Comparison: China and United States
Regulatory Authority
Regulatory Authority
Scope of Assessment
Regulatory Fees
Ethics Committee
Ethics Committee
Scope of Review
Ethics Committee Fees
Authorizing Body
Clinical Trial Lifecycle
Submission Process
Submission Content
Timeline of Review
Trial Initiation
Safety Reporting
Progress Reporting
Sponsorship
Definition of Sponsor
Trial Authorization
Insurance
Compensation
Quality, Data & Records Management
Site/Investigator Selection
Informed Consent
Documentation Requirements
Required Elements
Compensation Disclosure
Participant Rights
Special Circumstances/Emergencies
Vulnerable Populations
Children/Minors
Pregnant Women, Fetuses & Neonates
Prisoners
Mentally Impaired
Investigational Products
Definition of Investigational Product
Manufacturing & Import
IMP/IND Quality Requirements
Labeling & Packaging
Product Management
Specimens
Definition of Specimen
Specimen Import & Export
Consent for Specimen
Sources
Requirements
Additional Resources
Forms
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China
United States
QUICK FACTS
Standard Chinese (overseas trial data also in original language) Clinical trial application language English
Yes Regulatory authority & ethics committee review may be conducted at the same time Yes
Yes Clinical trial registration required Yes
Yes In-country sponsor presence/representation required No
Unspecified Age of minors Determined at the State Level
Yes, in collaboration with Chinese research institutions Specimens export allowed Yes
Regulatory Authority > Regulatory Authority
Last content review/update: October 28, 2021

Overview

National Medical Products Administration

As per the DRR, the NMPA-Org, the DAL, the RegImplemDAL, the RegImplemDAL-Amndt, the SC-Opinions-No44, the NMPA-No50-2018, and the NMPA-No230-2015, the National Medical Products Administration (NMPA) (the Chinese name translates as “State Drug Administration”) 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 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. See CHN-61 for contact and logistical information for NMPA’s administrative service hall.

Ministry of Science and Technology

The Bioscrty-Law and the MgmtHumanGen delineate that the Ministry of Science and Technology (MOST) is responsible for China's management of human genetic resources (HGR). 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 departments of the State Council 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.

The MgmtHumanGen stipulates 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 committee’s work involves collecting and preserving Chinese HGR, as well as license applications for the transportation, mailing, and carrying of HGR in China. MOST is also charged with strengthening the construction of e-government and facilitating the use of the internet for applicants; for example, see CHN-76. In addition, MOST is authorized to develop and strengthen examination and approval guidelines and model texts on the collection, preservation, utilization, and external provision of HGR in China. The administrative departments for science and technology in the provinces, autonomous regions, and municipalities directly under the Central Government are responsible for managing HGR in that administrative region. All levels of government are responsible for strengthening supervision and inspecting all aspects of the collection, preservation, utilization, and provision of HGR activities.

Per the Bioscrty-Law, the following HGR activities must be authorized by MOST:

  • Collecting HGR of China’s important genetic families
  • Preserving Chinese HGR
  • Using Chinese HGR to carry out international scientific research cooperation
  • Delivering, mailing, and exporting Chinese 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 security review and provide or open to use information on HGR 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

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

The following is the NMPA’s contact information:

National Medical Products Administration
No. 1 Beiluyuan, Zhanhan Road
Xicheng District
Beijing 100037
P.R. China
Phone: 68311166

The following is MOST’s contact information:

Ministry of Science and Technology
Office address:
Guoyi Hotel (transitional office)
No. 1 Wenxing East Street
Xicheng District
Beijing
P.R. China

Postal address:
No 15. Fuxing Road B
Haidian District
Beijing 100862
P.R. China

Chapter II (Articles 10-11) and Chapter VI (Articles 53-57)
Chapter I (Articles 2 and 5-10) and Chapter II
Chapter I (Article 8), Chapter II (Article 16), and Chapter II (Articles 14-16)
39
Chapter I (Articles 1-6), Chapter III (Articles 20-33), and Chapter VIII (Articles 104-107)
9
9
9
9
Articles 1, 2, and 3
Articles 1-4
Chapter V (Articles 29 and 30)
Chapter I (Articles 4-5), Chapter II (Article 11), Chapter IV, and Chapter V (Article 36)
Drug Registration Management Department and Drug Administration Department
Address, NMPA Organizations, and Affiliated Institutions
Last content review/update: January 20, 2021

Overview

As per the FDCAct, 21CFR50, and 21CFR312, the Food & Drug Administration (FDA) is the regulatory authority that regulates clinical investigations of medical products in the United States (US). This profile is specifically focused on the FDA’s role 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 relating to compliance with federally funded or sponsored human subjects research protections, known as the CommonRule, which the Department of Health & Human Services (HHS) implements in subpart A of 45CFR46, are also examined. (See USA-65 for a list of federal agencies that implement the CommonRule). 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.

According to USA-32, the FDA, which is an agency within the HHS, started undergoing a reorganization on March 31, 2019. One of the purposes of the reorganization is to elevate the role of the centers, offices, and field forces. An overview of the new 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, the Office of Good Clinical Practice (OGCP) plays a pivotal role in the FDA’s oversight of good clinical practice and human subject protection issues stemming from clinical research.

The RevisedCommonRule applies to all research initially approved by an ethics committee (EC) on or after January 21, 2019, or to research that had EC review waived or that was determined to be exempt on or after that date. (Per USA-55 and USA-74, the RevisedCommonRule is also known as the “2018 Requirements.”) For 2018 Requirements Decision Charts consistent with the RevisedCommonRule, see USA-74.

The HHS’ Office for Human Research Protections (OHRP) guides the agency’s efforts to safeguard the rights, welfare, and well-being of human research subjects for studies conducted or supported by the HHS. The OHRP also provides oversight to all federal agencies engaged in human subjects research under the CommonRule and the RevisedCommonRule. For more information about the RevisedCommonRule, see USA-66.

Per the RevisedCommonRule, the CommonRule requirements apply to research that, prior to January 21, 2019, was either approved by an EC, had EC review waived, or was determined to be exempt from the CommonRule. Institutions conducting research approved prior to January 21, 2019, may choose to transition to the RevisedCommonRule 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 RevisedCommonRule beginning on that date. For pre-2018 Requirements Decision Charts consistent with the CommonRule, see USA-74.

See USA-54 for additional information regarding compliance with the CommonRule and the RevisedCommonRule.

Application of FDA and Common Rule Requirements

Although the FDA and HHS have endeavored to harmonize their respective human subjects regulations, differences still exist given the agencies’ separate authority and unique statutory mandates. Consequently, the FDA, despite being a part of the HHS, is not a CommonRule agency. Rather, the agency is governed by its own regulations including the earlier referenced FDCAct and 21CFR50. 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.

Contact Information: FDA
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993
Telephone: (888) 463-6332
Email: druginfo@fda.hhs.gov

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

Contact Information: HHS
US Department of Health & Human Services
Hubert H. Humphrey Building
200 Independence Avenue, S.W.
Washington, D.C. 20201
Call Center: (877) 696-6775
HHS Employee Directory: http://directory.psc.gov/employee.htm

Subchapter V, Part A, Sec. 355
Subpart A (312.1), Subpart B (312.20), and Subpart C (312.40)
Subpart A (50.1)
46.101
46.101
Transition Provision
Regulatory Authority > Scope of Assessment
Last content review/update: October 28, 2021

Overview

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) (the Chinese name translates as “State Drug Administration”) 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 DRR stipulates that foreign applicants should designate an enterprise legal person in China to handle relevant drug registration matters.

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 speed up the 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. Following are the 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

The DRR states that a Chinese legal entity must submit the drug registration application for clinical trials of drugs, marketing approval of drugs, re-registration, and other supplementary applications. 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.

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.

Per the VaccineLaw, the NMPA must approve vaccine clinical trials. 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. 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).

With regard to reviewing and approving international cooperative research and export license applications for human genetic resources (HGR), in accordance with the Bioscrty-Law and the MgmtHumanGen, the Ministry of Science and Technology (MOST) is responsible for the entire nation's efforts to manage HGR, comprising genetic material and data. 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

Clinical Trial Review Process

As delineated in the DRR, NMPA is the regulatory authority responsible for national drug registration management, which includes management of clinical trial applications. NMPA’s Center for Drug Evaluation (CDE) is responsible for evaluating drug clinical trial applications, drug marketing authorization applications, supplementary applications, and overseas production drug re-registration applications. 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. As required in the NMPA-No50-2018, if the existing data, numerical data, or supplemental data can support the clinical trial, the applicant can submit the clinical trial application after the communication meeting or following the submission of supplemental data. The applicant may directly submit a clinical trial application without requesting a communication meeting with the CDE if: 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 multi-centered 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.

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, 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 NMPA will conduct the inspections and testing. The drug registration inspection of overseas-produced drugs must be implemented by the port drug inspection agency.

Per the DRR, the DAL, and the NMPA-No50-2018, 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.

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, Submission Content, and Timeline of Review sections. CHN-19 and CHN-43 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-22, CHN-9, and CHN-11 also provide useful information on the NMPA’s overall clinical trial application review and approval process.

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. However, the regulation permits foreign entities with limited use of Chinese HGR 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 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 (CHN-76), which will generate a record number. See the HGR-IntlRecordMgtGuide, the HGR-IntlApprovLicenseGuide, and the HGR-ExprtLicenseGuide for details on the HGR processes and policies. See Submission Process and Submission Content sections and the Specimens topic for additional information on HGR regulatory management.

Regarding multi-center clinical research using HGR in international cooperative clinical trials, the HGR-IntlApprovLicenseGuide and the HGR-IntlRecordMgtGuide indicate that the lead unit can go through the ethical review process to apply for approval. Documentation showing EC approval and a letter of commitment signed and sealed by the lead unit should be submitted to the online platform (CHN-76).

Chapter VI (Articles 53-59)
Chapter I (Article 6), Chapter II (Article 19), and Chapter III (Article 38)
1-2 and 16-18
1-4 and Annexes 1-3
Chapter I (Articles 2-7), Chapter II (Articles 9-10, 13-16), Chapter III (Articles 20-26, 41, 45-49), Chapter VIII (Article 104)
1-3
Chapters 1 and 2
4
1-8, 11-12, and 14
Chapter I (Articles 1-4 and 7-9), Chapter II (Article 11), and Chapter III (Articles 21-22)
1 and 2
Introduction and Regulatory Regime
Table 1
Clinical Trials
NMPA Issues Requirements for Registration Classification and Application Dossiers of Chemical Drugs
Human Genetic Resource Management
Last content review/update: January 20, 2021

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 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 completed 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 set forth in USA-5 and USA-15, the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) coordinate the IND submission review process for drugs and therapeutic biological products respectively. Per the FDCAct, 21CFR312, USA-5, and USA-15, the CDER and CBER review teams will evaluate all initial INDs and, within 30 calendar days of receipt of the original IND, contact the sponsor when a clinical hold is being imposed. A clinical hold is an order the FDA issues to delay or suspend a clinical investigation. If the team 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. An IND automatically goes into effect 30 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 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.

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.

(See the Clinical Trial Lifecycle topic, Submission Content and Trial Initiation subtopics for detailed submission requirements.)

Subchapter V, Part A, Sec. 355
Subpart A (312.1-312.3), Subpart B (312.20-312.23), Subpart C (312.40 and 312.42), and Subpart E (312.85)
Subpart A (50.1)
Subpart A (56.102)
II-IV
VIII
III (C)
Definitions and Policy
I, II, III, V, and VI
Regulatory Authority > Regulatory Fees
Last content review/update: October 28, 2021

Overview

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) (the Chinese name translates as “State Drug Administration”) in accordance with the following requirements. As per the NMPA-No75-2020, NMPA-No53-2015, CHN-63, CHN-64, CHN-65, CHN-66, CHN-67, and CHN-68, the NMPA charges the following drug registration fees to review and approve clinical trials as part of the drug registration process:

  • New drugs made in China: 192,000 Renminbi
  • New drugs made outside China: 376,000 Renminbi
  • Generic drugs made in China: 318,000 Renminbi
  • Generic drugs made outside China: 502,000 Renminbi

As specified in the NMPA-No53-2015, the NMPA-No75-2020, CHN-63, CHN-64, CHN-65, CHN-66, CHN-67, and CHN-68, 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 the NMPA-No53-2015 and the NMPA-No75-2020.

Chapter VI (Article 85)
Annex 1 – Drugs, medical equipment, products registered fees and Annex 2 – Drug Registration Implementation Detail (Trial)
Charges
Charges
Charges
Charges
Charges
Charges
Last content review/update: January 20, 2021

Overview

The Food & Drug Administration (FDA) does not levy a fee to review investigational new drug (IND) 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 (US). The data gathered during the animal studies and human clinical trials of an IND become part of the NDA.

Part C, Subpart 2 (379g and 379h)
Title 1, Prescription Drug User Fee Amendments of 2017
Ethics Committee > Ethics Committee
Last content review/update: October 28, 2021

Overview

As per the RegEthics, the EC-Guide, the NMPA-GCP-No57-2020, the DRR, and the DAL, an ethics committee (EC) must approve a clinical trial application prior to a sponsor initiating a clinical trial. The DRR indicates that the EC review may be submitted in parallel to the regulatory authority review, but the study cannot be initiated until after review and approval by the EC. The NMPA-GCP-No57-2020, the RegEthics, and the EC-Guide also state that the EC must review and approve any protocol amendments prior to those changes being implemented.

As delineated in the RegEthics and interpreted in CHN-41, the National Health Commission (NHC) is responsible for managing ECs nationwide, 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 and CHN-12, China has approved establishing a National Science and Technology Ethics Committee to strengthen the ethics governance system with comprehensive coverage, clear orientation, and orderly coordination.

The provincial, autonomous regional, and municipal health authorities also have ECs set up under their own administration. The Provincial Committee of Medical Ethics Experts assists in promoting the institutionalization and standardization of the ethical review work of human biomedical research across the regions, and guides, inspects, and evaluates the work of institutional ECs engaged in research involving human beings. The local health department at or above the county level is responsible for the supervision and management of the ethical review work of biomedical research involving people in its region. For additional details and analysis of China’s ethics review system and structure, see CHN-45.

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. 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.

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 EC-Guide and the RegEthics, ECs should have at least seven (7) members. 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. However, no strict parameters are required to be followed. In areas where minority ethnic groups reside, the institution should consider including members of those groups on the EC. The EC-Guide and the RegEthics provides 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 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) (the Chinese name translates as “State Drug Administration”).

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 his/her duties.

ECs should not accept any research project applications that are against 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 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. 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.

Chapter II (Articles 19-20)
Chapters I, II, III, IV, V, and VI
Chapter III (Articles 25-26)
Chapter 1 (Articles 1-6), Chapter 2 (Articles 7-13), and Chapter 3 (Articles 17, 21, and 25), Chapter 5 (Articles 40-43)
Chapter I (Article 1), Chapter II (Articles 1-7), and Chapter III (Article 1)
Chapter 1 (Article 3) and Chapter 3 (Articles 12-15)
5 and 13
China’s Ethics Review System and Its Structure
Last content review/update: January 20, 2021

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 CommonRule and the RevisedCommonRule 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 CommonRule to such research. However, the RevisedCommonRule 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. A list of such technologies will be made available by the Department of Health & Human Services (HHS) on a publicly accessible website. See USA-65, USA-66, and USA-54, and the Regulatory Authority topic, Regulatory Authority subtopic for more information on the RevisedCommonRule and agency-specific compliance.

Ethics Committee Composition

As stated in 21CFR56, the CommonRule, and the RevisedCommonRule, 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 such issues 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 law, 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 Informed Consent topic, Vulnerable Populations subtopic for details on vulnerable populations.

At 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 he/she 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 CommonRule, the RevisedCommonRule, 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 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.

See G-IRBProcs for detailed 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 CommonRule, and RevisedCommonRule, 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.

Per 21CFR56 and the CommonRule, the EC must conduct reviews at intervals appropriate to the degree of risk, but not less than once per year.

Per the RevisedCommonRule, the EC must conduct reviews at intervals appropriate to the degree of risk, but not less than once per year, except in the following circumstances:

  • Research eligible for expedited review that involves no more than minimal risk or for minor changes in approved research (unless the reviewer explicitly justifies why continuing review would enhance protection of research participants)
  • Research for which limited EC review is a condition of exemption
  • 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

Refer to the G-RevComRule-FDA for clarification on the impact of the RevisedCommonRule on studies that must also comply with FDA regulations.

See Ethics Committee topic, Scope of Review subtopic for additional details on expedited review and limited EC review. Refer to the CommonRule, the RevisedCommonRule, 21CFR56, the G-IRBProcs, and the G-IRBFAQs for detailed EC procedural requirements.

Federal Assurance Requirement

Per the CommonRule and RevisedCommonRule, institutions engaging in research conducted or supported by a federal department/agency must also obtain an approved assurance that it will comply with the CommonRule or RevisedCommonRule requirements and certify to the federal 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 CommonRule or RevisedCommonRule 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 (CommonRule or RevisedCommonRule) 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 the RevisedCommonRule, 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 RevisedCommonRule. 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.

Per USA-54, institutions with an FWA do not need to change it under the RevisedCommonRule.

Subpart A (312.3), Subpart B (312.23), and Subpart C (312.40)
Subpart A (50.3)
Subpart A (56.101-56.103) and Subpart C (56.108-56.109)
46.101-46.104 and 46.107-46.111
46.101-46.103 and 46.107-46.111
Foreword, Introduction, 1.24, 1.27, 2.6, 3, and 5.11
IV and V
Definitions, Assurance Process
Ethics Committee > Scope of Review
Last content review/update: October 28, 2021

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). The RegEthics specifies that the EC’s review must comply with the provisions of national laws and regulations and respect the participant’s willingness to participate in the research, while observing the principles of benefit, non-harm, and fairness.

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 Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections 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.

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) (the Chinese name translates as “State Drug Administration”) 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.

The EC-Guide and the NMPA-GCP-No57-2020 provide that the EC’s scope of review must include the following (Note: the regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

  • Whether the qualifications and experience of the investigator meet clinical research requirements
  • Whether the research plan meets the required scientific and ethical principles
  • 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’ 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
  • 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
  • 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 the corresponding ethical issues, laws, and regulations are fully considered in the trial plan
  • 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

Per the EC-Guide, the EC will make one (1) of the following decisions:

  • Approval: The EC unconditionally approves an initial review 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.
  • 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 EC-Guide delineates that the EC must give written notice of its decision to the applicant within 10 working days after the review. An approval is valid for no more than 12 months, at which point the EC will conduct a follow-up review. However, the EC may set more frequent follow-up reviews if it finds a higher degree of risk. The review schedule and plan approval date must be documented. 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 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.

