research where any federal department or agency supporting or conducting the research determines that the use of a single EC is not appropriate.

Designed to complement the RevComRule, per the NIHNotice16-094 and the NIHNotice17-076, the National Institutes of Health (NIH) issued a final policy requiring all institute-funded multicenter clinical trials conducted in the US to be overseen by a single EC, unless prohibited by any federal, tribal, or state law, regulation, or policy.

For more information on multicenter research, see the FDA’s G-CoopRes. For more information on how new sites added to ongoing cooperative research can follow the same version of the Common Rule, see the HHS Office for Human Research Protections (OHRP)’s G-ComRuleCnsstncy.

No information is currently available.

Many institutional ethics committees (ECs) (referred to as institutional review boards (IRBs) in the United States (US)) charge fees to review research proposals submitted by industry-sponsored research or other for-profit entities. However, this varies widely by institution. Neither the Department of Health & Human Services (HHS) nor the Food & Drug Administration (FDA) regulate institutional EC review fees. Because each EC has its own requirements, individual ECs should be contacted to confirm their specific fees.

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 ethical review of biomedical research involving human beings, establishing the National Committee of Medical Ethics Experts, and for developing policies relating to ethical review. The National Committee of Medical Ethics Experts 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.

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 Committee assists in promoting the institutionalization and standardization of the ethical 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 ethical 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 delineated in 21CFR56 and 45CFR46-B-E, the Department of Health & Human Services (HHS) and the HHS’ Food & Drug Administration (FDA) have mandatory registration programs for institutional ethics committee (ECs), referred to as institutional review boards (IRBs) in the United States (US). A single electronic registration system (USA-28) for both agencies is maintained by HHS’ Office for Human Research Protections (OHRP).

Registration, Auditing, and Accreditation

In accordance with the G-IRBReg-FAQs and USA-61, EC registration with the HHS OHRP system (USA-28) is not a form of accreditation or certification by either the FDA that the EC is in full compliance with 21CFR56, or by the HHS that the EC is in full compliance with 45CFR46-B-E. Neither EC competence nor expertise is assessed during the registration review process by either agency.

Food & Drug Administration

According to 21CFR56 and the G-IRBReg-FAQs, the FDA requires each EC in the US, that either reviews clinical investigations regulated by the agency under the FDCAct or reviews investigations intended to support research or marketing permits for agency-regulated products, to register electronically in the HHS OHRP system (USA-28). Only individuals authorized to act on the EC’s behalf are permitted to submit registration information. Non-US ECs may register voluntarily. The G-IRBReg-FAQs also indicates that while registration of non-US ECs is voluntary, the information the FDA receives from them is very helpful.

As stated in 21CFR56 and the G-IRBReg-FAQs, any EC not already registered in the HHS OHRP system (USA-28) must submit an initial registration prior to reviewing a clinical investigation in support of an investigational new drug application (IND). The HHS OHRP system (USA-28) provides instructions to assist users, depending on whether the EC is subject to regulation by only the OHRP, only the FDA, or both the OHRP and the FDA.

21CFR56 and the G-IRBReg-FAQs indicate that FDA EC registration must be renewed every three (3) years. EC registration becomes effective after review and acceptance by the HHS.

See 21CFR56 and the G-IRBReg-FAQs for detailed EC registration submission requirements. See the G-IRBInspect for FDA inspection procedures of ECs.

Office for Human Research Protections

Per the Pre2018-ComRule and RevComRule, institutions engaging in research conducted or supported by a Common Rule department/agency (as identified in USA-65) must obtain an approved assurance that it will comply with the Pre2018-ComRule or RevComRule requirements and certify to the department/agency heads that the research has been reviewed and approved by an EC provided for in the assurance.

Per USA-59, a Federalwide Assurance (FWA) of compliance is a document submitted by an institution (not an EC) engaged in non-exempt human subjects research conducted or supported by HHS that commits the institution to complying with Pre2018-ComRule or RevComRule requirements. FWAs also are approved by the OHRP for federalwide use, which means that other federal departments and agencies that have adopted the Federal Policy for the Protection of Human Subjects (Pre2018-ComRule or RevComRule) may rely on the FWA for the research that they conduct or support. Institutions engaging in research conducted or supported by non-HHS federal departments or agencies should consult with the sponsoring department or agency for guidance regarding whether the FWA is appropriate for the research in question.

Per USA-54, institutions do not need to change an existing FWA because of the RevComRule. See USA-57 for more information on FWAs.

Per 45CFR46-B-E and USA-61, all ECs that review human subjects research conducted or supported by HHS and are to be designated under an OHRP FWA must register electronically with the HHS OHRP system (USA-28). An individual authorized to act on behalf of the institution operating the EC must submit the registration information. EC registration becomes effective for three (3) years when reviewed and approved by OHRP.

Per USA-59, an institution must either register its own EC (an “internal” EC) or designate an already registered EC operated by another organization (“external” EC) after establishing a written agreement with that other organization. Additionally, each FWA must designate at least one (1) EC registered with the OHRP. The FWA is the only type of assurance of compliance accepted and approved by the OHRP.

See 45CFR46-B-E, USA-58, and USA-61 for detailed registration requirements and instructions.

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.

The Bioscrty-Law, the MgmtHumanGen, and the Rules-MgmtHGR delineate that the Ministry of Science and Technology (MOST) is responsible for China's management of human genetic resources (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 ethical review of ECs that have been registered with the relevant management departments. Further, applications for administrative licenses for international scientific research cooperation, HGR must pass an ethical review in the respective countries (regions) where both parties are located. As part of the application for the filing of 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 review cannot occur in parallel.

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. 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.) The NMPA-No23-2023 provides guidance on common issues and general requirements for the Phase III pre-clinical trial meeting with CDE in regards to innovative drugs.

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 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.

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 at 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 translation 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).

See the Regulatory Authority section for contact information on submitting the application materials on CD-ROM. 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 (formerly it was a review and approval procedure). 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 will achieve innovations and expedited 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

Ministry of Science and Technology

Per the MgmtHumanGen and the Rules-MgmtHGR, the foreign entity and the Chinese entity must jointly file an application for approval to MOST and pass an ethics review in the partners’ countries. The only exception to the MOST 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, which will generate a record number (see below for steps) and pass an ethics review in the partners’ countries. See CHN-76 for MOST’s service webpage that contains HGR administrative license information, including service guides, contact information, decision results, handling, etc. The HGR-Procedures outlines the procedural steps in applying for MOST’s review and approval for collecting HGR, exporting HGR, HGR international cooperative research, and record filing (i.e., notifying) for an international clinical trial that does not involve the export of HGR.

Per HGR-Procedures, for applications on collection, preservation, international cooperation research, and export of Chinese HGR, the applicant must submit an electronic version of the application materials through the online platform. (Note that HGR-WorkUpdt indicates that MOST has initiated operation of a new online platform for HGR at CHN-6. Per HGR-InfoSys, the original online platform is available at CHN-23. For help with the two systems, contact Xu Penghui, Department of Social Development and Science and Technology, MOST at 010-58881479; Zhu Min, China Biotechnology Development Center, at 010-88225151 or 010-88225168; or the information system support at 17610386080.) For additional HGR guidance and procedures, see CHN-76.

As indicated in the HGR-Procedures, MOST will screen the electronic application to ensure it is complete within one (1) working day of submission. If the application passes MOST’s screening for completeness and format compliance, the applicant must print out the online, pre-accepted electronic application materials on A4 paper, with one (1) additional copy. The cover and signature/seal pages should be printed single-sided and the rest of the document should be double-sided. Attachments should be bound to the application using glue.

Per HGR-Procedures, regarding clinical trials of international cooperation research where there is no export, the Chinese legal entity can directly file the clinical trial to CHN-6 or CHN-23. After the filing materials are successfully submitted and the filing number is obtained, international cooperative clinical trials can begin. Where multicenter clinical trials are involved, the team leader can conduct the filing procedures. After the other participating medical institutions obtain the filing number of the team leader unit, they can upload their ethical approval documents and the required documentation to the online platform to carry out international cooperative clinical trials. MOST will publicly announce information on international studies, which will include the applicant’s record number. During clinical trials, if there is a major change of event (e.g., research purpose, research content, research plan, or cooperation period), the Chinese sponsor must terminate the record, upload the summary report, and re-record the case. After obtaining a new record number, the sponsor can continue conducting the international cooperative clinical trial.

Per the HGR-ExprtLicenseGuide, the following is the notification and application submission contact information for MOST:

Ministry of Science and Technology
China Biotechnology Development Center
1st Floor, Building 4, No. 16 Yard
Xisihuan Middle Road
Haidian District, 100039
P.R. China
Phone: 010-88225151

See the HGR-ExprtLicenseGuide and the HGR-Procedures for additional information related to HGR licenses.

Ethics Review Submission

Each EC has its own required submission procedures.

Overview

As delineated in 21CFR312, USA-42, and USA-52, the United States (US) requires the sponsor to submit an investigational new drug application (IND) for the Food & Drug Administration (FDA)'s review and authorization to obtain an exemption to ship investigational drug or biological products across state lines and to administer these investigational products in humans. Per 21CFR312 and the G-IND-Determination, whether an IND is required to conduct an investigation of a drug to be marketed (this includes biological products under the FDCAct) primarily depends on the intent of the investigation, and the degree of risk associated with the use of the drug in the investigation. See the Scope of Assessment section for more information.

In addition, per 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the US) review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.

Regulatory Submission

According to 21CFR312, meetings between a sponsor and the FDA may be useful in resolving questions and issues raised during the course of a clinical investigation. The FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution of scientific problems concerning the drug, to the degree the FDA's resources permit. See 21CFR312 for more information on meetings with the FDA.

A sponsor who is conducting a clinical trial to support a future marketing application may ask to meet with the FDA for a special protocol assessment (SPA) to help ensure the clinical trial can support the application. For more information, see G-SPA.

Additionally, the G-FDAComm describes the FDA’s philosophy regarding timely interactive communication with IND sponsors, the scope of appropriate interactions between review teams and sponsors, the types of advice appropriate for sponsors to seek from the FDA in pursuing their drug development programs, and general expectations for the timing of FDA response to sponsor inquiries. See the G-FDAComm for more information.

According to the G-PharmeCTD, which implements FDCAct requirements, and as described in USA-34 and USA-53, commercial IND submissions must be submitted in the Electronic Common Technical Document (eCTD) format. Noncommercial INDs are exempt from this eCTD format submission requirement. “Noncommercial products” refer to products not intended to be distributed commercially, including investigator-sponsored INDs and expanded access INDs (e.g., emergency use and treatment INDs). However, the G-AltrntElecSubs indicates that sponsors and applicants who receive an exemption or a waiver from filing in eCTD format should still provide those exempted or waived submissions electronically, in an alternate format.

The G-AltrntElecSubs and USA-35 indicate that for both eCTD and alternate electronic formats, submissions should include only FDA fillable forms and electronic signatures. Scanned images of FDA fillable forms should not be submitted. In addition, before making an electronic submission, a pre-assigned application number should be obtained by contacting the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER). See USA-35 for more information on requesting an application number.

For more information and detailed requirements on eCTD submissions, see the G-PharmeCTD, the G-eCTDTech, USA-35, and USA-36. Additionally, the G-CBER-ElecINDs provides instructions on how to submit an IND using an electronic folder structure on a CD-ROM.

According to the G-eCTDspecs and USA-7, eCTD submissions sized 10 GB and under for most applications must be submitted via the FDA Electronic Submissions Gateway (ESG) (USA-44). However, the G-eCTDspecs adds that the FDA also recommends the use of USA-44 for submissions greater than 10 GB when possible. See USA-8 for information on how to create an account.

As indicated in the G-eCTDspecs, physical media greater than 10 GB should be submitted using a USB drive. For specific instructions on how to submit physical media, email CDER at esub@fda.hhs.gov or CBER at esubprep@fda.hhs.gov. See the G-eCTDspecs for additional physical media information.

The IND must be submitted in English. As indicated in 21CFR312, the sponsor must submit an accurate and complete English translation of each part of the IND that is not in English. The sponsor must also submit a copy of each original literature publication for which an English translation is submitted.

According to USA-41 and USA-94, paper submissions of INDs should be sent to CDER or CBER at the following locations, as appropriate:

Drugs (submitted by Sponsor-Investigators):

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Central Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266

Therapeutic Biological Product (submitted by Sponsor-Investigators):

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Therapeutic Biological Products Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266

Center for Biologics Evaluation and Research-Regulated Products:

Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
Document Control Center
10903 New Hampshire Avenue
WO71, G112
Silver Spring, MD 20993-0002

(Note: Per USA-94, CBER also accepts electronic media via mail, but electronic or email submission is preferred.)

Based on information provided in 21CFR312, for paper IND submissions, the sponsor must submit an original and two (2) copies, including the original submission and all amendments and reports.

For more information on CDER and CBER internal policies and procedures for accepting and reviewing applications, see USA-96 and USA-95, respectively.

Ethics Review Submission

Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for clinical trial submission processes.

Regulatory Authority Requirements

National Medical Products Administration

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 National Medical Products Administration (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-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.

Ministry of Science and Technology

With regard to human genetic resources (HGR) licenses, the HGR-LicenseSummary summarizes the license and application contents, which is regulated by the Ministry of Science and Technology (MOST):

• Collection of Chinese HGR – requires the application, legal person qualification materials, ethics review approval, informed consent form (ICF), collection plan, HGR management system, and a cooperation agreement
• Preservation of Chinese HGR – requires the application, legal person qualification, ICF, ethics review approval, preservation plan and management system, and preservation of technical documents
• International cooperation in the use of Chinese HGR for research – requires the application; legal person qualification; ethics review approval; ICF; the research protocol; international cooperation agreements; agreements involving the collection, transfer, testing, and destruction of HGR; and clinical trial approvals, notices, or filing and publication materials; and a letter of commitment
• Export of Chinese HGR for international cooperation – requires the application, legal person qualification, ICF, ethics review approval, the decision on the international cooperation research, and the decision on the approval of the export of Chinese HGR resource material; also see the HGR-ExprtLicenseGuide for more information on this license
• Filing of international cooperation clinical trials using HGR – requires the filing form; legal person qualification; ICF; ethics review approval; the research protocol; the international cooperation agreement; the cooperation agreement signed between the clinical institution and its commissioned testing institution; agreement texts involving the transshipment of HGR; clinical trial approval documents, notices, or filing announcement materials; and the letter of commitment (provided by participating medical institutions)
• Filing Chinese HGR information for public use – requires the filing form, legal person qualifications, and the decision on international cooperation research; also see HGR-DataUse for more information on this license

Additional 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, the RegEthics, and the EC-Guide to exemplify the common elements shared by the various application forms (Note: the requirements provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

• Application for Human Research Ethics Review (See CHN-35 and CHN-34 for sample institutional forms)
• 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: the requirements provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

• 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 21CFR312, an investigational new drug application (IND) to the Food & Drug Administration (FDA) must include the following documents, in the order provided below:

• Cover sheet (Form FDA 1571 (USA-76)) (including, but not limited to: sponsor contact information, investigational product (IP) name, application date, phase(s) of clinical investigation to be conducted, and commitment that the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) will conduct initial and continuing review and approval of each study proposed in the investigation)
• Table of contents
• Introductory statement and general investigational plan
• Investigator’s brochure (IB)
• Protocols
• Chemistry, manufacturing, and control data
• Pharmacology and toxicology data
• Previous human experience with the IP
• Additional information (e.g., drug dependence and abuse potential, radioactive drugs, pediatric studies)
• Relevant information (e.g., foreign language materials and number of copies - see Submission Process section for details)

For detailed application requirements, see 21CFR312. In addition, see USA-40 for other IND forms and instructions.

