Policy Interpretation of Measures for the Administration of Drug Registration
By Jianqing Chang, Vice President of Drug Regulatory Policy, Tigermed Co., Ltd.
1、What is the background for revision of Measures?
Pharmaceuticals are closely related to the health of the public. The CPC Central Committee and the State Council have attached great importance to pharmaceuticals. Important documents have been issued since 2015, such as Opinions of the State Council on Reform of the System of Evaluation, Review and Approval of Pharmaceuticals and Medical Devices (No. 44  of the State Council, hereinafter referred to as the No. 44 Document) and Opinions on Deepening the Reform of the Evaluation and Approval Systems and Encouraging Innovation on Pharmaceuticals and Medical Devices (No. 42  of the General Office of the CPC Central Committee, hereinafter referred to as the No. 42 Document). A series of reform measures have been deployed and promoted, such as Marketing Authorization Holder (MAH) system on a trial basis, implied license in drug clinical trials, bundling review and approval, and priority review and approval. Vaccine Administration Law and the newly revised Pharmaceutical Administration Law, as deliberated and adopted by the Standing Committee of the National People’s Congress in June and August, 2019 respectively, shall come into force on December 1st.
MAH system will be comprehensively implemented, and a series of management systems will be established in the two laws, such as implied license in drug clinical trials, conditional approval, priority review and approval, and categorized management for post-marketing changes. Also, it is required in the two laws to improve the drug evaluation, review and approval work system, optimize the procedures for evaluation, review and approval, and improve the efficiency of evaluation, review and approval. Promulgated in 2007, the existing Provisions for Drug Registration has played an important role in ensuring the safety, efficacy and quality control of medicines, as well as regulating drug registration behavior; but it has not adapted to the newly developed and revised laws, the requirements for the reform of the drug evaluation, review and approval system, the scientific progress or rapid development of the pharmaceutical industry. Therefore it is necessary to make a comprehensive revision.
2、What is the idea for revision of Measures?
These revised Measures are developed to adhere to the implementation of the requirements of newly developed and revised laws, absorb results of the reform of drug evaluation, review and approval system, center on and clarify basic requirements on the administration work of drug registration, and make provisions on the basic systems, basic principles and basic procedures for drug registration, as well as primary liabilities and obligations of parties concerned, etc., and highlight management attributes of Measures. Considering that the specific technical requirements in the drug registration management will be constantly adjusted and improved in conjunction with technological development, it is not appropriate to make specific provisions in the regulations. Subsequent issuance will be in the form of supporting documents and technical guiding principles etc to better reflect the scientific laws of drug research and development.
3、How to strengthen full lifecycle management?
In these revised Measures, drug regulatory concept is innovated, the drug full lifecycle management concept is introduced and systematically designed, and whole-process and full-chain regulatory system is strengthened for all links from drug development and marketing as well as post-marketing management to cancellation of drug registration certificate. First, relevant contents of supervision and inspection performed by GLP institutions and GCP institutions are added, daily supervisory authority of provincial drug regulatory departments is strengthened, and full play is given to the supervision role of provincial drug regulatory departments to ensure continuous compliance with GLP and GCP as well as the work quality. Second, the time limit is specified for corresponding work that must be completed after conditionally approved pharmaceuticals are marketed. Where the work has not been completed within the prescribed time limit, relevant measures have been clarified and even the drug registration certificate can be cancelled. Third, a new chapter “Post-marketing Change and Re-registration” is added to fully reflect the requirements of the newly revised Pharmaceutical Administration Law, strengthen relevant requirements on post-marketing researches and management of changes, require MAHs to proactively conduct post-marketing researches to further confirm and verify the safety, efficacy and quality controllability of pharmaceuticals, strengthen the continuous management of marketed pharmaceuticals, and clarify the categorization, application, filing and reporting channels of post-marketing changes, reflecting the full lifecycle management of pharmaceuticals. Fourth, information technologies are adopted to strengthen drug registration management, establish drug variety files and lay the foundation to accomplish daily supervision of the full lifecycle of pharmaceuticals and the seamless connection of information in various regulatory links.
