Abstract
Background:
China’s ethics committees alone are unable to meet the growing need for human participant protection. Several scandals in recent years indicate weaknesses in the protection of human participants in China.
Objectives:
The aim of the study is to summarize the status and problems of human research protection program in China and to explore its establishment proposals at national and hospital levels.
Research design:
To conduct literature retrieval, Chinese National Knowledge Infrastructure, Chinese Biomedical Document Database, and English databases Web of Science and PubMed were searched; laws, guidelines, and regulations were also searched on web by Google and Chinese search engine Baidu.
Ethical considerations:
No data were collected from human participants, and ethical review was not required.
Findings:
There are problems for China’s Human Research Protection Program, such as weak relevant legal systems, insufficient administrative supervision, and incompetent ethics committee capacities. To fully protect human participants, China should promote the development of Human Research Protection Program, which can formulate ethics-related laws, improve regulations for the protection of the safety and rights of human participants, strengthen supervision, and enforce compensation for human participants. Owing to the frequency with which human participants are recruited in hospitals in China, hospitals can utilize existing ethics committees and establish data and safety monitoring committees, quality control, fund and contract management, and conflict of interest management offices.
Discussion:
As a growing program, it remains necessary to learn from the experience of developed countries with high ethics standards and reformulate them to fit China’s conditions to explore potential future development. The program will also be an experience for other developing countries.
Conclusion:
Human Research Protection Program can strengthen communication and coordination among various hospital departments to effectively protect the rights and welfare of human participants.
Introduction
The “golden rice,” “head transplant,” “gene-edited baby,” and “anti-cancer of malaria” events exposed the sometimes insufficient protections of human participants in China. 1 –4 With quick development of human research and large number of international clinical trials for drug and medical device in China, though laws and regulations related to human participant protection are constantly improving, participants protection in the procedure of ethics review and supervision needs to keep up with the pace of development. Therefore, China is a typical representative of developing countries that need to urgently establish the Human Research Protection Program, which will also be an experience for other developing countries.
Current China’s policies and regulations cannot match the rapid development of biomedical human research and their varied contexts. 5 Since 2010, human research funds supported by the government and hospitals have expanded exponentially, and colleges, universities, and research institutes have been involved in human research. A growing number of researches involving human participants have extended beyond a single-center project across China and even international sphere. Furthermore, large-scale population cohort research was established to collect, preserve, and re-use biological samples to carry out diverse research methods such as genetic testing. 6 The use of new technologies has not only provided different tools for human research but has also highlighted higher requirements and challenges for the protection of human participants.
Status and problems of the Human Research Protection Program in China
The Human Research Protection Program is an institutional-wide program coordinated by hospital and/or higher education institution and composed of ethics committees and other entities that are responsible for protecting the safety and rights of participants in research conducted or reviewed by the institution. 7 Since the first ethics committee was established in China over 30 years ago, human participant protections have been strengthened by ethics committees in various hospital levels with imbalanced development of review capabilities. 8 Currently, even in drug and medical device clinical trials initiated by sponsors for registration in China, providing compensation to human participants following damages is often difficult to accomplish. 9 For the other human research works initiated by sponsors and investigators, compensating human participants is even more difficult. 10
To better protect the safety and rights of human participants and in line with international ethical guidelines, China should nationally solve the problems; China should gradually establish the Human Research Protection Program on the foundation of an ethics committee, continuously explore its mode of operation, and effectively protect the safety and rights of human participants through facilitating communication and coordination among multiple departments to ensure a high quality of human research. The Human Research Protection Program should first be established in hospital and then in higher education institutions because the development of ethics committee in higher education institutions is far behind in hospitals.
Weak relevant legal systems
As one of a few China’s laws that specifically protect the safety and rights of human research participants, the Civil Code will be effective on 1 January 2021, which mentions the rights of human participants. There are no detailed penalties including civil and criminal liability for sponsor or investigator violations of human participants’ rights and welfare. The content of human participant protection is also mentioned in relevant regulations, such as in “Regulation for Ethical Review of Clinical Research of Traditional Chinese Medicine” in 2010, “Measures for the Ethical Review of Biomedical Research Involving Humans” in 2016, and “Good Clinical Practice” in 2020.