Furthermore, for information on the appropriate use of adaptive designs for clinical trials and additional information to provide to the FDA to support its review, see G-AdaptiveTrials.

The G-RWDRWE-Doc states that to facilitate the FDA’s internal tracking of submissions that include real-world data (RWD) and real-world evidence (RWE), sponsors and applicants are encouraged to identify in their submission cover letters certain uses of RWD/RWE. For more information, see the G-RWDRWE-Doc.

The FDCAct, as amended by the FDORA, requires sponsors to submit diversity action plans for certain clinical trials, such as a clinical investigation of a new drug that is a phase 3 study. See the FDORA for more details. (Note: The FDA’s guidance on diversity action plans is currently in draft. The ClinRegs team will continue to monitor this requirement and incorporate any updates as appropriate).

According to the G-PedStudyPlans, a sponsor who is planning to submit to the FDA a marketing application (or supplement to an application) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration is required to submit an initial pediatric study plan (iPSP), if required by the Pediatric Research Equity Act (PREA). An exception to this is if the drug is for an indication granted an orphan designation. For additional details and recommendations to sponsors regarding the submission of an iPSP, see the G-PedStudyPlans.

Ethics Committee Requirements

Each EC has its own application form and clearance requirements, which can differ significantly regarding application content requirements. However, the requirements listed below comply with 21CFR56 as well as the US-ICH-GCPs and are basically consistent across all US ECs.

As per 21CFR56, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the EC should obtain the following documents and must ensure the listed requirements are met prior to approving the study (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• Clinical protocol
• Informed consent forms (ICFs) and participant information (the RevComRule also requires information regarding whether informed consent was appropriately sought and documented, or waived)
• Participant recruitment procedures
• IB
• Safety information
• Participant payments and compensation
• Investigator(s) current Curriculum Vitaes (CVs)
• Additional required EC documentation
• Risks to participants are minimized and are reasonable in relation to anticipated benefits
• Participant selection is equitable
• Adequate provisions are made to protect participant privacy and maintain confidentiality of data, where appropriate; the Department of Health & Human Services (HHS) will issue guidance to assist ECs in assessing what provisions are adequate to protect participant privacy and maintain the confidentiality of data

Per the RevComRule, where limited EC review applies, the EC does not need to make the determinations outlined above. Rather, limited EC review includes determinations that broad consent will be/was obtained properly, that adequate protections are in place for safeguarding the privacy and confidentiality of participants, and (for secondary studies) that individual research results will not be returned to participants. See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

See 21CFR56, the Pre2018-ComRule, the RevComRule, and section 3 of the US-ICH-GCPs for additional EC submission requirements.

Clinical Protocol

According to the US-ICH-GCPs, the clinical protocol should contain the following elements:

• General information
• Background information
• Trial objectives and purpose
• Trial design
• Participant selection/withdrawal
• Participant treatment
• Efficacy assessment
• Safety assessment
• Statistics
• Direct access to source data/documents
• Quality control/quality assurance
• Ethics
• Data handling/recordkeeping
• Financing/insurance
• Publication policy
• For complete protocol requirements, see section 6 of the US-ICH-GCPs.

Per the NIHNotice17-064, and provided in USA-29 and USA-27, the National Institutes of Health (NIH) and the FDA developed a clinical trial protocol template with instructional and example text for NIH-funded investigators to use when writing protocols for phase 2 and 3 clinical trials that require IND applications.

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.

The Bioscrty-Law, the MgmtHumanGen, and the Rules-MgmtHGR, delineate that the Ministry of Science and Technology (MOST) is responsible for China's management of human genetic resources (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 ethical review of ECs that have been registered with the relevant management departments. Further, for an application for the filing of 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.

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) will affect the timeline of review. The CDE conducts technical reviews and the NIFDC tests drug samples. 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.

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

Ministry of Science and Technology

Per HGR-Procedures, for applications on collection, preservation, and international cooperation research with export of Chinese HGR, MOST will pre-screen the electronic application to ensure it is complete within one (1) working day of submission to CHN-6 or CHN-23. If the application does not pass, then the applicant will be informed of the content that needs to be corrected on the online platform. If the application materials are complete and comply with the prescribed form, the applicant must print the accepted electronic submission and submit a paper format, which is then examined for completeness within five (5) working days. Per Rules-MgmtHGR, the MOST must make an administrative licensing decision on applications for administrative licensing of HGR within 20 working days of acceptance. 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, 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. Per HGR-Procedures, upon acceptance, MOST issues an acceptance slip and initiates the technical review. MOST organizes experts to conduct technical reviews of accepted applications and form opinions. MOST decides whether to approve or disapprove an application and announces the results and reasons on the MOST website (CHN-76). If the approval is granted, MOST will send the approval decision letter to the provincial science and technology administrative department by mail within 10 working days and publish the mailing details on its website (CHN-76). The applicant should then go to the provincial science and technology administrative department to receive the approval decision letter with the acceptance form.

Ethics Committee Approval

In accordance with the Measures-Ethics, the EC must carry out an ethical review and issue its opinion within 30 days of acceptance. In urgent situations, an ethical review must be promptly carried out. In the case of emergencies such as outbreaks, ethical reviews and review opinions are generally carried out within 72 hours, and the requirements and quality of ethical 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

As delineated in 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) review of the clinical investigation may be conducted in parallel with the Food & Drug Administration (FDA)'s review of the investigational new drug application (IND). However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.

Regulatory Authority Approval

Per the FDCAct and 21CFR312, initial INDs submitted to the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) automatically go into effect in 30 calendar days, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. As indicated in 21CFR312, the FDA will provide the sponsor with a written explanation of the basis for the hold as soon as possible, and no more than 30 days after the imposition of the clinical hold. See 21CFR312 for more information on clinical hold timelines. For more information on CDER and CBER internal policies and procedures for reviewing applications, see USA-96 and USA-95, respectively.

According to USA-41 and USA-42, clinical studies must not be initiated until 30 days after the FDA receives the IND, unless the FDA provides earlier notification that studies may begin.

Ethics Committee Approval

Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for a standard timeline of review and approval of the clinical trial. However, according to the US-ICH-GCPs, the institutional EC should review a proposed clinical trial within a reasonable time.

Overview

Per the DRR, clinical trials must be conducted in drug clinical trial institutions 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.

The Bioscrty-Law, the MgmtHumanGen, and the Rules-MgmtHGR delineate that the Ministry of Science and Technology (MOST) is responsible for China's management of human genetic resources (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 ethical review in the partner countries and be filed with MOST before initiating the study. The Rules-MgmtHGR also state that clinical trial applications must pass a security review organized by MOST 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.

Overview

In accordance with 21CFR312, USA-41, and USA-42, a clinical trial can only commence after the investigational new drug application (IND) is reviewed by the Food & Drug Administration (FDA), which will provide a written determination within 30 days of receiving the IND. No waiting period is required following the 30-day FDA review period, unless the agency imposes a clinical hold on the IND or sends an earlier notification that studies may begin. Per 21CFR312 and 21CFR56, ethics approval from an institutional ethics committee (EC) (known as institutional review board (IRB) in the United States (US)) is also required before a clinical trial can commence.

As per 21CFR312, once an IND has been submitted and following the 30-day review period, the sponsor is permitted to import an investigational product (IP). (See the Manufacturing & Import section for additional information).

See the G-CTDiversity for FDA recommendations to sponsors on increasing enrollment of underrepresented populations in their clinical trials.

Clinical Trial Agreement

Prior to the trial’s commencement, as addressed in the 21CFR312 and the G-1572FAQs, the sponsor must obtain from the investigator(s) a signed Statement of Investigator, Form FDA 1572 (USA-77). This form serves as the investigator’s agreement to provide certain information to the sponsor and to ensure compliance with the FDA’s clinical investigation regulations. Refer to the 21CFR312, the G-1572FAQs, and USA-40 for further information.

The US-ICH-GCPs indicates that the sponsor must obtain the investigator’s/institution’s agreement:

• To conduct the trial in compliance with good clinical practice (GCP), with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the EC;
• To comply with procedures for data recording/reporting;
• To permit monitoring, auditing, and inspection; and
• To retain the trial-related essential documents until the sponsor informs the investigator/institution these documents are no longer needed.

The sponsor and the investigator/institution must sign the protocol, or an alternative document, to confirm this agreement.

Clinical Trial Registration

The FDAMA, the FDAAA, and 42CFR11 require the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to register electronically with the ClinicalTrials.gov databank (USA-78). Per the FDAAA and 42CFR11, the sponsor/PI must register no later than 21 calendar days after the first human participant is enrolled in a trial.

42CFR11 expands the legal requirements for submitting clinical trial registration information and results for investigational products that are approved, licensed, or cleared by the FDA.

The National Institutes of Health (NIH) issued NIHTrialInfo to complement 42CFR11 requirements. This policy requires all NIH-funded awardees and investigators conducting clinical trials, funded in whole or in part by the NIH, regardless of study phase, type of intervention, or whether they are subject to the regulation, to ensure that they register and submit trial results to ClinicalTrials.gov (USA-78).

See 42CFR11, the NIHTrialInfo, and USA-49 for detailed information on ClinicalTrials.gov (USA-78). See also the FDA’s G-DataBankPnlty for clarification on the types of civil money penalties that may be issued for failing to register a clinical trial.

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.

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 IB). 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

In accordance with 21CFR312, the G-IND-Safety, 42CFR11, and USA-38, the following definitions provide a basis for a common understanding of safety reporting requirements in the United States (US):

• Adverse Event – Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related
• Suspected Adverse Reaction – Any adverse event where there is a reasonable possibility that the drug caused the adverse event
• Adverse Reaction – Any adverse event caused by a drug. Adverse reactions are a subset of all suspected adverse reactions where there is reason to conclude that the drug caused the event
• Serious Adverse Event/Serious Suspected Adverse Reaction – An adverse event/suspected adverse reaction that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, causes persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or leads to a substantial disruption of the participant’s ability to conduct normal life functions
• Unexpected Adverse Event/Unexpected Suspected Adverse Reaction – An adverse event/suspected adverse reaction that is not listed in the investigator’s brochure (IB), or is not listed at the specificity or severity that has been observed; or if an IB is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the application
• Life-threatening Adverse Event/Life-threatening Suspected Adverse Reaction – An adverse event/suspected adverse reaction is considered “life-threatening” if its occurrence places the participant at immediate risk of death. It does not include an adverse event/suspected adverse reaction that, had it occurred in a more severe form, might have caused death

According to the G-HHS-AEReqs, the Department of Health & Human Services (HHS)’s 45CFR46 regulations (the Pre2018-ComRule, the RevComRule, and 45CFR46-B-E) do not define the terms “adverse event” or “unanticipated problems.” However, the Pre2018-ComRule and the RevComRule do contain requirements relevant to reviewing and reporting these incidents. See the G-HHS-AEReqs, the G-IRBRpting, the Pre2018-ComRule, and the RevComRule for further information.

See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

Safety Reporting Requirements

Investigator Responsibilities

As delineated in 21CFR312 and the G-IND-Safety, the investigator must comply with the following reporting requirements:

• Serious adverse events, whether or not considered drug related, must be reported immediately to the sponsor
• Study endpoints that are serious adverse events must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event. In that case, the investigator must immediately report the event to the sponsor
• Non-serious adverse events must be recorded and reported to the sponsor according to the protocol specified timetable
• Report promptly to the ethics committee (EC) all unanticipated problems involving risk to human participants or others where adverse events should be considered unanticipated problems

Sponsor Responsibilities

As delineated in 21CFR312, the G-IND-Safety, and USA-38, the sponsor must report any suspected adverse reaction or adverse reaction that is both serious and unexpected. An adverse event is only required to be reported as a suspected adverse reaction if there is evidence to suggest a causal relationship between the drug and the adverse event.

The sponsor is required to notify the Food & Drug Administration (FDA) and all participating investigators in a written safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but no later than 15 calendar days after the sponsor determines the information qualifies for reporting. Additionally, the sponsor must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but no later than seven (7) calendar days following receipt of the information. The sponsor is required to submit a follow-up safety report to provide additional information obtained pertaining to a previously submitted safety report. This report should be submitted without delay, as soon as the information is available, but no later than 15 calendar days after the sponsor initially receives the information.

Per 21CFR312 and the G-IND-Safety, the sponsor must also report the following:

• Any findings from epidemiological studies, pooled analyses of multiple studies, or clinical studies (other than those reported in the safety report), whether or not conducted under an investigational new drug application (IND), and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug
• Any findings from animal or in vitro testing, whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug
• Any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or IB

In each safety report, the sponsor must identify all safety reports previously submitted to the FDA concerning a similar suspected adverse reaction and must analyze the significance of the suspected adverse reaction in light of previous, similar reports, or any other relevant information. Refer to 21CFR312 and the G-IND-Safety for more details on these safety reporting requirements.

As part of the clinical trial results information submitted to ClinicalTrials.gov (USA-78), 42CFR11 requires the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to submit three (3) tables of adverse event information. The tables should consist of the following summarized data:

• All serious adverse events
• All adverse events, other than serious adverse events, that exceed a frequency of five (5) percent in any arm of the trial
• All-cause mortalities

Per 42CFR11 and USA-70, this information must be submitted no later than one (1) year after the primary completion date of the clinical trial. Submission of trial results may be delayed as long as two (2) years if the sponsor or PI submits a certification to ClinicalTrials.gov (USA-78) that either: 1) the FDA has not yet approved, licensed, or cleared for marketing the investigational product (IP) being studied; or 2) the manufacturer is the sponsor and has sought or will seek approval within one (1) year.

See 42CFR11 for detailed adverse event reporting requirements.

Form Completion & Delivery Requirements

As per 21CFR312, the G-IND-Safety, and USA-38, the sponsor must submit each safety report in a narrative format on Form FDA 3500A (USA-75), or in an electronic format that the FDA can process, review, and archive, and be accompanied by Form FDA 1571 (USA-76) (cover sheet).

