Author: Shao Rong, Yan Jianzhou, National Center for drug policy and pharmaceutical industry economics, China Pharmaceutical University
The current measures for the administration of drug registration was promulgated by the former State Food and Drug Administration in 2007. Since its implementation for more than ten years, it has effectively guaranteed the safety, effectiveness and quality control of drugs from the source of drug R & D and listing, and played an important role in improving the accessibility of drugs and promoting the healthy development of the pharmaceutical industry in China. Under the background of the rapid development of China's pharmaceutical industry and the increasingly perfect concept, system and method of drug supervision, the State Administration of Market Supervision issued the newly revised Measures for the administration of drug registration (hereinafter referred to as the new measures) on March 30, 2020 by order No. 27 of the State Administration of market supervision, which will come into effect on July 1, 2020. The new method is condensed from 177 articles in 15 chapters of the 2007 version to 126 articles in 10 chapters, with a greatly reduced length. However, there are many innovations in principles, concepts and contents, showing many highlights.
Implement the "four strictest" requirements
The new measures fully reflect the determination of the state to strengthen the supervision and management of drug registration, strengthen the supervision of the whole process, strictly prevent and control drug safety risks, and firmly hold the bottom line of drug safety.
Strengthening the process management of drug clinical trials
The new measures make it clear that the sponsor shall regularly submit the safety update report during the research and development period on the website of the drug review center. The safety update report shall be submitted once a year during the research and development period, and within two months after each full year after the approval of drug clinical trials. The drug evaluation center may require the sponsor to adjust the reporting period according to the review situation. The sponsor shall report the suspicious and unexpected serious adverse reactions and other potential serious safety risk information to the drug review center in time according to the relevant requirements. According to the severity of the safety risk, the sponsor may be required to take measures to strengthen risk control, such as adjusting the clinical trial scheme, informed consent, investigator's manual, etc., and the sponsor may be required to suspend or terminate the clinical trial if necessary. In the part of legal responsibility, the new "measures" stipulates that if the sponsor fails to register in the drug clinical trial registration and information publicity platform as required, fails to submit the safety update report during the research and development period as required, and fails to register the clinical trial results after the drug clinical trial is completed, he / she will be ordered to make corrections within a time limit. If he / she fails to make corrections within the time limit, he / she will be punished A fine of not less than 10000 yuan but not more than 30000 yuan.
Implement the requirements of drug life cycle management
The implementation of full life cycle management of drugs is essential to ensure drug safety. The new measures strengthen the requirements of full life cycle management covering drug development, registration and post marketing supervision; increase the requirements for supervision and inspection of GLP institutions and GCP institutions and strengthen the daily supervision authority of provincial drug supervision and management departments; clarify the connection between pre marketing review and post marketing evaluation research, and clarify It is necessary to complete the time limit requirements of the corresponding work after the conditional approval of the drug listing. For those not completed according to the time limit, it is necessary to define the corresponding treatment measures until the cancellation of the drug registration certificate; it is necessary to attach importance to the effective connection between drug registration and drug production to ensure the effective implementation and continuous compliance of the drug production quality management norms; it is necessary to strengthen the drug registration management by means of information technology and establish the drug products Kinds of files lay the foundation for the seamless connection of daily supervision and information of all supervision links in the whole life cycle of drugs; give full play to complaints, information disclosure and other means, accept social supervision, and realize social co governance.
Crack down on illegal activities such as data fraud and strengthen accountability
Illegal behaviors such as data falsification will seriously threaten the quality and safety of drugs. In order to ensure the data quality as the core basis for review and approval, the new measures clearly put forward the application for drug registration in the basic system and requirements, and shall provide authentic, sufficient and reliable data, materials and samples to prove the safety, effectiveness and quality controllability of drugs. In the part of legal responsibility, the responsibility for illegal behaviors such as data fraud shall also be clarified. The specific contents include providing false certificates, data, data, samples or other means to defraud the clinical trial license or drug registration license in the process of drug registration. According to Article 123 of the drug administration law, not only the relevant license shall be revoked, Impose the qualification penalty of "not accepting the corresponding application within ten years" and a fine of not less than 500000 yuan but not more than 5000000 yuan; if the circumstances are serious, implement the double penalty system, and impose a fine of not less than 20000 yuan but not more than 200000 yuan on the legal representative, the main person in charge, the person in charge who is directly responsible and other persons in charge; prohibit the production and operation of drugs within ten years, and may be imposed by The public security organ shall be detained for not less than five days but not more than 15 days. In the case of applying for clinical trial of vaccine, providing false data, data, samples or other deceptive behaviors, it shall be dealt with more severely in accordance with Article 81 of the vaccine management law, taking property penalty as an example: the unit shall be imposed with a fine of 15 times to 50 times the value of illegally produced and sold vaccines, and if the value of goods is less than 500000 yuan, it shall be calculated as 500000 yuan（ That is to say, a fine of at least 7.5 million yuan may be imposed on the individual (legal representative, main person in charge, directly responsible person in charge, key post personnel and other responsible personnel) to confiscate the income obtained from the unit during the period of the illegal act and impose a fine of not less than 50% but not more than 10 times the income obtained.