These regulations are released by the National Health Commission or National Medical Products Administration and are suitable for medical institutions, such as hospital and medical research institute. Nevertheless, these regulations cannot supervise higher education institutions, which belong to the Ministry of Science and Technology and the Ministry of Education. There is no national special department to supervise all human research works in China.
Insufficient administrative supervision
The fifth regulation of “Measures for the Ethical Review of Biomedical Research Involving Humans” in 2016 states, “The National Health and Family Planning Commission is responsible for the supervision and management of the national ethics review of biomedical research involving human participants, and the establishment of the National Medical Ethics Expert Committee.” The state administration of traditional Chinese medicine is responsible for supervising and managing medical research ethics review processes and establishing a national Chinese medicine ethics expert committee. The provincial health and family planning administrative department established a provincial medical ethics expert committee. The local health and family planning administrative department at or above the county level is responsible for supervising and managing a biomedical research ethics review of human participants involved in the administrative region. The national medical ethics expert committee and the national Chinese medicine ethics expert committee provide guidance and consultation for major ethical issues in human research. The provincial medical ethics expert committee provides inspection, evaluation, training, consultation, and guidance.
However, there is insufficient human research administrative supervision system in China, and there is only mandatory registration for drug, medical device, and vaccine clinical trials for marketing that are required by National Medical Products Administration. Most investigators register in www.clinicaltrials.gov or Chinese Clinical Trial Registry, which is one of the International Clinical Trial Registration Platforms of World Health Organization, to comply with publication requirements regarding human research papers in international/China’s medical journals. Chinese Clinical Trial Registry is under the responsibility of the China Evidence-Based Medicine Center of the former Ministry of Health. It is not a government action without legal support and cannot be supervised by an administrative department.
Incompetent ethics committee capacities
Currently, China’s ethics reviews are at least partly limited regarding review quality and capacity. 1 Although the related China’s departments clearly stipulate that a hospital conducting human research must establish an ethics committee, most ethics committee members are selected from the hospital. Leadership intention and the interests of other departments sometimes influence the independent review of ethics committees, which impairs ethics committees’ ability to guarantee objectivity and neutrality, thus making it difficult to comprehensively protect human participants. 11
The latest information on Good Clinical Practice and ethics review is not regularly trained to ethics committee members, thus leading to questionable and potentially low-quality reviews. 8 Under the unfavorable conditions of insufficient capacity and resource shortages, hospitals require more human research to promote their competitiveness, the number of human research initiated by investigators is too large, and neither ethics review quality nor process supervision after ethical approval can be guaranteed. 12 Most China’s ethics committees have no self-evaluation indicators or external accreditation, which cause the difficulty to monitor the quality and efficiency of ethics review. Ethics committees may delay research initiation and implementation, and overprotect lower risk human participants, which not only waste resources but also deviate from the original intention of protecting human participants with higher risk.
Improve Human Research Protection Program at the national level
On 26 February 2019, the National Health Commission of the People’s Republic of China issued a draft of the “Regulations on the Management of Clinical Applications of New Biomedical Technologies,” which proposed more stringent requirements for human research, transformation, and application of biomedical new technologies and their supervision and management. 13 On 24 July 2019, the Central People’s Government of China published “National Science and Technology Ethics Committee Formation Plan” to establish a national science and technology ethics committee that may improve human participant protection and health development research in China. 14
Risks associated with new biomedical technology are difficult to predict, and the increasing self-awareness and rights of the public along with multicultural differences make problems associated with human participant protection increasingly prominent and complex. Specifically, the issues of informed consent, placebo use, compensation, and equitable distribution of risk and benefits in international multi-center human research are growing increasingly acute and explicit. International multi-center human research not only abide by international ethics guidelines but also consider local regulation to respect the culture, dignity, and wishes of participants for better protection. To further strengthen the modernization of the Human Research Protection Program, improve the protection of human participants and enhance ethical supervision, and promote the development of valuable research, government departments, hospitals, sponsors, ethics committees, investigators, and human participants should each assume corresponding responsibilities to ensure the scientific and ethical nature of human research.