As per the G-IND-Safety and USA-38, the submission must be identified as follows:

• “IND safety report” for 15-day reports
• “7-day IND safety report” for unexpected fatal or life-threatening suspected adverse reaction reports
• “Follow-up IND safety report” for follow-up information

The report must be submitted to the appropriate review division (i.e., Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER)). Per USA-38, the FDA recommends that sponsors submit safety reports electronically. Other means of rapid communication to the respective review division’s Regulatory Project Manager (e.g., telephone, facsimile transmission, email) may also be used. Per USA-90, fatality reports to CBER should be sent to fatalities2@fda.hhs.gov.

Additionally, 21CFR312 and the G-IND-Safety indicate that the FDA will accept foreign suspected adverse reaction reports on CIOMS Form I (See USA-13 and USA-3) instead of Form FDA 3500A (USA-75). See USA-38 and USA-48 for additional information.

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 the results of clinical trials on the Applicant’s Window (CHN-58).

Interim and Annual Progress Reports

As per the US-ICH-GCPs, the investigator should promptly provide written reports to the sponsor and the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) on any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants.

As specified in 21CFR312, the investigator must furnish all reports to the sponsor who is responsible for collecting and evaluating the results obtained. In addition, per 21CFR56 and the US-ICH-GCPs the investigator should submit written summaries of the trial status to the institutional EC annually, or more frequently, if requested by the institutional EC.

21CFR312 states that the sponsor must submit a brief annual progress report on the investigation to the Food & Drug Administration (FDA) within 60 days of the anniversary date that the investigational new drug went into effect. The report must contain the following information for each study:

• Title, purpose, and description of patient population, and current status
• Summary of the participants screened (e.g., failed screenings; participants enrolled, withdrawn, or lost to follow-up; and other challenges)
• Summary information - including information obtained during the previous year’s clinical and nonclinical investigations
• Description of the general investigational plan for the coming year
• Updated investigator’s brochure, if revised
• Description of any significant Phase 1 protocol modifications not previously reported in a protocol amendment
• Brief summary of significant foreign marketing developments with the drug
• A log of any outstanding business for which the sponsor requests a reply, comment, or meeting

As indicated in 42CFR11, trial updates must be submitted to ClinicalTrials.gov (USA-78) according to the following guidelines:

• Not less than once every 12 months for updated general trial registration information
• Not later than 30 calendar days for any changes in overall recruitment status
• Not later than 30 calendar days after the trial reaches its actual primary completion date, the date the final participant was examined or received an intervention for the purposes of final collection data for the primary outcome

Final Report

As indicated in 21CFR312, an investigator must provide the sponsor with an adequate report shortly after completion of the investigator’s participation in the investigation. There is no specific timeframe stipulated for when the report should be completed.

The US-ICH-GCPs also states that upon the trial’s completion, the investigator should inform the institution and the investigator/institution should provide the EC with a summary of the trial’s outcome, and supply the FDA with any additional report(s) required of the investigator/institution.

Additionally, per 42CFR11 and USA-70, the sponsor or the principal investigator (PI) designated by the sponsor must submit results for applicable investigational product (IP) clinical trials to USA-78 no later than one (1) year following the study’s completion date. Submission of trial results may be delayed as long as two (2) years if the sponsor or PI submits a certification to USA-78 that indicates either: 1) the FDA has not yet approved, licensed, or cleared the IP being studied for marketing; or 2) the manufacturer is the sponsor and has sought or will seek approval within one (1) year. The results information must include data on the following:

• Participant flow
• Demographic and baseline characteristics
• Outcomes and statistical analysis
• Adverse events
• The protocol and statistical analysis plan
• Administrative information

See USA-49 for more information and 42CFR11 for more detailed requirements. See NIHTrialInfo for specific information on dissemination of NIH-funded clinical trial data.

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.

As per 21CFR312, 21CFR50, and the US-ICH-GCPs, a sponsor is defined as a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. 21CFR312, 21CFR50, and the US-ICH-GCPs define a sponsor-investigator as an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational product is administered or dispensed.

In addition, 21CFR312 and the US-ICH-GCPs state that a sponsor may transfer responsibility for any or all obligations to a contract research organization (CRO).

Any trial-related responsibilities transferred to and assumed by a CRO should be specified in writing, and those obligations not covered by the written description will be deemed not to have been transferred. Further, a CRO that assumes any sponsor obligations must comply with the specific regulations delineated in 21CFR312 and will be subject to the same regulatory action as the sponsor for failure to comply with any obligation assumed under these regulations. However, per the US-ICH-GCPs, although a sponsor may transfer all trial-related duties and functions to a CRO, the sponsor is ultimately responsible for the study data’s quality and integrity.

As indicated in 21CFR312, a sponsor may be either domestic or foreign.

Overview

Per the DRR, drug clinical trials must be conducted in drug clinical trial institutions 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 drug clinical trial 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. The NMPA is establishing a record management information platform for the registration and operation management of drug clinical trial institutions, 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 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 the Ministry of Science and Technology (MOST) 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 time, 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 21CFR312 and the US-ICH-GCPs, the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial and for ensuring that the investigator(s) are qualified by training and experience. Prior to permitting an investigator(s) to conduct a study, the sponsor must obtain the following:

• Signed investigator’s statement (Form FDA 1572 (USA-77))
• Curriculum vitae
• Clinical protocol
• Financial disclosure information

As addressed in the G-1572FAQs, Form FDA 1572 (USA-77) serves as the investigator’s agreement to provide certain information to the sponsor and to assure compliance with the Food & Drug Administration (FDA)'s clinical investigation regulations. Refer to the G-1572FAQs and USA-40 for further information.

In addition, prior to the start of the study, the sponsor must provide the investigator(s) with the protocol and the investigator’s brochure.

See G-InvstgtrResp for more information on investigator responsibilities.

As per the G-InvstgtrAdmin, the FDA may disqualify a clinical investigator from receiving investigational drugs (including biologics) if the FDA determines that the investigator has repeatedly or deliberately violated the agency’s regulations, or submitted false information to the sponsor or FDA in any required report. See the G-InvstgtrAdmin for more details.

Foreign Sponsor Responsibilities

No information is currently available.

Data and Safety Monitoring Board

As per 21CFR50 and the G-DMCs, Data and Safety Monitoring Boards (DSMBs), (also known as a Data Monitoring Committees (DMCs)), are not required by FDA regulations, except in the case of research conducted in emergency settings in which fulfilling the informed consent requirement is unfeasible. In this case, as stated in 21CFR50, the FDA requires the establishment of an independent data monitoring committee to exercise oversight of the clinical investigation. See the G-DMCs for FDA recommendations on DSMB/DMC establishment.

Additionally, the Pre2018-ComRule and the RevComRule indicate that for all human subjects research funded and/or sponsored by a Common Rule department/agency (as identified in USA-65), the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must ensure that, when appropriate, the research plan makes adequate provisions for monitoring the data collected during the study to ensure participant safety. Moreover, per the NIHDataSftyMntrng and USA-72, all National Institutes of Health (NIH)-funded clinical trials require a Data and Safety Monitoring Plan and monitoring should be commensurate with risk. DSMBs are also required for multi-site clinical trials with interventions that involve potential participant risk. See the NIHDataSftyMntrng and USA-72 for detailed Department of Health & Human Services (HHS)/NIH requirements.

Although not specified as a sponsor requirement, the US-ICH-GCPs states that a DSMB may be established 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

For all human subjects research funded and/or sponsored by a Common Rule department/agency, institutions that are located in the US and engaged in multicenter research/cooperative research studies must use a single EC to review the research. See the Scope of Review section, the RevComRule, and G-CoopRes for additional information.

The US-ICH-GCPs indicates that 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, and given EC approval
• 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 among investigators is facilitated

See US-ICH-E17 for additional FDA guidance related to multi-regional clinical trials.

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 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.

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

The United States (US) regulations do not require insurance.

Compensation

The G-IRBFAQs state that institutional policy, not Food & Drug Administration (FDA) regulation, determines whether compensation and medical treatment(s) will be offered and the conditions that might be placed on participant eligibility for compensation or treatment(s).

Injury or Death

According to the US-ICH-GCPs, the sponsor's policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s).

As specified in 21CFR50, the Pre2018-ComRule, the RevComRule, and US-ICH-GCPs, for research involving more than minimal risk, participants must be informed as to whether any compensation or medical treatments are available in the event of trial-related injuries. See the Required Elements section for additional information.

Trial Participation

As per the FDA’s G-SbjctPayment, compensation for participation is considered a recruitment incentive and not a benefit, and is often offered when the participant’s health benefits are remote or non-existent. Payment amounts and schedules should be presented to the institutional ethics committee (EC) (institutional review board (IRB) in the US) at the time of the initial review. The EC should ensure the payment amount and the proposed method and timing of disbursement are not coercive or present undue influence and are also included in the informed consent document. Payment to participants who withdraw may be made at the time that they would have completed the study. While the entire payment should not be contingent upon completion of the entire study, a small payment provided as an incentive for completion is acceptable to the FDA. Further, the FDA does not consider reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence.

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:

• PatientCtr-Risk, PatientCtr-Imp, and PatientCtr-Design provide technical guidelines for patient-centered drug clinical trials, including design and risk assessment
• NMPA-No15-2023 provides technical guidelines for clinical trials of chemical compound drugs
• NMPA-No34-2022 lays out guidelines for protocol changes during drug clinical trials
• NMPA-No32-2022 has guidelines for clinical trials of topically administered local effective drugs
• NMPA-No31-2022 has guidelines for conduct of research with in vivo gene therapy products
• NMPA-No30-2022 has guidelines for conduct of research involving immune cell therapy products
• NMPA-No29-2022 has guidelines for conduct of research with in vitro gene modification
• NMPA-No27-2022 has guidelines for conduct of research involving specific human immunoglobulins
• NMPA-No22-2021 describes a research and development model to guide researchers in managing pharmaceutical changes of innovative drugs
• NMPA-No17-2022 has guidelines for clinical pharmacological research of biosimiliars
• NMPA-No4-2022 has guidelines for research of human bioavailability of bioequivalence of innovative drugs
• NMPA-No71-2021 has guidelines for research of drugs for rare diseases
• NMPA-No68-2021 lays out guiding principles for writing the clinical risk management plan
• NMPA-No66-2021 offers 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 provides guidelines for drug clinical trial data management and statistical analysis plan
• NMPA-No62-2021 provides guidelines for the application of patient-reported outcomes in drug clinical development
• NMPA-No59-2021 offers guidelines for analyzing the effectiveness of clinical studies of drugs
• NMPA-No50-2021 has guidelines for long-term follow-up for clinical research of gene therapy products
• NMPA-No6-2021 aims to guide sponsors in adopting and implementing an adaptive design to improve the success and quality of the research results
• Chngs-MktChem includes technical guidelines for pharmaceutical change research of listed chemicals
• Chngs-MktChemBio offers technical guidelines for clinical changes in marketed chemicals and biological products
• NMPA-No21-2021 provides technical requirements of pharmaceutical research and evaluation of overseas listed and domestic unlisted chemicals
• NMPA-No54-2020 describes technical guidelines for clinical trials of improved chemical drugs
• Chngs-MktBio offers 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. 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

Per the US-ICH-GCPs, the sponsor should implement a system to manage quality throughout all stages of the trial process, focusing on trial activities essential to ensuring participant protection and the reliability of trial results. The quality management system should use a risk-based approach that includes:

• During protocol development, identify processes and data that are critical to ensure participant protection and the reliability of trial results
• Identify risks to critical trial processes and data
• Evaluate the identified risks, against existing risk controls
• Decide which risks to reduce and/or which risks to accept
• Document quality management activities and communicate to those involved in or affected by these activities
• Periodically review risk control measures to ascertain whether the implemented quality management activities are effective and relevant
• In the clinical study report, describe the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and remedial actions taken

As stated in the US-ICH-GCPs, the sponsor is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data generated, recorded, and reported in compliance with the protocol, the US-ICH-GCPs, and the applicable regulatory requirements. The sponsor is responsible for obtaining 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. A written agreement must be signed by both the sponsor and the investigator or any other parties involved with the clinical trial, verifying that all parties agree to the trial protocol, the monitoring and auditing practices, the SOPs, and their respective duties.

Per the G-ICH-E19, the Food & Drug Administration (FDA) has adopted the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s E19 guidance, A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-Approval or Post-Approval Clinical Trials. The document describes circumstances in which it may be appropriate to reduce the collection of safety data in late-stage pre-approval and post-approval clinical trials, e.g., long-term outcome trials, when appropriate and with agreement from regulatory authorities. See the G-ICH-E19 for more information.

Furthermore, the FDA’s G-CTEmrgncy provides general considerations to assist sponsors, institutional ethics committees (ECs) (institutional review boards (IRBs) in the United States (US)), and clinical investigators in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during disasters and public health emergencies that may lead to a major disruption of clinical trial conduct and operations. See the G-CTEmrgncy for more information.

See the G-eHealthRecords for the FDA’s guidance related to the use of electronic health records in clinical research.

Additionally, the G-CovariatesCT provides the FDA’s recommendations for the use of covariates in the analysis of randomized, parallel group clinical trials that are applicable to both superiority trials and noninferiority trials. See the G-CovariatesCT for more information.

The G-RWDRWE-Reg, issued as part of the FDA’s Real-World Evidence (RWE) Program (see USA-17), discusses the applicability of the 21CFR312 IND regulations to various clinical study designs that utilize real-world data (RWD). See the G-RWDRWE-Reg for more information.

Additionally, see USA-47 for a list of FDA clinical trials related guidance documents.

See USA-6 for information on the National Institutes of Health (NIH)’s data management and sharing policy, the NIHDataMngmnt, which applies to all research that is funded or conducted in whole or in part by the NIH, and results in the generation of scientific data.

Monitoring Requirements

As part of its QA system, the US-ICH-GCPs notes that the sponsor should ensure the trial is monitored and audited. The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, the US-ICH-GCPs, and other applicable regulatory requirements. The sponsor should appoint auditors to review the clinical trial. The sponsor should ensure that the auditors are qualified by training and experience, and the auditor’s qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with the sponsor’s own SOPs and the auditor observations are documented. The sponsor should develop 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 FDA’s G-RiskMntrng states that for each clinical trial, the sponsor should develop a monitoring plan that describes the monitoring methods, responsibilities, and requirements for the trial. The monitoring plan should include a brief description of the study, its objectives, and the critical data and study procedures, with particular attention to data and procedures that are unusual in relation to clinical routine. The monitoring plan should also require training of study site staff. Additionally, the plan should communicate the specific risks to be addressed by monitoring and should provide those involved in monitoring with adequate information to effectively carry out their duties. The FDA also encourages greater use of centralized monitoring practices, where appropriate, with correspondingly less emphasis on on-site monitoring. Centralized monitoring techniques should be used to the extent appropriate and feasible to:

• Supplement or reduce the frequency and extent of on-site monitoring with monitoring activities that can be done as well or better remotely or with monitoring activities that can be accomplished using centralized processes only. Examples include monitoring data quality through routine review of submitted data, as well as completing administrative and regulatory tasks.
• Target on-site monitoring by identifying higher risk clinical sites (e.g., sites with data anomalies or a higher frequency of errors, protocol violations, or dropouts relative to other sites).