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. CHN-45 provides more information on the EC review.

Chapter II (Articles 19-20)
Chapter III (Articles 25-26)
Chapter 1, Chapter 2 (Article 8), Chapter 3 (Articles 18, 20, 22-25, 27-29, and 32), and Chapter 7 (Article 50)
Chapter I (Articles 1-2), Chapter III (Articles 1-4), Chapter IV (Articles 1-2), Chapter V (Articles 1-2), Chapter VII (Articles 3, 5, and 7), and By Laws I
Chapter 1 (Article 3) and Chapter 3 (Article 12)
China’s Ethics Review System: Current Status, Problems, and Responses
Last content review/update: January 20, 2021

Overview

21CFR56, 21CFR312, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs state that the primary scope of information assessed by the 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 CommonRule, and the RevisedCommonRule, 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 Informed Consent topic and the subtopics of Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses, & Neonates; Prisoners; and Mentally Impaired 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.

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.

An EC may review studies that are not performed on-site. For more information, see G-IRBReview.

In the event of multicenter clinical studies, also known as cooperative research studies, which must comply with the RevisedCommonRule, it is required that all federally-funded or sponsored institutions located in the US and engaged in multicenter research use a single EC to review that study for the portion of the study conducted in the US, known as the EC policy. This policy will streamline the EC review process and eliminate duplicative reviews. 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 RevisedCommonRule, 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 G-CoopRes.

Although the regulations do not specify an expiration for EC 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. Per the CommonRule, the EC must conduct reviews at intervals appropriate to the degree of risk, but not less than once per year.

The RevisedCommonRule provides the following exceptions:

  • Research eligible for expedited review (unless the reviewer explicitly justifies why continuing review would enhance protection of research participants)—A list of minimal-risk categories of research published by the Secretary of Department of Health & Human Services, which is evaluated and amended every eight (8) years; an EC may determine, however, that the study involves more than minimal risk
  • Minor changes in previously approved research during the period for which approval is authorized
  • Certain types of exempt research, as long as a limited EC review was conducted (per Section 104 of the RevisedCommonRule): Research that only includes educational tests, surveys, interviews, or observations of public behavior if the information obtained is recorded by the investigator in such a manner that the identity of the human subjects can readily be ascertained, directly or through identifiers linked to the subjects; Research involves benign behavioral interventions and is recorded by the investigator in such a manner that the identity of the human subjects can be readily ascertained; Storage or maintenance for secondary (future) research for which broad consent is required to use private information or identifiable biospecimens; Broad consent for storage and secondary research use of identifiable private information or identifiable biospecimens in lieu of obtaining study-specific informed consent; but note that this exemption does not apply if the investigator includes returning individual research results in the study plan
  • 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

Refer to the G-RevComRule-FDA for clarification on the impact of the RevisedCommonRule on studies that must also comply with FDA regulations.

In addition, per the RevisedCommonRule revisions, 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 104 of the RevisedCommonRule 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 RevisedCommonRule, 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.

See the G-IRBFAQs, the G-OHRP-IRBApprvl, and USA-54 for more information on EC procedures, approval with conditions, example research, expedited review, limited review, and continuing review.

Further, the RevisedCommonRule 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.

Due to varying institutional EC schedules, specific timeline review schedules are not available.

Subpart A (312.3) and Subpart B (312.20 and 312.23)
Subpart A (56.102 and 56.103) and Subpart C (56.108, 56.109, 56.111, and 56.114)
46.101, 46.102, 46.104, 46.107, 46.109-6.111, and 46.114
46.101, 46.102, 46.107, 46.109-46.111, and 46.114
Foreword, 1.27, 2, and 3
III (F)
IV and V
Definitions, Exemptions, IRB Review
Ethics Committee > Ethics Committee Fees
Last content review/update: October 28, 2021

Overview

No relevant provisions are currently available that provide ethics committee fee information.

Last content review/update: January 20, 2021

Overview

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.

Ethics Committee > Authorizing Body
Last content review/update: October 28, 2021

Overview

Per the NMPA-NHC-No101-2019, the National Medical Products Administration (NMPA) (the Chinese name translates as “State Drug Administration”) 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. The RegEthics states that all biomedical research institutions in China should establish their own ethics committee(s) (ECs). Per SC-Opinions-No42, 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.

As delineated in the RegEthics, the National Committee of Medical Ethics Experts provides policy and guidance that must be followed by ECs nationwide. With respect to supervision and management of ECs, the RegEthics delineates that the National Health Commission (NHC) is responsible for organizing the inspection and management of the national ethical review of biomedical research involving human beings, and the establishment of the National Committee of Medical Ethics Experts. The National Committee of Medical Ethics Experts is responsible for conducting research on major ethical issues in biomedical research involving humans, providing policy advice and guiding provincial medical ethics.

The provincial health administrative departments established a Provincial Medical Ethics Expert Committee. 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. For additional information about supervision and management of ECs, including inspections, see the RegEthics.

Chapter 1 (Articles 5 and 6), Chapter 2 (Article 7), and Chapter V
Last content review/update: January 20, 2021

Overview

As delineated in 21CFR56 and 45CFR46-B-E, the Food & Drug Administration (FDA) and the Department of Health & Human Services (HHS) 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).

In addition, per the CommonRule, the RevisedCommonRule, and the G-HHS-Inst-Engagemt, any institution engaged in non-exempt human subjects research conducted or supported by any federal department or agency must also submit a written assurance of compliance to HHS 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.

Per the RevisedCommonRule, which took effect January 21, 2019, 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 RevisedCommonRule. 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.

Registration, Auditing, and Accreditation

Food and Drug Administration Registration

According to 21CFR56 and the G-IRBReg-FAQs, 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 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 IND. The HHS OHRP system (USA-28) provides instructions to assist users, depending on whether the EC is subject to regulation by only OHRP, only FDA, or both OHRP and FDA.

FDA EC registration must be renewed every three (3) years. EC registration becomes effective after review and acceptance by HHS. If an EC lacks the ability to register electronically, it must send its registration information in writing to:

Office of Good Clinical Practice
Office of Special Medical Programs
Food and Drug Administration
10903 New Hampshire Ave.
Bldg. 32, Rm. 5129
Silver Spring, MD 20993

See 21CFR56 and the G-IRBReg-FAQs for detailed EC registration submission requirements.

Health and Human Services Registration

Per 45CFR46-B-E, USA-61, and USA-58, 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.

As delineated in 45CFR46-B-E, USA-56, and USA-61, an EC must be registered in the HHS OHRP system (USA-28), before it can be designated under an OHRP FWA. 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 OHRP. The FWA is the only type of assurance of compliance accepted and approved by OHRP.

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

See the G-IRBInspect for FDA inspection procedures of ECs.

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.

Subchapter V, Part A, Sec. 355
Subpart B (56.106)
46.103 and 46.104
46.103
Subpart E (46.501-505)
I and II
III
Filing a New Registration for an Institutional Review Board (IRB) by an Institution or Organization (IORG)
Clinical Trial Lifecycle > Submission Process
Last content review/update: October 28, 2021

Overview

As per the DRR, the National Medical Products Administration (NMPA) (the Chinese name translates as “State Drug Administration”) 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. NMPA’s Center for Drug Evaluation (CDE) is responsible for the evaluation of clinical trial applications. 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. Each EC has its own required submission procedures, which can differ significantly regarding the application format and number of copies. CHN-9 offers an analysis and overview of the NMPA application submission process and reforms.

As per the NMPA-No50-2018, the applicant should comply with the following review and approval procedures for clinical trials. (More detail on the contents and timing are provided in the Submission Content and Timeline of Review sections). The applicant should prepare materials and apply for a communication meeting with the NMPA’s 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), which must be submitted to the CDE via its Applicant Window at CHN-58. 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. 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.)

Per the DRR, after completing the pharmacology, toxicology, and other studies supporting the clinical trials of the drug, the applicant must submit relevant research materials to the NMPA. Drug registrations and associated clinical trial application forms should be sent to NMPA’s Administrative Acceptance Service Hall (CHN-71 and CHN-61). Following administrative acceptance, clinical trial consultations and data submittals are handled at the CDE’s Applicant’s Window (CHN-58). The DRR clarifies that it regulates only clinical trials conducted for drugs seeking market approvals in China, which may include Phase I, II, III, IV, and bioequivalence studies. As delineated in the DRR, the NMPA-No51-2016, and the SC-Opinions-No44, the drug classification determines the drug and clinical trial registration pathway. (See the Scope of Review section for information on the drug classifications.) If a sponsor intends to carry out a bioequivalence test, he/she must carry out relevant research work in accordance with the filing plan after completing the filing of the bioequivalence test on the CDE’s website via CHN-58. See CHN-63, CHN-64, CHN-65, CHN-66, CHN-67, CHN-68, CHN-70, and CHN-69 for 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. The receiving personnel at the Administrative Acceptance Service Hall examine the application materials to verify that they comply with the administrative requirements. If the application is rejected, the applicant will be notified in person or within five (5) days of what must be corrected. Per the DRR, the DAL, and the NMPA-No50-2018, the CDE must decide upon a drug clinical trial application within 60 days from the date of acceptance, and the applicant must be notified of the result by the CDE via CHN-58. If the notification is not given within the time limit, approval is implied and the applicant may develop the drug according to the submitted plan. The DRR specifies that applicants who are approved to conduct clinical trials are clinical trial sponsors (hereinafter referred to as sponsors). Clinical trials must be implemented within three (3) years after approval. If no participant has signed an informed consent within three (3) years from the date of approval, the clinical trial license will automatically become invalid.

In addition, 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. Pursuant to NMPA-No230-2015, if one (1) of the prescribed conditions are met, a separate queue will be implemented to speed up the examination and approval. The conditions are: innovative drugs with a plan to transfer their manufacturing site to China; global Clinical Trial Application (CTA) applied in China in parallel with the United States or the European Union; innovative drugs for HIV/AIDS, viral hepatitis, rare disease(s), malignant tumors and pediatric indications; and newly-launched generic drugs. Further, the NMPA-No82-2020 states that 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 as 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. In addition, 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.

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. (See Timeline of Review section for additional details on expedited review.)

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. However, the regulation permits foreign entities with limited use of Chinese HGR 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 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 simply 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. The following service guides detail the processes in even greater specificity:

  • HGR-Collection covers license application procedures for collecting Chinese HGR in China
  • HGR-DataUse covers filing procedures to transfer HGR data to foreign organizations
  • HGR-Preservation covers license application procedures for preserving Chinese HGR in China in suitable environmental conditions to ensure its quality and safety for future scientific research activities
  • HGR-ImpFamilies-DeclReg covers procedures for declaring and registering activities for the use of HGR from important genetic families and in specific areas of China
  • HGR-IntlApprovLicenseGuide covers license application procedures for international cooperation in the use of Chinese HGR for research
  • HGR-ExprtLicenseGuide covers license application procedures for international cooperation in exporting Chinese HGR for research (See the Specimens topic for more information on applying for an export license for HGR)
  • HGR-IntlRecordMgtGuide covers filing procedures for clinical institutions to obtain authorization to use HGR in international cooperative clinical trials in China

As specified in the HGR-Collection, only a Chinese entity may apply for and hold a MOST license for the actual collection of Chinese HGR. See the HGR-Procedures and the HGR-Collection for details on submittal and review procedures.

Per the HGR-Procedures and the HGR-IntlApprovLicenseGuide, the following is the submission process for MOST’s review and approval of HGR international cooperative research. The applicant submits an electronic version of the application materials to the online platform (CHN-76). MOST will complete the pre-examination within five (5) working days after receiving the electronic version of the application materials. 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 will not be passed, and the applicant will be notified of the contents that need to be corrected through the online platform. For applicants that pass the pre-examination, they must print out the online, pre-accepted electronic application materials on A4 paper. The cover and signature stamp page should be printed single-sided and the rest of the document should be double-sided. There should be one (1) copy with plastic binding. Attachments should be bound to the application. After receiving and formally accepting a complete package of the paper application materials submitted by the applicant, MOST will conduct a formal examination within five (5) working days. MOST’s experts will conduct a technical review of the accepted application and develop an expert review opinion. MOST will publish the results on its 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.

With regard to the record-filing procedure (i.e., notification) for an international clinical trial using HGR that will not leave the country, the HGR-Procedures and the HGR-IntlRecordMgtGuide specify that the applicant should submit the required materials to MOST through CHN-76. Following the submission and after the applicant receives the record number, the international cooperative clinical trial can begin. A legal entity established in accordance with Chinese law must handle the filing formalities. Documentation showing EC approval and a letter of commitment signed and sealed by the Chinese applicant should be submitted. MOST will publicly announce its decision, which will include the applicant’s record number. In the course of 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.

Delivery Information for Clinical Trial Application

Per CHN-61, drug registrations and associated clinical trial application forms should be sent to NMPA’s Administrative Acceptance Service Hall (CHN-71 and CHN-61). Per the DRR, clinical trial research materials should be submitted to the CDE via CHN-58. (Note that only Chinese legal persons can register for an account on CHN-58.)

NMPA Administrative Acceptance Service Center
1st Floor, Gate 3, Dacheng Plaza
28 Xuanwumen West Street
Xicheng District
Beijing 100053
P.R. China
Phone: +86-010-88331793 (drug acceptance); +86-010-88331734 (consultation of drug matters)
Email:
xzslfwdt@nmpa.gov.cn

Per the HGR-Collection, HGR-IntlApprovLicenseGuide, HGR-Preservation, and the HGR-ExprtLicenseGuide, the following is 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

Assembly and Number of Copies

The NMPA-No44-2020, the NMPA-No43-2020, and the NMPA-No10-2018 require applicants to apply the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M4: Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD) (CHN-38). M4 must be applied to the registration applications for drugs, therapeutic biological products, and vaccines. Further, per the NMPA-No16-2018, Phase I clinical trial applications must be submitted in electronic and hard copy formats and may be provided on a compact disc (CD). 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).

Per the NMPA-No194-2017, the applicant must submit four (4) copies of the chemical and biologic clinical trial applications, with at least one (1) original. Application materials for domestic and foreign applicants within the different registration categories are provided in CHN-63, CHN-64, CHN-65, CHN-66, CHN-67, CHN-68, CHN-70, and CHN-69.

See the HGR-IntlApprovLicenseGuide, the HGR-ExprtLicenseGuide, and the HGR-Procedures for assembly and number of copies information related to HGR licenses.

Clinical Trial Application Language Requirements

Per NMPA-No194-2017, drug registration and clinical trial application materials must be in Chinese. Foreign language materials should be translated into Chinese. For foreign language materials with translations, the translation should be first and the original text should follow. The applicant is responsible for the accuracy of the translation.

Chapter VI (Articles 53-57)
Chapter II (Articles 19-20)
Chapter I (Article 8), Chapter II (Article 16)
Introduction, Sections 1-3, and Annex 1 (Communication meeting application form), Annex 2 (Communication meeting materials), and Annex 3 (Phase I clinical trial application materials)
Chapter I (Articles 1-5), Chapter II (Article 13), Chapter III (Articles 20-26 and 32), and Chapter IV (59-75), and Chapter VII (Article 96)
Annexes 1 - 8
1 and 8-11
1 and 8-11
2-3
1-3
1 and 8-11
1 and 8-11
5 and Annex 1
Chapters 2 and 3, and Appendices 1 and 2
Annexes 1-3
1-8, 11-12, and 14
1 and 3-5
Chapter I (Articles 4-5), Chapter II (Article 11), Chapter IV, and Chapter V (Article 36)
1
Chapter 3 (Article 12)
Part One (2) and Part Two (2)
3
Annex
1
Human Genetic Resource Management
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Last content review/update: January 20, 2021

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 Regulatory Authority topic, Scope of Assessment subtopic 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.

Delivery Information for Clinical Trial Application

According to USA-53 and USA-41, paper submissions of INDs should be sent to the following locations:

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 Products:
U.S. 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

Assembly and Number of Copies

Currently, IND submissions may be submitted in either paper or electronic format.

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.

According to the G-PharmeCTD, which implements section 745A(a) of the FDCAct, and as described in USA-34, commercial IND submissions must be submitted in the Electronic Common Technical Document (eCTD) format. Noncommercial INDs are exempt from this 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). For more information, and detailed requirements, see the G-PharmeCTD and G-eCTDTech. 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 10GB and under for most applications must be submitted via the FDA Electronic Submissions Gateway (USA-44). See USA-8 for information on how to create an account.

As indicated in the G-eCTDspecs, physical media should comply with the following requirements:

  • For submissions between 10 and 45GB - use a CD-ROM (CD-R) or DVD (DVD-R, DVD+R, DVD+/-R)
  • For submissions greater than 45GB - use a USB drive (Note: email CDER (esub@fda.hhs.gov) or CBER (esubprep@fda.hhs.gov) for specific instructions on how to send

See the G-eCTDspecs for additional physical media information.

Clinical Trial Application Language Requirements

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.

Subchapter V, Part A, Sec. 355 (a and b) and Subchapter VII, Part D, Sec. 379k-1
Subpart A (312.1 - 312.3), Subpart B (312.20 - 312.23), and Subpart C (312.40)
Subpart A (56.102)
II-IV
I, II, and III (A, B, C, K, L, and M)
II and IV
I and II
Clinical Trial Lifecycle > Submission Content
Last content review/update: October 28, 2021

Overview

In accordance with DRR and the DAL, the sponsor must apply to the National Medical Products Administration (NMPA) (the Chinese name translates as “State Drug Administration”) and an ethics committee (EC) to conduct a clinical trial for all drugs that will be registered in China. As stated in the DRR, EC review may be submitted parallel to the NMPA’s review, but the study cannot be initiated until after review and approval by the EC. The DRR also 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.

See CHN-20 and CHN-9 for additional analyses and overview of the China clinical trial application submission content.

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 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-63, CHN-64, CHN-65, CHN-66, CHN-67, CHN-68, 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 exactly 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

Pursuant to the SC-Opinions-No42, the NMPA announced in the NMPA-No10-2018 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). M4 must be applied to the registration applications for drugs, therapeutic biological products, and vaccines.

