Regulation of Drug Clinical Trials in China: Course and Development Trend

* Corresponding author: Tian Lijuan (1973-), associate professor.Major research area: pharmaceutical law and drug policy. Tel: 024-23986549, E-mail: tianlijuan_8@126.com.

Abstract Objective To provide a basis for future regulation reform of drug clinical trials in China in the context of the continuous deepening of drug regulation reform. Methods Literature review and regulation study were conducted to analyze the course and development trend of drug clinical trial regulation in China. Results and Conclusion It is found that the regulation system and the standardization for clinical trials in China are gradually improving, but there is still a gap compared with developed countries. In the future, the regulation authorities still need to further improve relevant regulations, clarify regulation responsibilities, and to improve the drug clinical trial review system to ensure the quality of clinical trials and the safety and effectiveness of listed drugs.

Keywords: drug clinical trial; administration; development course

Drug clinical trials are the only way for drugs from research and development to the market,which is also the longest and most costly stage in the development of new drugs. Besides, it is an important way to ensure public medication safety and the demand for drugs. Therefore, they must be strictly regulated. China’s drug clinical trials and their supervision started quite late. Most of the early clinical trials were carried out by medical workers in clinical practice, and there were no large-scale clinical trials[1].With the rapid development of China’s pharmaceutical industry, more and more attention has been paid to the safety and effectiveness of listed drugs. After drawing on international advanced laws and regulations,the national health and drug regulatory authorities gradually established a drug regulatory system based on China’s actual conditions.

1 Development of drug clinical trial supervision in China

1.1 Initial phase of clinical trial supervision (1949-1984)

When the People’s Republic of China was founded in 1949, safety issues of drugs were managed by the health department. In 1963, the Ministry of Health, in collaboration with the Ministry of Chemical Industry and the Ministry of Commerce, promulgated the Regulations on Drug Administration. For the first time, it put forward relevant regulations on clinical trials and attached importance to the safety of drugs. The regulations made clear definition and classification of new drugs, explained the clinical trials of new drugs and listing of new drugs, and required the establishment of drug review and approval departments[2]. In 1965, the Ministry of Health and the Ministry of Chemical Industry issued the first regulatory document on the management of new drugs in China - the Interim Provisions on the Administration of New Drug Products. However, due to the ten-year Cultural Revolution and the stagnation of development, this method was not implemented.

Since the reform and opening up in 1978,China’s pharmaceutical industry has gradually recovered, and the State Administration of Medicine was established. From then on, drug regulatory work has been on the right track. In the same year,the State Council promulgated the Regulations on Pharmaceutical Administration, in which Article 15 stipulated that new drug research and development units should submit research materials to the health bureau after the development of new drugs, and the clinical trials of new drugs should be organized by the provincial, municipal and autonomous regional health bureaus[3]. Article 16 stipulated that in order to ensure the standardization of drug clinical trials,local health bureaus should set up new drug clinical trial bases and conduct clinical trials in the bases.In 1979, the Ministry of Health issued the Measures for the Administration of New Drugs. According to the regulations on the review and approval of new drugs and the clinical trials, detailed instructions on clinical trials, review and approval of new drugs were made. It clearly stated that drug must undergo clinical trials to prove its safety and effectiveness before it can be approved for production and marketing.Medications for clinical trials should be provided free of charge by the R&D units as planned, and the cost of clinical trials should be solved by the health bureaus[4]. Subsequently, according to the regulations on the establishment of clinical trial bases proposed in the Regulations on Drug Administration, the Ministry of Health authorized 14 medical institutions with comprehensive strength and scientific research capabilities, including Peking Union Medical College Hospital, to become the first batch of clinical pharmacology bases in 1983. Then new drugs could apply for clinical trials before their listing.