For more FDA guidance on a risk-based approach to monitoring and monitoring plans, see the G-RiskMntrng and the G-RiskMntrngQA.

Premature Study Termination/Suspension

As delineated in 21CFR312 and the US-ICH-GCPs, if the sponsor determines the study presents an unreasonable and significant risk to the participants, the sponsor must discontinue the study as soon as possible, and no later than five (5) working days after making the determination. The sponsor must also notify the FDA, all ECs, and all investigators who have participated in the study about the termination. Additionally, the sponsor must ensure the disposition of all remaining drugs and provide the FDA with a full report on the sponsor’s actions.

According to the US-ICH-GCPs, 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 EC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor.

The G-InfrmdCnsnt, which is the FDA’s discussion of the regulations in 21CFR50, further states that if a study is terminated, participants should be provided with as much information as possible regarding the reason for the termination. Such a discussion provides an opportunity to address questions that participants may have about an investigational product (IP) that was administered to them (e.g., immediate safety concerns, ability to participate in another clinical trial, and appropriate waiting period to do so) and what long-term follow-up may be available or necessary.

21CFR312 indicates that if the FDA terminates an investigational new drug application (IND) based on deficiencies in the IND or in the conduct of an investigation under an IND, the sponsor must end all clinical investigations conducted under the IND and recall or otherwise provide for the disposition of all unused supplies of the drug. See 21CFR312 for more information on FDA termination.

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 the visibility of the data conversion 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

Per the US-ICH-GCPs, 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 subject 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. Refer to the US-ICH-GCPs for additional information.

Records Management

As set forth in 21CFR312 and the US-ICH-GCPs, the sponsor must retain all sponsor-specific essential documents pertaining to the trial for at least two (2) years after a marketing application (known as a new drug application (NDA)) is approved for the drug; or if a NDA is not approved, until two (2) years after shipment and delivery of the drug for investigational use is discontinued and the Food & Drug Administration (FDA) has been notified. The sponsor should also inform the investigator(s)/institution(s) in writing of the need for record retention and when the trial-related records are no longer needed. Additionally, per 21CFR312, the sponsor must upon request from the FDA, permit an officer or employee to access, copy, and verify any records and reports relating to the clinical investigation. Upon written request by the FDA, the sponsor must also submit the records or reports (or copies of them) to the agency.

In addition, the US-ICH-GCPs 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 the sponsor is a data processor and must independently determine the purpose and method of processing personal information.

Data Protection

Per the PIPL, the sponsor 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 of people located within the country. In addition, the PIPL applies 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 sponsor 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 sponsor 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 sensitive personal information, which includes medical health information, the sponsor 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.

Per the PIPL, to send personal information outside of China, the sponsor must meet one (1) of the following conditions:

• 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

The sponsor must inform the participant of the name of the foreign recipient, contact information, processing purpose, processing method, and types of personal information. In addition, the foreign sponsor 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. For additional analysis of the China’s personal information protection legislation, see CHN-25.

The DataScrty requires the sponsor 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. Sponsors 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 assessment report must be submitted to CAC through the provincial-level department where the sponsor 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 sponsor 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.)

Responsible Parties

As stated in USA-86, the HIPAA Privacy Rule establishes the conditions under which protected health information (PHI) may be used or disclosed by covered entities for research purposes (Per USA-87, the Privacy Rule is located at 45CFR160 and Subparts A and E of 45CFR164; see USA-87 for more information). The Privacy Rule builds upon protections, described in Department of Health & Human Services (HHS) (the Pre2018-ComRule and the RevComRule) and Food & Drug Administration (FDA) (21CFR50 and 21CFR56) regulations, that help ensure the privacy of participants and the confidentiality of information. (Please note: ClinRegs does not provide information on state level personal data protection requirements.)

Per the Privacy Rule, a covered entity means: a health plan; a health care clearinghouse; or a health care provider who transmits any health information in electronic form in connection with a transaction covered by the Privacy Rule.

Data Protection

According to the FDA’s G-CertCnfdntlty, a Certificate of Confidentiality (CoC) is intended to help protect the privacy of human subject research participants from whom identifiable, sensitive information is being collected or used in furtherance of the research. CoCs must be issued for federally funded human subject research that collects or uses identifiable, sensitive information (mandatory CoCs). For non-federally funded research, issuance of CoCs is not required but may be issued at the discretion of the FDA (discretionary CoCs). If an institutional ethics committee (EC) (institutional review board (IRB) in the United States) determines that data collected in a clinical trial are sufficiently sensitive to warrant requesting a CoC, then the EC may request that a CoC be obtained in order to secure EC approval. Any disagreement between an EC, sponsor, and/or investigators regarding the need to request a CoC for a study should be resolved by communications among the parties. See the G-CertCnfdntlty for more information on CoCs.

NIH Privacy Requirements

The NIHPrvcy indicates that the HHS’ National Institutes of Health (NIH) follows the PrvcyAct, which includes procedures for: 1) protecting records that can be retrieved by personal identifiers such as a name, social security number, or other identifying number or symbol, and 2) persons to access their identifiable records and to request correction(s) of these records. See the NIHPrvcy and the PrvcyAct for more information.

Consent for Processing Personal Data

Per USA-86, the Privacy Rule defines the means by which individuals will be informed of uses and disclosures of their medical information for research purposes, and their rights to access information about themselves held by covered entities. Researchers may obtain, create, use, and/or disclose individually identifiable health information in the course of conducting research. Under the Privacy Rule, covered entities are permitted to use and disclose PHI for research with individual authorization, or without individual authorization under limited circumstances. To use or disclose PHI without authorization by the research participant, a covered entity must obtain one (1) of the following:

• Documented EC or privacy board approval
• Representations from the researcher that the use or disclosure of the PHI is solely to prepare a research protocol (or for similar purposes preparatory to research), the researcher will not remove any PHI from the covered entity, and PHI for which access is sought is necessary for the research purpose
• Research on protected health information of decedents
• Limited data sets with a data use agreement
• Research use/disclosure with individual authorization
• Accounting for research disclosures

See USA-86 for more information on these circumstances.

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 and HGR-LicenseSummary, the ICF must also be provided to the Ministry of Science and Technology (MOST) 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 and/or the legal representative(s) or guardian(s).

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 and/or the legal representative(s) or guardian(s). 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(s) or guardian(s) 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 and/or the legal representative(s) and/or guardian(s) 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 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.

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(s) or guardian(s) and make corresponding records. Per the RegEthics and the Measures-Ethics, the investigator should obtain re-consent under the following circumstances (Note: the requirements provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• 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(s) or guardian(s), 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(s) or guardian(s) 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(s) and/or guardian(s)
• The participant and the legal representative(s) and/or guardian(s), 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(s) and/or guardian(s) 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: the regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

• 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 States (US) clinical trials, a freely given informed consent is required to be obtained from each participant in accordance with the requirements set forth in 21CFR50 for Food & Drug Administration (FDA) regulated clinical trials, and the Pre2018-ComRule or the RevComRule for federally funded or sponsored clinical trials. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on agency-specific compliance.) Department of Health & Human Services (HHS)-funded or sponsored clinical trials must also comply with 45CFR46-B-E. The FDA has also adopted the US-ICH-GCPs as guidance.

As per 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an institutional ethics committee (EC) (institutional review board (IRB) in the US) and provided to the FDA with the investigational new drug application (IND).

Per the G-RevComRule-FDA, the informed consent requirements of the RevComRule are not inconsistent with FDA regulations. Therefore, there may not be a need for sponsors or investigators to develop, and have ECs review, two (2) separate ICFs for research that must comply with both the RevComRule and FDA regulations. (See the Required Elements section for ICF content details.) Per the RevComRule, which took effect January 21, 2019, for each clinical trial conducted or supported by a federal department or agency, one (1) EC-approved ICF used to enroll subjects must be posted by the awardee or the federal department or agency component conducting the trial on a publicly available federal website that will be established as a repository for such ICFs. According to USA-12, two (2) federal websites have been identified to meet this requirement: ClinicalTrials.gov (USA-78) and a docket folder on Regulations.gov (USA-79). According to the RevComRule, if the federal department or agency supporting or conducting the clinical trial determines that certain information should not be made publicly available on a federal website (e.g., confidential, commercial information), such federal department or agency may permit or require redactions to the information posted. The ICF must be posted on the federal website after the clinical trial is closed to recruitment and no later than 60 days after the last study visit by any subject, as required by the protocol.

According to 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the investigator must provide detailed research study information to the participant and/or the legal representative(s) or guardian(s). ICF content should be briefly and clearly presented orally and in writing, in a manner that is easy to understand and commensurate with the comprehension level of the research participants, and without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant and/or the legal representative(s) or guardian(s), should also be given adequate time to consider whether to participate.

As indicated in 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, none of the oral and written information concerning the research study should contain any language that causes the participant and/or the legal representative(s) or guardian(s) to waive or appear to waive legal rights, or that releases or appears to release the investigator, sponsor, institution or its agents from liability for negligence.

Additionally, per the RevComRule, participants must be provided with the information that a “reasonable person” would want to have in order to make an informed decision and an opportunity to discuss that information. Furthermore, the RevComRule requires that the informed consent, except for broad consent, must begin with a concise and focused presentation of the key information and organized to facilitate comprehension. Broad consent may be obtained in lieu of a full informed consent only with respect to the storage, maintenance, and secondary research uses of private identifiable information and identifiable biospecimens. See USA-54 and USA-60 for additional information regarding informed consent and broad consent requirements.

In addition, per 21CFR50, the Pre2018-ComRule, and the RevComRule, the ICF may be presented as either a full length written ICF or as a short form stating the consent requirements have been presented orally. The full length written ICF may be presented orally but must then be provided to the participant and/or a legal representative(s) or guardian(s) to read before it is signed.

See the FDA’s G-ElectronicIC for recommendations on the use of electronic systems and processes that may employ multiple electronic media to obtain informed consent for both HHS-regulated human subject research and FDA-regulated clinical investigations of medical products.

See the G-InfrmdCnsnt for the FDA’s discussion of the regulations in 21CFR50. Also, see USA-54 and USA-60 for additional information regarding informed consent.

Re-Consent

According to 21CFR50, the US-ICH-GCPs, and the G-IRBFAQs, the EC should determine the need to re-consent enrolled participants in the event of an ICF modification due to protocol changes or new information which may, in turn, affect the willingness of already enrolled participants to continue in the study. The communication of this information should be documented.

The G-IRBFAQs indicates that the FDA does not require re-consenting of participants who have completed their active participation in the study, or of participants who are still actively participating when the change will not affect their participation. One such case is when the change will be implemented only for subsequently enrolled participants.

Language Requirements

21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs state that any information provided must be in a language understandable to the participant and/or the legal representative(s) or guardian(s).

As delineated in the FDA’s G-InfrmdCnsnt, when non-English speaking participants are enrolled in a study, ECs and investigators must ensure that the information provided to prospective participants and/or their legal representative(s) or guardian(s) is in a language that is understandable to them. The EC must review and approve all consent documents that are to be used by investigators to document the informed consent. When translation and interpretation are needed for written and oral information to be presented to participants, the FDA recommends that the EC review and approve reasonable procedures for ensuring that the translations will be prepared by a qualified individual or entity, and that interpretation assistance is available. The FDA also recommends that whenever non-English speaking participants are enrolled in a study, appropriate interpreter services be made available throughout the course of the study.

USA-63 also states that when an oral presentation of the ICF is provided, the witness present should be fluent in both English and the participant’s language, and the translator may serve as the witness. See the G-InfrmdCnsnt and USA-63 for detailed information.

Documenting Consent

As set forth in 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the participant and/or a legal representative(s) or guardian(s) must sign and date an EC-approved written ICF. A written copy of the form must be given to the participant and/or a legal representative(s) or guardian(s). In addition, the RevComRule explicitly allows electronic signatures for consent documentation.

Per 21CFR50, the Pre2018-ComRule, and the RevComRule, if the consent information is only presented orally using the short form, the participant and/or the legal representative(s) or guardian(s) must sign the form, the witness must sign both the short form and a copy of the summary once consent has been provided, and the person obtaining the consent must sign a copy of the summary. A copy of both the summary and the short form must be given to the participant and/or the legal representative(s) or guardian(s). The FDA’s G-InfrmdCnsnt further states that participants who cannot write can instead indicate their consent by "making their mark" on the consent document. In these situations, a note should be included in participant case histories indicating the reason for the lack of a signature and date as required in 21CFR50. The date consent was obtained should be recorded in this note.

According to the US-ICH-GCPs, where the participant is illiterate and/or the legal representative(s) and/or guardian(s) is illiterate, an impartial witness should be present during the entire informed consent discussion. 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 or the legal representative(s)/guardian(s)
• The participant or the legal representative(s)/guardian(s), has orally consented to the participant’s involvement in the trial, and has signed and dated the ICF, if capable of doing so

Per the US-ICH-GCPs, before participating in the study, the participant or the legal representative(s)/guardian(s) should receive a copy of the signed and dated ICF.

Waiver of Consent

Per the Pre2018-ComRule and the RevComRule, the EC may waive the requirement to obtain a signed ICF if it finds any of the following:

• The ICF would risk a breach of confidentiality by linking the participant to the study
• The research presents minimal risk and involves no procedures for which written consent is required outside of the study

The RevComRule also adds that the EC may waive the requirements to obtain a signed ICF if the participants are part of a distinct cultural group or community in which signing the form is not the norm, the research presents minimal risk, and there is an alternative approach to document informed consent.

The Pre2018-ComRule and the RevComRule further indicate that in cases where the documentation requirement is waived, the EC may require the investigator to provide the participant or the legal representative(s)/guardian(s) with a written statement regarding the research.

In addition, the Pre2018-ComRule states that for an EC to approve a general waiver or alteration of consent, the EC must find that:

• The research involves no more than minimal risk
• The research could not practicably be carried out without the requested waiver or alteration
• If the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable format
• The waiver or alteration will not adversely affect the rights and welfare of the participants
• Whenever appropriate, the participant will be provided with additional pertinent information after participation

In the G-MinRiskWaiver, the FDA informs sponsors, investigators, and ECs that it does not intend to object to an EC waiving or altering informed consent requirements for certain minimal-risk, clinical investigations.