The NMPA-No35-2017 and interpretations in CHN-43 adjust 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. 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 for the NMPA-No52-2018 requirements for clinical trial and drug registration applications of imported new drugs or therapeutic biological products using trial data generated entirely overseas, they 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—a requirement that typically delayed projects by several years. Overseas clinical trial data is acceptable for direct China registration provided that:

  • The data is reliable, authenticated, and complies with the requirements of the 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 approval of these drug registrations exempted from conducting 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

With regard to reviewing and approving human genetic resources (HGR) licenses, and in accordance with the Bioscrty-Law and the MgmtHumanGen, the Ministry of Science and Technology (MOST) is responsible for China’s efforts to manage HGR, comprising genetic material and data. MOST’s online platform (CHN-76) provides links to procedures, requirements, and online submissions. The HGR-Procedures and CHN-56 summarize the license and application contents.

The following service guides detail the submission content in greater specificity and include the templates:

  • HGR-Collection covers license application procedures for collecting Chinese HGR in China and requires legal person qualification materials, ethics review approval, informed consent form (ICF), collection plan, HGR management system, and a cooperation agreement
  • HGR-DataUse covers filing procedures to transfer HGR data to foreign organizations and requires the record information form, legal person qualification with electronic signature, and cooperative scientific research approval
  • HGR-Preservation covers license application procedures for preserving Chinese HGR and requires legal person qualification, ICF, ethics review approval, preservation plan and management system, and preservation of technical documents
  • HGR-ImpFamilies-DeclReg covers content requirements for declaring and registering activities for the use of HGR from important genetic families and in specific areas of China
  • HGR-IntlApprovLicenseGuide covers license application procedures for international cooperation in the use of Chinese HGR for research and requires legal person qualification; two (2) letters of commitment (provided by participating medical institutions); research proposal text; ethics review approval; ICF; international cooperative agreement text; agreements involving the collection, transportation, testing, and destruction of HGR; clinical trial approval documents, notices, or filing announcement materials; and past administrative approval of the project
  • HGR-ExprtLicenseGuide covers license application procedures for international cooperation in exporting Chinese HGR for research and requires legal person qualification, ethics review approval, and the ICF
  • HGR-IntlRecordMgtGuide covers filing procedures for clinical institutions to obtain authorization to use HGR in international cooperative clinical trials in China; it requires legal person qualification, list of other participating clinical institutions, ICF, ethics review approval, the research plan, the international cooperative 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)

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

Ethics Committee Requirements

Each 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 RegEthics and the EC-Guide to exemplify the common elements shared by the various application forms (Note: the regulations 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
  • 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
  • Other relevant materials that the EC believes need to be submitted

Clinical Protocol

As delineated in the NMPA-GCP-No57-2020 and CHN-37, the clinical protocol should include the following elements (Note: the regulations 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 VI of the NMPA-GCP-No57-2020 and Section 6 of CHN-37.

Chapter VI (Articles 53-57)
Chapter II (Articles 19-20)
Chapter I (Article 5), Chapter II (Articles 9-10), Chapter III (Articles 20-26)
1, 7-8, and Annex 1
1, 7-8, and Annex 1
3 and Annexes 1-2
3 and Annex 1
1, 7-8, Annex 1
1, 7-8, and Annex 1
Annex 1
Chapter 3 (Article 19)
1 and 3-5
Chapter I (Articles 1-4 and 7-9)
Chapter VI (Article 2)
Chapter 6
Annex
1
6
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Last content review/update: January 20, 2021

Overview

As set forth 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 agency exemption to ship investigational drugs and biological products across state lines and to administer these investigational products (IPs) in humans. See the Regulatory Authority topic, Scope of Assessment subtopic for more information.

In addition, per 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the US) approval of the proposed clinical trial is required prior the sponsor being permitted to initiate the study.

According to G-PedStudyPlans, a sponsor who is planning to submit 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 G-PedStudyPlans.

FDA IND Requirements

As specified in 21CFR312, the IND 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, IP name, application date, phase(s) of clinical investigation to be conducted, and commitment that the EC will conduct initial and continuing review and approval of each study proposed in the investigation) (See USA-40)
  • 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 investigational drug
  • Additional information
  • Relevant information (e.g., foreign language materials and number of copies - see Submission Process subtopic for details)

For detailed application requirements, see 21CFR312.

Furthermore, 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.

EC Requirements

Each EC has its own application form and clearance requirements, which can differ significantly regarding the number of copies supplied and application format 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 CommonRule, the RevisedCommonRule, 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:

  • Clinical protocol
  • Informed consent forms (ICFs) and participant information, (the RevisedCommonRule 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 to protect participant privacy and maintain confidentiality of data are made, 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 RevisedCommonRule, which took effect January 21, 2019, 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 21CFR56, the CommonRule, the RevisedCommonRule, and section 3 of the US-ICH-GCPs for additional EC submission requirements.

Clinical Protocol

  • 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 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.

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.

Subpart A (312.1-312.3), Subpart B (312.20-312.23), and Subpart C (312.40 and 312.42)
Subpart A (56.102 and 56.103) and Subpart C (56.111)
46.104, 46.109, and 46.111
46.109, and 46.111
VIII
3 and 6
Sections I and III
Clinical Trial e-Protocol Tool and Template Documents
Form FDA 1571
Clinical Trial Lifecycle > Timeline of Review
Last content review/update: October 28, 2021

Overview

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

Regulatory Authority Approval

National Medical Products Administration

As described below, China has adopted reforms to speed up the clinical trial review and approval processes within the Center for Drug Evaluation (CDE) and the National Institutes for Food and Drug Control (NIFDC). The CDE conducts technical reviews and the NIFDC tests drug samples. According to CHN-17, the likely time period for regulatory approval of clinical trial applications is now shortened from 265 days to 65 days, with the average review timeline at approximately 40 workdays.

The NMPA-No50-2018 and the NMPA-No48-2020 specify that 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. The NMPA-No48-2020 describes deadlines and procedures and indicates that the applicant must include the meeting materials in the application. 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 NMPA. Drug registrations and associated clinical trial application forms should be sent to the NMPA’s Administrative Acceptance Service Hall (CHN-71 and CHN-61). Following administrative acceptance, clinical trial consultations and data submittals are handled at the CDE’s Applicant’s Window (CHN-58). 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. Per the DRR, the NMPA-No50-2018, CHN-63, CHN-64, CHN-65, CHN-66, CHN-67, and CHN-68, 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 time to conduct the following actions 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
  • Where overseas verification is initiated, the time taken by this activity

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. The timelines for review and decisions 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, 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 application materials. For applications to conduct clinical trials with drugs treating rare diseases, the CDE completes the technical review within three (3) months after acceptance; for other overseas new drugs, the technical review is completed within six (6) months after acceptance. The NMPA-No23-2018 states that for drugs that have been listed overseas and 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.

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.

In another reform directed at streamlining the review process, per the NMPA-No230-2015, the NMPA adopted a one-time approval for clinical trial applications of new drugs. For additional details, see the Scope of Assessment section. In addition, for generic drugs, the 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.

Ethics Committee Approval

In accordance with the NMPA-GCP-No57-2020, an applicant must also submit the clinical trial application for review and approval by an institutional EC. 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. The EC-Guide delineates that the EC must give written notice of its decision to the applicant within 10 working days after the review.

1-4 and Annexes 1-3
Chapter II (Article 13), Chapter III (Articles 23 and 25-26), Chapter IV (Articles 59-75) and Chapter VII (Articles 94-96, and 103)
Chapters 1-3
1-8, 11-12, and 14
Chapter VII (Article 7)
Chapter 3 (Articles 12 and 13)
3.1.2
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information, Process, and Application Materials
Basic Information and Process
Basic Information, Process, and Application Materials
Last content review/update: January 20, 2021

Overview

As delineated in 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) review of 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.

FDA IND Review and Authorization

Per the FDCAct, 21CFR312, USA-5, and USA-15, the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) review teams will evaluate all initial INDs for drugs and therapeutic biological products respectively. Within 30 calendar days of receipt of the original IND, the CDER/CBER team will contact the sponsor when a clinical hold is being imposed. A clinical hold is an order the FDA issues to delay or suspend a clinical investigation. If the team 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. An IND automatically goes into effect in 30 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.

According to USA-41, with respect to sponsor-investigators, once the FDA receives the IND application, 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/sponsor-investigator providing notification of the assigned IND number, date of receipt of the original application, address where future submissions to the IND application should be sent, and the name and telephone number of the FDA person to whom questions about the application should be directed. Clinical studies shall not be initiated until 30 days after the date of receipt of the IND application by the FDA unless earlier notification is received from the FDA 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.

Subchapter V, Part A, Sec. 355
Subpart A (312.1-312.3), Subpart B (312.20-312.23), Subpart C (312.40 and 312.42), and Subpart E (312.85)
Subpart A (56.102)
3.1.2
Definitions and Policy
I, II, III, V, and VI
Clinical Trial Lifecycle > Trial Initiation
Last content review/update: October 28, 2021

Overview

In accordance with the NMPA-GCP-No57-2020, the DRR, the DAL, the RegEthics, and the EC-Guide, the sponsor must apply to the National Medical Products Administration (NMPA) (the Chinese name translates as “State Drug Administration”) and an ethics committee (EC) to conduct a clinical trial for all drugs to be registered in China. As stated in the DRR, EC review may be submitted parallel to NMPA review, but the study cannot be initiated until after review and approval by the EC. Clinical trial applications are also considered drug registration applications. The DRR states that a Chinese legal entity must submit the drug registration application. Overseas drug manufacturers without legal representation in China must apply for drug registration through Chinese legal persons who will handle relevant drug registration matters.

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, investigator's brochure, 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 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. 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. 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.

As delineated in MgmtHumanGen, an international clinical trial using human genetic resources (HGR) in country must be filed with the Ministry of Science and Technology (MOST) before it begins. MOST must also review and approve collections of HGR of important genetic families and specific areas in China or HGR as specified by MOST and international cooperative scientific research before a trial begins. See Clinical Trial Lifecycle and Specimens topics for more information.

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. As stated in the NMPA-GCP-No57-2020 and CHN-37, all investigators must possess appropriate qualifications, training, and experience.

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

Ethics Committee Confirmation of Review and Approval

The NMPA-GCP-No57-2020 mandates that the sponsor receive written confirmation of EC review and approval of the protocol prior to the trial’s commencement. The EC-Guide stipulates that research can start or continue immediately after the EC’s approval. (See Scope of Review and Submission Content sections for additional details on the EC review process).

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 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

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.

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.

Chapter II (Articles 19-20)
Annex 3
Chapter II (Articles 9 and 10) and Chapter III (Articles 25-26, and 33)
Chapter 8 (Article 119)
Chapters 1 and 2
Chapters 1 and 2
Chapter V (Article 36)
Chapter I (Article 1), Chapter IV (Article 5), Chapter VI (Article 2), and Chapter VII (Article 5)
Chapter 2 (Article 4), Chapter 3 (Article 12), Chapter 4 (Articles 16 and 19), and Chapter 5 (Articles 32, 36, and 38)
1.17, 1.25, 4.1, 5.1.2, 5.5.2, 5.6, and 8.2.6
Last content review/update: January 20, 2021

Overview

In accordance with 21CFR312, 21CFR56, and USA-42, a clinical trial can only commence following the Food & Drug Administration (FDA)’s review of the investigational new drug application (IND) within 30 calendar days of receiving the IND and ethics approval from an institutional ethics committee (EC) (known as institutional review board (IRB) in the United States (US)). No waiting period is required following the 30-day review period unless the FDA imposes a clinical hold on the IND.

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 Investigational Products topic, Manufacturing & Import subtopic for additional information).

Clinical Trial Agreement

As stated in 21CFR312 and the US-ICH-GCPs, all investigators must possess appropriate qualifications, training, and experience. Prior to the trial’s commencement, as addressed in 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 assure that he/she will comply with the FDA’s clinical investigation regulations. Refer to the G-1572FAQs and USA-40 for further information.

Ethics Committee Confirmation of Review and Approval

Per 21CFR56, 21CFR312, the CommonRule, and the RevisedCommonRule, EC review of the clinical investigation must be obtained prior to the sponsor being permitted to initiate the trial.

Clinical Trial Registration

FDAMA, 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 FDAAA, 42CFR11, and USA-26, the sponsor/PI must register 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, USA-26, and USA-49 for detailed information on ClinicalTrials.gov (USA-78). See also the G-DataBankPnlty for clarification on the types of civil money penalties that may be issued for failing to register a clinical trial.

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 additional DSMB/DMC establishment requirements.

The US-ICH-GCPs recommends establishing a 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.

Additionally, as indicated in the CommonRule and the RevisedCommonRule, for all human subjects research funded and/or sponsored by the Department of Health & Human Services (HHS), the institutional EC shall ensure that, when appropriate, the research plan makes adequate provisions for monitoring the data collected during the study to ensure participant safety and privacy. Moreover, per the NIHDataSftyMntrng and USA-72, all 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 HHS/NIH requirements.

Title VIII (Section 801)
113
Subpart A (312.1-312.3), Subpart B (312.20-312.23), Subpart C (312.40), Subpart D (312.53), and Subpart F (312.110)
Subpart B (50.24)
Subpart A (56.102)
Subparts A, B, and C
46.103 and 46.111
46.103 and 46.111
1
1.17, 1.25, 4.1, 5.1.2, 5.5.2, 5.6, and 8.2.6
I (1)
NIH Policy, Purpose, and Scope
Data and Safety Monitoring
Form FDA 1572
Clinical Trial Lifecycle > Safety Reporting
Last content review/update: October 28, 2021

Overview

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.

Reporting Requirements for AE/ADRs

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 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 EC with other required information, such as autopsy reports and final medical reports.

Sponsor Responsibilities

Per the DRR, the sponsor must regularly submit a safety update report to the National Medical Products Administration’s (NMPA) (the Chinese name translates as “State Drug Administration”) Center for Drug Evaluation (CDE) at 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.

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 and 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. The NMPA-No5-2020 provides guidance on evaluating and managing safety issues in accordance with the G-SftyRptStds. It requires sponsors to actively cooperate with clinical trial institutions and other relevant parties to strictly implement the main responsibility of safety risk management. Pharmacovigilance and quality management systems should be established; risk monitoring, identification, assessment and control should be carried out; safety problems and risks should be discovered in time; and necessary risk management measures should be taken proactively, such as adjusting clinical trial plans, and suspending or terminating clinical trials, etc.

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 ethics committees (EC). 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.

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 NMPA’s CDE in Chinese (CHN-58). Potentially serious security risks can be sent as a “Quick Report” through e-mail to: lcqjywjj@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.

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 full-time staff to monitor clinical trial safety information and manage SAE 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.

The ICH’s Guideline for Good Clinical Practice E6(R2) (CHN-37) recommends establishing a 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.

Biotechnology Safety Monitoring and Reporting

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 departments of the State Council for science and technology (Ministry of 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.

Chapter II (Articles 10-11 and 14) and Chapter IV (Articles 34-40)
Chapter II (Article 22)
16 and Annex 3
Chapter II (Article 28)
Chapter 8
Chapter VI (Article 2) and Chapter IX (Articles 3, 10, 29, and 30)
Chapter 2 (Article 4), Chapter 4 (Article 26), and Chapter 5 (Article 48)
1-17
2
1.25 and 5.5.2
Last content review/update: January 20, 2021

Overview

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 (AE) - Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related
  • Adverse Reaction (AR) - Any AE caused by a drug. ARs 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 (SAE/SSAR) - An AE/SSAR 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
  • Suspected Adverse Reaction (SAR) - Any AE where there is a reasonable possibility that the drug caused the AE
  • Unexpected AE/Unexpected SAR - An AE or SAR 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 AE/SAR is considered “life-threatening” if its occurrence places the participant at immediate risk of death. It does not include an AE/SAR 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) does not define or use the terms “adverse event” or “unanticipated problems.” However, the CommonRule and the RevisedCommonRule do contain requirements relevant to reviewing and reporting these incidents. See the G-HHS-AEReqs, the CommonRule, and the RevisedCommonRule for further information.

Reporting Requirements for AEs/ARs

Investigator Responsibilities

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

  • SAEs, whether or not considered drug related, must be reported immediately to the sponsor
  • Study endpoints that are SAEs 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 AEs must be recorded and reported to the sponsor according to the protocol specified timetable
  • Report promptly to the institutional ethics committee (EC) (institutional review boards (IRBs) in the US) all unanticipated problems involving risk to human participants or others where AEs should be considered unanticipated problems

Sponsor Responsibilities

As delineated in 21CFR312, the G-IND-Safety, and USA-38, the sponsor must report any SAR/AR that is both serious and unexpected. An AE must only be reported as a SAR if there is evidence to suggest a causal relationship between the drug and the AE.

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 he/she determines the information qualifies for reporting. Additionally, the sponsor must notify the FDA of any unexpected fatal or life-threatening SAR as soon as possible, but no later than seven (7) calendar days following his/her 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 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 an SSAR 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 SAR, and must analyze the significance of the SAR in light of previous, similar reports, or any other relevant information. Please 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 AE/adverse drug reaction (ADR) information. The tables should consist of the following summarized data:

  • All SAEs/serious adverse drug reactions (SADRs)
  • Other AEs/ADRs that exceed a frequency of five (5) percent in any arm of the trial
  • All-cause mortalities

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 AE/ADR reporting requirements.

Form Completion and 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). See USA-38 and USA-48 for additional information.

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 also be submitted to the appropriate review division (Center for Drug Evaluation and Research (CDER)/Center for Biologics Evaluation and Research (CBER)). Additionally, the FDA will accept foreign SARs on a CIOMS Form I (See USA-13 and USA-3) instead of Form FDA 3500A (USA-75) (See USA-48 for additional details).

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 additional DSMB/DMC establishment requirements.

The US-ICH-GCPs recommends establishing a 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.

Additionally, as indicated in the CommonRule and the RevisedCommonRule, for HHS funded or sponsored human subjects research, the institutional EC shall ensure that, when appropriate, the research plan makes adequate provision 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 specifically required for NIH-funded, multi-site clinical trials with interventions that involve potential participant risk. See the NIHDataSftyMntrng and USA-72 for detailed HHS/NIH requirements.