Develop ethics laws
France enacted the Law of Bioethics in July 1994 15,16 and the United States enacted the 45 CFR 46 (Common Rule) for ethics committees. 17 France and the United States both establish ethics law to cover all human research governed by different national ministries. These laws have been periodically revised to better protect the rights and welfare of participants. China can learn from these countries and establish effective ethical laws, which not only strengthen the ethics committee supervision but also provide legal bases for punishing offenders to effectively manage and guide human research practices.
Improve regulations on human participant protections
Several regulations have already been implemented in China, such as “Good Clinical Practice” in 2020 and “Guiding Principles of Ethical Review of Drug Clinical Trials” in 2010, which emphasize the issues related to protection of human participants in drug clinical trials but not in the other human research. “Good Clinical Practice” in 2020 emphasizes to protect the rights and welfare of vulnerable participants. “Measures for the Ethical Review of Biomedical Research Involving Humans” in 2016 addresses human participant protection in all types of medical and health institutions at all levels, but has no legal effects, particularly regarding the protection of vulnerable participants.
Related regulations should clarify the implementation of participants’ rights in all human research, including basic medical services, informed consent, privacy, autonomy, and compensation, as well as specify the details of protection operations. If informed consent is required, the human participant should be informed in detail about the risks and benefits from the proposed research. The human participant can withdraw from human research for any reason without having to justify their withdrawal to the investigator or compensate sponsor and investigator for any losses incurred.
Administrative system for human participant protections
An administrative system should be established to effectively enforce the protection of human research participants. The transparency of human research funds should be improved by forcing online registration of all levels of funds, and an accountability system should be established. The functions of China’s health management departments should be improved to supervise human research and standardize management-related units (sponsors, hospitals) and personnel (investigators, human participants). To minimize high-risk and low-benefit research and better protect human participants’ rights and welfare, sponsors’ work processes and investigators’ prior admission approvals of research projects and ethical review should be supervised.
Mandatory human participant compensation
Human participants inevitably face a number of risks, such as physical (invasive procedure, adverse events), psychological, social (privacy, discrimination), economic, legal, and dignitary harms. 18 If the participants are compromised, their legal rights and welfare must be protected. If the sponsor fault leads to damage for any human participants, the sponsor should appropriately compensate the participants. Sponsors should purchase human research liability insurance for human participants. In the case that the clinical trial drug or medical device is found to be at fault following human participant damage, human participants should be sufficiently compensated by sponsors. When investigators are at fault, human participants should be compensated by investigators. It is inevitable that some human participants will be harmed in high-risk research; therefore, if sponsors are required to be responsible for fully compensating human participants in the event of damage, there may be no sponsors willing to conduct human research, which will delay the emergence of new drugs, medical devices, or medical technologies, thus ultimately impairing patient interests overall.
Constructing Human Research Protection Program in hospitals
China must develop ethics committees and their regulatory mechanisms, and first build the Human Research Protection Program at hospital level and then at higher education institution level. The implementation of the Human Research Protection Program is a new concept, and its mode of operation is still being explored. It is primarily carried out among human research protocol management institutions (such as hospitals, higher education institutions), ethics committees (such as in hospitals, in higher education institution), investigators and fund agencies (such as government fund departments), and human participants or their legal guardian. The program in hospital is directly managed, funded, and administratively supported. It will form an operational mechanism through which effective cooperation, integration, and supervision among hospital authorities, ethics committees, departments, and investigators may be assured. In the process of exploration of the Human Research Protection Program, the following related functions are performed by the existing related departments or newly established departments of the hospital.