Furthermore, the Pre2018-ComRule, the RevComRule, and the G-MinRiskWaiver specify that although voluntary informed consent is always a requirement for every trial, the EC may approve a waiver or alteration of consent if the study involves a public benefit and service program conducted by or subject to the approval of state or local officials and could not be carried out without the waiver or alteration.

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: the requirements provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

• 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 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the informed consent form (ICF) must include the following statements or descriptions, as applicable (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• The study purpose, procedures, and expected duration of the trial
• Identification of any experimental procedures
• Any expected risks or discomforts to the participant, and when applicable, to an embryo or fetus
• Any expected benefits to the participant
• Disclosure of appropriate alternative procedures that might be advantageous to the participant
• Confidentiality of records identifying the participant will be maintained and the possibility that the Food & Drug Administration (FDA) may inspect the records
• Compensation and/or treatment available for the participant in the case of trial-related injury
• Contact information for relevant individuals to contact in the event of a trial-related injury
• That participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the participant is otherwise entitled, and that the participant can withdraw from the trial at any time without penalty or loss of otherwise entitled benefits
• Foreseeable circumstances under which the investigator may remove the participant without consent
• Any expenses the participant needs to pay to participate in the trial
• The consequences of a participant’s decision to withdraw from the study, and procedures for orderly withdrawal by the participant
• Any significant new findings developed during the study that may affect a participant’s willingness to continue participation
• Approximate number of participants in the study

As per 21CFR50, for FDA-regulated research, the following statement must be included on the informed consent documents: “A description of this clinical trial will be available on https://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

In the G-InfrmdCnsnt, the FDA also recommends the consent document advise participants that data collected on them up until the point of their withdrawal from a study will remain part of the study database and may not be removed. See the G-InfrmdCnsnt for additional FDA discussion of the regulations in 21CFR50.

The RevComRule also requires the following statements to be included in the ICF:

• Whether research results will be disclosed to participants
• Whether or not the participant’s information or biospecimens will be used or distributed for future research
• That participant’s biospecimens (even if identifiers are removed) may be used for commercial profit and if the participant will share in this profit
• Whether biospecimens research may include whole genome sequencing

See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

Compensation Disclosure

The FDA’s G-InfrmdCnsnt further states that if no compensation in the event of injury is available, the consent process should include a statement informing the participant. See the G-InfrmdCnsnt for an example statement.

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 ethical 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 the legal representative(s) or guardian(s) 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 and/or the legal representative(s) or guardian(s) 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 and/or the legal representative(s) or guardian(s) 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 21CFR50, 21CFR312, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the United States’ (US) ethical standards promote respect for all human beings and safeguard the rights of research participants. 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 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, a potential participant and/or a legal representative(s) or guardian(s) must 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 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, a potential research participant and/or a legal representative(s) or guardian(s), 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.

The Right to Privacy and Confidentiality

As per 21CFR50, the Pre2018-ComRule, and the RevComRule, participants should be given a statement describing the extent, if any, to which confidentiality of records identifying them will be maintained. Per the US-ICH-GCPs, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. 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 RevComRule does allow the use of identifiable private information or biospecimens in instances where the institutional ethics committee (EC) (institutional review board (IRB) in the US) determines the research could not practicably be carried out without the information. Furthermore, it removes the requirement for the investigator to seek a waiver of informed consent to obtain information or biospecimens to screen, recruit, or determine eligibility of prospective participants. See USA-54 for additional information on identifiable private information or biospecimens, USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

The G-InfrmdCnsnt, which is the Food & Drug Administration (FDA)’s discussion of the regulations in 21CFR50, delineates how data should be handled when an enrolled participant decides to withdraw from a trial. Data collected on participants up to the time of withdrawal from clinical investigations of drugs conducted under an investigational new drug application (IND) must remain in the study database to maintain the scientific validity of the research. The FDA recommends that participants be advised in the consent document that the data collected on them up until the point of their withdrawal will remain part of the study database and may not be removed. If a participant withdraws from the interventional portion of the clinical investigation but agrees to continued follow-up not addressed in the original consent document, the investigator must obtain the participant’s informed consent for this limited participation using an EC-approved consent document. If a participant withdraws from the interventional portion of a clinical investigation and does not consent to continued follow-up of associated clinical outcome information, the investigator must not access the participant’s medical record or other confidential records that would require additional consent from the participant. However, such records may be accessed consistent with the original consent process, without additional consent, to obtain information collected prior to the participant’s withdrawal from the study. See the G-InfrmdCnsnt for additional information.

The Right of Inquiry/Appeal

21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs state that the research participant and/or a legal representative(s) or guardian(s), should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries and/or to appeal against a violation of the participant’s rights.

The Right to Safety and Welfare

The US-ICH-GCPs clearly states that a research participant’s right to safety and the protection of the participant’s health and welfare 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(s) or guardian(s), 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 and/or the legal representative(s) or guardian(s) 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 researcher must provide materials to the EC in a simplified format, including the informed consent form. The EC must pay special attention to the informed consent process and consider the special circumstances during the outbreak and the participant’s vulnerability. Because the participant’s autonomy is challenged, is vulnerable to improper use, and is subject to high risks, the EC must ensure that the participant is fully informed, understands the risk, and voluntarily chooses to participate.

21CFR50, 21CFR56, the US-ICH-GCPs, and the G-ICEmrgncyReqs make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by life-threatening medical emergencies, public health emergencies, or military operations.

Medical Emergencies

As per the US-ICH-GCPs, in an emergency, if the signed informed consent form (ICF) has not been obtained from the research participant and/or a legal representative(s) or guardian(s), or if an effective treatment is lacking but the investigational product (IP) could address the participant’s emergency needs, the clinical trial may be conducted. However, the method used on the participant must be explained clearly in the trial protocol, and the institutional ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) must approve the protocol in advance. The participant and/or the legal representative(s) or guardian(s) should be informed about the trial as soon as possible, and consent to continue and other consent should be requested, as appropriate.

Emergency Use Situation

21CFR56 describes emergency use as the use of a test article, such as an IP, on a human participant in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain EC approval.

21CFR50 and the G-EmrgncyUse indicate that even in an emergency use situation, obtaining participant consent is required unless the investigator and a physician not participating in the trial certify in writing the following:

• The participant is confronted by a life-threatening situation
• Informed consent cannot be obtained due to an inability to communicate with the participant
• Time is insufficient to obtain consent from the participant’s legal representative(s) and/or guardian(s)
• No alternative methods of approved or generally recognized therapy are available

Per 21CFR50 and the G-EmrgncyUse, if immediate use of the IP is, in the investigator's opinion, required to preserve the participant’s life and time is not sufficient to obtain an independent physician’s determination prior to using the IP, the investigator’s determinations should be carried out. However, within five (5) working days following the use of the IP, the investigator’s decision must be reviewed and evaluated in writing by a physician not participating in the investigation. According to 21CFR50, 21CFR56, and the G-EmrgncyUse, the investigator must also notify the EC within five (5) working days.

21CFR56, the G-EmrgncyUse, and the G-IRBFAQs further state that following emergency use of the IP, EC review and approval is required for any subsequent use of the IP.

Emergency Research

The G-ICEmrgncyReqs defines emergency research as a planned clinical investigation that requires prior written Food & Drug Administration (FDA) authorization to proceed, and involves participant(s) who are in a life-threatening situation for which available treatments or in vitro diagnostic tests are unproven or unsatisfactory.

21CFR50 and the G-ICEmrgncyReqs delineate that for emergency research, the EC may approve the investigation without requiring the consent of all the participants if the EC (with the concurrence of a licensed physician who is an EC member or EC consultant, and not otherwise participating in the investigation) finds and documents the following:

• The participants are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence is necessary to determine the safety and effectiveness of particular interventions
• Obtaining informed consent is not feasible because: (i) the participants will not be able to give their informed consent as a result of their medical condition; (ii) the intervention under investigation must be administered before consent from the participants’ legal representative(s) and/or guardian(s) is feasible; and (iii) there is no reasonable way to identify prospectively the individuals likely to become eligible for participation in the clinical investigation
• Participation in the research holds out the prospect of direct benefit to the participants
• The clinical investigation could not practicably be carried out without the waiver
• The proposed investigational plan defines the length of the potential therapeutic window based on scientific evidence, and the investigator has committed to attempting to contact a legal representative and/or guardian for each participant within that window of time and, if feasible, to asking them for consent within that window rather than proceeding without consent
• The EC has reviewed and approved informed consent procedures and an informed consent document consistent with 21CFR50
• Additional protections of the rights and welfare of the participants will be provided

See 21CFR50 and the G-ICEmrgncyReqs for more details.

USA-60 notes that in certain emergency circumstances, the Department of Health & Human Services (HHS) Secretarial waiver of informed consent under 46.101(i) of the RevComRule may be applicable. The HHS waiver applies to research that may be carried out in human participants who need emergency therapy and for whom, because of the participants’ medical condition and the unavailability of the participants’ legal representative(s) and/or guardian(s), no legally effective informed consent can be obtained. Furthermore, if the research is regulated by the FDA, the HHS waiver permits the research to be conducted under a comparable provision. See the G-HHS-Emrgncy for additional guidance, USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the RevComRule applies to research.

Military Operations

21CFR50 and 10USC55 indicate that in the case of IP administration to a member of the armed forces in connection with participation in a particular military operation, the requirement for the member’s prior consent may be waived only by the US President. The US President may grant the waiver only after determining, in writing, that obtaining consent is not feasible; is contrary to the best interests of the military personnel; or is not in the interests of national security. See 21CFR50 and 10USC55 for detailed requirements.

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 21CFR56, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, in all United States (US) clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. Institutional ethics committees (ECs) (institutional review boards (IRBs) in the US) must pay special attention to protecting such participants. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

21CFR56 and the US-ICH-GCPs require special considerations for vulnerable populations and characterize them as those whose willingness to volunteer in a trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response for refusing to participate. Examples of these participants include members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students; subordinate hospital and laboratory personnel; pharmaceutical industry employees; members of the armed forces; and persons kept in detention. Per 21CFR56 and US-ICH-GCPs, other vulnerable subjects include children, pregnant women, physically or mentally disabled persons, patients with incurable diseases, persons in nursing homes, economically or educationally disadvantaged persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

The Pre2018-ComRule describes children, prisoners, pregnant women, handicapped persons, mentally disabled persons, or economically or educationally disadvantaged persons as vulnerable populations. The RevComRule describes children, prisoners, individuals with impaired decision-making capacity, or economically or educationally disadvantaged persons as vulnerable populations.

For more guidance documents related to vulnerable populations, see USA-64.

See the Children/Minors; Pregnant Women, Fetuses, & Neonates; Prisoners; 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 legal representative(s) or guardian(s). 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

Assent Requirements

No information is currently available.

As set forth in 21CFR50 and 45CFR46-B-E, children are defined as persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the study will be conducted. USA-25 further states that the age of majority in most states is 18 and therefore for legal purposes, children are those individuals who have not reached the age of 18. See USA-25 for a table delineating the legal age of majority by state in the United States (US).

Per the Pre2018-ComRule and the RevComRule, children require additional safeguards to be included in any research study in order to protect their rights and welfare. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

As delineated in the US-ICH-GCPs, when the research participant is a minor, informed consent should be obtained from a legal representative(s) or guardian(s). All pediatric participants should be fully informed about the trial and its risks and benefits in a language and in terms that they are easily able to understand. If capable, the participant should sign and date the written informed consent.

For all clinical trials that do not involve greater than minimal risk, 21CFR50 and 45CFR46-B-E state that a study may only be conducted if adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardian(s).

For all clinical trials that involve greater than minimal risk but present the prospect of direct benefit to the child, 21CFR50 and 45CFR46-B-E indicate that a study may only be conducted if the following applies:

• The risk is justified by the anticipated benefit to the child
• The anticipated benefit is greater than or equal to the available alternative approaches
• Adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardians

For all clinical trials involving children/minors that involve greater than minimal risk and do not present the prospect of direct benefit to the child, but will likely result in increased knowledge about the child’s disorder or condition, 21CFR50 and the 45CFR46-B-E state that a study may only be conducted if the following applies:

• The risk is slightly greater than minimal
• The trial presents experiences that are similar to those associated with the child’s actual or expected medical, dental, psychological, social, or educational situation
• Adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardian(s)

For all clinical trials that present a reasonable opportunity to further understand, prevent, or alleviate a serious problem affecting the health or welfare of children/minors but is not otherwise approvable per 21CFR50 and 45CFR46-B-E, a study may only be conducted if the following applies:

• The institutional ethics committee (EC) (institutional review board (IRB) in the US) finds that the investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children, and,
• The Commissioner of Food and Drugs consults with an expert panel and has an opportunity for public review and comment to determine that the investigation satisfies the conditions of one (1) of the other earlier described research types, or the following conditions are met: the investigation will be conducted in accordance with sound ethical principles and adequate provisions are made for soliciting the assent of children and the permission of their legal representative(s) or guardian(s)

Per the RevComRule, certain exemptions may apply to observational research involving children. See the RevComRule for details.

For additional Food & Drug Administration (FDA) guidance on clinical research in children, see US-ICH-E11 and USA-60. Additionally, see the G-InfrmdCnsnt for FDA discussion of the regulations in 21CFR50.

Assent Requirements

Per 21CFR50 and 45CFR46-B-E, when determining whether children/minors are capable of providing assent, the EC must consider their age, maturity, and psychological state. Assent from a child/minor is not necessary for proceeding with the clinical trial if the following applies:

• The capability of some or all of the children/minors is so limited that they cannot reasonably be consulted
• The trial presents a potential direct benefit that is important to the health or well-being of the children/minors and is only available through the investigation

Further, the EC may waive assent, even if the children/minors are capable of providing assent, if it finds and documents the following:

• Trial involves no more than minimal risk
• The waiver will not negatively affect the rights and welfare of the children/minors
• The trial could not be implemented without the waiver
• The children/minors will be given additional information after participation, whenever appropriate

When legal representative or guardian permission is necessary, the EC must determine whether the permission of one (1) legal representative or guardian is sufficient, or if permission from both is required. If the EC determines assent is required, it must also determine whether and how assent must be documented. 21CFR50 and 45CFR46-B-E do specify, however, that the consent of both legal representative(s) or guardian(s) is required in the following cases:

• When there is greater than minimal risk to the child with no direct benefit to the child, but the study will likely result in increased knowledge about the child’s disorder or condition
• Research that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children/minors, but is not otherwise approvable

Exceptions to the two (2) legal representatives’ and/or guardians’ consent requirement are when one (1) legal representative or guardian is deceased, unknown, incompetent, or not reasonably available, or, when only one (1) legal representative or guardian has legal responsibility for the care and custody of the child.