Subpart B (312.32) and Subpart D (312.64 and 312.66)
Subpart B (50.24)
Subparts A (11.10) and Subpart C (11.44 and 11.48)
46.108, 46.109, 46.111, and 46.113
46.103, 46.109, 46.111, and 46.113
1
III-VIII and Appendix B
1.25 and 5.5.2
Regulatory Background and Guidance (I and II)
Data and Safety Monitoring
Form 3500A and Form 1571
Form FDA 3500A - Mandatory Reporting and Instructions for Completing Form FDA 3500A
Results Information
Clinical Trial Lifecycle > Progress Reporting
Last content review/update: October 28, 2021

Overview

Per the NMPA-GCP-No57-2020, investigators must provide clinical trial progress reports.

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 in writing to the sponsor, the EC, and the clinical trial institution as soon as possible. Per the DRR and the NMPA-No65-2021, during the clinical trial, the sponsor must conduct an annual review and evaluation of the drug-related safety information. This annual safety update report should be submitted within two (2) months after the full year following approval of the drug clinical trial. The DRR clarifies that the Center for Drug Evaluation (CDE) may require the sponsor to adjust the reporting cycle based on the situation. Additional guidance on the safety update report is provided in the NMPA-No7-2020 and the NMPA-No65-2021.

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.

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).

Chapter III (Article 28 and 33)
Chapter 8 (Article 129)
Chapter 4 (Article 28)
4.10 and 4.13
Last content review/update: January 20, 2021

Overview

In accordance with 21CFR312 and the US-ICH-GCPs, the investigator and the sponsor share responsibility for submitting progress reports on the status of a clinical trial and for submitting final study reports upon the trial’s completion.

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 (IND) went into effect. The report must contain the following information for each study:

  • Title, purpose, 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, USA-70, and USA-49, the sponsor or the principal investigator (PI) designated by the sponsor must submit results for applicable investigational product (IP) clinical trials to ClinicalTrials.gov (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 ClinicalTrials.gov (USA-78) that either: 1) the FDA has not yet approved, licensed, or cleared for marketing the IP being studied; 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 42CFR11 for more detailed requirements. See NIHTrialInfo for specific information on dissemination of NIH-funded clinical trial data.

Subpart B (312.33) and Subpart D (312.64 and 312.66)
Subpart A (56.108)
Subpart C
4.10 and 4.13
NIH Policy and Purpose
Results Information and Updates and Other Required Information
Sponsorship > Definition of Sponsor
Last content review/update: October 28, 2021

Overview

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 marketing license,” 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 marketing license is fully responsible for the quality of the drug used in a clinical trial. When the holder of the license is an overseas entity, their designated legal person in China must fulfill the same obligations as the holder of the drug marketing license and bear joint and several liability with the holder of the drug marketing license.

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 processors must take necessary measures to 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. In addition, 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. See CHN-25 for additional details about data protection legislation in China. For specific details on information technology standards to secure clinical research data, see DataScrty-Stds. In addition, see the Quality, Data & Records Management section for more information on the sponsor’s responsibilities with respect to personal information protection requirements.

Chapter 1 (Articles 2, 3, and 6)
Chapter III (Articles 30, 38, and 40)
Chapter I (Articles 7 and 9) and Chapter VIII (Article 73)
Chapter II (Article 9) and Chapter III (Articles 23 and 29)
11.3
Chapter 2 (Article 7) and Chapter 5 (Article 33)
Are any legislative changes proposed or expected in the near future?
1.53, 1.54, and 5.2
Last content review/update: January 20, 2021

Overview

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. The term does not include any person other than an individual.

In addition, 21CFR312 and the US-ICH-GCPs state that a sponsor may transfer responsibility for any or all of his/her 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 shall 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 shall 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 of his/her trial-related duties and functions to a CRO, he/she is ultimately responsible for the study data’s quality and integrity.

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

Subpart A (312.3), Subpart D (312.52), and Subpart F (312.110)
Subpart A (50.3)
1.53, 1.54, and 5.2
Sponsorship > Trial Authorization
Last content review/update: October 28, 2021

Overview

In accordance with the NMPA-No50-2018, the sponsor or its contract research organization (CRO) is responsible for submitting a clinical trial application to the National Medical Products Administration (NMPA) (the Chinese name translates as “State Drug Administration”) to obtain approval to conduct a study. Per the NMPA-GCP-No57-2020, before the start of a clinical trial, the sponsor must submit relevant clinical trial materials to the NMPA, and obtain the appropriate license for the clinical trial or complete the requisite filing. The sponsor must obtain the following information from the investigator and clinical trial institution: the name and address of the ethics committee (EC), the list of EC members participating in the review, the review statement in compliance with relevant laws and regulations, and the documents approved by the EC. When the sponsor is developing a clinical trial program, it must have sufficient safety and effectiveness data to support its route of administration, dosage, and duration of continuous medication. When important new information is obtained, the sponsor must update the Investigator's Brochure (IB) in a timely manner.

The DRR states that a Chinese legal entity must submit the drug registration application. Overseas drug manufacturers without legal representation in China must apply for drug registration through Chinese legal persons to handle relevant drug registration matters.

Per the DRR, after completing the pharmacology, toxicology, and other studies supporting the clinical trials of the drug, the applicant must submit relevant research materials to the NMPA. Drug registrations and associated clinical trial application forms should be sent to the NMPA’s Administrative Acceptance Service Hall (CHN-71 and CHN-61). Following administrative acceptance, clinical trial consultations and data submittals are handled at the NMPA’s Center for Drug Evaluation (CDE)’s Applicant’s Window (CHN-58). (Note that only Chinese legal persons can register for an account on the Applicant’s Window.) 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. (See Submission Process and Submission Content sections for handling guidelines and content.) The NMPA-No44-2020, the NMPA-No43-2020, and the NMPA-No10-2018 require applicants to apply the (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M4: Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD) (CHN-38). The NMPA-No16-2018 provides additional guidance on technical information to be included in the application dossier for Phase I clinical trials:

  • Introductory description and overall research plan
  • IB
  • Clinical trial plan
  • Pharmacy research information
  • Pharmacology and toxicology information
  • Description of previous clinical use experience
  • Overseas research material

Per the NMPA-No50-2018 and CHN-61, the electronic files and a hard copy of the application must be submitted to the NMPA. The NMPA Administrative Acceptance Service Center provides links to download and submit applications, and to check the status of an application. The NMPA announced in the NMPA-No10-2018 that applicants should apply the ICH’s M4: Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD) (CHN-38). M4 must be applied to the registration applications for drugs, therapeutic biological products, and vaccines. Further, the NMPA-No16-2018 states that the applications of Phase I clinical trials must be submitted in electronic and hard copy formats and may be provided on a compact disc (CD).

In accordance with the DRR and the NMPA-No50-2018, 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. Upon submittal, the CDE 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, then the CDE will notify the applicant, who must submit the additional information within five (5) days of the CDE’s notice. If the applicant has not received any other questions from the CDE within 60 days from the supplementary information submission date, then the clinical trial may be initiated with the revised plan.

Per the VaccineLaw, the sponsor of the vaccine clinical trial must submit a clinical trial plan, establish a clinical trial safety monitoring and evaluation system, carefully select the subjects, reasonably set the subject group and age group, and take effective measures according to the degree of risk to protect the legal rights of the participant. 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 when applying for vaccine clinical trials (e.g., false data).

Additional documentation that must be submitted is covered in the Submission Content section.

16-18
16
Chapter II (Articles 9 and 10), Chapter III (Article 23) and Chapter VII (Articles 94-96)
4
Chapter 5 (Articles 40-43)
Part One (2) and Part Two (2)
3
Annex
1
Last content review/update: January 20, 2021

Overview

In accordance with 21CFR312, USA-42, and USA-52, the sponsor is responsible for submitting an investigational new drug application (IND) for the Food & Drug Administration (FDA)'s review to obtain an exemption to ship investigational drug or biological products across state lines and to administer these investigational products in humans.

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

Per 21CFR312, to complete the IND application package, the sponsor must provide the following information in paper format or electronically:

  • 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 EC will conduct an initial and continuing review and approval of each study proposed in the investigation) (See USA-40)
  • Protocols
  • Chemistry, manufacturing, and control data
  • Pharmacology and toxicology data
  • Previous human experience with the investigational drug

Additional documentation and paper/electronic submission instructions are covered in the Clinical Trial Lifecycle topic, Submission Process and Submission Content subtopics.

Furthermore, 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. The G-CTDiversity also provides recommendations to sponsors for increasing enrollment of underrepresented populations in their clinical trials.

Subpart A (312.1 and 312.3), Subpart B (312.20 and 312.23), and Subpart C (312.40)
Subpart A (56.102 and 56.103)
VIII
Form FDA 1571
Sponsorship > Insurance
Last content review/update: October 28, 2021

Overview

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.

Chapter 5 (Article 39)
Clinical Trials, Insurance
5.8
Last content review/update: January 20, 2021
No relevant provisions
Sponsorship > Compensation
Last content review/update: October 28, 2021

Overview

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. (See Compensation Disclosure section for more information on participant compensation rights).

In addition, the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (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.

Chapter I (Article 2) and Chapter IV (Article 1)
Chapter 5 (Article 39)
4.8 and 5.8
Last content review/update: January 20, 2021

Overview

The United States (US) regulations do not require compensation for trial participants either for participation in a trial or in the event of trial-related injuries or death.

However, as specified in 21CFR50, the CommonRule, the RevisedCommonRule, and US-ICH-GCPs, for research involving more than minimal risk, the sponsor is responsible for providing information as to whether there is compensation to research participants and/or their legal heirs in the event of trial-related injuries. The sponsor must also inform participants who suffer any trial-related injuries of any available medical treatments, what they consist of, and where further information can be obtained.

As per the 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 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 Food & Drug Administration (FDA). Further, 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.

Subpart B (50.20 and 50.25)
46.116
46.116
4.8 and 5.8
Sponsorship > Quality, Data & Records Management
Last content review/update: October 28, 2021

Overview

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, the NMPA-No112-2016, 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. 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) (the Chinese name translates as “State Drug Administration”), 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 is 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 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). 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.

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 guidelines for conduct during clinical trials. See each of these documents, for additional details:

  • The NMPA-No22-2021 describes a research and development model to guide researchers in managing pharmaceutical changes of innovative drugs. As the clinical trial progresses and understanding deepens, the researchers should adapt standards to improve production and quality control.
  • The NMPA-No6-2021 aims to guide sponsors in adopting and implementing an adaptive design to improve the success and quality of the research results. An adaptive design allows the sponsor to make changes to the clinical trial protocol during a mid-term analysis of the initial data.
  • The 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. This guidance offers methods to control the rate of errors or false positive findings.
  • The NMPA-No54-2020 describes the clinical features of new uses of chemical drugs and associated principles of clinical trial design and evaluation.

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.

Data Protection

Per the PIPL, the sponsor (known as the “data processor” in data protection legislation) 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 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.

The PIPL, delineates that sponsors may process personal information only if certain conditions are met, which include, but are not limited to, obtaining personal consent, public health emergencies, and circumstances stipulated by law. (Note: consent to data processing is not the same as informed consent to the research described in the Informed Consent topic.) 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. 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, 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 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. 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. See the DataScrty, for additional details on the sponsor’s obligations to ensure data security in China. For specific details on information technology standards to secure clinical research data, see DataScrty-Stds.

Per the PIPL, in order 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 informatization department
  • Conduct personal information protection certification by professional institutions in accordance with the requirements of the Cyberspace Administration of China
  • Enter into a contract with the overseas recipient in accordance with the standard contract formulated by the Cyberspace Administration 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 Cyberspace Administration. For more details on sponsor responsibilities, see Chapter V of the PIPL. For additional analysis of the China’s personal information protection legislation, see CHN-25.

Electronic Data Processing System

For purposes of personal data protection requirements, the PIPL and the DataScrty stipulate that personal data includes any record of information, electronic or otherwise. In addition to the processing requirements above, 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 SOPs that cover the setting, 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.

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

In addition, as per 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 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 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.

Audit 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.

Further, researchers and clinical trial institutions must agree to supervision and inspection organized by the sponsor and the NMPA. The sponsor must provide an inspection report or certificate when requested by the NMPA. In accordance with the DRR and CHN-8, NMPA’s Center for Drug Evaluation (CDE) will make a risk-based decision on whether to conduct an inspection of a clinical trial, based on the level of drug innovation and the past verification history of the clinical trial site.

See the NMPA-GCP-No57-2020 and CHN-37 for additional guidance on audits and inspections.

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.

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.

Multicenter Studies

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 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.

Chapter I (Articles 2, 3, and 6) and Chapter IV
Chapter I (Articles 1-9), Chapter II (Articles 13-19 and 28-32), Chapter III (Articles 38-43), Chapter V, and Chapter VIII (Article 73)
11 and 17
Chapter I (Article 3) and Chapter III (Articles 25, 28-31, and 46-47)
11.3
Chapter 8 (Articles 116, 121, 128, and 130-131)
Chapter III (Article 24)
Chapter 4 (Article 16 and 25) and Chapters 5 and 8
Overview and II(A) The Responsibility of the Relevant Personnel
Clinical Trial Inspections
1.65, 5.0, 5.1, 5.2, 5.5, 5.18, 5.19, 5.21, 5.23, 6.10, and 8
Last content review/update: January 20, 2021

Overview

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.

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 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.

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

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 marketing application (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.

Audit 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 auditor’s qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with his/her 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).

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, he/she 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 institutional ethics committees (ECs) (institutional review boards (IRBs) in the United States), 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 his/her 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.

Multicenter Studies

In the event of multicenter clinical studies, also known as cooperative research studies, which are required to comply with the RevisedCommonRule, all federally-funded or sponsored institutions that are located in the US and engaged in multicenter research must use a single EC to review that study, known as the EC policy. This policy will streamline the EC review process and eliminate duplicative reviews. The exceptions to this requirement include: when multiple-EC 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 RevisedCommonRule, which took effect January 21, 2019, 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 United States be overseen by a single EC, unless prohibited by any federal, tribal, or state law, regulation, or policy.

In addition, the US-ICH-GCPs specifies that the sponsor must ensure all investigators conduct the trial in strict compliance with the FDA and EC approved protocol.

Per the NIHDataSftyMntrng and USA-72, Data Safety and Monitoring Boards are also specifically required for NIH-funded, multi-site clinical trials with interventions that involve potential participant risk.

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

Subpart D (312.56-312.58)
46.101 and 46.114
1.65, 5.0, 5.1, 5.2, 5.5, 5.18, 5.19, 5.21, 5.23, 6.10, and 8
Data and Safety Monitoring
Sponsorship > Site/Investigator Selection
Last content review/update: October 28, 2021

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. 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.

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, the 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 required conditions.

Institutional Registration

Per the SC-Opinions-No42, the NMPA-NHC-No101-2019, and CHN-5, the National Medical Products Administration (NMPA) (the Chinese name translates as “State Drug Administration”) 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 drug clinical trial institution 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.

Foreign Sponsor Responsibilities

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

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.

Annex 3
Chapter II (Articles 9 and 10) and Chapter III (Article 22)
1 and 2
Chapter 8 (Articles 118-119)
Chapter VI (Article 2)
Chapter 4 (Articles 16-17) and Chapter 5 (Articles 37-38)
8
1.25, 5.5, and 5.6
Last content review/update: January 20, 2021

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 that he/she will comply 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.

Data Safety and Monitoring Board

Although not specified as a sponsor requirement, the US-ICH-GCPs states that a Data and Safety Monitoring Board 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.

Foreign Sponsor Responsibilities

No applicable regulatory requirements.

Subpart D (312.50 and 312.53)
1.25, 4.1, 5.5.2, 5.6, and 8.2.6
I (3)
Form FDA 1572
Informed Consent > Documentation Requirements
Last content review/update: October 28, 2021

Overview

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 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) (the Chinese name translates as “State Drug Administration”) with the clinical trial application. (See the Required Elements section for details on what should be included in the form.) The RegEthics provides that the EC may apply for the provincial medical ethics expert committee to provide advice on the ethical review of research involving a relatively high-risk or special population. Per the MgmtHumanGen and CHN-56, 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. See Specimens topic and Submission Process and Submission Content sections for more details.

The NMPA-GCP-No57-2020 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 his/her legal representative(s) or guardian(s). As delineated in the NMPA-GCP-No57-2020 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 his/her legal representative(s) or guardian(s) should also be given adequate time to consider whether to participate.

The RegEthics further states that the ICF must contain necessary and complete information expressed in a language that the participant can understand. The investigator must explain each ICF item to the participant, including:

  • Purpose, significance, and expected effects
  • Risks and benefits
  • Whether there are other measures or treatment options that are beneficial to the participant
  • The scope and measures of confidentiality
  • Compensation
  • Voluntary participation and the right to opt out
  • The contact person to report problems

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.

The following cases may be exempted from signing the ICF after examination and approval by the EC:

  • The specimen or data that can identify the participant can be used for research but the participant cannot be found 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

(Note: Consent to participate in research is not the same as consent as the legal basis for processing personal data under the data protection legislation. For more information about the sponsor’s responsibilities to comply with the data protection legislation, see the Quality, Data, & Records Management section.)

Re-Consent

The NMPA-GCP-No57-2020 and CHN-37 require investigators to use the latest version of the ICF approved by the EC and, if necessary, participants in the clinical trial process should sign an updated ICF again. If new information may affect the participant’s continued participation in the trial, the investigator must promptly notify the participant and his/her legal representative(s) or guardian(s) and make corresponding records. Per the RegEthics, the investigator should obtain re-consent under the following circumstances:

  • 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
  • Other changes occur during the research

Language Requirements

CHN-4 states that all clinical trial applications and supporting materials, including the ICF, must be in Chinese. The NMPA-GCP-No57-2020, the RegEthics, and the EC-Guide require the ICF to be presented in oral or written form in a simple language that the participant is able to understand.

Documentation Copies

Per the NMPA-GCP-No57-2020, CHN-37, and the EC-Guide, the participant and his/her legal representative(s) or guardian(s), and researchers who perform informed consent should sign and date the ICF. If the ICF is not signed by the participant, the relationship should be marked on the form. If the participant and his/her 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 his/her legal representative(s) and/or guardian(s)
  • The participant and his/her 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 his/her legal representative(s) and/or guardian(s) should receive a copy of the signed and dated ICF.

