The past 2020 is the year when China has completed building a well-off society in an all-round way and the 13th five year plan. China's medical reform continues to advance to the deep water area and deepen the reform of three medical linkage. The year 2020 was also an extraordinary year. The state responded positively to COVID-19, and launched a large number of epidemic policies in the first half of this year. In July, the State Council issued the notice on printing and distributing the key tasks of deepening the reform of the medical and health system in the second half of 2020. In the second half of the year, the work of medical reform was in full swing, and the supporting policies were issued accordingly. The above two factors make 2020 the year with the largest number of health reform policies.

　　In this year, more than 600 policies related to the pharmaceutical industry were released at the national level, of which pharmaceutical policies accounted for about half of the total. As the main Department of pharmaceutical policy release, the food and Drug Administration ranked first in the number of policy releases among the issuing agencies. Faced with a large number of policy documents and limited space, this paper focuses on the main policies related to drug review and approval in pharmaceutical policies, especially the supporting rules for accelerating the review and approval of innovative drugs.

　　1、 Promulgation of programmatic regulations

　　On March 30, 2020, the State Administration of market supervision and administration announced the 2020 new version of the measures for the administration of drug registration and the measures for the supervision and administration of drug production, in which the measures for the administration of registration are a major revision after 13 years on the basis of the 2007 version. This revision involves the reform of drug registration classification, optimizing the review and approval process, and strengthening accountability. The two programmatic documents have been officially implemented since July 1, 2020. The main points of the measures for the administration of drug registration (hereinafter referred to as the "measures") include the following five aspects.

　　Optimize and improve review efficiency

　　The approach emphasizes clinical value orientation, encourages research and innovation in pharmaceuticals, and actively promotes the development of generic drugs. The State Food and Drug Administration continued to promote the reform of the review and approval system, optimize procedures, improve efficiency, and establish a drug registration management system dominated by review and supported by inspection, verification, monitoring and evaluation.

　　Four channels to speed up the listing of new drugs

　　In comparison with FDA, the State Food and drug administration has established four special review channels: Breakthrough therapeutic drugs, conditional approval, priority review and approval, and special approval procedures. The breakthrough therapeutic drug program is positioned at the stage of drug clinical research and development; The approval procedures of conditional approval and priority review are positioned at the stage of drug listing registration; Special approval procedures are for public health emergencies.

　　Further shorten the review time

　　The application for drug clinical trial is changed to decide whether to agree within 60 days from the date of acceptance, and the bioequivalence test can be implemented after filing. The time limit for the review of drug marketing license application is 200 days, including 130 days for priority review and approval, and 70 days for drugs for rare diseases that have been listed abroad in urgent clinical need; It is 200 days to apply for the imitation of domestic listed chemical APIs separately; The review of drug re registration is 120 days.

　　Fully implement the drug marketing license holder system

　　Make it clear that the marketing license holder (MAH) is an enterprise or drug development institution that can bear corresponding responsibilities. It is required to establish a drug quality assurance system, manage the whole life cycle of drugs, carry out post marketing research, and bear the responsibility for the safety, effectiveness and quality of listed drugs.

　　Emphasize the associated approval of original and auxiliary packages

　　When examining and approving drug preparations, relevant reviews shall be conducted on chemical APIs, excipients and packaging materials and containers in direct contact with drugs. Whoever imitates the chemical raw materials used by drugs already on the market in China may apply for independent review and approval.

　　In order to ensure the smooth implementation of the 2020 version of the measures for the administration of drug registration, the State Food and drug administration has successively issued the draft for comments of a series of supporting documents such as drug registration classification and drug review, so as to speed up the drug review and approval, improve the drug accessibility and the enthusiasm of enterprises to develop new drugs.

　　2、 The registration classification of chemical drugs, biological products and traditional Chinese medicine in 2020 was issued

　　On June 30, 2020, the State Food and Drug Administration issued a notice on the registration classification and application data requirements of chemical drugs and biological products. The registration classification shall be implemented from July 1, 2020 and the application data requirements shall be implemented from October 1, 2020. In September 2020, the State Food and Drug Administration issued a circular on the registration classification and application data requirements of traditional Chinese medicine. From January 1, 2021, all application data will be submitted according to the new requirements.

　　Figure 1. Basic framework of drug registration classification in 2020

　　Source: State Food and drug administration, Zhongkang Industrial Capital Research Center

　　2020 chemical drug registration classification

　　There is little difference between this version and the registration classification of chemical drugs in 2016. There are three main changes: "APIs and preparations" and "preparations" are unified as "drugs"; Consistency evaluation is emphasized in the definitions of category 2, 3 and 4 drugs; 5.1 improved new drugs and overseas original drugs listed in China are added to the classification, and the new indications are applied for listing in China.