Pay equal attention to innovation and imitation? Improve the accessibility of drugs
To clarify the procedures for accelerating the listing of drugs and improve the policy environment for R & D and listing of innovative drugs in China
In the new measures, the fourth chapter "procedures for accelerating the registration of drugs on the market" is specially set up. Through defining the breakthrough treatment drug procedures, conditional approval procedures, priority review and approval procedures and special approval procedures, four differentiated channels for accelerating the listing of drugs that need to speed up the listing process for different reasons are set up. The scope of application, application and approval procedures and supporting policies of each type of accelerated listing and registration procedures are clearly defined, which significantly improves the operability of relevant procedures in the process of implementation, and plays an important role in promoting innovative drug research and development and accelerating the listing of new drugs in China. Especially in novel coronavirus pneumonia, the implementation of relevant regulations can enable the regulatory authorities to make special approval for the drugs needed for epidemic prevention and control, and accelerate the listing process of related drugs.
Clear the principle of equal emphasis on innovation and imitation, and actively promote the development of generic drugs
The general provisions of the new measures are clearly guided by clinical value, encourage research and development of new drugs, and actively promote the development of generic drugs. It is clear that generic drugs should be consistent with the quality and efficacy of the reference preparations, and it is proposed that the State Drug Administration should establish a catalog of chemicals to receive new approval for listing and to pass the consistency evaluation of the quality and efficacy of generic drugs. For generic drugs, according to whether the corresponding production range of drug production license has been obtained and the same dosage form of drug has been listed, based on the risk, we will carry out on-site inspection of drug registration and production quality management standard inspection before listing, and take multiple measures to jointly promote the improvement of generic drug quality and efficacy, and promote the healthy development of generic drug industry.
Drug registration management model based on "classified management"
The new measures fully reflect the innovation of drug registration management mode based on the concept of "classified management".
Registration and classification of innovative drugs
Under the premise of paying full attention to the characteristics of traditional Chinese medicine, chemical medicine and biological products, and taking into account modern and traditional medicine, the new method carries out classified registration management according to traditional Chinese medicine, chemical medicine and biological products. Among them, the registration of traditional Chinese medicine is classified according to the innovative medicine of traditional Chinese medicine, the improved new medicine of traditional Chinese medicine, the traditional Chinese medicine compound preparation of ancient classic prescription, the medicine with the same name, etc.; the registration of chemical medicine is classified according to the innovative medicine of chemical medicine, the improved new medicine of chemical medicine, the generic medicine, etc.; the registration of biological products is classified according to the innovative medicine of biological products, the improved new medicine of biological products, and the listed biological products (including biology Similar drugs). The registration application of drugs produced abroad shall be implemented according to the detailed classification of drugs and the requirements of corresponding application materials, that is, the unified evaluation standards and quality requirements shall be implemented instead of "import" in the registration classification, so as to lay the foundation for the integration of China's pharmaceutical industry into the global supply chain system.
Diversified choice of drug marketing license and scientific registration management
According to the different characteristics of the drugs to be applied for listing, Articles 34 to 36 of the new measures set up three paths for drug listing license. After completing the research on pharmacy, pharmacology, toxicology and clinical trials supporting drug registration, determining the quality standards, completing the verification of commercial scale production process, and preparing for the inspection of drug registration, the applicant shall apply for drug listing license, and submit relevant research materials according to the requirements of the application materials. After the evaluation of the applicant, it is deemed that there is no need or no need For those who can carry out clinical trials of drugs and meet the conditions for exemption from clinical trials of drugs, the applicant can directly apply for drug listing license, of course, this is mainly for generic drugs, in vitro diagnostic reagents under drug management and other conditions that meet the conditions; for some non prescription drugs that meet the conditions, the applicant can directly apply for listing license. There is no doubt that, given different path choices based on different situations, its scientificity will be greatly improved.
Implement classified management for changes after drug listing
Based on the concept of risk management, the new measures implement classified management for changes after drug listing according to the risk and impact degree affecting drug safety, effectiveness and quality controllability, which are divided into approval changes, record changes and report changes. For major changes in the process of drug production, changes in the contents of the drug specification related to the effectiveness and other contents that increase the safety risk, the holder of the transfer of the drug listing license and other holders shall apply in the form of supplementary application, which shall be implemented after approval; for medium changes in the process of drug production and changes in the contents of the drug packaging label, the holder shall make changes in the process of drug production Before implementation, it shall be reported to the drug regulatory department of the province, autonomous region or municipality directly under the central government where it is located for the record; for minor changes in the process of drug production, the holder shall report in the annual report.
Strengthen the main responsibility and improve the efficiency of review and approval
Optimize clinical trial management
In the new measures, the examination and approval management of clinical trial institutions is changed to record management, and it is proposed that clinical trials of drugs should be carried out in drug clinical trial institutions that have corresponding conditions and record according to regulations. The new method specifies the implied license system of clinical trial application. For the drug clinical trial application, it shall decide whether to approve or not within 60 days from the date of acceptance, and notify the applicant of the approval result through the website of drug evaluation center. If the applicant fails to notify within the time limit, it shall be deemed to agree, and the applicant can carry out the drug clinical trial according to the submitted scheme. If the applicant intends to carry out the bioequivalence test, it shall carry out the relevant research work in accordance with the filing scheme after completing the bioequivalence test filing on the website of the drug review center as required. According to the "double filing" provisions of the new "measures", the requirements of "releasing tube and clothing" are well implemented, and the responsibility consciousness and responsibility responsibility of clinical trial institutions and applicants are strengthened; however, implied permission is implied