Chapter II (Article 21)
Chapter 3 (Articles 18, 19, and 28) and Chapter 4 (Articles 33-39)
Chapter I (Article 9) and Chapter II (Article 12)
Chapter I (Article 1), Chapter IV (Article 5), and Chapter IX (Article 31)
Chapter 1 (Article 3), Chapter 3 (Article 12), and Chapter 4 (Article 23)
Pages 66-70
2, 4.4, 4.8, 8.2, and 8.3
Last content review/update: January 20, 2021

Overview

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, or the CommonRule or the RevisedCommonRule for federally funded or sponsored clinical trials. 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 CommonRule, the RevisedCommonRule, 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). (See the Informed Consent topic, Required Elements subtopic for ICF content details.)

Per the RevisedCommonRule, which took effect January 21, 2019, for each clinical trial conducted or supported by a federal department or agency, one (1) EC-approved informed consent form 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 RevisedCommonRule, 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 CommonRule, the RevisedCommonRule, and the US-ICH-GCPs, the investigator must provide detailed research study information to the participant and/or his/her 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 his/her legal representative(s) or guardian(s), should also be given adequate time to consider whether to participate.

Additionally, per the RevisedCommonRule, 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 RevisedCommonRule 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 for additional information regarding informed consent and broad consent requirements.

In addition, per 21CFR50, the CommonRule, and the RevisedCommonRule, 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 his/her legal representative(s) or guardian(s) to read before it is signed.

See G-ElectronicIC for further guidance related to electronic 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 CommonRule, the RevisedCommonRule, and the US-ICH-GCPs state that any information provided must be in a language understandable to the participant and/or his/her legal representative(s) or guardian(s). As delineated in the G-ICInfoSheet, 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 and at a level they can comprehend. The EC must review and approve all English and non-English language versions of consent documents. The FDA also recommends that whenever non-English speaking participants are enrolled in a study, appropriate interpreter services be made available.

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-ICInfoSheet and USA-63 for detailed information.

Documentation Copies

As set forth in 21CFR50, the CommonRule, and the US-ICH-GCPs, the participant and/or his/her legal representative(s) or guardian(s) must sign and date an EC-approved written ICF. The RevisedCommonRule explicitly allows electronic signatures for consent documentation. See G-ElectronicIC for further guidance related to electronic informed consent. A written copy of the form must be given to the participant and/or his legal representative(s) or guardian(s). Per the CommonRule and the RevisedCommonRule, 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 RevisedCommonRule 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.

Per 21CFR50, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs, if the consent information is only presented orally using the short form, the participant and/or his/her legal representative(s) or guardian(s) must sign the form (if capable), 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 should be given to the participant and/or his/her legal representative(s) or guardian(s).

According to the US-ICH-GCPs, where the participant is illiterate and/or his/her 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 and his/her legal representative(s) and/or guardian(s)
  • The participant and his/her 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 his/her legal representative(s) and/or guardian(s) should receive a copy of the signed and dated ICF.

Per the G-RevComRule-FDA, the informed consent requirements of the RevisedCommonRule are consistent 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 RevisedCommonRule and FDA regulations.

Subpart B (50.20, 50.25, and 50.27)
46.116 and 46.117
46.116 and 46.117
Subparts B-D
2.9 and 4.8, 8.2, and 8.3
III
Non-English Speaking Subjects
V (45)
Broad Consent in the Revised Common Rule, Informed Consent
Informed Consent > Required Elements
Last content review/update: October 28, 2021

Overview

As delineated in the NMPA-GCP-No57-2020, the EC-Guide, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37), prior to beginning a clinical trial, the investigator is required to obtain ethics committee (EC) approval for the written informed consent form (ICF), and any other information being provided to the research participant and/or his/her legal representative(s) or guardian(s). Per the VaccineLaw, in carrying out a vaccine clinical trial, the investigator is required to obtain a written ICF from the participant and/or his/her legal representative(s) or guardian(s).

The NMPA-GCP-No57-2020, the EC-Guide, the RegEthics, and CHN-37 state that information should be presented in easily understandable language, and may be presented in written and/or oral form. Adequate time should be given to the participant and/or his/her legal representative(s) or guardian(s) to inquire about the details of the study and have all questions answered to his/her satisfaction.

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. 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.

No Coercion

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 his/her legal representative(s) and/or guardian(s) to waive or appear to waive his/her 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. See CHN-26 for an analysis of clinical trial participants’ rights in China.

Informed Consent Form Required Elements

Based on the NMPA-GCP-No57-2020, the EC-Guide, the RegEthics, and CHN-37, the ICF should 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 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 EC, the National Medical Products Administration (NMPA), and drug authorities in the provinces, autonomous regions, and municipalities may be required to review participant data
  • 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 and during 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.
  • 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 this 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

See the Compensation Disclosure and Vulnerable Populations sections for additional information.

18
Chapter 4 (Articles 33-37)
Chapter II (Article 12)
Chapter I (Article 1), Chapter IV (Article 5), Chapter VI (Article 2), Chapter IX (Article 31), and Annex I (Article 4)
Chapter 1 (Article 3) and Chapter 4 (Articles 23-24)
4.4 and 4.8
Last content review/update: January 20, 2021

Overview

As delineated in 21CFR50, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs, prior to beginning a clinical trial, the investigator is required to obtain ethics committee (EC) (institutional review board (IRB) in the United States (US)) approval for the written informed consent form (ICF) and any other information being provided to the research participant and/or his/her legal representative(s) or guardian(s). 21CFR50, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs state that information about the study should be presented in easily understandable language and in a format that facilitates understanding. The participant and/or his/her legal representative(s) or guardian(s) should also be given adequate time to consider whether to participate.

Per the RevisedCommonRule, 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 RevisedCommonRule, 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.

No Coercion

As indicated in 21CFR50, the CommonRule, the RevisedCommonRule, 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 his/her legal representative(s) or guardian(s) to waive or appear to waive his/her legal rights, or that releases or appears to release the investigator, sponsor, institution or its agents from liability for negligence.

Informed Consent Form Required Elements

Based on 21CFR50, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs, the 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 benefits to which he/she is otherwise entitled
  • Foreseeable circumstances under which the investigator may remove the participant without his/her 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 ClinicalTrials.gov (USA-78), 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.”

The RevisedCommonRule, which took effect January 21, 2019, 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

Per the G-RevComRule-FDA, the informed consent requirements of the RevisedCommonRule are not consistent with FDA regulations. Therefore, there may not be a need for sponsors or investigators to develop, and have ECs review, two separate ICFs for research that must comply with both the RevisedCommonRule and FDA regulations.

Subpart B (50.20, 50.25, and 50.27)
46.116 and 46.117
46.116 and 46.117
4.8
III
What are the basic elements of informed consent?
Informed Consent
Informed Consent > Compensation Disclosure
Last content review/update: October 28, 2021

Overview

In accordance with the NMPA-GCP-No57-2020, 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 contain a statement describing the compensation or medical treatment participants can receive for participating in a clinical trial.

Compensation for Participation in Research

As stated in the EC-Guide, the RegEthics, and the NMPA-GCP-No57-2020, the ICF should contain a statement with a description of the nature, form, and extent of compensation for study participation. The ICF should also inform the participants if they will need to pay for any expenses in order to participate in the trial.

Per CHN-37, the ICF should contain a statement with a description of the anticipated prorated payment to the participants that is reasonably expected for participation in the trial. Any compensation or incentive to participants must not be so excessive that it may unfairly influence participants, or cause them to overlook important facts and risks.

Compensation for Injury

As per the NMPA-GCP-No57-2020, the EC-Guide, the RegEthics, and CHN-37, the ICF should include a statement advising the participants that compensation and medical treatment is available in the event of any trial-related injury.

Chapter 4 (Articles 36-37)
Chapter VI (Article 2) and Annex 1 (Article 4)
Chapter 4 (Article 24)
3.1 and 4.8
Last content review/update: January 20, 2021

Overview

In accordance with 21CFR50, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs the informed consent form (ICF) should contain a statement describing the compensation or medical treatment a participant can receive for participating in a clinical trial.

The G-IRBFAQs further 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).

Compensation for Participation in Research

Per the 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 ethics committee (EC) (institutional review board (IRB) in the United States (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 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.

21CFR50, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs also state that the ICF should inform the participants if they will need to pay for any expenses in order to participate in the trial.

Compensation for Injury

As per 21CFR50, the CommonRule, the RevisedCommonRule, the US-ICH-GCPs, the G-ICInfoSheet, and the G-IRBFAQs, the participant should be told whether compensation and any medical treatment(s) are available for research involving more than minimal risk. Because available compensation and treatments may vary depending on the medical circumstances of the participant, or, the institutional policies, the consent process should include an explanation of where participants may obtain further information. This information must be explained in the ICF and cannot waive or appear to waive the participant’s rights or release or appear to release those conducting the study from liability for negligence.

According to the G-ICInfoSheet, when no system has been established to provide funds, the preferred wording is: “no funds have been set aside for,” “[the cost] will be billed to you or your insurance,” or similar wording that explains the provisions or the process.

Subpart B (50.25)
46.116
46.116
3.1 and 4.8
Assent of Children Elements of Informed Consent, 21 CFR 50.25 and Compensation v. Waiver of Subject's Rights
I
Informed Consent > Participant Rights
Last content review/update: October 28, 2021

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 EC-Guide, the RegEthics, and CHN-37, the participant or his/her legal representative(s) or guardian(s) should be informed that participation is voluntary, that he/she 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 EC-Guide, the NMPA-GCP-No57-2020, the RegEthics, and CHN-37, a potential research participant and/or his/her 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 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 EC-Guide, the NMPA-GCP-No57-2020, and CHN-37 state that the research participant and/or his/her 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 his/her 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 his/her health and welfare must take precedence over the interests of science and society.

Chapter 3 (Articles 18 and 19) and Chapter 4 (Articles 33-39)
Chapter IV (Article 1), Chapter VI (Articles 1-2), and Chapter IX (Article 32)
Chapter 1 (Article 3) and Chapter 4 (Articles 23-24)
3.1 and 4.8
Last content review/update: January 20, 2021

Overview

In accordance with 21CFR50, 21CFR312, the CommonRule, the RevisedCommonRule, 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 CommonRule, the RevisedCommonRule, and the US-ICH-GCPs, a potential participant and/or his/her legal representative(s) or guardian(s) must be informed that participation is voluntary, that he/she 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 CommonRule, the RevisedCommonRule, and the US-ICH-GCPs, a potential research participant, and/or his/her 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 CommonRule, and the RevisedCommonRule, 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 shall 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 RevisedCommonRule does allow the use of identifiable information or biospecimens in instances where the ethics committee (EC) 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 more information.

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

The Right of Inquiry/Appeal

21CFR50, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs state that the research participant, and/or his/her 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 his/her 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 his/her health and welfare must take precedence over the interests of science and society.

Subpart A (312.3)
Subpart A (50.1) and Subpart B (50.25)
46.116
46.103, 46.109, 46.116, and 46.117
Introduction, 1.27, 2.2, 2.3, 3.1, and 4.8
Informed Consent
Informed Consent > Special Circumstances/Emergencies
Last content review/update: October 28, 2021

Overview

The NMPA-GCP-No57-2020 and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (CHN-37) make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by special circumstances. Special circumstances can be medical emergencies, or when a participant is mentally incapacitated. See CHN-26 for an analysis of clinical trial participants’ rights in China.

Medical Emergencies

The EC-Guide, states that even 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 CHN-37, in an emergency, if the signed informed consent form (ICF) has not been obtained from the research participant or his/her 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 his/her 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.

Chapter V (Article 3) and Annex VIII (Articles 4 and 7)
Chapter 3 (Article 12) and Chapter 4 (Articles 23-24)
4.8
Last content review/update: January 20, 2021

Overview

21CFR50, 21CFR56, the US-ICH-GCPs, and the G-ICEmergencyReqs make provisions to protect the rights of a research participant during the informed consent (IC) process when the procedure is complicated by special circumstances. Special circumstances may include life-threatening medical emergencies, public health emergencies, military operations, or when a participant is mentally incapacitated.

Medical Emergencies

Unplanned Emergency Research

As stated in 21CFR50, 21CFR56, and the G-EmrgncyUse, in an unplanned emergency situation, obtaining participant consent is required before using the investigational product (IP) unless the investigator and a physician not participating in the trial certify in writing the following:

  • Participant is confronted by a life-threatening situation
  • IC 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 is available

The investigator(s) must obtain ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) review and approval for any subsequent use of the IP.

Further, per 21CFR50, 21CFR56, the G-EmrgncyUse, and the G-IRBFAQs, 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 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 and submitted to an EC within five (5) working days.

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 his/her legal representative(s) or guardian(s), or, if an effective treatment is lacking but the 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 EC must approve the protocol in advance. The participant and/or his/her 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.

Planned Emergency Research

As delineated in 21CFR50, the G-ICEmergencyReqs, and the G-EmrgncyUse, in a planned emergency research study, if a ICF cannot be obtained from the participant and/or his/her legal representative(s) or guardian(s), the EC may approve the investigation without requiring the consent of all the participants, if a licensed physician who is an EC member, or, an EC consultant, and not otherwise participating in the trial, certifies in writing the following:

  • Participant is confronted by a life-threatening situation and available treatments are unproven or unsatisfactory
  • IC cannot be obtained due to an inability to communicate with the participant
  • It is unfeasible to obtain consent from the participant’s legal representative and/or guardian(s) due to his/her life-threatening condition
  • No alternative methods of approved or generally recognized therapy is available
  • The research must have the prospect of direct benefit to the participant
  • The collection of scientific evidence is necessary to determine the safety and effectiveness of the intervention

See 21CFR50, the G-ICEmergencyReqs, and the G-EmrgncyUse for additional information.

Military Operations Emergencies

21CFR50 and 10USC55 require the Secretary of Defense to request that the President waive the IC requirement prior to a member of the armed forces being administered an IP in connection with his/her participation in a particular military operation. The President must determine 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.

Waiver or Alteration of Consent

The CommonRule, the RevisedCommonRule, and 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. In addition, the CommonRule states that the EC may approve a waiver or alteration of consent if the study satisfies all of the following conditions:

  • The research involves no more than minimal risk
  • The research could not practicably be carried out without the requested waiver or alteration
  • The waiver or alteration will not adversely affect the rights and welfare of the participants
  • Whenever appropriate, the participants will be provided with additional pertinent information after participation

The RevisedCommonRule, which took effect January 21, 2019, adds the following conditions:

  • 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
  • Whenever appropriate, the legally authorized representatives will be provided with additional pertinent information after participation

Per G-MinRiskWaiver, the Food & Drug Administration (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.

Subpart B (50.23 and 50.24)
Subpart A (56.102 and 56.104)
46.116
46.116
1107
4.8
II (20) and V (44)
IV
III (18)
Is it possible to obtain legally effective informed consent to research in an urgent or emergency care setting?
Informed Consent
Informed Consent > Vulnerable Populations
Last content review/update: October 28, 2021

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.

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.

Chapter 3 (Article 18)
Chapter I (Article 5), Chapter IV (Article IV), and Chapter IX (Article 5)
Chapter 1 (Article 3), Chapter 2 (Article 11), Chapter 3 (Article 12), and Chapter 4 (Article 23)
1.61, 3.1, and 4.8
Last content review/update: January 20, 2021

Overview

As per 21CFR56, the CommonRule, the RevisedCommonRule, 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.

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 CommonRule describes children, prisoners, pregnant women, handicapped persons, mentally disabled persons, or economically or educationally disadvantaged persons as vulnerable populations.

The RevisedCommonRule, which took effect January 21, 2019, describes children, prisoners, individuals with impaired decision-making capacity, or economically or educationally disadvantaged persons as vulnerable populations.

21CFR56, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs also specify that ethics committees (ECs) (institutional review boards (IRBs) in the US) must pay special attention to protecting participants who are from vulnerable populations. 

See the Informed Consent topic, and the subtopics of Children/Minors; Pregnant Women, Fetuses, & Neonates; Prisoners; and Mentally Impaired for additional information about these vulnerable populations.

Subpart C (56.111)
46.111
46.107 and 46.111
1.61 and 3.1
Informed Consent > Children/Minors
Last content review/update: October 28, 2021

Overview

The applicable regulatory requirements do not specify the age of minors.

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 he/she is willing 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
(B) (3) Special Consideration, Special Population
Chapter VII (Article 3)
Chapter 2 (Article 11) and Chapter 4 (Article 23)
4.8
Last content review/update: January 20, 2021

Overview

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 CommonRule and the RevisedCommonRule, children require additional safeguards to be included in any research study in order to protect their rights and welfare.

As delineated in the US-ICH-GCPs, when the research participant is a minor, informed consent should be obtained from his/her 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 risk
  • 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 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 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 RevisedCommonRule, certain exemptions may apply to observational research involving children. See the RevisedCommonRule for details.

For additional Food & Drug Administration (FDA) guidance on clinical research in children, see US-ICH-E11.

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.

Subpart A (50.3) and Subpart D
46.104 and 46.111
46.111
Subpart D
4.8.12
5, Appendix B, and Table B2
How can the consent and parental permission processes be designed to facilitate understanding?; Can an electronic signature be used to document consent or parental permission?; Is a faxed copy of the signed consent or parental permission form acceptable to document informed consent?; Who must sign the informed consent or parental permission document?
HHS Subparts
Informed Consent > Pregnant Women, Fetuses & Neonates
Last content review/update: October 28, 2021

Overview

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. See CHN-26 for an analysis of clinical trial participants’ rights in China.

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.

Chapter 3 (Article 18)
(B) (3) Special Consideration, Special Population
Chapter 4 (Article 24)
4.8
Last content review/update: January 20, 2021

Overview

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 CommonRule, pregnant women require additional safeguards to be included in any research study in order to protect their rights and welfare.

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.

Per the RevisedCommonRule, all of the available exemptions of the RevisedCommonRule for observational research may be applied to research involving pregnant women, fetuses, and neonates. See the RevisedCommonRule for details.

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 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 RevisedCommonRule and subparts B and D of 45CFR46-B-E.

Subpart B (50.25)
46.104
46.111
Subparts B and D
4.8.10
HHS Subparts
Informed Consent > Prisoners
Last content review/update: October 28, 2021

Overview

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. See CHN-26 for an analysis of clinical trial participants’ rights in China.

Chapter 2 (Article 11)
1.61
Last content review/update: January 20, 2021

Overview

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 CommonRule and the RevisedCommonRule, prisoners require additional safeguards to be included in any research study in order to protect their rights and welfare.