　　The registration classification of chemical drugs in 2020 is divided into five categories, and the basic contents are as follows: Category 1 is innovative drugs that are not listed at home and abroad; Class 2 is an improved new drug that has not been listed at home and abroad; Category 3 refers to the drugs that imitate the original drugs listed abroad but not listed in China; Category 4 refers to the drugs that imitate the original drugs that have been listed in China; Category 5 drugs listed abroad apply for listing in China.

　　Biological products registration classification 2020

　　Biological products for prevention, biological products for treatment and in vitro diagnostic reagents managed by biological products are classified according to the degree of innovation and listing at home and abroad. Biological products for prevention are divided into innovative vaccines (Category 1), improved vaccines (Category 2) and vaccines listed at home or abroad (Category 3). There are sub categories under each category. Similarly, therapeutic biological products are divided into three categories.

　　Drug registration classification is an important index for drug positioning, which has an impact on drug clinical trial, application, pricing, access and so on. In the context of encouraging innovation, class 1 new drugs can be included in the priority review and approval procedure, with smooth market access and relatively high pricing after listing. Category 4 generic drugs have basically no preferential treatment, and need to undergo the baptism of volume procurement. After a sharp price reduction, they can almost only obtain production profits. The new drug registration classification is more strictly based on the degree of innovation, combined with the new measures for the administration of drug registration and the measures for the supervision and administration of drug production, so that drugs with different degrees of innovation can be properly managed.

　　Registration classification of traditional Chinese medicine in 2020

　　In the registration of traditional Chinese medicine, it is divided into four categories: innovative traditional Chinese medicine, improved traditional Chinese medicine, traditional Chinese medicine compound preparations of ancient classical famous prescriptions, and drugs with the same name. The first three categories belong to new traditional Chinese medicine. Note that the classification of traditional Chinese medicine does not represent the level of drug development and efficacy, but only indicates that the requirements for registration and application materials are different. In order to strengthen the carding and excavation of the essence of classical medical books, 3 kinds of Chinese herbal medicines are subdivided into 3.1 types of Chinese herbal preparations administered according to the catalogue of ancient classics, and 3.2 traditional Chinese medicine preparations from other ancient classics. Category 3.2 includes traditional Chinese medicine compound preparations of ancient classic famous prescriptions not managed according to the catalogue of ancient classic famous prescriptions and traditional Chinese medicine compound preparations based on the addition and subtraction of ancient classic famous prescriptions. This also reflects the state's support and encouragement to the traditional Chinese medicine industry.

　　3、 The early resolution mechanism of drug patent disputes in China was introduced for the first time

　　On September 11, 2020, the State Food and Drug Administration and the State Intellectual Property Office issued the measures for the implementation of the early resolution mechanism of drug patent disputes (Trial) (Draft for comments) (hereinafter referred to as the "draft for comments") to further improve the patent linkage system. The purpose of this policy is to try to solve drug patent disputes before patent litigation, so as to reduce resource waste and speed up the reasonable substitution of generic drugs for patented drugs. On the premise of protecting the legitimate rights and interests of drug patentees, promote the research and development of high-level generic drugs (first generic drugs) and stimulate the research and development of more original new drugs.

　　In October 2017, the office of the CPC Central Committee and the office of the State Council issued the opinions on deepening the reform of the review and approval system and encouraging the innovation of drugs and medical devices, one of the programmatic documents for the policy reform of China's drug administration, namely the famous Document No. 42, which requires exploring the establishment of a drug patent link system. In the following years, several institutions issued documents for promotion for many times. The opinion draft issued this time is a continuation of the previous policy, and it is also the first time that China has introduced an early resolution mechanism for drug patent disputes.

　　In order to promote the high-quality development of generic drugs in China, the draft explores early solutions to drug patent disputes from many aspects, including establishing a Chinese listed drug patent information level platform, clarifying the scope of drug patent information level, stipulating the patent status declaration system of generic drug applicants, clarifying the realization of objections raised by patentees or interested persons Set the waiting period for review and approval for chemicals, implement classified treatment for drug review and approval, and give the first imitation drug market monopoly period with successful patent challenge.

　　It is worth highlighting that Article 11 of the draft opinion stipulates: "For the chemical generic drugs with the first successful patent challenge and the first approved for marketing, the market monopoly period shall be granted. The drug regulatory department under the State Council shall no longer approve the marketing of the same generic drugs within 12 months from the date of approval of the drug, and the market monopoly period shall not exceed the patent period of the challenged drugs. During the market monopoly period, the national drug review institution shall not stop the technical review. The technical application shall be reviewed For the approved registration application of chemical generic drugs, the relevant application of chemical generic drugs shall be transferred to the "administrative examination and approval link" 20 working days before the expiration of the market monopoly period The draft basically refers to a series of practices of the US FDA, but it encourages the generic drug patent challenge more. The maximum 12-month market monopoly period is twice the 6-month market monopoly period of the first generic drug successfully challenged by the US patent. This will greatly mobilize the R & D enthusiasm of pharmaceutical enterprises and lay out the first generic drug in the patent challenge mode, which will help to improve the R & D quality of generic drugs and lower than that of the first generic drug Challenge the price of the original drug to benefit patients.