The supervision of GLP institutions and GCP institutions and relevant requirements for drug safety credit files are added. Information disclosure contents are added to publicize the review conclusion and evidence, be subject to social supervision, and promote co-governance by whole society. The package insert is listed as the information disclosure content and updated in time to provide convenience for public inquiry and use. Fifth, according to the authority of the regulations, circumstances where a punishment shall be imposed as prescribed by the law shall be appropriately specified, the accountability of regulatory personnel shall be strengthened, violations of laws and regulations, including data fraud in the development link, shall be restrained and punished, and a good environment that encourages innovation shall be created. Sixth, MAH’s (Marketing Authorization Holder) capabilities for quality management, risk prevention and control, and payment of damages shall be established and improved in all links throughout the full lifecycle of pharmaceuticals. The drug registration link is comprehensively reflected in the compliance of MAHs in non-clinical studies, clinical trials, trial manufacturing and production of pharmaceuticals, pre-marketing inspection and verification, post-marketing researches, adverse reaction reporting and handling, and pharmaceutical production and marketing authorization with corresponding management norms, standards and requirements. The applicant (MAH) should continue strengthening the management of full lifecycle of pharmaceuticals and assume primary responsibilities in accordance with the law.
4、How to implement the requirements for the reform of “simplification of administrative procedures and decentralization of powers; combination of decentralization with appropriate control; and optimization of services”?
In these Measures, drug registration administration methods are innovated in accordance with requirements of the State Council for “simplification of administrative procedures and decentralization of powers; combination of decentralization with appropriate control; and optimization of service”. First, bundling review and approval system is established, chemical active ingredients shall be managed as pharmaceuticals, and the access approval system shall be implemented according to provisions of newly revised Pharmaceutical Administration Law. Manufacturers of chemical active ingredients shall register on the “registration platform of chemical active ingredients, excipients and packaging materials and containers in direct contact with pharmaceuticals” in accordance with requirements of Announcement of the National Medical Products Administration on Further Improving Matters concerning the Bundling Evaluation, Review and Approval as well as Supervision for Pharmaceuticals (No. 56 ), submit technical files in accordance with relevant registration requirements and clarify production site address, etc. Where the Applicant of drug products manufactures chemical active ingredients by itself, the Applicant of drug products shall register on the “registration platform of chemical active ingredients, excipients and packaging materials and containers in direct contact with pharmaceuticals”, and the registration on the platform shall be bundled when filing the registration applications of drug products.
Where other manufacturers of chemical active ingredients are selected, the manufacturer of chemical active ingredients shall register on the “registration platform of chemical active ingredients, excipients and packaging materials and containers in direct contact with pharmaceuticals”, and the registration on the platform shall be bundled by the Applicant of drug products when filing the registration applications of drug products. Separate evaluation, review and approval matters for excipients and packaging materials and containers in direct contact with pharmaceuticals are cancelled, and the evaluation shall be conducted when drug products are approved so as to reduce approval matters. The management responsibility and dominant position of drug product holders for excipients and packaging materials and containers in direct contact with pharmaceuticals are more prominent while the efficiency of evaluation and approval is improved. Second, the implied license system will be implemented for review and approval of drug clinical trials, and the original licensing system is changed to recordation system for bioequivalence trials. Third, categorized management will be implemented for pharmaceutical changes, recordation management for medium-degree changes will be implemented by provincial drug regulatory authorities, and management of annual reporting by enterprises will be implemented for minor changes.
The management responsibilities of site changes and technique changes are also further specified. Fourth, based on product innovation and risk characteristics, risk-based evaluation, inspection and test modes are implemented, the circumstances where on-site inspection for drug registration is mandatory are clarified, and simultaneous conduct of on-site inspection for drug registration and examination of quality management standard for pre-marketing drugs is allowed, which improve the evaluation and approval efficiency. Fifth, the drug registration inspection process is scientifically set up, which is adjusted to be that the drug registration test can be initiated before acceptance of the registration, and the Applicant can choose a drug testing institute where the Applicant or the manufacturer is located to conduct the inspection. Sixth, interim and ex post regulation is strengthened, continuous compliance of research and development activities is emphasized, requirements on management of post-marketing researches is enforced, information disclosure and social supervision is strengthened, and full lifecycle management is intensified for pharmaceuticals.
5、How to continue promoting the reform of the drug evaluation and approval system?
These revised Measures not only reflect and solidify the results of the reform in pharmaceutical field, but also lead and promote continuous and comprehensive deepening. First, solidify the results of the reform of drug evaluation and approval system, resolutely fulfill the reform arrangements and spirits of newly developed and revised laws of the CPC Central Committee and the State Council, and consolidate the results of the reform arranged in No. 42 Document and No. 44 Document. Timely reflect reform measures proved effective in practice in departmental rules, providing a strong guarantee for the reform of evaluation and approval system. Second, continue to promote the reform of evaluation and approval system. According to general ideas of the revised Measures, principle expressions shall be in the body of Measures to leave room for deepening the reform continuously. According to the newly revised Measures, National Medical Products Administration will continue to promote the reform of the evaluation and approval system, optimize procedures for evaluation and approval, improve the efficiency of evaluation and approval, and establish a drug registration management system based on evaluation supported by the test, inspection, monitoring and evaluation.
