The Regulatory Requirements and Key Points of Drug Clinical Trials Registration in China

May 20, 2020
Zhuxing Yao

,
Haixue Wang

Applied Clinical Trials

Following the implement of new Drug Registration Regulation in July 2020, the clinical trial registration system will have some major changes in China.

This article is mainly to introduce the basic information and requirements regarding clinical trial registration in China. Following the implement of new Drug Registration Regulation in July, 2020, the clinical trial registration system will have some major changes, this article will also introduce some key points for clinical trial registration in China.

I. Background Information

The Declaration of Helsinki says that every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject.1Currently many global authorities also require that clinical trials conducted in their countries or regions should be registered in their official websites or database, such as the clinicaltrials.gov in United States and EudraCT (EU Clinical Trials Register as the public version) in European Union member states and the European Economic Area.]

In China, the Center for Drug Evaluation (CDE), affiliated to the former China Food and Drug Administration (CFDA), currently the National Medical Products Administration (NMPA, a subordinate agency of the State Administration for Market Regulation) launched a pilot database of Registration and Publicity for Drug Clinical Trials (hereinafter referred to as China Register) for the first time on its official website in November, 2012. China Register was in trial run since then and clinical trials authorized by CFDA since the 1st January, 2012 could be registered in this database.The completion guidance and instruction were also available on the website at the same time and updated as required accordingly.

On the 6th September, 2013, CFDA officially released the Notice of the Register for Drug Clinical Trial Information([2013], No. 28),stipulating that the holders with clinical trial approvals (also named as applicants) should register and have the clinical trials information public in China Register that are approved by CFDA and to be conducted in China,  including bioequivalence(BE), pharmacokinetics (PK), phase I, II, III and IV studies. 3The notice also set deadlines for updating the information for each milestone during clinical trials. In November of the same year, the exclusive website was finally launched.

Since the December 1, 2015, BE studies for chemical products were managed on filing instead of review and approval process. Applicants should get a filing number firstly, then complete the registration of trial information.4  In the light of this policy, the module for BE trials filing was also built and added into China Register together for convenience. 

II. Current Status of Registration

The holders with clinical trial approvals in valid should complete the registration within 3 months since the release of the Notice No. 28. Therefore, the number of registered clinical trials surged quickly since its first launch in 2012 and reached more than 3056 cases (counted based on CTR, the same below) in 2013. In following 3 years, the quantity of annual registered trials remained 800 to 1000 cases. Besides, due to releases of the Opinions on Reforming the Review & Approval System for Drugs and Medical Devices(the State Council [2015] , No. 44) by the State Councilin August 20155and the Opinions on Deepening the Reform of Review & Approval System to Encourage Innovation in Drugs and Medical Devices(General Office [2017], No. 42) by the General Office of Central Committee of the Communist Party of China and the State Councilin October 2017 6, the review and approval process for clinical trial application was optimized and accelerated. Therefore, the annual number of registered trials was more than before in recent years and reached 1685, 2570, and 2756 cases in 2017, 2018 and 2019 separately. Till to the first quarter of 2020, China Register has more than 4200 primary accounts and the total number of registered trials amounts to 13,504 cases. See Figure 1 for the whole picture with the annual data.

Currently, China Register can assort the registration based on drug categories, i.e. chemicals, biologics, Chinese and natural medicinesand the territory where the trials are conducted, i.e. domestic and global trials (or multi-regional clinical trials, MRCTs). Till now, chemicals and domestic trials still dominate the main parts for China Register and there is no significant change according to the statistics since 2012. See the Figure 2 and 3 for the percentage separately in the end of 2019. 

III. Some Key Points in Updated Laws and Regulations

According to the Opinions No. 42 mentioned above, NMPA issued the Notice of Optimizing the Review and Approval Processes for Drug Clinical Trial Application(NMPA [2018], No. 50).7The notice states that applicants can conduct clinical trials in China as to the protocols in application packages if they have NOT received any negative comments or queries from the authority within 60 working days since the date of application. Besides, the requirement for clinical trial registration is also highlighted again in this notice. 

Revised and adopted by the Twelfth Session of the Standing Committee of the 13th National People's Congress on August 26, 2019, the newly revised Drug Administration Law of the People's Republic of China (hereinafter referred to as DAL) has been enforced since December 1, 2019, marking the second systematically and structurally major revision of the Law since its initial promulgation in 1984. The practical and effective experience of reforms in pharmaceutical industry were transformed into laws.8

 

In accordance with the new DAL, NMPA is now working in an orderly fashion on the development, formulation and revision of matching regulations, normative documents and technical guidelines. The Drug Registration Regulation (Decree No. 27 of State Administration for Market Regulation, hereinafter referred to as DRR) was released in March, 2020 and shall be in practice as from July 1, 2020.The requirement of registration of clinical trial is also involved in this new DRR for the first time, which stipulates that applicants should register protocols and related information on the official database prior to initiating clinical trials. Besides, applicants should persistently update the information and also need to upload the results when clinical trials are completed. The clinical trial information will be disclosed for public after it is reviewed by authority and applicants should be responsible for its authenticity.