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 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 his/her intent to approve such research

Per the RevisedCommonRule, 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.

Ethics Committee Responsibilities

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 his/her 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 his/her 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.

Subpart C (56.111)
46.104 and 46.111
46.111
Subpart C
1.61
HHS Subparts
Informed Consent > Mentally Impaired
Last content review/update: October 28, 2021

Overview

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). See CHN-26 for an analysis of clinical trial participants’ rights in China.

Chapter 3 (Article 18)
Chapter 4 (Article 23)
1.61 and 3.1
Last content review/update: January 20, 2021

Overview

In accordance with 21CFR56, the CommonRule, and the US-ICH-GCPs, an 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.

Per the CommonRule and the RevisedCommonRule, 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.

USA-60 further indicates that while the 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.

Subpart C (56.111)
46.111
46.111
1.61
What should be considered in seeking informed consent from individuals with diminished decision-making capacity?
Investigational Products > Definition of Investigational Product
Last content review/update: October 28, 2021

Overview

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.

Chapter 2 (Article 11)
1.33
Last content review/update: January 20, 2021

Overview

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 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.

Subpart A (312.3)
1.33
Investigational Products > Manufacturing & Import
Last content review/update: October 28, 2021

Overview

According to the DAL and the NMPA-No28-2020, the National Medical Products Administration (NMPA) (the Chinese name translates as “State Drug Administration”) is responsible for authorizing the manufacture of investigational products (IPs) in China. Per the DAL and the DRR, and as explained in CHN-18, NMPA established a drug marketing authorization holders (MAHs) system across China. All entities or drug research institutions holding drug marketing authorizations are regarded as MAHs, who 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 DRR and the NMPA-No28-2020 stipulate that foreign applicants should designate an enterprise legal person in China to handle relevant drug registration matters. 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 a drug marketing license may produce the drug or entrust a pharmaceutical production enterprise to produce it. For the former, the holder of the drug marketing license must obtain a drug production license, which can be found at NMPA-No72-2019. If an entrusted production enterprise is used, the drug marketing license 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.

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

The NMPA-GCP-No57-2020 specifies that the manufacture of clinical trial drugs must meet the relevant requirements for quality management as laid out in the NMPA-No28-2020. 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.

The NMPA is also responsible for authorizing the import of IPs. The DAL provides that prior to IP import or manufacture, a 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.

Pursuant to the NMPA-No35-2017, 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 for the NMPA-No52-2018 requirements for clinical trial and drug registration applications of imported new drugs or therapeutic biological products using trial data generated entirely overseas, they 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—a requirement that typically delayed projects by several years. Overseas clinical trial data can 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 U.S. or EU 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.

Chapter I (Articles 5-7), Chapter III (Article 30-33), Chapter IV (Articles 41-47A), and Chapter X (Articles 98-100 and 103)
Chapter I (Articles 3 and 9) and Chapter III (Article 47)
Chapter I, Chapter II (Articles 6-7), Chapter III (Article 47), and Chapter IV (Article 52)
Chapter 1 (Article 8) and Chapter 5 (Articles 44-45)
I-V
Attachment 2
Trends and developments and Supply
2.12, 5.13, and 6
Last content review/update: January 20, 2021

Overview

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, unless FDA notifies the sponsor that the investigation(s) described in the IND are subject to a clinical hold, or,
  • On earlier FDA authorization to ship the IP

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 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

Per 21CFR312, the FDA will permit the export of an IP from the US for use in a clinical investigation under any of the following conditions:

  • An IND is in effect for the IP, the drug complies with the laws of the country to which it is being exported, and, each person who received the IP is an investigator in a study submitted to the FDA and allowed to proceed under the IND, or,
  • The IP has valid marketing authorization in Australia, Canada, Israel, Japan, New Zealand, Switzerland, South Africa, or in any country in the European Union or the European Economic Area, and complies with the laws of the country to which it is being exported, or,
  • The IP is being exported to any one of the aforementioned countries (see previous bullet), or,
  • The person exporting the drug sends a written certification to the FDA’s Office of International Programs when the IP is first exported and maintains records documenting compliance with the FDA requirements

See Section 312.110 of 21CFR312 for additional detailed IP export requirements.

Subpart B (312.22 and 312.23), Subpart C (312.40) and Subpart F (312.110)
Investigational Products > IMP/IND Quality Requirements
Last content review/update: October 28, 2021

Overview

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.

Per the DAL, the IP manufacturer must 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 standards in the NMPA-GMPs and the NMPA-GMPsAmnd. The legal representative and principal responsible person of the drug production enterprise are fully responsible for the drug production activities of the enterprise.

The NMPA has issued the following quality management guidelines for conduct during clinical trials. For additional details, see the following documents:

  • The NMPA-No22-2021 describes a research and development model to guide researchers in managing pharmaceutical changes of innovative drugs. As the clinical trial progresses and understanding deepens, the researchers should adapt standards to improve production and quality control.
  • The 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. This guidance offers methods to control the rate of errors or false positive findings.
  • The NMPA-No54-2020 describes the clinical features of new uses of chemical drugs and associated principles of clinical trial design and evaluation.

Investigator’s Brochure Content Requirements

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 content guidelines.

The NMPA-GCP-No57-2020 states that the sponsor must also provide the clinical trial drugs to investigators and clinical trial institutions. The sponsor must not provide the drugs 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 Chinese name translates as “State Drug Administration”). The sponsor must provide the investigator and the clinical trial institution with a written description of the drug, including directions for its use and storage. Further, the sponsor must formulate procedures for supply and management, including reception, storage, distribution, use, and recovery. The sponsor must ensure that the drugs 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. (See Product Management section for additional information on IP supply, storage, and handling requirements). See CHN-11 for an analysis of drug supply requirements in China.

Per the NMPA-GCP-No57-2020, 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.

Continuous Compliance

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-GMPs and the NMPA-GMPsAmnd. The legal entity or person is fully responsible for the manufacturing activities of the enterprise throughout the whole process. NMPA-No65-2021 reiterates that sponsors must establish a quality management and pharmacovigilance system. 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 the participant safety. The NMPA-No28-2020 further clarifies the link between on-site inspection of drug registration and the pre-market 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., NMPA’s Center for Drug Evaluation (CDE), province, autonomous region, or municipality). See the NMPA-No28-2020 for detailed inspection requirements. In addition, the sponsor’s internal inspection and audit requirements are provided in the NMPA-GCP-No57-2020, which includes providing an inspection/audit report to regulatory authorities when needed.

Certificate of Analysis

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.

Chapter II (Articles 24-25) and Chapter IV (Articles 43-44)
Chapter 8 (Article 116)
Chapter IV (Articles 49-52)
Chapter 4 (Article 21), Chapter 5 (Article 37), and Chapter 7
Supply
7
Last content review/update: January 20, 2021

Overview

In accordance with 21CFR312 and the US-ICH-GCPs, the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB), and for complying with the principles of good manufacturing practice (GMP) as specified in 21CFR210, the G-CGMP-Phase1, and the G-INDPrep. 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, including pharmacological, toxicological, pharmacokinetic, safety, efficacy, and adverse events data. The sponsor must also update the IB as significant new information becomes available.

Investigator's Brochure Content Requirements

As specified in 21CFR312 and the US-ICH-GCPs, 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 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.

As specified in the US-ICH-GCPs, the sponsor must ensure that the products are manufactured in accordance with GMPs.

Certificate of Analysis

According to USA-39 and USA-67, 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 Certificate of Analysis to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.

210.2
312.23 and 312.120
I-V
2.12, 5.12, 5.13, 7, and 8.2
I-IX
Investigational Products > Labeling & Packaging
Last content review/update: October 28, 2021

Overview

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 (the Chinese name translates as “State Drug Administration”) requirements as mandated in the preceding regulations. See CHN-11 for an analysis of clinical trial labeling in China.

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.

The ProvLabel and the DAL state that the following labeling information 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. The IPs must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

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

Chapter IV (Articles 46 and 48-49)
Chapters I and III
Chapter 5 (Article 44)
Labelling
5.13
Last content review/update: January 20, 2021

Overview

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. The IPs must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Subpart A (312.6)
5.13
Investigational Products > Product Management
Last content review/update: October 28, 2021

Overview

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. The IP pre-clinical study documents supplied by the investigator must also include formulation, manufacturing process, and quality inspection results of the IP. The information should conform to the requirements of the respective corresponding phases of the clinical trial.

Investigational Product Supply, Storage, and Handling Requirements

The NMPA-GCP-No57-2020 states that the sponsor must also 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 Chinese name translates as “State Drug Administration”). 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. In addition, 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.

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

  • IP product quality
  • IP manufactured according to good manufacturing practices (GMPs), as per the NMPA-GMPs and the NMPA-GMPsAmnd
  • 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 marketing license—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

The NMPA-GCP-No57-2020 requires the sponsor to keep clinical trial records for at least five (5) years after the IP is approved for marketing.

Chapter III (Articles 33 and 36)
Chapter 5 (Article 44)
5.5, 5.12, 5.13, 5.14, and 7
Last content review/update: January 20, 2021

Overview

In accordance with 21CFR312 and the US-ICH-GCPs, the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB), and for complying with the principles of good manufacturing practice (GMP) as specified in 21CFR210, the G-CGMP-Phase1, and the G-INDPrep. The IB must contain all of the relevant information on the investigational new drug(s) (INDs)/investigational product(s) (IPs) obtained through the earlier research phases, including pharmacological, toxicological, pharmacokinetic, safety, efficacy, and adverse events data. The sponsor must also update the IB as significant new information becomes available.

Investigational Product Supply, Storage, and Handling Requirements

As defined in 21CFR312, the US-ICH-GCPs, the G-CGMP-Phase1, and the G-INDPrep, the sponsor must also supply the investigator(s)/institution(s) with the IP(s), including the comparator(s) and placebo, if applicable. The sponsor must ensure the following:

  • IP product quality and stability over the period of use
  • IP manufactured according to any applicable GMPs
  • Proper coding, packaging, and labeling of the IP(s)
  • Records maintained for document shipment, receipt, disposition, return, and destruction 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

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 a marketing application (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.

210.2
Subpart B (312.23) and Subpart D (312.55, 312.57, 312.59 and 312.62)
I-V
5 and 7
I-IX
Specimens > Definition of Specimen
Last content review/update: October 28, 2021

Overview

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 refers 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.

CHN-76 is the portal for China’s management of specimens. For an overview of key considerations on the use of biospecimens during research in China and abroad see, CHN-27.

Chapter One (Article 2)
Last content review/update: January 20, 2021

Overview

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, 42CFR72 and 42CFR73, define specimen or diagnostic specimen, as any human or animal material including, but not limited to, excreta, secreta, blood and its components, tissue and tissue fluids, or environmental samples to be used for diagnosis, verification, or proficiency testing.

The RevisedCommonRule, which took effect January 21, 2019, defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator. Federal agencies will reexamine what is an identifiable biospecimen within one (1) year of the effective date of the RevisedCommonRule revisions and at least every four (4) years thereafter.

Subpart F (72.1)
Subpart F (73.1)
46.102
Subpart D (173.134)
Specimens > Specimen Import & Export
Last content review/update: October 28, 2021

Overview

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. However, the regulation permits foreign entities with limited use of Chinese HGR 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 (CHN-76), which will generate a record number. See the HGR-IntlRecordMgtGuide, the HGR-IntlApprovLicenseGuide, and the HGR-ExprtLicenseGuide for details on the HGR processes and policies. For analyses of China’s implementation of HGR regulations, see CHN-10 and CHN-16.

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.

As delineated in MgmtHumanGen and the HGR-ExprtLicenseGuide, the export of Chinese HGR materials in approved international collaborations are subject to prior approval by MOST. The applicant may apply for the export license separately, or with the application for international cooperative research (CHN-76). (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 CHN-56, the following must be submitted:

  • Application (see CHN-56 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-76). 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.

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.

Chapter VI (Articles 53-59)
Article 11
Chapters 1 and 2
1-19 and all attachments
1-3
4
Chapter I (Articles 1-4 and 7-9), Chapter II (Article 11), and Chapter III (Articles 21-22)
Human Genetic Resource Management
China's human genetic resources materials exit approval
Last content review/update: January 20, 2021

Overview

The import and export of human specimens, also known as patient/ diagnostic specimens/substances or human biological materials in the United States (US), is governed by several federal agencies working cooperatively to ensure the safe transport of these materials. These agencies, include, but are not limited to, the Department of Transportation (DOT)’s Pipeline and Hazardous Materials Safety Administration (PHMSA), the Centers for Disease Control and Prevention (CDC)’s Import Permit Program (IPP), the Department of Health & Human Services (HHS), the United States Postal Service (USPS), and the International Air Transport Association (IATA). The IATA has also adopted all of the hazardous materials requirements set forth in the Technical Instructions for the Safe Transport of Dangerous Goods by Air (USA-10) published biannually by the United NationsInternational Civil Aviation Organization (ICAO).

According to USA-14 and USA-68, the first step in preparing a specimen for import or export is to classify the specimen as either infectious or non-infectious. Packaging and shipping of these specimens must then comply with all applicable federal and international ground and air transport standards.

Non-Infectious Specimens

A non-infectious specimen/substance is referred to as a Category B Biological Substance by DOT‘s PHMSA in 49CFR173, and an exempt human specimen or exempt animal specimen by IATA and USPS in USA-21 and USA-4 respectively. These specimens are not considered to be hazardous materials for import, transfer, or export by these agencies because they do not contain infectious substances, or, they are not substances likely to cause disease in humans or animals. However, they are subject to specific packaging and labeling procedures that must be followed when shipped. Please refer to 49CFR173, USA-21, USA-4, and USA-11 for detailed DOT, IATA, and USPS shipping instructions.

Infectious Specimens

Per 49CFR173, 42CFR73, 42CFR71, USA-21, USA-4, USA-11, and USA-31, DOT’s PHMSA, IATA, USPS, and CDC’s IPP refer to an infectious specimen/substance as a Category A Biological Substance, or, a select agent, etiologic agent, toxin, or a vector of human disease. The CDC’s IPP is specifically responsible for the importation of infectious specimens/substances/biological agents/vectors of human disease per 42CFR71 and for regulating the possession, use and transfer of select agents and toxins per 42CFR73. See 42CFR71, 42CFR73, USA-31, and USA-73 for further information and permit applications for these import/transfer programs.

Additionally, the Department of Commerce (DOC)’s Bureau of Industry and Security is responsible for regulating the export of a wide range of infectious specimens that may require a DOC license. Refer to the Commerce Control List (CCL) in 15CFR774 and USA-30 to determine if a DOC export permit is required for specific specimens.

NIH Import/Export Specimen Requirements

The HHS’ National Institutes of Health (NIH) researchers must also comply with all applicable federal and international air and ground transport laws and regulations as well as receive prior authorization from the NIH’s Quarantine Permit Service Office to obtain permits for the import, transfer, or export of all specimens. Detailed instructions about how to proceed are outlined in USA-71.

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.

Category 1
Subpart F (71.54)
Subpart F (73.1)
Subpart D (173.134)
C.5 and Appendix 4
346.1-346.3
Section J
Important Notice, Import Biological Materials to the NIH, Export Biological Materials from the NIH, and Biological Export Form
Specimens > Consent for Specimen
Last content review/update: October 28, 2021

Overview

The MgmtHumanGen indicates that the Ministry of Science and Technology (MOST) is responsible for China's efforts on the management of human genetic resources (HGR). As delineated in the MgmtHumanGen, HGR-Procedures, HGR-IntlApprovLicenseGuide, HGR-Collection, HGR-ExprtLicenseGuide, and HGR-IntlRecordMgtGuide, 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. CHN-56 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.

For an overview of key considerations on the use of biospecimens during research including consent, see CHN-27.

8
8
8
8
1, 3, and 4
Chapter IV (Article 31)
Last content review/update: January 20, 2021

Overview

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

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

Per the CommonRule, and the G-SpecimensResrch, HHS views human subject specimens as research involving human participants, and subject to IC 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 RevisedCommonRule 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 CommonRule, RevisedCommonRule, the G-SpecimensResrch, USA-2, USA-9, and USA-1 for additional information. See also the G-SpecimensResrch for exemptions to this definition.

Additionally, according to 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 CommonRule, the RevisedCommonRule, 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 his/her legal representative(s).

The RevisedCommonRule requires the informed consent form to provide one 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; or
  • 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 RevisedCommonRule 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 his/her 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 RevisedCommonRule does allow the use of identifiable information or biospecimens in instances where the ethics committee (EC) 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 G-StoredData-Tissues and USA-2 recommend that the following be included in IC 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

As stated in USA-2, the National Institutes of Health (NIH)’s National Cancer Institute (NCI) has also developed the following list of recommended elements to include in an informed consent form (ICF):

  • Participants have the right to refuse biospecimen donation, and this will in no way influence their treatment or eligibility to participate in research studies/clinical trials
  • Why particular specimens/data are being sought and why participants are being asked to participate
  • The biospecimens source that will be collected for research (e.g., ascertaining what procedure will the specimen come from)
  • Who will be the custodian of the biospecimens and what will be the custodian’s role
  • How the biospecimens will be used and whether they will be used in secondary research
  • How data collected or generated will be shared
  • Whether biospecimens will continue to be stored in an identifiable or non-identifiable manner
  • Who may access biospecimens/associated data

See USA-2 for detailed NCI biospecimen recommendations and best practices.

(See the Informed Consent topic, Required Elements and Participant Rights subtopics for additional information on informed consent).