　　4、 Implementation of accelerated channel policy rules for new drug review and approval

　　On July 8, 2020, the State Food and Drug Administration issued three supporting detailed documents: working procedures for the review of breakthrough therapeutic drugs (for Trial Implementation), working procedures for the review and approval of conditional approval of drugs for listing (for Trial Implementation) and working procedures for the priority review and approval of drug marketing license (for Trial Implementation), so as to speed up the implementation of new drug listing registration procedures in the 2020 administrative measures for drug registration.

　　These three working procedures are three special review channels established by China to encourage new drug research and development and accelerate new drug listing, referring to the four special review channels of FDA: Breakthrough therapy, accelerated approval, priority review and fast track It is required to see in the preliminary clinical trial that the drug has significantly improved compared with the existing therapy in one or more clinically meaningful endpoints; "accelerated approval" can approve the drug according to the alternative endpoint or intermediate endpoint of the clinical trial; "priority review" shortens the review cycle of marketing application from standard 10 months to 6 months; "fast track" Pharmaceutical enterprises are allowed to submit listing application materials in the R & D process.

　　Figure 2. Four special review channels for FDA to accelerate the listing of innovative drugs

　　Source: FDA, Zhongkang Industrial Capital Research Center

　　The purpose of FDA's special review channel is to promote the listing of innovative drugs with important therapeutic value as soon as possible, and ensure that the safety and effectiveness standards of drugs will not be damaged in the review process. One important reason why the United States has become the country with the largest number of innovative drugs approved every year in the world is the acceleration channel set by FDA in new drug review.

　　Although China's drug regulatory agencies have learned from the FDA's accelerated channel model, the introduction and development of several special review channel policies in China are closely related to the development of the overall situation of innovative drug R & D in China, reflecting the change of focus from "quantity" to "quality".

　　One of the acceleration channels of innovative drugs in China: priority review and approval

　　The priority review and approval originated from one of the guiding documents for the policy reform of China's drug administration. The "No. 44 document" opinions of the State Council on reforming the review and approval system of drugs and medical devices, issued in August 2015, proposed to speed up the review and approval of innovative drugs. In February 2016, the former State Food and Drug Administration (CFDA) Releasing opinions on priority assessment for priority application of drug registration applications, covering innovative drugs not listed at home and abroad, high-quality clinical generic drugs, innovative drugs for diseases such as cancer, child medication, rare diseases, tuberculosis, viral hepatitis and other diseases. 2020 edition of the procedures for examination and approval of drug marketing permission assessment (Trial Implementation) It is based on the opinions on encouraging drug innovation to implement priority review and approval issued on December 28, 2017. Before the release of the 2020 version of the working procedures, the policy tends to solve the problem of "quantity" of innovative drugs with clinical value and high-level generic drugs urgently needed in clinic After the backlog of drug registration applications is basically solved and the domestic clinical needs are basically met, the scope of application of the priority review and approval procedure is more inclined to new drugs with obvious clinical value.

　　Figure 3. Scope of application of priority review and approval procedures in 2020 and 2017

　　Source: State Food and drug administration, Zhongkang Industrial Capital Research Center

　　The second channel for accelerating innovative drugs in China: Breakthrough therapeutic drug program

　　The China food and Drug Administration introduced the "breakthrough treatment drug procedure" similar to the "breakthrough treatment channel" of FDA late. In November 2019, the drug examination and approval center (CDE) issued the working procedure for breakthrough treatment drugs (Exposure Draft). The 2020 version of the measures for the administration of drug registration incorporated the relevant provisions of breakthrough treatment drugs, which was issued in July 2020 The working procedure for the review of breakthrough therapeutic drugs (for Trial Implementation) is the supporting detailed rules.

　　Drugs that can apply for breakthrough therapeutic drug identification need to meet two conditions at the same time: (1) for the prevention and treatment of diseases that seriously endanger life or seriously affect the quality of life; (2) There is no effective prevention and treatment means or there is sufficient evidence to show that there are innovative drugs or improved new drugs with obvious clinical advantages compared with the existing treatment means. The drug review center communicates and exchanges the priority allocation resources of drugs included in the breakthrough treatment drug program, strengthens guidance, and includes them in the priority review and approval at the listing application stage. Favorable treatment means breakthrough treatment drugs More stringent screening.