  • The Marketing Authorization Holders System
    The newly revised DAL fully implements the drug marketing authorization holders (MAHs) system across China. Starting from December 1, 2019, all practitioners or drug R&D institutions holding drug marketing authorizations (marketing licenses for domestic products, imported drug licenses, or medical product registration certificates) shall be regarded as MAHs, who should strictly perform their obligations and take responsibilities for drug safety, effectiveness and quality controllability in the whole process of drug R&D, production, distribution and use. Based on this system, the holders, also named as applicants or sponsors during clinical trials, are responsible for clinical trial registration. The holders may also authorize or transfer their approval letters to the third parties for subsequent registration and taking the responsibilities accordingly.
    As to the new DAL, MAHs should amend protocols, hold or terminate clinical trials if there are safety concerns during trials and report them to the authorities of the State Council for medical products. Therefore, MAHs should update the information in China Register in time once these situations occur. If necessary, authorities may order MAHs to amend protocols, hold or terminate clinical trials as to regulations and make it public immediately in China Register.

  • Scope and Terms of Clinical Trial Registration
    According to the current laws and regulations in China, only the following kinds of trials can be accepted for registration in China Register. Other kinds, such as the Investigator Initiated Trials (ITTs), clinical trials of medical devices or trials initiated by MAHs themselves rather than authorized by China authority cannot be accepted.
    -The trials with approval letters or without negative comments and queries from China authority within 60 working days since the date of application;
    -The BE trials which have been filed in China Register and authorized filing number;
    -The phase IV studies and post-marketing studies listed in the licenses of marketing authorization or subject to the authority notices;
    -Other situations if necessary. 

  • Validity Period of Clinical Trial Authorization
    The new DRR says the drug clinical trial shall be conducted within three years after the drug clinical trial is approved. If there are no subjects with the signing of the informed consent form (ICF) within three years from the date when the application for clinical trial of the drug is approved, the drug clinical trial permission shall be invalid automatically. Where the applicant plans to continue the clinical trial, a new application shall be submitted.

  • Now the new DRR clearly defines the validity of clinical trial authorization, so applicants need to ensure the authorizations to be in valid when filling clinical trial information in China Register. If not valid, the registration will be rejected by China Register. Besides, once there is updated information, applicants need to update it in China Register within 30 calendar days since it happens, for example the date of the first subject signing ICF and the trial completion date. 

  • Protocol Number or Study Number-based Registration
    Generally, each clinical trial will be designated an exclusive protocol number and/or study number. For China Register, each registration corresponds to one protocol or study number and will be assigned an exclusive registration number, i.e. CTR.
    In some special situations, one protocol may have two-stage design and different objectives for each stage, so it is suggested that sponsors complete the registration separately for each stage as to the protocol. Therefore, there will be some registrations with different CTRs for the same protocol or study number in China Register. 

  • Record-filing Management of Clinical Trial Institutions 
    As to the newly revised DAL, NMPA and National Health Commission of the People's Republic of Chinajointly released the Announcement on Regulations for the Administration of Drug Clinical Trial Institutions(DCTIs) (2019, No.101).10 As from December 1, 2019, DCTIs shall be, invariably, subject to record filing management. DCTI-qualification applications accepted before December 1, 2019, with pending examination & approval results, shall be subject to record filing per the current regulations. An exclusive record-filing system was already launched.
    So, MAHs should ensure the Chinese institutions or sites in which trials are conducted and registered in China Register have valid qualification certificates or have been filed in the official record-filing system as mentioned above. 

IV. Next Steps 

As the newly revised DAL has already in practice now and the new DRR will be effective in July 1, 2020, CDE is now drafting the implementation guidance regarding clinical trial registration, which will underline MAH’s obligations and clearly define the scope of trial registration, the nature and standard of trial information review, the deadline for information submission, update and review, etc.  

The new DRR further requires that study results also need to be submitted in China Register, which is also the requirement of the Declaration of Helsinki, so the current registry system also need to be upgraded for this and will be optimized for convenient use. Meanwhile, the completion guidance for registration will be updated based on new regulations and new system and will also be available on China Register for downloading. 

In order to enhance the supervision of drug safety in the period of clinical trial and gradually improve the life cycle management, the registration information in China Register would be incorporated into the pharmacovigilance system step by step as a whole for drug safety supervision. Therefore, it is also very important for MAHs to ensure the trial information in China Register is authentic and well quality controlled, besides completing and updating the registration in a timely manner. 

 

Zhuxing Yao, Clerk, Office of Clinical Trial Management, CDE, NMPA. E-mail: yaozhx@cde.org.cn Haixue Wang, Director, Office of Clinical Trial Management, CDE, NMPA. E-mail: wanghx@cde.org.cn

 

Reference:

  • WMA DECLARATION OF HELSINKI. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/

  • Former China Food and Drug Administration. Notice of the Register for Drug Clinical Trial Information (CFDA [2013], No.28). http://www.nmpa.gov.cn/WS04/CL2138/299952.html

  • Former China Food and Drug Administration. Notice of Filing Policy for Bioequivalence Studies on Chemical Medicinal Products(CFDA [2015], No.257). http://www.nmpa.gov.cn/WS04/CL2138/300077.html

  • State Council. Opinions on Reforming the Review & Approval System for Drugs and Medical Devices (State Council[2015], No.44). http://www.gov.cn/zhengce/content/2015-08/18/content_10101.htm.

  • General Office of Central Committee of the Communist Party of China, State Council.Opinions on Deepening the Reform of Review & Approval System to Encourage Innovation in Drugs and Medical Devices (General Office [2017], No. 42).http://www.gov.cn/zhengce/2017-10/08/content_5230105.htm.

  • National Medical Products Administration,National Health Commission of the People's Republic of China. Announcement on Regulations for the Administration of Drug Clinical Trial Institutions ([2019], No.101). http://www.nmpa.gov.cn/WS04/CL2138/371670.html

 

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