46.102 and 46.116
46.102, 46.116, and 46.117
Subparts B-D
1 and 2
Background and Guidance
2 and 3
B3.3, B5.2, and C
Human Specimens and Cell Lines
Broad Consent in the Revised Common Rule, Informed Consent
Sources > Requirements
(Legislation) Biosecurity Law of the People's Republic of China (Bioscrty-Law – Standard Chinese) (Effective April 15, 2021)
National People’s Congress
(Legislation) Data Security Law of the People’s Republic of China (DataScrty - Standard Chinese) (Effective September 1, 2021)
National People’s Congress
(Legislation) Drug Administration Law of the People's Republic of China (DAL – Standard Chinese) (Effective December 1, 2019)
National People’s Congress
(Legislation) Personal Information Protection Law of the People’s Republic of China (PIPL) (Effective November 1, 2021)
National People’s Congress
(Legislation) Rules for the Implementation of Frontier Health and Quarantine Law of the People’s Republic of China (QuarantineLaw – Standard Chinese) (GoogleTranslate-QuarantineLaw) (March 6, 1989)
National People’s Congress
(Legislation) State Council Institutional Reform Plan (SC-IRP – Standard Chinese) (GoogleTranslate-SC-IRP) (March 17, 2018)
National People’s Congress
(Legislation) Vaccine Administration Law (VaccineLaw – Standard Chinese) (Effective December 1, 2019)
National People’s Congress
(Regulation) Adjusting the Review and Approval Procedures for Drug Clinical Trials (No. 50 of 2018) (NMPA-No50-2018 – Standard Chinese) (July 24, 2018)
National Medical Products Administration, State Administration for Market Regulation
(Regulation) Administrative Measures for the Development of Clinical Research Projects by Medical and Health Institutions (NHC-ClinProjMgmt - Standard Chinese) (Effective October 16, 2014)
National Health Commission
(Regulation) China Entry-Exit Inspection and Quarantine Process Management Rules (QuarantineRules - English, unofficial translation) (Effective November 1, 2017)
General Administration of Quality Supervision, Inspection & Quarantine
(Regulation) Decision Concerning the Adjustment of Imported Drug Registration and Administration (No. 35 of 2017) (NMPA-No35-2017 – Standard Chinese) (October 10, 2017)
National Medical Products Administration, State Administration for Market Regulation
(Regulation) Decision of the State Council on Amending Some Administrative Regulations (Decree No. 709) (RegImplemDAL-Amndt – Standard Chinese) (GoogleTranslate-RegImplemDAL-Amndt) (Effective March 2, 2019)
State Council
(Regulation) Drug Registration Regulation (Order No. 27) (DRR – Standard Chinese) (GoogleTranslate-DRR) (Effective July 1, 2020)
National Medical Products Administration, State Administration for Market Regulation
(Regulation) Guidelines for Acceptance and Review of Drug Registration (for Trial Implementation) (No. 194 of 2017) (NMPA-No194-2017 – Standard Chinese) (November 30, 2017)
National Medical Products Administration, State Administration for Market Regulation
(Regulation) Health and Quarantine Regulations for the Entry and Exit of Special Items (AQSIQ-No160 - Standard Chinese) (GoogleTranslate-AQSIQ-No160) (Effective March 1, 2015)
General Administration of Quality Supervision, Inspection & Quarantine
(Regulation) Human Genetic Resources – Approval for Export, Administrative Licensing Service Guide (HGR-ExprtLicenseGuide – Standard Chinese) (Date Unavailable)
Ministry of Science and Technology
(Regulation) Human Genetic Resources – Collection and Approval of HGR in China, Administrative Licensing Service Guide (HGR-Collection – Standard Chinese) (Date Unavailable)
Ministry of Science and Technology
(Regulation) Human Genetic Resources – Filing Scope and Procedures for the Use of China's HGR Information by Foreign Entities, Service Guide (HGR-DataUse – Standard Chinese) (Date Unavailable)
Ministry of Science and Technology
(Regulation) Human Genetic Resources – International Cooperative Clinical Trials, Record and Filing Management Service Guide (HGR-IntlRecordMgtGuide – Standard Chinese) (Date Unavailable)
Ministry of Science and Technology
(Regulation) Human Genetic Resources – International Cooperative Research Approval, Administrative Licensing Service Guide (HGR-IntlApprovLicenseGuide – Standard Chinese) (Date Unavailable)
Ministry of Science and Technology
(Regulation) Human Genetic Resources – Preservation of HGR in China, Administrative Licensing Service Guide (HGR-Preservation – Standard Chinese) (Date Unavailable)
Ministry of Science and Technology
(Regulation) Important Genetic Families and Human Genetic Resources in Specific Areas, Declaration and Registration Measures (Interim) (HGR-ImpFamilies-DeclReg – Standard Chinese) (July 1, 2019)
Ministry of Science and Technology
(Regulation) Information Security Technology Health and Medical Data Security Guidelines (DataScrty-Stds) (Effective July 1, 2021)
National Information Security Standardization Technical Committee
(Regulation) Issuing the Registration Fees for Drugs and Medical Device Products (No. 53 of 2015) (NMPA-No53-2015 – Standard Chinese) (May 27, 2015)
National Medical Products Administration, State Administration for Market Regulation
(Regulation) Management Measures for Communication and Exchange of Drug R&D and Technical Review (No. 48 of 2020) (NMPA-No48-2020 - Standard Chinese) (GoogleTranslate-NMPA-No48-2020) (December 10, 2020)
National Medical Products Administration, State Administration for Market Regulation
(Regulation) Management Regulations for Safety Update Reports During R&D (No. 7 of 2020) (NMPA-No7-2020 – Standard Chinese) (Effective July 1, 2020)
Center for Drug Evaluation, National Medical Products Administration
(Regulation) Matters Relating to the Optimization of Drug Registration Review and Approval (No. 23 of 2018) (NMPA-No23-2018 – Standard Chinese) (GoogleTranslate-NMPA-No23-2018) (May 17, 2018)
National Medical Products Administration, State Administration for Market Regulation, and the National Health Commission
(Regulation) National Medical Products Administration's Functional Allocation, Internal Organization and Staffing Requirements (NMPA-Org – Standard Chinese) (GoogleTranslate-NMPA-Org) (Effective July 29, 2018)
State Council
(Regulation) Notice on Propaganda and Implementation of the Vaccine Administration Law (No. 23 of 2019) (NMPA-No32-2019 – Standard Chinese) (July 25, 2019)
National Medical Products Administration, State Administration for Market Regulation
(Regulation) Opinions on Deepening the Reform of the Review and Approval System and Encouraging the Innovation of Drugs and Medical Devices (No. 42 of 2017) (SC-Opinions-No42 – Standard Chinese) (GoogleTranslate-SC-Opinions-No42) (October 8, 2017)
Chinese Communist Party’s Central Committee and State Council
(Regulation) Opinions on Reforming the Review and Approval System for Drugs and Medical Devices (No. 44 of 2015) (SC-Opinions-No44 – Standard Chinese) (GoogleTranslate-SC-Opinions-No44) (August 9, 2015)
State Council
(Regulation) Pharmacological Vigilance Quality Management Standards (No. 65 of 2021) (NMPA-No65-2021 - Standard Chinese) (May 7, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Regulation) Provisions on the Jurisdictions, Departments and Staffing of the State Administration for Market Regulation (SAMR-Org – English, unofficial translation) (Standard Chinese) (Effective July 30, 2018)
State Council
(Regulation) Re-issuance of Drug Registration Fees (No. 75 of 2020) (NMPA-No75-2020 – Standard Chinese) (Effective July 1, 2020)
National Medical Products Administration, State Administration for Market Regulation
(Regulation) Regulations for Drug Clinical Trial Registration and Information Disclosure Management (No. 9 of 2020) (NMPA-No9-2020 – Standard Chinese) (Effective July 1, 2020)
Center for Drug Evaluation, National Medical Products Administration
(Regulation) Regulations for Implementation of the Drug Administration Law of the People’s Republic of China (Decree No. 360) (RegImplemDAL – Standard Chinese) (GoogleTranslate-RegImplemDAL) (Effective September 15, 2002) (Amended February 6, 2016)
State Council
(Regulation) Regulations for Safety Information Evaluation and Management During Drug Clinical Trials (No. 5 of 2020) (NMPA-No5-2020 – Standard Chinese) (GoogleTranslate-NMPA-No5-2020) (Effective July 1, 2020)
Center for Drug Evaluation, National Medical Products Administration
(Regulation) Regulations on Ethical Reviews of Biomedical Research Involving Humans (RegEthics – Standard Chinese) (Effective December 1, 2016)
National Health Commission
(Regulation) Service Platform Human Genetic Resource Management (HGR-Procedures – Standard Chinese) (GoogleTranslate-HGR-Procedures) (Data Unavailable)
Ministry of Science and Technology
(Regulation) Several Policies for Drug Registration Review and Approval (No. 230 of 2015) (NMPA-No230-2015 – English, unofficial translation) (Standard Chinese) (November 11, 2015)
National Medical Products Administration, State Administration for Market Regulation
(Regulation) Technical Requirements for Evaluation of Chemical Drugs Marketed Overseas But Not Marketed in China (No. 21 of 2021) (NMPA-No21-2021 – Standard Chinese) (GoogleTranslate-NMPA-No21-2021) (March 8, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Regulation) Management of Human Genetic Resources (No. 717) (MgmtHumanGen – Standard Chinese) (GoogleTranslate-MgmtHumanGen) (Effective July 1, 2019)
Ministry of Science and Technology
(Guidance) Amendments to Good Manufacturing Practice for Drugs (No. 28) (NMPA-GMPsAmnd – Standard Chinese) (GoogleTranslate-NMPA-GMPsAmnd) (June 30, 2016)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Good Manufacturing Practices for Drugs (No. 13) (NMPA-GMPs – Standard Chinese) (GoogleTranslate-NMPA-GMPs) (Effective May 18, 2015)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Guidelines for General Considerations of Drug Clinical Trials (No. 11 of 2017) (NMPA-No11-2017 – Standard Chinese) (GoogleTranslate-NMPA-No11-2017) (January 18, 2017)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Guidelines for Submission of Drug Clinical Trial Data (No. 16 of 2020) (NMPA-No16-2020 – Standard Chinese) (Effective October 1, 2020)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Guidelines for the Construction of Ethical Review Committees for Clinical Research Involving People (EC-Guide – Standard Chinese) (October 2020)
Office of Medical Ethics Expert Committee of the National Health Commission and the Chinese Hospital Association
(Guidance) Guidelines for the Preservation of Essential Documents for Drug Clinical Trials (No. 37 of 2020) (NMPA-No37-2020 – Standard Chinese) (Effective July 1, 2020)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Guiding Principles for the Adaptive Design of Drug Clinical Trials (No. 6 of 2021) (NMPA-No6-2021 – Standard Chinese) (GoogleTranslate-NMPA-No6-2021) (January 29, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Guiding Principles for the Multiplicity of Drug Clinical Trials (No. 66 of 2020) (NMPA-No66-2021 – Standard Chinese) (GoogleTranslate-NMPA-No66-2021) (December 31, 2020)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Information Guide for Innovative Medicine (Chemicals) Phase III Clinical Trial Pharmaceutical Research (No. 48 of 2018) (NMPA-No48-2018 - Standard Chinese) (GoogleTranslate-NMPA-No48-2018) (March 9, 2018)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Measures for the Supervision and Administration of Drug Production (No. 28 of 2020) (NMPA-No28-2020 – Standard Chinese) (Effective July 1, 2020)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Provisions for Drug Insert Sheets and Labels (SFDA Decree No.24) (ProvLabel – English, unofficial translation) (Standard Chinese) (Effective June 1, 2006)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Quality Management Practices for Drug Clinical Trials (No. 57 of 2020) (NMPA-GCP-No57-2020 – Standard Chinese) (Effective July 1, 2020)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Registration Classification and Application Information for Biological Products (No. 43 of 2020) (NMPA-No43-2020 – Standard Chinese) (Effective July 1, 2020 (registration) and October 1, 2020 (application))
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Registration Classification and Application Information for Chemical Drugs (No. 44 of 2020) (NMPA-No44-2020 – Standard Chinese) (Effective July 1, 2020 (registration) and October 1, 2020 (application))
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Requirements for Drug Records and Data Management for Trial Implementation (No. 74 of 2020) (NMPA-No74-2020 – Standard Chinese) (Effective December 1, 2020)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Standards and Procedures for the Rapid Reporting of Safety Data during Clinical Trials (G-SftyRptStds – Standard Chinese) (GoogleTranslate-G-SftyRptStds) (Effective May 1, 2018)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Technical Guidelines for Clinical Trials of Improved New Chemical Drugs (No. 54 of 2020) (NMPA-No54-2020 – Standard Chinese) (GoogleTranslate-NMPA-No54-2020) (December 31, 2020)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Technical Guidelines for Pharmaceutical Changes During Clinical Trials of Innovative Drugs (No. 22 of 2021) (NMPA-No22-2021 – Standard Chinese) (GoogleTranslate-NMPA-No22-2021) (March 12, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Technical Guidelines for the Application of Phase I Clinical Trials of New Drugs (No. 16 of 2018) (NMPA-No16-2018 – Standard Chinese) (GoogleTranslate-NMPA-No16-2018) (January 11, 2018)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Technical Guiding Principles for Accepting Data from Overseas Clinical Trials of Drugs (No. 52 of 2018) (NMPA-No52-2018 – Standard Chinese) (July 6, 2018)
National Medical Products Administration, State Administration for Market Regulation
(Guidance) Working Procedures for Review of Breakthrough Therapeutics (Clinical Trials) (No. 82 of 2020) (NMPA-No82-2020 – Standard Chinese) (Effective July 8, 2020)
National Medical Products Administration, State Administration for Market Regulation
(Notice) Administration of Drug Clinical Trial Institutions (No. 101 of 2019) (NMPA-NHC-No101-2019 – Standard Chinese) (GoogleTranslate-NMPA-NHC-No101-2019) (Effective December 1, 2019)
National Medical Products Administration, State Administration for Market Regulation, and the National Health Commission
(Notice) Application of the Second Level Guiding Principles of the International Human Drug Registration Technical Coordination Committee (No. 10 of 2018) (NMPA-No10-2018 – Standard Chinese) (GoogleTranslate-NMPA-No10-2018) (January 25, 2018)
State Council
(Notice) Publication of Technical Guidelines for Clinical Trial Data Management (No. 112 of 2016) (NMPA-No112-2016 – Standard Chinese) (July 27, 2016)
National Medical Products Administration, State Administration for Market Regulation
(Notice) Publication of the Work Plan for the Reform of the Classification and Registration of Chemical Drugs (No. 51 of 2016) (NMPA-No51-2016 – Standard Chinese) (GoogleTranslate-NMPA-No51-2016) (March 4, 2016)
National Medical Products Administration, State Administration for Market Regulation
(Notice) Review and Approval Procedures for New Overseas Drugs for Clinical Urgent Needs (No. 79 of 2018) (NMPA-No79-2018 – Standard Chinese) (GoogleTranslate-NMPA-No79-2018) (October 23, 2018)
National Medical Products Administration, State Administration for Market Regulation, and the National Health Commission
(Notice) Use of the New Version of the Drug Production License and Other Licenses (NMPA-No72-2019 – Standard Chinese) (GoogleTranslate-NMPA-No72-2019) (July 25, 2019)
National Medical Products Administration, State Administration for Market Regulation
(Legislation) 21 US Code Chapter 9: Federal Food, Drug, and Cosmetic Act (FDCAct) (June 25, 1938)
US Congress
(Legislation) FDA Reauthorization Act of 2017 (FDARA) (August 18, 2017)
US Congress
(Legislation) Food and Drug Administration Amendments Act of 2007 (FDAAA) (Effective October 1, 2007)
US Congress
(Legislation) Food and Drug Administration Modernization Act of 1997 (FDAMA) (November 21, 1997)
US Congress
(Regulation) Code of Federal Regulations - Title 15, Part 774 - The Commerce Control List (15CFR774) (Data Current as of January 15, 2021)
Bureau of Industry and Security, US Department of Commerce
(Regulation) Code of Federal Regulations - Title 21, Part 210 - Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General (21CFR210) (Data Current as of January 15, 2021)
Food & Drug Administration, US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 21, Part 312 - Investigational New Drug Application (21CFR312) (Data Current as of January 15, 2021)
Food & Drug Administration, US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 21, Part 50 - Protection of Human Subjects (21CFR50) (Data Current as of January 15, 2021)
Food & Drug Administration, US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 21, Part 56 - Institutional Review Boards (21CFR56) (Current as of January 15, 2021)
Food & Drug Administration, US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 42, Part 11 - Clinical Trials Registration and Results Information Submission (42CFR11) (Data Current of January 15, 2021)
US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 42, Part 71 - Foreign Quarantine (42CFR71) (Data Current as of January 15, 2021)
Public Health Service, US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 42, Part 72 - Interstate Shipment of Etiologic Agents (42CFR72) (October 1, 2007)
Public Health Service, US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 42, Part 73 - Select Agents and Toxins (42CFR73) (Data Current as of January 15, 2021)
Public Health Service, US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 45, Part 46, Subpart A - Basic HHS Policy for Protection of Human Research Subjects (RevisedCommonRule) (Data Current as of January 15, 2021)
US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 45, Part 46, Subpart A - Basic HHS Policy for Protection of Human Research Subjects (CommonRule) (Spanish – unofficial translation) (Amended June 23, 2005)
US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 45, Part 46, Subparts B through E (45CFR46-B-E) (Spanish – unofficial translation) (Data Current as of January 15, 2021)
US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 49, Part 173 - Shippers - General Requirements for Shipments and Packagings (49CFR173) (Data Current as of January 15, 2021)
Pipeline and Hazardous Materials Safety Administration, US Department of Transportation
(Regulation) US Code - Title 10, Chapter 55: Medical and Dental Care (10USC55) (2013)
US Congress
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Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees (G-DMCs) (March 2006)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry and Investigators: Safety Reporting Requirements for INDs (Investigational New Drug Applications) and BA/BE (Bioavailability/Bioequivalence) Studies (G-IND-Safety) (December 2012)
Food and Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Adaptive Designs for Clinical Trials of Drugs and Biologics (G-AdaptiveTrials) (November 2019)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Current Good Manufacturing Practice (CGMP) for Phase 1 Investigational Drugs (G-CGMP-Phase1) (July 2008)
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Food & Drug Administration, US Department of Health and Human Services
(Guidance) Guidance for Industry: E17 General Principles for Planning and Design of Multiregional Clinical Trials (US-ICH-E17) (July 2018)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) (US-ICH-GCPs) (March 2018)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Enhancing the Diversity of Clinical Trial Populations - Eligibility Criteria, Enrollment Practices, and Trial Designs (G-CTDiversity) (November 2020)
Food & Drug Administration, US Department of Health & Human Services
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Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Providing Regulatory Submissions in Electronic Format - Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (G-PharmeCTD) (Revision 7) (February 2020)
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(Guidance) Guidance for Industry: Providing Regulatory Submissions to CBER in Electronic Format - Investigational New Drug Applications (INDs) (G-CBER-ElecINDs) (March 2002)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Special Protocol Assessment (G-SPA) (Revision 1) (April 2018)
Food & Drug Administration, US Department of Health and Human Services