　　Breakthrough therapeutic drug identification requires preliminary clinical trials to prove that the drug has significantly improved over existing therapies in one or more clinically meaningful indicators. Clinically meaningful endpoints usually refer to endpoints related to disease occurrence, development, death and function, and can also include validated alternative endpoints, alternative endpoints that may predict clinical benefits, or intermediate clinical endpoints Points, safety endpoints, etc. Generally speaking, alternative endpoints, intermediate clinical endpoints and safety endpoints can be collected more easily and reached faster than conventional clinical endpoints, so it helps to speed up the research and development process of innovative drugs. It should be noted that the inclusion of drugs in the breakthrough treatment drug program does not mean that they can be approved for marketing. If CDE finds the drug clinical trials included in the program When the inclusion conditions are no longer met, the termination procedure will be initiated.

　　Figure 4. Cases where breakthrough therapeutic drug procedures have obvious clinical advantages

　　Source: CDE, Zhongkang Industrial Capital Research Center

　　The breakthrough therapeutic drug program received a warm response from innovative drug R & D enterprises. After the release of the working program on July 8, three enterprises submitted applications on July 10, among which the legendary biological car-t therapy lcar-b38m targeting BCMA obtained the first breakthrough therapeutic drug recognition by the State Food and Drug Administration on August 12.

　　From July 10 to the end of 2020, in less than 6 months, a total of 23 innovative drugs were recognized as breakthrough therapeutic drugs by CDE. These drugs have a wide range of types, including car-t therapy, ADC, double antibody, Aso (antisense single chain oligonucleotide), and small molecule drug targets include RET, EGFR, JAK, Rock2 and PI3K δ The R & D enterprises of these innovative drugs include multinational pharmaceutical enterprises such as Pfizer, Novartis and Takeda, as well as local pharmaceutical enterprises such as Hengrui medicine, kangfang biology, biotechnology, etc.

　　Figure 5. Innovative drugs incorporated into breakthrough therapeutic drug programs in 2020

　　Source: CDE, Zhongkang Industrial Capital Research Center

　　The third channel for accelerating innovative drugs in China: conditional approval for listing

　　The 2007 edition of the "drug registration administration measures" refers to the special examination and approval of new drugs that have obvious clinical advantages in treating AIDS, malignant tumors, rare diseases and other diseases. This is the earliest policy statement on conditional approval in China. In the following more than 10 years, only a handful of drugs were included in the conditional approval channel. In November 2019, CDE was released. The technical guidelines for conditional approval and listing of clinically urgently needed drugs (Exposure Draft) gives detailed guidance on how pharmaceutical enterprises use the conditional approval channel. The 2020 version of the measures for the administration of drug registration has officially incorporated the policy of conditional application, and stipulates that drugs included in the conditional approval channel can apply for priority review and approval.

　　China's conditional approval channel draws on the accelerated approval of FDA Channel is a drug supervision mode of approval before verification. Conditional approval channel is applicable to drugs for the treatment of diseases and rare diseases that are seriously life-threatening and have no effective means of treatment, and drugs urgently needed in public health. The existing clinical research data have not met all the requirements of routine market registration, but the existing data of clinical trials show curative effect and can predict its clinical value Drugs can be declared for marketing before the final phase III clinical results are obtained.

　　Figure 6. Basic conditions for incorporating conditional approval channels

　　Source: State Food and drug administration, Zhongkang Industrial Capital Research Center

　　The conditional approval channel speeds up the listing process of a number of innovative drugs with significant clinical value. On the one hand, pharmaceutical enterprises can recover R & D costs in advance and improve the sustainability of R & D; on the other hand, it improves the accessibility of domestic patients to some seriously life-threatening drugs. Especially in the event of major diseases seriously endangering public health, conditional approval is passed In recent years, both multinational pharmaceutical enterprises and local pharmaceutical enterprises have obtained conditional approval for the listing of some innovative drugs and vaccines.

　　Figure 7. Some drugs and vaccines listed through conditional approval channels in recent years

　　Source: State Food and drug administration, company website, Zhongkang Industrial Capital Research Center

　　epilogue

　　The drug administration policies such as the 2020 version of the measures for the administration of drug registration, the new classification of chemical and biological products, the early resolution mechanism of drug patent disputes, and the review of special channels (priority review and approval, breakthrough therapeutic drugs, conditional approval for listing) reflect the change in the direction of reform, which has shifted from solving the problem of "quantity" to improving "quality" The policy supports drugs with a high degree of innovation, prominent clinical advantages and significant clinical value. The drug supervision policy, combined with the medical insurance and medical policy, will help to improve the clinical drug use structure and promote the realization of medical value.