6、What new ideas and systems have been introduced?
Compared with 2007 version of Measures, many designs of new ideas and systems have been introduced in these newly revised Measures. First, new measures introduced in recent years for the reform of drug evaluation and approval system are solidified, and some new core systems in drug regulation are reflected in the newly revised Measures, such as MAH system, implied license in drug clinical trials, priority evaluation and approval, bundling evaluation and approval for chemical active ingredients, excipients and packaging materials and containers in direct contact with pharmaceuticals and drug products, communication and expert consultation, etc. Second, the evaluation and approval procedures are further optimized, including new ideas that drug registration test can be initiated before acceptance of the registration, and simultaneous conduct of on-site inspection for drug registration and examination of quality management standard for pre-marketing drugs is allowed.
7、What are the new measures to encourage drug development and innovation?
Innovation is the source of power to promote the high-quality development of medicines. These revised Measures enrich the contents of encouraging drug development and innovation to improve accessibility of drugs. First, a new chapter “Expedited Registration Procedures for Marketing” is added, and four expedited channels, i.e. breakthrough therapeutic drugs, conditional approval, priority evaluation and approval, and special review and approval, are established in combination with the development of China’s pharmaceutical industry and the actual needs for clinical treatments by reference to international experience. The inclusion scope, procedures, supportive policies and other requirements are specified for each channel. Second, inadequate pharmaceutical products in urgent clinical need, pharmaceuticals for children’s use, orphan drugs, drugs used in major infectious diseases, vaccines urgently needed for disease prevention and control and innovative vaccines, etc listed in Pharmaceutical Administration Law, Vaccine Administration Law and documents issued by the State Council are explicitly included in the scope of expedited registration for marketing.
8、How to reflect the laws of drug development and registration?
These revised Measures pay more attention to the scientific laws of drug development and registration management. First, the communication system is incorporated into the basic system of drug registration management. Good communication is the basis for improving the quality and efficiency of evaluation and approval. On one hand, the Applicant may communicate with CDE and other specialized technical institutions in respect of critical issues prior to IND, during clinical trial, before MAA and at other key stages. On the other hand, in the process of drug registration, the CDE and other specialized technical institutions may communicate with the Applicant as needed. Second, management systems in compliance with characteristics of drug clinical trials are established. For example, implied license system is implemented in drug clinical trials, and recordation system is implemented in bioequivalence trials. From the perspective of protecting the safety of subjects, the management and application channel of changes during drug clinical trials are clarified. Third, management systems of marketing license and post-marketing changes better complying with drug development and regulatory practice are established. Marketing authorization channels include “complete channel”, “direct application for marketing” channel and “non-prescription drugs” channel. Application and approval procedures are optimized. Categorized management is implemented for post-marketing changes in accordance with approval, filing and reporting matters.
9、How to encourage the inheritance and innovation of traditional Chinese medicines (TCM)?
Supporting the inheritance and innovation of traditional Chinese medicines has always been an important part of drug regulatory work. In order to highlight the advantages of traditional Chinese medicines and in full consideration of the characteristics of traditional Chinese medicines, it is specified in these revised Measures that the state encourages the use of modern science and technology and traditional research methods to develop traditional Chinese medicines. The registration classification and technical evaluation system of TCM characteristics are established and improved to promote the inheritance and innovation of traditional Chinese medicines. Also, attention is paid to the protection of TCM resources to promote the sustainable use of resources. Subsequently, special provisions for TCM registration and management will be formulated to better promote the high-quality development of the TCM industry.
10、How is the management of drug clinical trials optimized and strengthened?
Licensing recordation of drug clinical trials and management of the process of drug clinical trials are specified and optimized in these revised Measures. First, the decision on whether to approve the application for implementation for any drug clinical trial shall be made within 60 days from the date of accepting the application for clinical trial. The review results shall be notified to the Applicant via the CDE (Center for Drug Evaluation) website; the failure in notification shall be deemed as approval, and the Applicant can carry out the clinical trial as per the protocol submitted. Where the Applicant intends to conduct bioequivalence study, relevant study shall be conducted as per the protocol filed for the record after completing the filing of the bioequivalence study. Second, the management of the process of drug clinical trials is strengthened. During the course of drug clinical trials, the Sponsor shall submit periodic safety update reports and report suspected and unexpected serious adverse reactions occurring during drug clinical trials and other potential serious safety risk information. According to the seriousness of safety risks, the CDE may require the Sponsor to take measures that can strengthen risk control, such as modifying the clinical study protocol, informed consent form, investigator’s brochure, etc., and may require the Sponsor to suspend or discontinue the drug clinical trial if necessary. Third, channels for changes in drug clinical trials are added. Changes appearing during drug clinical trials shall be applied or reported accordingly based on the effect on subjects’ safety. Fourth, standards for the implementation of drug clinical trials are specified. It is specified that the license for drug clinical trial shall be invalid if no subject signs the ICF within three years upon the approval of clinical trial application. Requirements on registration of drug clinical trials are raised. Fifth, relevant penalty provisions on implementation of drug clinical trials not in compliance with specifications are added to legal liabilities.