Ethics committee
As the core part of the Human Research Protection Program, ethics committees should comprise members of different genders, be multi-disciplinary, and at least have one lay person with no affiliation to the institution according to international ethics guidelines 19,20 and China’s regulation. 21 Ethics committees must be supervised and registered by an independent national ethics committee. Ethics committee should formally review human research protocols according to its standard operating procedure for high review quality. To better protect human participants from suffering unnecessary damage, ethics committee members’ ethics review knowledge and skills should be enhanced so that the risks in human research protocol can be prospectively discovered and minimized. Ethics committees regularly use internal quality systems to conduct their own review and management procedures. In the Human Research Protection Program, ethics committees must perform initial and continuing reviews; participate in training, communication, and coordination with other departments; organize documents; and revise standard operating procedures.
To perform one of the essential functions of ethics committee, training centers are responsible for initial Good Clinical Practice training and ethics training for all hospital investigators, as well as maintaining these practices. Training centers also train ethics committee members and staff of ethics committee office. In particular, when a protocol violation occurs, ethics committees and sponsors must force the investigators to participate in training. The investigators will be allowed to continue research after training is complete.
Quality control office
Quality control office primarily performs auditing and management functions for investigators who initiated human research, but not for sponsors who launched clinical trials of drug and medical device for the purpose of registration. Drug clinical trial institution conducts quality control for clinical trials of drug and medical device, which aims to supervise the specific implementation process, including either regular or irregular audits to ensure that human research is being conducted according to the protocol, following standard operating procedures and Good Clinical Practice, and respecting laws and regulations related to recording, analyzing, and maintaining research data to reduce protocol violations. Quality control office regularly examines scientific misconduct and violations of the ethical approval protocols to ensure quality control and process supervision. Quality control office staff may conduct routine and forward-looking on-site audits as well as targeted visits, and then submit interview reports to the ethics committee. These reports may be further reviewed by the ethics committee. The ethics committee will transmit review opinion of the interview reports to quality control office; then, quality control office staff will follow up and supervise the effective resolution of relevant issues in a timely manner. Furthermore, quality control office staff may participate in ethics committee board meetings (but have no voting rights). The ethics committee also regularly reports the conditions of submitted protocol to quality control office. It may also be stipulated that ethics committee office, quality control office, and other hospital departments regularly attend meetings to discuss quality control reports and to solve human participant protection issues that arise during the research.
Data and safety monitoring committee
Data and safety monitoring committees should review cumulative research data to evaluate safety, research conduct, and scientific validity and integrity of the research. Data and safety monitoring committee, which is composed of experts, independently reviews human research processes to ensure that the obtained data are authentic and reliable to ensure the safety of human participants. For clinical trials of drug and medical device that require registration, the sponsor may entrust or establish its own data and safety monitoring committee. However, for the other human research works, hospital may need to establish its data and safety monitoring committee, which can also be provided to service the sponsor with clinical trials for registration. Research with high-risk interventions, innovative at early stage, or long-term with complex design often requires the establishment of data and safety monitoring committees. For large-scale, multi-center research, especially with complex or high-risk designs, data and safety monitoring committee can closely and independently monitor the research.
Committee members should have relevant professional qualifications, work experience in data and safety monitoring, familiarity with human research processes, and no significant conflict of interest. Members should be from multi-disciplinary backgrounds, including clinical medicine, clinical trial management, ethics, epidemiology, and statistics. At least one member should have mastered biostatistics and interim analysis with a deep understanding of protocol processes and common problems to evaluate research safety and interpret research data. Data and safety monitoring committee should be developed on the basis of human research deadlines, risks, program design, populations, disease/symptoms, interventions, and endpoint/result indicators. Odd-number memberships of at least three members are conducive to achieving a majority during voting. Reviewing the interim data is the most basic and the primary responsibility in evaluating whether the ethical approval protocols can be carried out reasonably and advising sponsors accordingly. The essence of data and safety monitoring committee lies in its proposed organization, and its operation is independent and confidential. This is the only committee to review the data and analysis results, which are otherwise confidential and only to be seen by sponsors and investigators. 22 The level of monitoring should be consistent with the risk, scale, and complexity of the research. 22
Fund and contract management office
As an independent department or a part function of financial department, fund and contract management office is responsible for providing necessary financial and management support for fund and contract. The human research contract is an important legal document between sponsors with hospitals and/or investigators to clarify their respective rights, responsibilities, and obligations, which detail the full protection of human participants’ rights and welfare. By auditing the human research contract, the authenticity, legality, and validity of the audit contract can be pre-examined in advance, and possible risks in the research process can be avoided. To protect human participants’ rights and welfare on legal level, human research contract should be audited on a standardized basis, including standardizing the contract, clarifying the responsibilities of each party, and ensuring that the respective responsibilities of sponsors, hospitals, and investigators are clearly outlined. Human research contract should also detail the research behavior of each party and outline the implementation of research process in accordance with regulations, which will contribute to protecting human participants’ rights and welfare.