1.2 Clinical trial supervision enters the legal stage(1985-2000)

Since the Regulations on Drug Administration and the Administrative Measures on New Drugs are administrative regulations and departmental regulations respectively, their legal effects are not high and the coercive power is insufficient. In view of the special properties of drugs, it is necessary to supervise drug clinical trials at the legislative level to ensure drug safety and effectiveness. On July 1, 1985, the first Drug Administration Law of the People’s Republic of China was officially implemented. This bill imposed mandatory regulations on the management of new drugs, that is, after the development of new drugs, the research materials should be submitted to the national,provincial, municipal, and autonomous regional health bureaus. Clinical trials can be conducted after approval. In the same year, according to the requirements of the Drug Administration Law, the Ministry of Health promulgated the Measures for the Examination and Approval of New Drugs and the Measures for the Examination and Approval of New Biological Products, which specifically clarified the examination and approval of new drugs. And a relatively complete new drug evaluation system was established. At the same time, the new drug research and development unit must carry out clinical trials at the clinical pharmacology base designated by the Health Bureau, and the cost of the clinical trials should be paid by new drug research and development unit. Therefore, the main body of the clinical trials is transformed from the health department to the new drug research and development unit[5].

At the same time, international clinical trials are in the ascendant. While emphasizing the scientific nature of clinical trials, they begin to focus on protecting the safety of subjects and respecting their legitimate rights and interests. In 1964, the 18th World Medical Association Joint Conference was held in Finland. The conference officially adopted the Helsinki Declaration. On the basis of the Nuremberg Code, a more comprehensive and specific ethical code for medical research with human body was formulated. The guidelines, Good Clinical Practice(GCP), began to take shape. Since then, various countries successively formulated and promulgated GCP, and carried out clinical trials in accordance with GCP regulations, stipulating the responsibilities of all parties in clinical trials, ensuring the safety of the subjects and the scientific nature of the trials. Since 1986, China has paid attention to the supervision and management of clinical trials. By studying the relevant regulations of clinical trials and supervision in developed countries and combining with the actual situation in China, the Guidelines for the Administration of Clinical Trials of Drugs (Trial)(GCP) was issued in 1998. In the same year, the State Drug Administration (SDA) was established, and began to revise the Measures for New Drug Approval and GCP regulations. In 1999, SDA officially promulgated the revised GCP and reviewed the clinical pharmacology bases identified by the Ministry of Health in accordance with GCP and renamed then the Clinical Research Bases. China officially began GCP examinations in clinical trials and clinical research institutions. At that time, GCP examination was one of the main means for the government to supervise drug clinical trials[6].

1.3 Dual admission stage for drug clinical trials(2001-2018)

In 2001, the National People’s Congress promulgated the revised Drug Administration Law,in which Article 29 stipulated that new drug research and development units must submit research materials and samples in accordance with regulations before conducting drug clinical trials and they can carry out clinical trials after that. In 2003, China Food and Drug Administration (CFDA) revised the Quality Management Regulations for Clinical Trials of Drugs and renamed it Code for Quality Control of Clinical Trials, emphasizing that drugs are commodities for sale on the market. An ethical review of clinical trials is intensified in the new GCP to protect subjects in the primary position. Since then, China’s drug clinical trials have begun to be more strictly regulated.

In 2004, in order to better manage the clinical research base and ensure the smooth development and standardization of clinical trials, CFDA and the Ministry of Health issued the Methods for Qualification of Drug Clinical Trial Institutions(Trial)[7]. 152 clinical research bases that previously undertook drug clinical trials were required to be reviewed again. The recognized clinical research base was officially renamed as National Drug Clinical Trial Institution (hereinafter referred to as institution).When the applicants were required to conduct clinical trials, they had to choose an institution that passed the qualification examination, which started the qualification admission system for drug clinical trial institutions. China’s clinical trials entered the double admission period, that is, the clinical trials need to be approved by the drug regulatory authorities before the trials, and the trial participants also should obtain the qualifications from the drug clinical trial institutions.

In order to strengthen the management of clinical trial data, CFDA promulgated the Regulations on Drug Registration in 2007. For the first time, it proposed to have the on-site verification of clinical trials in the verification of drug registration. In the following year,the Regulations for the On-site Verification of Drug Registration was issued, and the original records of the clinical trials of the drugs for registration were checked to confirm the authenticity, accuracy and completeness of the clinical trial data.