The G-InfrmdCnsnt indicates that when obtaining legal representative or guardian permission, in the event that the legal representative(s) or guardian(s) of a child does not understand English, the permission must be obtained and documented in a language that is understandable to the legal representative(s) or guardian(s). The child who will be participating in the research should not be used as an interpreter for the legal representative(s) or guardian(s), even if the child is fluent in English and may be able to assent. Further, legal representative or guardian permission and child assent should be viewed as an ongoing process throughout the duration of a clinical investigation. If and when a child who was enrolled in a clinical investigation with legal representative or guardian permission reaches the legal age of consent, that participant no longer meets the definition of a child under 21CFR50, and the investigator should obtain the participant’s informed consent prior to performing any further research interventions and/or procedures involving that participant. See the G-InfrmdCnsnt for additional FDA discussion of the regulations in 21CFR50.

While RegEthics lists pregnant women as a vulnerable population, there are no relevant provisions regarding any special consent procedures for pregnant women, fetuses, or neonates.

Per NMPA-No11-2017, any research studies of pregnant women should include a follow-up evaluation of these participants during pregnancy, as well as the fetuses and the children from that pregnancy. If a research study is intended for lactating women, the researchers should test the secretion of the drug or its metabolites in human milk, if feasible. If lactating women are recruited into a clinical trial, the effects of the drug on their infants should be monitored and, if necessary, followed. Pregnant women should be excluded from any research study if the investigational product is not intended for use during pregnancy. In this case, if a pregnancy occurs during the clinical trial, the study should be terminated and reported to the ethics committee for follow-up and evaluation of the pregnancy, fetus, and child.

In accordance with the NMPA-GCP-No57-2020 and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37), informed consent requirements for conducting clinical trials with pregnant or nursing women or fetuses follow the general requirements listed in the Required Elements section. Specifically, the informed consent form should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant.

As per 21CFR50 and 45CFR46-B-E, for studies involving women of childbearing age or who are pregnant, a statement should be provided in the informed consent form (ICF) indicating that the treatment or procedure may involve risks to the participant, embryo, or fetus, which are currently unforeseeable. According to the US-ICH-GCPs, the ICF should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant.

Per the Pre2018-ComRule, pregnant women require additional safeguards to be included in any research study in order to protect their rights and welfare. Furthermore, according to the RevComRule, all of the available exemptions of the RevComRule for observational research may be applied to research involving pregnant women, fetuses, and neonates. See the RevComRule for details. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

All Department of Health & Human Services (HHS)-sponsored or -funded research involving pregnant women, human fetuses, neonates of uncertain viability, or nonviable neonates must comply with Subpart B of 45CFR46-B-E.

Pregnant Women and Fetuses

As per 45CFR46-B-E, pregnant women and fetuses may participate in research if all of the following criteria are met:

• Preclinical and clinical studies have been conducted and provide data for assessing potential risks, where scientifically appropriate
• Risk to the fetus is caused solely by procedures that provide potential direct benefit to the woman or fetus. If there is no potential direct benefit, then the risk to the fetus cannot be greater than minimal, and the intent of the study is to develop important biomedical knowledge that cannot be obtained otherwise
• Least possible risk involved for achieving the research objectives
• Consent is obtained from the woman for studies that provide potential direct benefit to the pregnant woman and/or fetus, and studies with minimal risk to the fetus conducted to develop important biomedical knowledge that cannot be obtained otherwise
• Consent is obtained from the pregnant woman and the father if the study provides potential direct benefit solely to the fetus. Paternal consent is not required if the father is unavailable, incompetent, temporarily incapacitated, or the pregnancy was a result of incest or rape
• All individuals providing consent are fully informed about the foreseeable impact on the fetus or neonate
• No inducements will be offered to terminate a pregnancy
• Participants will not be involved in determining the timing, method, or procedures for terminating a pregnancy
• Participants will not be involved in determining the viability of a neonate

Neonates

45CFR46-B-E states that neonates may not be involved in research unless all of the following criteria are met:

• Preclinical and clinical studies have been conducted and provide data for assessing potential risks, where scientifically appropriate
• All individuals providing consent are fully informed about the foreseeable impact on the neonate

Neonates of uncertain viability may not be involved in research unless the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) determines the following additional conditions are met:

• Research provides the potential for increasing the probability of survival to the point of viability, and involves the least possible risk
• The purpose is to develop important biomedical knowledge that cannot be obtained otherwise and there is no added risk resulting from the research
• Informed consent is obtained from either parent, or if neither parent is able to provide consent, then consent is obtained from the neonate’s legal representative and/or guardian. Paternal consent is not required if pregnancy was a result of incest or rape.

Nonviable neonates may not be involved in research unless the following additional conditions are met:

• Vital functions will not be maintained artificially
• Research will not terminate the heartbeat or respiration
• The purpose is to develop important biomedical knowledge that cannot be obtained otherwise, and there is no added risk resulting from the research
• Consent is obtained from both parents. If neither parent is able to provide consent, informed consent of one (1) parent will suffice. Paternal consent is not required if pregnancy was a result of incest or rape. Consent of a legal representative or guardian of either or both parents will not suffice.

Viable neonates may only be included in research to the extent permitted by and in accordance with the RevComRule and subparts B and D of 45CFR46-B-E.

The NMPA-GCP-No57-2020 and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37) list prisoners as a vulnerable population. Per CHN-37, because incarceration could affect their ability to make a voluntary decision regarding participation in research. A research study involving prisoners should ensure that these prospective participants are informed and are given the opportunity to make their own decisions without any interference from a higher authority. The ethics committee must also ensure that the study will be independently monitored to assure the dignity and rights of the prisoners involved in the research. In accordance with the NMPA-GCP-No57-2020 and CHN-37, informed consent requirements for conducting clinical trials with prisoners should follow the general requirements listed in the Required Elements section.

21CFR56, 45CFR46-B-E, and the US-ICH-GCPs include prisoners in their description of vulnerable populations. As set forth in 45CFR46-B-E, a prisoner is defined as any individual involuntarily confined or detained in a penal institution. Prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research.

Per the Pre2018-ComRule and the RevComRule, prisoners require additional safeguards to be included in any research study in order to protect their rights and welfare. As delineated in the RevComRule, none of its observational research exemptions may be applied to research involving prisoners, except for research aimed at involving a broader subject population that only incidentally includes prisoners. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

45CFR46-B-E states that prisoners may participate in biomedical or behavioral research conducted or supported by the Department of Health & Human Services (HHS) only if the following criteria are met:

• The institution conducting the research has certified to the HHS Secretary that the research has been approved by the institutional ethics committees (EC) (institutional review board (IRB) in the United States (US)); research involves minimal risk; and studies focus on the possible causes, effects, and processes of incarceration and criminal behavior, prisons as institutional structures, or prisoners as incarcerated persons
• Research should focus on conditions specifically affecting prisoners as a class, or practices that have the intent and likelihood of improving the health or well-being of participants only after the HHS Secretary has consulted the appropriate experts, and a Federal Register notice is published indicating intent to approve such research

See USA-62 for more HHS information on prisoner research.

As per 45CFR46-B-E, ECs have additional approval responsibilities when reviewing research studies involving prisoners. An EC must only approve these studies if it determines that:

• The research under review represents one (1) of the permissible categories of research delineated in Subpart C
• The prisoner’s judgement will not be impaired by any possible advantages accruing to the prisoner through participation in the research, when compared to the general living conditions, medical care, quality of food, amenities, and opportunity for earnings in the prison
• Research risks are commensurate with those that would be accepted by non-prisoner volunteers
• Procedures for participant selection within the prison are fair to all prisoners and immune from arbitrary intervention by prison authorities or prisoners
• Information is presented in a language understandable to the prisoner population
• Adequate assurance exists that parole boards will not take into account a prisoner's participation in the research in making decisions regarding parole, and each prisoner is clearly informed in advance that participation in the research will have no effect on parole
• As needed, adequate provisions have been made for follow-up examination or care of participants, taking into account the varying lengths of individual prisoners' sentences, and for informing participants of this fact

See Subpart C of 45CFR46-B-E for additional EC requirements related to prisoner research.

While the RegEthics lists mentally impaired people as a vulnerable population, there are no relevant provisions regarding any special consent procedures for them. The NMPA-GCP-No57-2020 and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37) allow the ethics committee to approve the participation of research participants who are incompetent, or mentally or physically incapable of giving consent under certain conditions. The informed consent form must be signed and dated by the participant’s legal representative(s) or guardian(s).

In accordance with 21CFR56, the Pre2018-ComRule, and the US-ICH-GCPs, an institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must approve the participation of research participants who are mentally incapable of giving consent. According to the G-InfrmdCnsnt, which is the Food & Drug Administration (FDA)’s discussion of the regulations in 21CFR50, impaired consent capacity may involve partial impairment, impairment that fluctuates over time, or complete impairment. Consent capacity can be affected by a wide range of disorders and conditions, such as dementia, stroke, traumatic brain injury, intellectual and developmental disabilities, serious mental illness, intoxication, and delirium.

Per the Pre2018-ComRule and the RevComRule, this population requires additional safeguards to be included in any research study to protect the rights and welfare of participants likely to be vulnerable to coercion or undue influence. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

USA-60 further indicates that while Department of Health & Human Services (HHS) regulations do not provide specific procedures, it is expected that for research involving adult participants with mental illnesses or cognitive impairments, the EC and investigator(s) must be knowledgeable about the condition and any level of impairment that is likely to be present in the participant population.

As stated in the FDA’s G-InfrmdCnsnt, ECs and investigators should carefully consider whether the inclusion in research of individuals who lack consent capacity is ethically appropriate and scientifically necessary. Considerations that may help address these challenges and provide additional safeguards include:

• Assessing consent capacity of prospective participants, for example, through use of an independent, qualified professional

• Establishing a waiting period in the decision-making process to allow additional time for decision-making

• Using methods to enhance consent capacity, for example through (1) simplification and/or repetition of information, (2) involvement of a participant advocate or trusted family member/friend to assist when sharing information about the clinical investigation, and (3) refraining from discussions during periods of heightened impairment, when possible

• Assessing a participant’s understanding after information about the clinical investigation has been imparted, for example, through use of a questionnaire

• Re-assessing consent capacity after initiation of the clinical investigation for participants with progressive disorders whose cognition may decline

• Involving a legally authorized representative and/or guardian either initially or later in the clinical investigation if consent capacity diminishes

• Assessing whether prospective participants who cannot provide legally effective consent on their own behalf may nonetheless be able to provide some form of oral agreement at the outset of the study and, as appropriate, throughout the course of the research (e.g., for participants with progressive disorders), and how such oral agreement would be documented

• Emphasizing the voluntary nature of the decision to participate and the right to withdraw at any time

• Determining whether the EC or a third party should observe the consent process

See the G-InfrmdCnsnt for additional information and FDA discussion of the regulations in 21CFR50.

As delineated in the NMPA-GCP-No57-2020, investigational products (IPs) are defined as experimental and reference drugs used in a clinical trial.

The International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37) define an IP as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial. This includes a product with a marketing authorization when it is used or assembled (formulated or packaged) in a different way from the approved form, when used for an unapproved indication, or when used to gain further information about an approved use.

As delineated in 21CFR312, an investigational new drug is defined as a new drug or biological drug that is used in a clinical investigation. This includes a biological product that is used in vitro for diagnostic purposes. The terms ‘investigational drug’ and ‘investigational new drug’ are deemed to be synonymous for the purposes of this part.

Additionally, the US-ICH-GCPs defines an investigational product as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.

Manufacturing

According to the DAL and the NMPA-No28-2020, the National Medical Products Administration (NMPA) is responsible for authorizing the manufacture of investigational products (IPs) in China. See CHN-11 for an analysis of the authorization procedure for manufacturing drugs in China.

Per the DAL and the NMPA-No28-2020, the holder of the drug registration certificate must obtain a drug production license (found at NMPA-No72-2019) to produce a drug or entrust a pharmaceutical production enterprise to produce it. If an entrusted production enterprise is used, the drug registration certificate holder and the entrusted production enterprise must sign an entrustment agreement and a quality agreement. Blood products, narcotic drugs, psychotropic drugs, medical toxic drugs, and pharmaceutical precursor chemicals cannot be entrusted to a pharmaceutical production enterprise for production, unless otherwise stipulated by the NMPA. According to CHN-29, a drug registration certificate is valid for five (5) years and renewable for another five (5) years; the renewal must be submitted six (6) months before the expiration.

As delineated in the DAL and the NMPA-No28-2020, the following conditions must be met for drug manufacturing:

• Pharmacy technicians, engineering, technical personnel, and skilled workers have been qualified according to law
• Sanitary plants and facilities are compatible with the production of pharmaceuticals
• Institutions, personnel, and equipment are capable of quality management and inspection of the produced drugs
• Rules and regulations are in place to ensure the quality of pharmaceuticals and compliance with quality management requirements

Specific guidance on drugs manufactured for clinical trials is provided in NMPA-No43-2022 (an annex to the NMPA-GMP), which states that the preparation and quality control of drugs for clinical trials must follow the requirements in the NMPA-GMP; minimize the risks of contamination, cross-contamination, confusion, and errors in the manufacturing process; and ensure the quality of clinical trial IPs to protect the safety of clinical trial participants. See NMPA-No43-2022 for detailed manufacturing requirements, including the quality management system, personnel, facilities and equipment, material management, file management, and management of the control drug.

The NMPA-GCP-No57-2020 specifies that the manufacture of clinical trial drugs must meet the relevant requirements for quality management. See NMPA-GMP, NMPA-No43-2022, NMPA-No28-2020, NMPA-No13-2015, and NMPA-No28-2016 for guidance on the quality management system during manufacturing. Per the DRR and the NMPA-No28-2020, the Center for Drug Evaluation (CDE) makes a risk-based decision on whether to initiate an on-site inspection of drug production based on the registered varieties, processes, facilities, and previous acceptance verification. However, on-site inspections must be conducted for innovative drugs, improved new drugs, and biological products.

The International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37) also requires IPs to be manufactured, handled, and stored in accordance with applicable good manufacturing practices and used in accordance with the approved protocol.

Import

The DAL provides that prior to IP import, an NMPA import drug license must be obtained for each IP. Per CHN-18, before each import, the import agent must file for a record with the local agency at the port of entry, which issues a customs clearance notice of imported drugs and port inspection notice of imported drugs. According to CHN-28, importers must apply for the drug import license via the China International Trade Single Window online platform (CHN-2). For IP shipments, only a party authorized under the corresponding clinical trial approval can register and apply for the drug import license.

Per NMPA-No75-2020, there is a one-time fee of 2,000 Yuan for the import of drugs.

Pursuant to the NMPA-No35-2017, researchers can conduct Phase I of multi-regional clinical trials (MRCT) of imported IPs 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. This removes the need to conduct local clinical trials in addition to existing overseas research. Overseas clinical trial data may be acceptable for direct China registration provided that:

• The data is reliable, authenticated, and complies with 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 drug registration requirements

See the NMPA-No52-2018 for additional details on the review and approval of overseas clinical trial data. For more information on application requirements, see the Submission Process and Submission Content sections.