Conflict of interest management office
Conflict of interest and its management have comprised a new area of focus for human research. The conflict of interest in human research involves sponsors, hospital administrator, staff of drug clinical trial institution, investigators, and ethics committee members and staff. Its management policy development and implementation must be further explored. However, the ethics committee should pay attention to conflict of interest related to human research, but cannot manage other conflicts of interest, which are not covered by ethics review, and affect the rights and welfare of human participants. Conflict of interest management office is a key in the Human Research Protection Program. When certain interests may affect research and infringe upon human participants’ rights and welfare, these are denoted as conflict of economic and non-economic interests. Private interest, family and close personal relationship, financial relationship, and personal benefit can all lead to conflict of interest. As competition of social and economic interests among hospitals and investigators in China intensifies, hospital administrations have refined various assessment indicators within the medical field, including the quantitative analysis of human research protocols, which have undoubtedly become a vague interest chain for hospitals and investigators. The pursuit of scientific truth also yields conflict of interest. 23,24 Therefore, ethics committees should review potential conflict of interest among research team members, research management department, and hospital administrators.
Offices should formulate a conflict of interest management approach, including defining conflict of interest for ethics committee members and staff, and clarify when ethics committee members are required to report conflicts of interest and cease ethics review when members have conflict of interests. Conflict of interest management office is responsible for formulating and publishing management methods for conflict of interest and is closely related to ethics committees to assist in management. Investigators are required to submit a conflict of interest statement and, if necessary, clarify conflicts of interest with clear and understandable language in informed consent forms. A conflict of interest should also be first stated in each board meeting review of ethics committee. Representatives of ethics committee may attend meetings of the conflict of interest management office and convey feedback reports to their respective ethics committee. Conflict of interest management office should promptly report conflict of interest management methods to ethics committee, and the two parties shall reach effective communication and cooperation.
Conclusion
Establishing the Human Research Protection Program is conducive to internationalizing human research and is a basis for enhancing the core competitiveness and influence of human research. Furthermore, it plays an important role in promoting the scientific development of human research. The relevant laws and regulations on the Human Research Protection Program are still weak, and there is no experience for reference in China. This is both a challenge and an opportunity. The aforementioned hospital-level Human Research Protection Program aims to emphasize the close cooperation between various hospital departments to ensure that scientific design and responsible research activities are sufficiently and accurately carried out and risks are minimized in compliance with laws, regulations, and hospital policies to protect the rights and welfare of human participants. Regular communication and meeting systems among departments help promote the effective operation of the Human Research Protection Program and implementation of internal supervision. In China, the Human Research Protection Program can learn from the experience of developed countries to improve the Program to fit to China’s conditions. The development proposals of the program will help nurses and other health professionals in China and elsewhere to understand their corresponding responsibilities and actively participate in human participant protection.
Footnotes
Conflict of interest
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was funded by grants from Humanities and Social Sciences Foundation of Army Medical University (2019XRW04, 2017XRW23) and Health Culture Research Center of Shaanxi (JKWH2019-Q07). The funding body also provides suggestion for the design of the study and writing the manuscript.