11、How are marketing authorization channels optimized?
Three channels to apply for marketing authorization are specified in these Measures. First, a complete application channel in which pharmaceutical, pharmacological and toxicological as well as clinical studies that support registration for marketing are completed, Specifications are determined, and the scaled production process for commercial purpose is validated. Second, the drug may be exempt from clinical trial as evaluated by the Applicant that the implementation of a clinical trial is not necessary or not available, the Applicant may directly file marketing authorization application. Third, marketing authorization applications for non-prescription drugs can be directly filed.
12、How are inspection procedures for drug registration optimized?
In these Measures, on-site inspections for drug registration are optimized. First, the on-side inspection mode for drug registration is optimized, and the mode that “inspection is mandatory for each review” will no longer be implemented. Decisions can be made whether to conduct the inspection at the R&D site under drug registration application according to the level of drug innovation and previous inspection results of clinical trial institutions based on risks. Decisions can be made whether to conduct on-site inspection under drug registration application according to the category, process, facility, previous inspection results and other factors of the product to be registered based on risks. Second, the inspection at manufacturing site under drug registration application shall be effectively connected with pre-marketing GMP inspection. Where pre-marketing GMP inspection is necessary, the Center for Food and Drug Inspection (CFDI) shall coordinate with relevant provincial drug regulatory authorities to carry out the pre-marketing GMP inspection synchronously with the inspection at production site under drug registration application, which accelerates the process for marketing and organically connects with post-marketing supervision and administration. Third, the positioning of drug registration inspection it is specified in these Measures. Drug registration inspection is not whole-system GMP inspection. Drug registration inspection is mainly to verify the authenticity and consistency of the application dossiers and commercial production conditions for marketing and to inspect the compliance of pharmaceutical R&D and data reliability.
13、How are drug registration inspection procedures optimized?
Drug registration inspection procedures are optimized in these Measures. After completing relevant pharmaceutical studies supporting marketing, determining Specifications and validating scaled production process for commercial purpose, the Applicant may file an application for drug registration inspection before the drug registration application is accepted. Where no application has been filed for drug registration inspection before the drug registration application is accepted, the CDE shall initiate the inspection within 40 days after accepting the drug registration application. In principle, the drug testing institution shall give feedback of comments on Verification of Specifications and test reports to the CDE within 40 days prior to expiry of the time limit for review. Under the premise of no reduction in requirements and no reduction in standards, according to the actual progress of product research and development, scientifically and rationally set up and optimize the registration process to shorten the total time limit for evaluation and approval of registration for marketing.
14、 How is the management of pharmaceutical changes optimized?
According to laws of pharmaceutical research and development, existing procedures and requirements for post-marketing changes are optimized in these Measures. Channels for changes during drug clinical trials and changes during evaluation of marketing authorization are newly specified. First, procedures and requirements for changes during drug clinical trials are specified. For the management of changes during clinical trials, respect laws of pharmaceutical research and development, add requirements and procedures for changes during clinical trials, and conduct management by applying for changes or reporting according to the effect on subjects’ safety. Second, principles for management of changes during the evaluation of marketing authorization are specified. During the review of MAA (marketing authorization application), the Applicant shall withdraw the original application in the occurrence of any major change that would have impact on the safety, efficacy and quality controllability of the drug, and re-apply upon completion of supplementary research. The CDE shall be timely informed in writing of any changes not requiring technical review, and certification materials shall be submitted. Third, the channel of annual report is added for the management of post-marketing changes on the basis that supplementary application and recordation are required in the original Measures. Fourth, changes for the product site shall be implemented in accordance with Article 16 in Measures for the Supervision and Administration of Pharmaceutical Production.
15、 How are procedures for supplementation of materials optimized?