Per NMPA-No230-2015 and CHN-18, the NMPA will prioritize the review and approval of foreign innovative drugs manufactured in China and drugs manufactured at a United States (U.S.) or European Union facility, and are simultaneously under review for marketing authorization by the U.S. Food and Drug Administration or the European Medicines Agency.

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

Manufacturing

According to 21CFR312 and USA-42, the Food & Drug Administration (FDA) is responsible for authorizing the manufacture of investigational products (IPs) (also known as investigational new drugs in the United States (US)).

Per 21CFR312, sponsors that use an IP not already subject to a manufacturer’s investigational new drug application (IND) or marketing application are required to provide all of the technical chemistry, manufacturing, and control (CMC) information outlined in the application content and format requirements section of 21CFR312, unless such information may be referenced from applicable scientific literature. Sponsors using an IP already subject to a manufacturer’s application should follow the same general application format but may, if authorized by the manufacturer, refer to the manufacturer’s application to provide the technical (CMC) information supporting the proposed clinical investigation.

Moreover, as stated in 21CFR312, a sponsor may ship an IP to the investigators named in the IND under the following conditions:

• Thirty (30) days after the FDA receives the IND, or
• FDA provides earlier authorization to ship the IP

The sponsor is responsible for complying with the principles of good manufacturing practice (GMP) as specified in 21CFR210, the G-CGMP-Phase1, and the G-INDPrep. The US-ICH-GCPs also states that the sponsor must ensure that the products are manufactured in accordance with GMPs.

Import

As set forth in 21CFR312, the FDA is also responsible for authorizing the import and export of IPs. An IP may be imported into the US if it is subject to an IND that is in effect for it and complies with one (1) of the following requirements:

• The IP consignee is the IND sponsor, or
• The consignee is a qualified investigator named in the IND, or
• The consignee is the domestic agent of a foreign sponsor, is responsible for the control and distribution of the IP, and the IND identifies the consignee and describes what, if any, actions the consignee will take with respect to the IP

Investigator’s Brochure

In accordance with 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 providing the investigators with an Investigator’s Brochure (IB). The IB must contain all of the relevant information on the investigational product(s) (IPs) including chemical, pharmaceutical, toxicological, pharmacological, and clinical information and data on the IP, including trials already completed or being conducted in other places.

As specified in the NMPA-GCP-No57-2020 and CHN-37, the IB must provide coverage of the following areas:

• Physical, chemical, and pharmaceutical properties and formulation parameters
• Pharmaceutical aspects
• Pharmacokinetics and metabolism
• Toxicological effects in any animal species tested under a single dose study, a repeated dose study, or a special study
• Results of clinical pharmacokinetic studies
• Information regarding safety, pharmacodynamics, efficacy, and dose responses obtained from prior clinical trials in humans

See the NMPA-GCP-No57-2020 and CHN-37 for detailed IB content guidelines.

Quality Management

Per the DAL, drug manufacturers are required to abide by quality management regulations, establish and improve the quality management system for drug production, and ensure that the entire process meets statutory requirements, including good manufacturing practice (GMP) standards in the NMPA-GMP and NMPA-No43-2022 (an annex to the NMPA-GMP). With respect to the manufacture of the clinical trial IP, NMPA-No43-2022 states that the manufacturing facility must establish a quality management system based on risks and a document system to ensure the effective operation of the quality management system. The sponsor must audit and confirm the quality management system of the entrusted manufacturing facility and sign an entrustment agreement and a quality agreement to clearly define the responsibilities of all parties to ensure that the clinical trial drug meets the intended use and quality requirements. Changes that may affect the safety of clinical trial drugs, such as changes in the preparation site, prescription process, batch size, quality standards, key raw and auxiliary materials, packaging materials of clinical trial drugs, and technology transfer, must be evaluated. Changes and assessments should be documented. Deviations from the preparation process, quality standards, and other deviations that may affect the quality of drugs for clinical trials should be investigated and evaluated, and corresponding records should be kept.

Per CHN-37, the sponsor must maintain a Certificate of Analysis to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.

Investigator's Brochure

In accordance with 21CFR312 and the US-ICH-GCPs, the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB). The IB must contain all of the relevant information on the investigational new drug(s)/investigational product(s) (IPs) obtained through the earlier research phases. The sponsor must also update the IB as significant new information becomes available.

As specified in 21CFR312 and the US-ICH-GCPs, the IB must provide coverage of the following areas (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• A brief description of the drug substance and the formulation, including the structural formula, if known
• A summary of the pharmacological and toxicological effects of the drug in animals and, to the extent known, in humans
• A summary of the pharmacokinetics and biological disposition of the drug in animals and, if known, in humans
• A summary of information relating to safety and effectiveness in humans obtained from prior clinical studies
• A description of possible risks and side effects to be anticipated on the basis of prior experience with the drug under investigation or with related drugs, and of precautions or special monitoring to be done as part of the investigational use of the drug
• Summary of data and guidance for the investigator

See 21CFR312 and the US-ICH-GCPs for detailed IB content guidelines.

For investigational new drug applications (INDs) that include clinical data provided from studies conducted outside of the United States (US), 21CFR312 states that the sponsor or applicant must submit a description of the actions taken to ensure that the research conformed to good clinical practices (GCPs). See Section 312.120 of 21CFR312 for detailed requirements.

Quality Management

According to USA-39, submitting a copy of the Certificate of Analysis (CoA) of the clinical batch is suggested, but not required by the Food & Drug Administration (FDA).

The US-ICH-GCPs state that the sponsor must maintain a CoA to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.

Investigational product (IP) labeling in China must comply with the requirements set forth in the NMPA-GCP-No57-2020, the ProvLabel, the DAL, and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (CHN-37). The name, insert sheet, and label of any drug for which registration is applied must comply with the National Medical Products Administration (NMPA)’s requirements as mandated in the preceding regulations.

As per the NMPA-GCP-No57-2020, the sponsor is responsible for ensuring the proper packaging and labeling of the IPs. The IPs, comparator, and placebo products must be labeled in conformity with the clinical protocol, and be easily recognizable, correctly coded, and marked with special labels indicating that the product is to be used for clinical trial purposes. For international multicenter clinical trials, NMPA-No2-2015 states that the label content of drugs should be complete and meet the requirements of the country or region where they are located to ensure the identification, traceability, and correct use of drugs. The label content should include clinical trial information and clinical trial drug information, as detailed below.

Per NMPA-No43-2022 (an annex to the NMPA-GMP), to ensure the accuracy of IP labeling for clinical trials, operating procedures should be established that include measures to prevent mislabeling, such as balance calculation of label quantity, site clearance, and intermediate control inspection by trained personnel. Where blinded trials are involved, effective measures should also be taken to prevent labeling errors between the test drug and the reference drug (including placebo). For operations that need to remove the original product labels and packaging, corresponding measures should be taken to prevent contamination, cross-contamination, confusion, and errors between the test drug and the reference drug (including placebo). IP labels for clinical trial use must be clear and easy to identify, and contain the following contents:

• The sponsor of the clinical trial
• The name of the drug used in the clinical trial
• The batch number and/or serial number of the product and the packaging operation (the label information of the clinical trial IP used for the blinded test should be able to remain blinded)
• The clinical trial number or other unique code corresponding to the clinical trial
• The words "only for clinical trials" or similar instructions
• Validity period, expressed in a way such as XXXX (year)/XX (month)/XX (day) or XXXX (year)/XX (month) that can clearly indicate the year, month, and day
• Specifications and instructions for use (the instructions for use or other written instructions provided to the participants may be attached, and the content should meet the requirements of the clinical trial protocol)
• Packaging specifications
• Storage conditions
• If the clinical trial drug is allowed to be taken home by the subjects, it must be specially marked to avoid misuse

NMPA-No43-2022 states that the inner and outer packaging must contain all of the label contents. If the size of the inner package label is too small to indicate all of the above contents, at least the first four (4) label contents in the bulleted list above must be included. If the validity period needs to be changed, the IP must be affixed with an additional label, and the additional label must be marked with the new validity period. The original batch number or drug code must not be overwritten when affixing additional labels. After the applicant's evaluation, the additional label operation of changing the validity period can be carried out in the institution conducting the clinical trial. The operation of affixing additional labels must be carried out in accordance with the operating procedures approved by the sponsor. Personnel must be trained and approved in these operating procedures, and the operation site must be reviewed and confirmed by personnel. Attachment of additional labels should be properly documented and traceable in clinical trial-related documents or batch records. The sponsor must conduct a quality review of the IPs with additional labels.

The ProvLabel and the DAL also provide labeling information that should be included on the outer packaging and immediate container of all drugs to be registered in China. (Note: the regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.)

• Adopted name in China
• Instructions
• Generic name
• License holder and their address
• Indications or functions
• Strength, dosage, and usage
• Production date and batch number
• Expiration (Should be marked as one (1) day or one (1) month earlier than the actual expiration date, depending on whether the date is labeled to a specific day or month)
• Manufacturer and their address
• Ingredients
• Adverse reactions
• Contraindications and precautions
• Storage information
• Approval number
• Labels and instructions for narcotic, psychotropic, medical toxic, radioactive, external, and non-prescription drugs must be printed with the prescribed marks

The label language must also be scientific, standardized, and accurate, and written in standard Chinese characters published by the National Language Commission. See ProvLabel and the DAL for detailed labeling instructions.

The NMPA-GCP-No57-2020 and CHN-37 state that the IP must be coded and labeled in a manner that protects the blinding, if applicable.

(See Product Management section for additional information on IP labeling requirements).

Investigational new drug/investigational product (IP) labeling in the United States (US) must comply with the requirements set forth in Section 312.6 of 21CFR312, which include the following:

• The immediate package of an IP intended for human use must bear a label with the following statement: “Caution: New Drug-Limited by Federal (or US) law to investigational use”
• The label or labeling of an IP must not bear any false or misleading statements and must not represent that the IP is safe or effective for the purposes for which it is being investigated

The appropriate Food & Drug Administration (FDA) Center Director may grant an exception or alternative to the requirements above for specific lots, batches, or other units of a human drug or biological product that is or will be included in the Strategic National Stockpile.

In addition, the US-ICH-GCPs states that the IP must be coded and labeled in a manner that protects the blinding, if applicable.

Supply, Storage, and Handling Requirements

Per NMPA-No43-2022, operating procedures should be established to ensure the accuracy of packaging investigational products (IPs) for clinical trials. The packaging of IPs for clinical trials should prevent and avoid its deterioration, contamination, damage, and errors during storage and transportation. The procedures should identify activities that open or change the packaging. The test drug and the reference drug are usually not allowed to be packaged in the same packaging line at the same time. For clinical trial IPs that need to be packaged simultaneously on the same packaging line, appropriate operating procedures and equipment should be in place, and relevant operators should be trained to avoid confusion and errors.

Further, NMPA-No43-2022 states that before approving the release of an IP for a clinical trial, the person responsible must evaluate the quality of each batch of IPs to ensure that they comply with laws, regulations, and technical requirements, including:

• Batch records
• Deviations and changes, subsequent investigations, and assessments
• Correct packaging and labels
• Production conditions
• Status of facilities, equipment, preparation process, and inspection method
• The release of raw and auxiliary materials and the inspection results of intermediate and finished products
• The relevant test results of the reference drug (including placebo) (if applicable)
• Stability study data and trends (if applicable)
• Storage conditions
• Qualification certificate of reference substance/standard product (if applicable)
• Audit report of the quality management system of the entrusted unit (if applicable)
• Proof of legal origin of the reference drug (if applicable)
• Other requirements related to the quality of the batch of clinical trial drugs

As per NMPA-No43-2022, the delivery of IPs must be carried out according to the sponsor’s delivery instructions and specific requirements. The sponsor must select an appropriate transportation method according to the packaging, quality attributes, and storage requirements of the IP, take corresponding measures to prevent deterioration, damage, pollution, temperature control failure, etc., and confirm the IP is sent to designated clinical trial institutions. The IPs delivered to the clinical trial institutions must at least be accompanied by a certificate of conformity, a delivery list, and a receipt confirmation from the research institution. IPs must not be directly transferred from a clinical trial institution to another clinical trial institution. If necessary, the sponsor and the clinical trial institutions of both parties should have complete quality assessment and operating procedures for the transfer of IPs, which can only be implemented after full assessment and approval by the sponsor.

The NMPA-GCP-No57-2020 states that the sponsor must provide the IPs to investigators and clinical trial institutions. The sponsor must not provide the IPs until the clinical trial has obtained the approval of the ethics committee and the approval or filing of the National Medical Products Administration (NMPA). The sponsor must provide the investigator and the clinical trial institution with a written description of the IP, including directions for use and storage. Further, the sponsor must formulate procedures for the supply and management, including reception, storage, distribution, use, and recovery. The sponsor must ensure that the IPs are delivered to researchers and clinical trial institutions in a timely manner. The sponsor must also take measures to ensure the stability of the trial drug during the trial period. Investigators and clinical trial institutions are responsible for the management of IPs provided by the sponsor. They must assign qualified pharmacists or other personnel to manage IPs.

CHN-37 provides additional guidance that the sponsor must ensure:

• IP product quality
• IP manufactured according to good manufacturing practices (GMPs), as per NMPA-GMP and NMPA-No43-2022
• Proper coding, packaging, and labeling of the IP in accordance with the protocol, and special marking to indicate that the drug is specifically to be used in a clinical trial
• IP use record which includes information on the quantity, loading, shipment, receipt, dispensing and handling, and the reclamation and destruction of the unused drug
• Establishment of IP management and filing systems
• Acceptable storage temperatures, conditions, and times for the IP
• Timely delivery of the IP

Refer to the NMPA-GCP-No57-2020 and CHN-37 for detailed sponsor-related IP requirements.

Per the DAL, the sponsor—also referred to as the holder of a drug registration certificate—must establish a drug release procedure that includes reviewing the drug to ensure compliance with national drug standards, and releasing it only after the quality attorney signs it. Further, drug license holders, pharmaceutical production enterprises, and medical institutions must establish and implement a drug traceability system, in accordance with regulations.

Record Requirements

Per NMPA-No43-2022 (an appendix to NMPA-GMP), sponsors should set up investigational drug files, which are documents and records of the preparation, packaging, quality inspection, the release of products in batches, delivery, and transportation. These files should be retained until at least two (2) years after the IP is withdrawn from the market, or at least two (2) years after the termination of the clinical trial or the registration application if the IP fails to get marketing authorization. The files should at least contain the known or potential key quality attributes and key process parameters in the research stage, re-evaluated with the development of the product, and updated when necessary. The files can be the original documents or certified copies.