(Guidance) Guidance for Industry: Use of Electronic Health Record Data in Clinical Investigations (G-eHealthRecords) (July 2018)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans (G-PedStudyPlans) (July 2020)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutional Review Boards (IRBs) Frequently Asked Questions - IRB Registration (G-IRBReg-FAQs) (July 2009)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent Requirements for Emergency Research (G-ICEmergencyReqs) (Updated April 2013)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutional Review Boards, Investigators and Sponsors: Use of Electronic Informed Consent in Clinical Investigations - Questions and Answers (G-ElectronicIC) (December 2016)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutions and IRBs: Institutional Review Board (IRB) Written Procedures (G-IRBProcs) (May 2018)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for IRBs, Clinical Investigators, and Sponsors: IRB Continuing Review After Clinical Investigation Approval (G-IRBContRev) (February 2012)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Responsible Parties, Submitters of Certain Applications and Submissions to FDA, and FDA Staff: Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank (G-DataBankPnlty) (August 2020)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Sponsors, Institutional Review Boards, and FDA Staff: Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable (G-IC-IVDs) (April 2006)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Sponsors, Investigators, and Institutional Review Boards: Impact of Certain Provisions of the Revised Common Rule on FDA-Regulated Clinical Investigations (G-RevComRule-FDA) (October 2018)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Sponsors, Investigators, and Institutional Review Boards: IRB Waiver or Alteration of Informed Consent for Clinical Investigations Involving No More Than Minimal Risk to Human Subjects (G-MinRiskWaiver) (July 2017)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance on Coded Private Information or Specimens Use in Research (G-SpecimensResrch) (October 16, 2008)
Office for Human Research Protections, US Department of Health & Human Services
(Guidance) Issues to Consider in the Research Use of Stored Data or Tissues (1996/1997) (G-StoredData-Tissues) (November 7, 1997)
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(Guidance) Transmitting Electronic Submissions Using eCTD Specifications (G-eCTDspecs) (Version 1.8) (April 1, 2019)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Unanticipated Problems Involving Risks and Adverse Events Guidance (G-HHS-AEReqs) (January 15, 2007)
Office for Human Research Protections, US Department of Health & Human Services
(Information Sheet) Guidance for Institutional Review Boards and Clinical Investigators: A Guide to Informed Consent (G-ICInfoSheet) (January 1998)
Food & Drug Administration, US Department of Health & Human Services
(Information Sheet) Guidance for Institutional Review Boards and Clinical Investigators: Cooperative Research (G-CoopRes) (January 1998)
Food & Drug Administration, US Department of Health & Human Services
(Information Sheet) Guidance for Institutional Review Boards and Clinical Investigators: Emergency Use of an Investigational Drug or Biologic (G-EmrgncyUse) (January 1998)
Food & Drug Administration, US Department of Health & Human Services
(Information Sheet) Guidance for Institutional Review Boards and Clinical Investigators: Institutional Review Boards Frequently Asked Questions (G-IRBFAQs) (January 1998)
Food & Drug Administration, US Department of Health & Human Services
(Information Sheet) Guidance for Institutional Review Boards and Clinical Investigators: Non-Local IRB Review (G-IRBReview) (January 1998)
Food & Drug Administration, US Department of Health & Human Services
(Information Sheet) Guidance for Institutional Review Boards and Clinical Investigators: Payment and Reimbursement to Research Subjects (G-SbjctPayment) (January 2018)
Food & Drug Administration, US Department of Health & Human Services
(Information Sheet) Guidance for IRBs, Clinical Investigators, and Sponsors: FDA Institutional Review Board Inspections (G-IRBInspect) (January 2006)
Food & Drug Administration, US Department of Health & Human Services
(Information Sheet) Guidance for Sponsors, Clinical Investigators, and IRBs: Frequently Asked Questions - Statement of Investigator (Form FDA 1572) (G-1572FAQs) (May 2010)
Food & Drug Administration, US Department of Health & Human Services
(Policy) Final NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research (NOT-OD-16-094) (NIHNotice16-094) (Effective January 25, 2018)
National Institutes of Health, US Department of Health & Human Services
(Policy) NIH and FDA Release Protocol Template for Phase 2 and 3 IND/IDE Clinical Trials (NOT-OD-17-064) (NIHNotice17-064) (May 2, 2017)
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(Policy) NIH Policy for Data and Safety Monitoring (NIHDataSftyMntrng) (June 10, 1998)
National Institutes of Health, US Department of Health & Human Services
(Policy) NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information (NIHTrialInfo) (Effective January 18, 2017)
National Institutes of Health, US Department of Health & Human Services
(Policy) Revision: Notice of Extension of Effective Date for Final NIH Policy on the Use of Single Institution Review Board for Multi-Site Research (NOT-OD-17-076) (NIHNotice17-076) (Effective January 25, 2018)
National Institutes of Health, US Department of Health & Human Services
Sources > Additional Resources
(Article) China (CHN-22) (April 2020)
Kingham, Richard; The Life Sciences Law Review, Edition 8
(Article) China and the Evolving Regulatory Landscape (CHN-9) (September 4, 2019)
Baruah, Megha; European Pharmaceutical Review
(Article) China Approves Ethics Advisory Group after CRISPR-babies Scandal (CHN-12) (August 8, 2019)
Jia, Hepeng; Nature
(Article) China National Drug Administration Sets Guidelines for Overseas Drug Trial Data (CHN-19) (August 9, 2018)
Liao, Todd; Morgan Lewis
(Article) China Passes Personal Information Protection Law (CHN-25) (September 10, 2021)
Ropes & Gray
(Article) China Promulgates Revised Drug Registration Regulation (CHN-8) (April 29, 2020)
Covington
(Article) China’s National Medical Products Administration Finalizes Two Implementing Rules of the Drug Administration Law (CHN-18) (April 2, 2020)
Li, Lei and Yang, Chen; Sidley Austin LLP
(Article) China’s New State Administration for Market Regulation: What to Know and What to Expect (CHN-21) (April 3, 2018)
Wang, Katherine; Ropes & Grey
(Article) China’s State Council Publishes New Regulations on the Management of Human Genetic Resources (CHN-16) (June 14, 2019)
Wang, Katherine; Ropes and Gray
(Article) China’s State Food and Drug Administration Discusses Drug Applications: A Q&A with Officers of the Departments of State Food and Drug Administration, China, moderated by Ji Xie (CHN-4) (November 2, 2010)
Pharmaceutical Technology
(Article) In Review: The Life Sciences Regulatory Regime in China (CHN-20) (March 24, 2021)
Covington & Burling
(Article) Interpretation of the "Methods for Ethical Examination of Biomedical Research Concerning People" (CHN-41 - Standard Chinese) (November 4, 2016)
National Health Commission
(Article) Interpretation of the Technical Guiding Principles for Accepting Data from Overseas Clinical Trials of Drugs (CHN-43 - Standard Chinese) (July 10, 2018)
National Medical Products Administration, State Administration for Market Regulation
(Article) Key Points of Concern for the Pharmaceutical Industry under the New Regulations of Human Genetic Resources: Interpretation of the Regulations on the Management of Human Genetic Resources (CHN-10 - Standard Chinese) (June 10, 2019)
Global Law Office, Lexology
(Article) Legal Protection of the Rights of Clinical Trial Subjects in China (CHN-26) (March 26, 2018)
Ren, Y., Jin, X., Jiang, S., Jiang, B.; The Journal of Biomedical Research
(Article) Life Sciences: Product Regulation and Liability in China (CHN-11) (January 7, 2019)
Wang, Katherine and Wu, Tina; Ropes & Gray
(Article) National Medical Products Newsletter, 2020. Volume 5 (CHN-1) (May 2020)
China Center for Food and Drug International Exchange (CCFDIE)
(Article) Provisions on the Filing and Management of Drug Clinical Trial Institutions (CHN-5 - Standard Chinese) (December 6, 2019)
Xinhuanet
(Article) The Regulatory Requirements and Key Points of Drug Clinical Trials Registration in China (CHN-7) (May 20, 2020)
Yao, Zhuxing and Wang, Haixue; Applied Clinical Trials
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CR Medicon
(Article) Xi Jinping Hosted the Ninth Meeting of the Central Committee for Comprehensive Deepening Reform (CHN-3 - Standard Chinese) (July 24, 2019)
Xinhua News Agency
(Document) Nagoya Protocol on Access and Benefit-sharing (CHN-30) (2011)
Convention on Biological Diversity, United Nations
(Document) The Chinese Ethical Review System and its Compliance Mechanisms (CHN-45) (2016)
Xinqing, Z., Wenxia, Z., Yandong, Z.; TRUST Equitable Research Partnerships
(International Guidance) Declaration of Helsinki (CHN-84) (October 19, 2013)
World Medical Association
(International Guidance) ICH Guideline E2B (R3) on Electronic Transmission of Individual Case Safety Reports (ICSRs) - Data Elements and Message Specification - Implementation Guide (CHN-40) (Step 5 Version) (July 2013)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(International Guidance) ICH Harmonised Guideline: The Common Technical Document for the Registration of Pharmaceuticals for Human Use (M4) (CHN-38) (Step 5 Versions) (Modules range from 2002-2016)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(International Guidance) ICH Harmonised Tripartite Guideline: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (E2A) (CHN-39) (Step 4 Version) (October 27, 1994)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(International Guidance) Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2) (CHN-37) (Step 5 Version) (November 16, 2016)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
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National Medical Products Administration, State Administration for Market Regulation
(Webpage) Administrative License (CHN-76 - Standard Chinese) (Current as of October 26, 2021)
Ministry of Science and Technology
(Webpage) Applicant's Window (CHN-58 - Standard Chinese) (Current as of October 26, 2021)
Center for Drug Evaluation, National Medical Products Administration
(Webpage) Approval of Clinical Trials of Domestic Chemicals, Handling Guideline (CHN-63 - Standard Chinese) (Current as of October 26, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Webpage) Approval of Clinical Trials of Domestic Preventive Biological Products, Handling Guideline (CHN-65 - Standard Chinese) (Current as of October 26, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Webpage) Approval of Clinical Trials of Domestic Therapeutic Biological Products, Handling Guideline (CHN-64 - Standard Chinese) (Current as of October 26, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Webpage) Approval of Clinical Trials of Imported Chemicals, Handling Guideline (CHN-66 - Standard Chinese) (Current as of October 26, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Webpage) Approval of Clinical Trials of Imported Preventive Biological Products, Handling Guideline (CHN-68 - Standard Chinese) (Current as of October 26, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Webpage) Approval of Clinical Trials of Imported Therapeutic Biological Products, Handling Guideline (CHN-67 - Standard Chinese) (Current as of October 26, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Webpage) Bioequivalence of Chemical Generic Drugs and Clinical Trial Filing, Handling Guideline (CHN-70 - Standard Chinese) (Current as of October 26, 2021)
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(Webpage) Drug and Medical Device Clinical Trial Institution Filing System (CHN-82 - Standard Chinese) (Current as of October 26, 2021)
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(Webpage) Drug Clinical Trial Registration and Information Disclosure Platform (CHN-53 - Standard Chinese) (Current as of October 26, 2021)
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(Webpage) ICH Guidelines (CHN-49 - Standard Chinese) (Current as of October 26, 2021)
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(Webpage) Integrated System Catalogue - Human Genetic Resource Management (CHN-56 - Standard Chinese) (Current as of October 26, 2021)
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(Webpage) Internal Organization (CHN-77 - Standard Chinese) (Current as of October 26, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Webpage) Main Duties of National Medical Products Administration (CHN-78 - Standard Chinese) (Current as of October 26, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Webpage) Members and Observers (CHN-59) (Current as of October 26, 2021)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(Webpage) National Medical Products Administration – Drug Regulatory Documents (CHN-60 - Standard Chinese) (Current as of October 26, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Webpage) National Medical Products Administration (CHN-81) (Standard Chinese) (Current as of October 26, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Webpage) Online Service Hall of the National Medical Products Administration (CHN-71 - Standard Chinese) (Current as of October 26, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Webpage) Priority Review and Approval of Drug Registration Applications, Handling Guideline (CHN-69 - Standard Chinese) (Current as of October 26, 2021)
National Medical Products Administration, State Administration for Market Regulation
(Webpage) Sanitary Quarantine Approval for Special Items (CHN-54) (Current as of October 26, 2021)
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(Webpage) What is AQSIQ? (CHN-46) (Current as of October 26, 2021)
General Administration of Quality Supervision, Inspection & Quarantine
(Document) Announcement: Federal Websites that will Satisfy the Revised Common Rule’s Requirement to Post Clinical Trial Consent Forms (45 CFR 46.116(h)) (USA-12) (August 15, 2018)
US Department of Health & Human Services
(Document) Attachment D: FAQ's Terms and Recommendations on Informed Consent and Research Use of Biospecimens (USA-9) (July 20, 2011)
Office for Human Research Protections, US Department of Health & Human Services
(Document) Dangerous Goods Regulations (USA-21) (61st Edition) (Effective as of January 2021)
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Food & Drug Administration, US Department of Health & Human Services
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(Webpage) Clinical Trials Guidance Documents (USA-47) (FDA reviewed January 21, 2020)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Clinical Trials Guidance Documents (USA-51) (Current as of June 25, 2021)
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(Webpage) ClinicalTrials.gov - Frequently Asked Questions (USA-26) (Last Reviewed December 2020)
National Institutes of Health, US Department of Health & Human Services
(Webpage) ClinicalTrials.gov (USA-78) (Current as of January 20, 2021)
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(Webpage) Commerce Control List (CCL) (USA-30) (Current as of January 20, 2021)
US Department of Commerce
(Webpage) Electronic Common Technical Document (eCTD) (USA-34) (FDA reviewed November 13, 2020)
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Food & Drug Administration, US Department of Health & Human Services
(Webpage) Electronic Submission System - Welcome to the Electronic Submission System for FWAs and IRB Registrations (USA-28) (Current as of January 20, 2021)
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(Webpage) Electronic Submissions Gateway (USA-44) (FDA reviewed November 20, 2020)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) FDA Organization (USA-32) (FDA reviewed January 17, 2020)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) FDA Overview Organization Chart (USA-33) (FDA reviewed December 30, 2020)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) FDA's Role: ClinicalTrials.gov Information (USA-49) (FDA reviewed February 12, 2020)
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(Webpage) Federal Policy for the Protection of Human Subjects ('Common Rule') (USA-65) (Last Reviewed March 18, 2016)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Federalwide Assurance (FWA) for the Protection of Human Subjects (USA-57) (Last Reviewed July 31, 2017)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Frequently Asked Questions: Human Subjects (USA-72) (Last Updated April 28, 2020)
National Institutes of Health, US Department of Health & Human Services
(Webpage) HHS and 16 Other Federal Departments and Agencies Issue a Final Rule to Delay for an Additional 6 Months the General Compliance Date of Revisions to the Common Rule While Allowing the Use of Three Burden-Reducing Provisions During the Delay Period (USA-55) (June 18, 2018)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Human Subject Regulations Decision Charts (USA-74) (Last Reviewed June 30, 2020)
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(Webpage) Import Permit Applications (USA-73) (Last Reviewed September 18, 2020)
Centers for Disease Control and Prevention, US Department of Health & Human Services
(Webpage) Import Permit Program (USA-31) (Last Reviewed September 17, 2020)
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(Webpage) IND Application Reporting: Safety Reports (USA-38) (FDA reviewed October 9, 2015)
Food & Drug Administration, US Department of Health & Human Services
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Food & Drug Administration, US Department of Health & Human Services
(Webpage) Information for Sponsor-Investigators Submitting Investigational New Drug Applications (INDs) (USA-41) (FDA reviewed June 27, 2017)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Information Sheet Guidance for Institutional Review Boards (IRBs), Clinical Investigators, and Sponsors (USA-50) (FDA reviewed August 19, 2020)
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(Webpage) Informed Consent FAQs (USA-60) (Current as of January 20, 2021)
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(Webpage) IRB Registration Process FAQs (USA-61) (Current as of January 20, 2021)
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(Webpage) Prisoner Research FAQs (USA-62) (Current as of January 20, 2021)
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(Webpage) Revised Common Rule Q&As (USA-54) (Last Updated February 25, 2019)
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(Webpage) Revised Common Rule (USA-66) (Current as of January 20, 2021)
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(Webpage) Single IRB Policy to Streamline Reviews of Multi Site Research (USA-69) (June 20, 2016)
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(Webpage) Submit Using eCTD (USA-35) (FDA reviewed February 23, 2017)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Summary of HHS/NIH Initiatives to Enhance Availability of Clinical Trial Information (USA-70) (September 15, 2016)
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(Webpage) The Drug Development Process - Step 3: Clinical Research (USA-46) (FDA reviewed January 4, 2018)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Types of Applications (USA-37) (FDA reviewed October 23, 2014)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Vaccines, Blood, and Biologics - Information on Submitting an Investigational New Drug Application (USA-53) (FDA reviewed January 29, 2018)
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(Webpage) Vulnerable Populations (USA-64) (Current as of January 20, 2021)
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Sources > Forms
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Independent Ethics Committee, Shanghai Clinical Research Center
(Form) Human Research Ethics Review Application Documents (CHN-34 - Standard Chinese) (Date Unavailable)
Independent Ethics Committee, Shanghai Clinical Research Center
(Form) CIOMS Form I (USA-13) (Date Unavailable)
Council for International Organizations of Medical Sciences
(Form) Form FDA 1571 (04/19): Investigational New Drug Application (IND) (USA-76) (Expires March 31, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Form) Form FDA 1572 (3/19): Statement of Investigator (USA-77) (Expires: March 31, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Form) Form FDA 3500A (2/19): MedWatch Medical Products Reporting Program - Mandatory (USA-75) (Expires November 30, 2021)
Food & Drug Administration, US Department of Health & Human Services
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Search example: serious adverse event
Result: Will contain serious and/or adverse and/or event
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Search example: serious +adverse event
Result: Will contain adverse and may contain serious and/or event
- Leading minus sign indicates that the word must not be present
Search example: serious adverse -event
Result: Will contain serious and/or adverse but won’t contain event
“ ” Exact phrase must be present
Search example: “serious adverse event”
Result: Will contain the phrase serious adverse event
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