Procedures and requirements for supplementary materials are specified and optimized in these Measures. First, Applicant is required to supplement new technical materials to the original application dossiers. That is to say, where the review for new study data is required, the CDE shall list all the issues when issuing the requirement on supplementary materials. In principle, the requirement on supplementary materials can only be issued at one time. The Applicant shall submit all the supplementary materials at one time in accordance with requirements. The time limit for such supplementary materials is 80 days. Second, a channel for interpretation of application dossiers is added. The Applicant is only required to give an interpretation of the original application dossiers, and not required to supplement new study data. The time limit for such supplementary materials is 5 days. The timekeeping for evaluation shall not be stopped. Third, implied license system is implemented for applications for clinical trials and supplementary applications during clinical trials. Since the time limit is only 60 days, no new technical materials shall be supplemented during the evaluation period, and only the interpretation of the original application dossiers is permitted. Fourth, where corrections cannot be made for material defects, the Applicant shall be no longer required to supplement materials, and a non-approval decision shall be made based on existing application dossiers. Fifth, where the Applicant fails to supplement materials within the prescribed time limit, the drug registration application shall not be approved.
16、How to achieve an expectable time limit for drug registration?
The time limit for drug registration that is generally concerned by the industry is optimized in these Measures. First, responsibilities of all departments in all links in the management of drug registration are specified. Effectively connect with all links for drug registration, including acceptance, evaluation, inspection and test, and improve the expectedness in the efficiency and time limit for drug registration. Second, clarify responsible departments of each specific work and arrange relevant responsible unit for each specific work. Third, the “series” implementation of the original evaluation, inspection and test is changed into “parallel” implementation. It is specified that within 200 days, the time limit for review, the inspection and test shall be initiated within 40 days after the drug registration application is accepted and be completed 40 days prior to expiry of time limit for the evaluation during the evaluation process, guaranteeing that the total time limit is controllable.
17、How to achieve open and transparent drug registration work?
Improving the transparency of evaluation and approval is an important task for the reform of the drug evaluation and approval system in recent years. It is specified in General Provisions of these revised Measures that the management of drug registration shall follow the principles of openness, fairness and justice. It is specified in the body of Measures that drug evaluation and approval process shall be open and transparent, social supervision shall be strengthened, legal rights of MAHs shall be protected and the fairness and justice of evaluation and approval shall be guaranteed. First, the NMPA shall disclose to the public the list and legal basis of drug registration approval matters, approval requirements and time limit for handling in accordance with the law, disclose the progress of drug registration to the Applicant, publish clinical study results, make public evaluation results and basis of the drug approved to be marketed and violations of laws and regulations discovered during supervision and inspection, accept public supervision and achieve social co-governance. Second, the package insert of the drug approved to be marketed shall be publicized and timely updated. For vaccines, the content of the label shall also be publicized and updated timely. Third, the NMPA shall establish catalogues of chemical drugs newly approved for marketing or passing the consistency evaluation for generic drugs regarding quality and efficacy. The catalogues specify drug names, active ingredients, dosage forms, strengths, the use as Reference Listed Drugs (RLDs) or not, and information of the MAH. Such information shall be timely updated and publicized. The procedures and requirements for inclusions into Catalogues of Chemical Drugs shall be formulated by the CDE and disclosed to the society.
18、What are the remedies for disputable evaluation and approval conclusions of drug registration applications?
According to the experience in reform in the earlier stage, the remedies for disputable evaluation and approval conclusions of drug registration applications are optimized in these revised Measures. First, simply procedures and improve actual effects, review procedures after the end of approval shall no longer be established separately in these Measures. Instead, the essential content of review work shall be completed by the end of evaluation. The Applicant can raise any objection to the evaluation conclusion at the evaluation stage and resolve the objection in earlier stage as soon as possible. Second, at the end of approval of drug registration application, if the Applicant has any objection, it may apply for administrative reconsideration or file an administrative litigation to
19、 What are relevant documents and work of Measures?
After Measures are issued, there are a number of supporting work to be implemented and documents to be issued, which will also be supplemented and added as needed for work. The development and revision of supporting regulatory documents and technical guidelines are being accelerated. Currently, focus on advancing the registration categorization of traditional Chinese medicines, chemical drugs and biological products and relevant requirements on application dossiers, the categorization of changes and relevant requirements on application dossiers, the requirements on re-registration application dossiers, MAH’s changes in marketing authorization and other supporting documents, which will be issued one after another once any of them is completed. Subsequently, technical guidelines system will be further enriched to improve comprehensiveness and systematicness, which both provides technical reference to evaluation and approval as well as inspection and test and provides guidance to support industrial development and encourage innovation.