In 2009, CFDA promulgated the Notice on Carrying out the Review and Examination of Qualifications for Drug Clinical Trials, to review the institutions whose qualification certificates were about to expire. This method could strengthen the management of institutions and recognized professions[8]. In 2010, CFDA issued the Guiding Principles for Ethical Review of Drug Clinical Trials,refining the review rules of the Ethics Committee to ensure the scientific nature of clinical trials as well as the safety of subjects.

1.4 Self-verification of drug clinical trial data (2015-present)

In the past, the supervision of clinical trials in China focused on examination before the trials,which neglected the trial process, resulting in the occurrences of clinical trial data fraud, such as incomplete data and the untraceable data. In order to ensure the authenticity, completeness and traceability of the clinical trial data of listed drugs, in 2015, CFDA issued the Notice on Carrying out Self-checking and Checking of Drug Clinical Trial Data (No. 117 of 2015) to verify clinical trial data on 1622 drugs applied for registration[9]. By the end of 2018, Food and Drugs Review and Inspection Center of CFDA organized 27 batches of clinical trial data on-site verification, 30 registered varieties were not approved,and 11 clinical trial institutions and contract research organizations (CROs) were involved in data fraud.1316 drug registration withdrew from applications[10].The self-checking and verification of drug clinical trial data become the normal supervision of clinical trials.After the applicant submits the registration application to the drug evaluation center, the National Audit and Inspection Center will prepare a verification plan to organize on-site verification. At present, China’s supervision of clinical trials focuses on the verification of drug clinical trial data. The verification of clinical trial data can ensure that the data provided by clinical trials is true and reliable, which provides a strong basis for drug listing. Meanwhile, it can also regulate all relevant parties in clinical trials so as to meet the public drug demands and safe medication.

2 Current situation and trend of drug clinical trial supervision

In order to improve technological innovation,speed up the listing of new drugs to meet the need of public, in 2017, the General Office of the CPC Central Committee and the General Office of the State Council issued the Opinions on Deepening the Reform of the Examination and Approval System to Encourage the Innovation of Pharmaceutical Medical Devices(referred to as Opinions)[11]. The Opinions pointed out that in order to speed up the examination and approval of clinical trials, the clinical trial institution qualification system should be changed to the filing system, the access conditions for clinical trials should be relaxed as well. Therefore, the process of clinical trials was strengthened. While providing a better environment for innovation, the quality of listed products should be strictly controlled[12]. In 2017, CFDA officially became a member of the ICH, and together with the health management authorities of other member countries and regions, accepting each other’s clinical data for human drug registration. China’s clinical trial supervision is in line with international standards nowadays. In 2018, the State Drug Administration issued the Notice on Adjusting the Approval Process for Clinical Trial Evaluation of Drugs, which implemented the reform of the drug clinical trial review and approval system in the Opinions. Applicants can conduct clinical trials within 60 days without receiving the advice of the Drug Evaluation Center after submitting clinical trial applications for acceptance and payment. At present,411 clinical trials have been carried out with implied permission[13].

China has made great achievements in drug clinical trials though they started late. However,compared with the level of international clinical trials, we are still lagging behind. At present, the legal construction of clinical trial supervision and supervision mode are not perfect. In the future, the responsibilities of the applicant, CROs and other participants in the regulations should be further clarified in the supervision of clinical trials. Besides,the penalties for all relevant parties in clinical trials should be strengthened as well as the responsibilities of the ethics committee. And the supervision of the clinical trial process must be regulated to accelerate clinical trials. Meanwhile, the construction of data protection system should be sped up and the frequency of inspection during the test should be increased. In addition, the responsibilities of the supervisory departments at all levels must be clarified so that they can refine the inspection standards and allocate inspection resources rationally. Last, relevant institutions should be supervised and inspected in accordance with the inspection standards and operating procedures formulated by the State Drug Administration, and penalties should be imposed in case of any violations.