Per NMPA-GCP-No57-2020, the sponsor must keep records of the transportation, receipt, distribution, recovery, and destruction of the IPs; establish a recycling management system to ensure the recall of defective products and recovery after the clinical trial and expiration; and establish a disposal system. The entire management process of all IPs must be documented. Finally, the retained samples must be kept until the end of the clinical trial or the time limit required by relevant laws and regulations, whichever time period is longer. If the two (2) are inconsistent, the longer period must be used. The sponsor must keep clinical trial records for at least five (5) years after the IP is approved for marketing.

In addition, as indicated in NMPA-GCP-No57-2020, there must be clear documentation of the IP’s quality evaluation, such as approval for release, non-release or other decisions, and must be signed by the person responsible for release. Before the IP is shipped to the clinical trial institution, the sponsor must confirm the following contents and keep relevant records:

• The IP has been approved for release
• The relevant requirements necessary for the initiation of clinical trials have been met, such as the approval or consent of the ethics committee and the NMPA
• Inspection and confirmation of transportation conditions

Per NMPA-GCP-No57-2020, complete written records should be kept for the delivery of IPs, which usually include the name or code of the IP, dosage form, strength, batch number or drug code, quantity, expiration date, applicant, preparation unit, packaging form, and storage requirements. Records should also be kept of the receiving unit and address, contact information, shipping date, transportation method, and the temperature monitoring measures. If the transportation is entrusted to a third-party carrier, the relevant information of the carrier shall also be included. The content of the shipping record can be adjusted as needed for blinding.

Supply, Storage, and Handling Requirements

As defined in the US-ICH-GCPs, the sponsor must supply the investigator(s)/institution(s) with the investigational new drug(s)/investigational product(s) (IP(s)), including the comparator(s) and placebo, if applicable. The IPs must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Per 21CFR312, the US-ICH-GCPs, the G-CGMP-Phase1, and the G-INDPrep, the sponsor must ensure the following (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• IP product quality and stability over the period of use
• IP manufactured according to any applicable good manufacturing practices (GMPs)
• Proper coding, packaging, and labeling of the IP(s)
• Acceptable storage temperatures, conditions, and times for the IP
• Timely delivery of the IP(s)

Refer to the US-ICH-GCPs, the G-CGMP-Phase1, and the G-INDPrep for detailed sponsor-related IP requirements.

Record Requirements

According to 21CFR312, the sponsor must maintain adequate records showing the receipt, shipment, or other disposition of the IP. These records are required to include, as appropriate, the name of the investigator to whom the drug is shipped, and the date, quantity, and batch or code mark of each such shipment. The sponsor is also required to maintain records showing financial interest paid to investigators. See 21CFR312 for more details.

As per 21CFR312 and the US-ICH-GCPs, the sponsor and the investigator(s) must retain the clinical investigation records and reports for two (2) years after a marketing application (known as a New Drug Application (NDA)) is approved for the IP; or, if an NDA is not approved, until two (2) years after shipment and delivery of the IP is discontinued for investigational use and the Food & Drug Administration (FDA) has been so notified.

The term “specimen” is not referenced within China. However, as per MgmtHumanGen, human genetic resources (HGR) are defined as including both human genetic resource materials and human genetic resource information. HGR materials refer to genetic materials, such as organs, tissues, and cells, which contain the human genome, genes, and their products. HGR information refers to genetic information or data generated by using the HGR materials.

The Measures-Ethics defines "human or human biological samples" as the human body itself, including human cells, tissues, organs, body fluids, flora, etc., as well as fertilized eggs, embryos, and fetuses.

The Rules-MgmtHGR clarifies that HGR information includes information materials such as human genes and genome data generated using HGR materials. It does not include clinical data, imaging data, protein data, and metabolic data.

A specimen, referred to as patient specimen in 49CFR173, is defined as human or animal material collected directly from humans or animals and transported for research, diagnosis, investigational activities, or disease treatment or prevention. Patient specimen includes excreta, secreta, blood and its components, tissue and tissue swabs, body parts, and specimens in transport media (e.g., transwabs, culture media, and blood culture bottles).

In addition, 42CFR73 defines specimen as samples of material from humans, animals, plants, or the environment or isolates or cultures from such samples for diagnosis, verification, or proficiency testing.

The RevComRule defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator or associated with the biospecimen. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the RevComRule applies to research.)

Import

Per the QuarantineLaw, the AQSIQ-No160, and CHN-54, imports of human tissue, biological products, blood, and hemoproducts are subject to health and quarantine inspection. The importer is required to declare the items for inspection with local offices governed by the General Administration of Quality Supervision, Inspection and Quarantine (AQSIQ). As described in CHN-46, AQSIQ operates 35 Entry-Exit Inspection and Quarantine Bureaus (CIQ) in China’s 31 provinces.

Per the AQSIQ-No160, the management of special articles is subject to risk control, which includes quarantine approval, inspection, and supervision as per risk levels upon assessment. Importers of special articles must apply for the quarantine approval by submitting the following documents to the local CIQ:

• A completed Application for Quarantine of Inbound/Outbound Special Articles (CHN-54)
• Specific descriptions of the special articles, including Chinese and English names, classification, composition, origin, purpose, import destination, etc.
• Approval documents from health authorities for inbound human blood, plasma, tissue, organs, cells, bone marrow, etc.
• For first-time importers, provide copies of the business license and the organization code certificate (copied)
• For first-time importers, firm information including management system certification status, address, place of production, laboratory setup, storage facilities, processing conditions, production processes, floor plan, etc.
• For first-time importers, biosafety documents including storage management rules, use management rules, waste disposal rules, professional management rules, emergency handling procedures, etc.

In addition, see QuarantineRules for more details on the procedures for the inspection and quarantine processes, the jurisdiction of AQSIQ and its local branches, and different levels of sample testing based on risk and the importer’s track record.

Export

The MgmtHumanGen and the Bioscrty-Law prohibit foreign entities or individuals from collecting or preserving China’s human genetic resources (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, the foreign entity and the Chinese entity must jointly file an application for approval to the Ministry of Science and Technology (MOST), and the research must pass ethical 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, and their products. Such clinical trial collaborations, however, must be filed with MOST on its online platform, which will generate a record number. (Note that HGR-WorkUpdt indicates that MOST has initiated operation of a new online platform for HGR at CHN-6. Per HGR-InfoSys, the original online platform is available at CHN-23. For help with the two (2) systems, contact Xu Penghui, Department of Social Development and Science and Technology, MOST at 010-58881479; Zhu Min, China Biotechnology Development Center, at 010-88225151 or 010-88225168; or the information system support at 17610386080.) For additional HGR guidance and procedures, see CHN-76 and for analyses of China’s implementation of HGR regulations, see CHN-16.

As delineated in MgmtHumanGen and the HGR-ExprtLicenseGuide, the applicant may apply for the export license separately, or with the application for international cooperative research. (See Regulatory Authority and Clinical Trial Lifecycle topics for details on MOST’s review and approval requirements for HGR collection and international cooperative research license applications.) Per the HGR-ExprtLicenseGuide, the export applicant must be a Chinese entity and the transportation, mailing, and carrying of Chinese HGR material must meet these conditions:

• There is no harm to public health, national security, and social public interests in China
• The activity has legal standing
• There are clear overseas partners and reasonable exit uses
• The collection of HGR materials is legal or from legal depository institutions
• The collection of HGR material passed an ethical review

Per the HGR-ExprtLicenseGuide and HGR-LicenseSummary, the following must be submitted:

• Application (see HGR-LicenseSummary for a template) – after the online declaration is completed, the paper stamp is submitted; see below for information on the declaration
• Legal person qualification
• Informed consent
• Ethics review approval
• Chinese HGR international cooperative research approval decision
• Chinese HGR materials exit approval decision

Per the HGR-Procedures and the HGR-ExprtLicenseGuide, the applicant submits the electronic version of the materials through the online platform (CHN-6 or CHN-23). To submit paper applications, the applicant should use the online, pre-accepted electronic application materials and print them double-sided on A4 paper; the cover and signature stamp page should be printed one-sided with plastic binding.

Per the HGR-Procedures and the HGR-ExprtLicenseGuide, MOST will complete the pre-examination of electronic applications within five (5) working days after receiving the application. If the application materials are complete and conform to the prescribed form, the applicant may print the paper materials through pre-examination; if the application materials are incomplete or do not meet the requirements, the pre-examination shall not be passed, and the applicant is notified of the content that should be corrected in the online platform. After receiving the paper application materials submitted by the applicant, MOST will complete the formal examination within five (5) working days. An acceptance form will be issued once the application materials are confirmed to be completed and in conformance with the prescribed format. If the application materials are incomplete or do not conform to the prescribed format, the application will be returned. MOST organizes experts to conduct technical reviews and form expert review opinions on the accepted applications. Next, MOST will approve or disapprove the application and publish the results on its website (CHN-76), including reasons why an application was not approved. MOST will send the approval decision letter to the provincial science and technology administrative department by mail within 10 working days and publish the mailing details on the website. The applicant should go to the provincial science and technology administrative department to receive the approval decision letter with the acceptance form.

Material Transfer Agreement

Per the Measures-Ethics, where establishments cooperate with enterprises and other institutions to carry out life science and medical research involving humans, or provide human biological samples and information data for enterprises and other institutions carrying 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 ethical review and follow-up review, and supervise their proper disposal after the research is completed.

Per USA-2, the NIH also requires researchers to use an agreement (e.g., Material Transfer Agreement (MTA) or contract) to transfer materials among academic, nonprofit, and/or industrial organizations. See USA-2 for detailed MTA requirements and Appendix 4 for a sample MTA.

The MgmtHumanGen indicates that the Ministry of Science and Technology (MOST) is responsible for China’s management of human genetic resources (HGR). As delineated in the MgmtHumanGen, the Rules-MgmtHGR, HGR-Procedures, and HGR-ExprtLicenseGuide, MOST, through its experts, is responsible for reviewing and approving license applications to collect HGR and conduct international collaborative projects using Chinese HGR. The applicant’s submission for these licenses must include the written informed consent of the provider of the HGR. The Rules-MgmtHGR states that the written informed consent must ensure that the lawful rights and interests of providers of HGR are not infringed. HGR-LicenseSummary summarizes the HGR license and application contents, including the consent form.

Per the MgmtHumanGen, to collect Chinese HGR for a clinical trial, the investigator must provide advance information to the participant on the purpose of collection, the possible impact on health, the protection of personal privacy, their participation is voluntary, and they have the right to withdraw unconditionally at any time. The participant must agree in writing. Information provided to the participant must be comprehensive, complete, true, accurate, and must not conceal information nor be misleading or deceiving.

The Measures-Ethics indicates that for the collection of biological samples involving humans, the informed consent must include the type, quantity, use, preservation, and utilization of biological samples (including whether they are directly used for product development, sharing, and secondary use), privacy protection, external provision, and destruction and disposal.

As delineated in the G-IC-IVDs, the Food & Drug Administration (FDA) only provides informed consent guidance with respect to its regulations governing the informed consent requirement when human specimens are used for FDA-regulated in vitro diagnostic device investigations.

Informed consent requirements guiding Department of Health & Human Services (HHS)-conducted or -supported research on human research participants is regulated by the Pre2018-ComRule and 45CFR46-B-E.

Per the Pre2018-ComRule and the G-SpecimensResrch, the HHS views research involving human subject specimens as research involving human participants and subject to informed consent requirements, if the specimens obtained may be classified as identifiable private information. Identifiable private information or identifiable specimens are those that can be linked to specific individuals by the investigator(s) either directly or indirectly through coding systems. The RevComRule further defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator. See the Pre2018-ComRule, RevComRule, the G-SpecimensResrch, USA-2, USA-9, and USA-1 for additional information. See also the G-SpecimensResrch for exemptions to this definition.

Additionally, as defined by the HHS’ National Institutes of Health (NIH) in USA-72, research with specimens, cells, cell lines, or data involves human subjects when:

• The specimens, cells, or data must be or must have been obtained from individuals who are alive, and must be or must have been obtained by an investigator conducting research; and
• The investigator either must be obtaining or must have obtained specimens, cells, or data through interaction or intervention with living individuals, or must be obtaining or have obtained individually identifiable private information.

See USA-72 for detailed frequently asked questions (FAQs) on this topic.

Per the Pre2018-ComRule, the RevComRule, and USA-2, prior to collecting, storing, or using a research participant’s biological specimen(s), consent must be obtained from the participant and/or a legal representative(s). See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

The RevComRule requires the informed consent form to provide one (1) of the following statements about any research that involves the collection of identifiable private information or identifiable biospecimens:

• A statement that identifiers might be removed from the identifiable private information or identifiable biospecimens and that, after such removal, the information or biospecimens could be used for future research studies or distributed to another investigator for future research studies without additional informed consent from the subject or the legally authorized representative, if this might be a possibility
• A statement that the subject's information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies
• A statement that the subject's biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will or will not share in this commercial profit
• Whether the research will (if known) or might include whole genome sequencing (i.e., sequencing of a human germline or somatic specimen with the intent to generate the genome or exome sequence of that specimen)

Furthermore, the RevComRule delineates the requirements of broad consent—an alternative consent process—for the storage, maintenance, and secondary research use of private information or identifiable biospecimens. Broad consent requires that the following information be provided to the participant and/or the legal representative(s) or guardian(s):

• Certain basic elements from the normal consent process related to risks, benefits, confidentiality, voluntary statement, commercial profit, contact information, and whole genome sequencing elements
• Types of research that may be conducted
• A description of the information or biospecimens that might be used in future research, whether sharing might occur; and the types of institutions or researchers that might conduct research
• A description of the length of time that the information or biospecimens may be stored, maintained, and used
• A statement that participants will or will not be informed of the details of any specific research studies that might be subsequently conducted
• A statement that research results either will or will not be disclosed to participants
• An explanation of whom to contact for answers to questions about the subject's rights and about storage and use of the subject's identifiable private information or identifiable biospecimens, and whom to contact in the event of a research-related harm.

The RevComRule does allow the use of identifiable information or biospecimens in instances where the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) determines the research could not practicably be carried out without the information in that form. Furthermore, it removes the requirement for the investigator to seek a waiver of informed consent to obtain information or biospecimens to screen, recruit, or determine eligibility of prospective participants. See USA-54 for more information on broad consent and informed consent waivers.

The HHS’ G-StoredData-Tissues and USA-2 recommend that the following be included in informed consent documents for biospecimen collection:

• A clear description of the operation of the biospecimen resource including details such as whether identifiable information will be maintained by the biospecimen resource and/or whether research results will be linked to the biospecimen
• Conditions under which samples and data will be released to recipient investigators
• Procedures for protecting the privacy of human research participants and confidentiality of data
• Specific descriptions of the nature and purpose of the research
• Information about the consequences of DNA typing if human genetic research is anticipated

(See the Required Elements and Participant Rights sections for additional information on informed consent).