2018~2020 Annual Report of Drug Review: Using review resources for new drugs with clinical value, regulatory observations

Since the National Medical Products Administration joined the International Technical Coordination Committee for Human Drug Registration (ICH) in 2017, the drug regulatory authorities have intensively issued a series of policies to encourage the research and development of innovative drugs.
This period is also a period when the innovative vitality of Chinese pharmaceutical companies has been strongly stimulated.

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The drug regulators, researchers and industry have made great strides in continuously improving the standards of review, drug development and production

1 .
Three years for examination and approval changes

1 Three-year reporting and approval changes

With the implementation of the new version of the Vaccine Administration Law, the Drug Administration Law on December 1, 2019, the Administration Measures for Drug Registration on July 1, 2020, and the implementation of the Drug Evaluation Center (hereinafter referred to as the Center for Drug Evaluation) ) Led the publication of 145 technical guidelines and the implementation of 12 ICH guidelines.
Many people in the industry have called for the establishment of a review process-oriented scientific management system, implied approval of clinical trials, encouragement and acceptance of overseas clinical trial data and Policies such as clinical urgent need for new drugs, priority review, and appointment-based communication meetings have been realized
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From the perspective of the approved varieties of innovative drugs from 2018 to 2020, more and more domestic biotechnology companies dare to dream and try
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From 2018 to 2020, China's acceptance of new drug registration applications continues to increase
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In 2018, the Center for Drug Evaluation accepted a total of 7,336 applications for traditional Chinese medicine, chemical medicine, and biological products (calculated by acceptance number, the same below)

2018

2018

The Center for Drug Evaluation accepts 239 applications for Category 1 Innovative Drug Clinical Trial (IND) and 25 applications for Category 1 Innovative Drug New Drugs (NDA)
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In the IND, there are more anti-tumor drugs, digestive system drugs, endocrine system drugs and anti-infective drugs, accounting for 68% of all innovative drugs approved in clinical trials

25 new drugs have been approved.
The majority of Class 1 innovative drugs are anti-cancer drugs, with 8 in total, mainly for major indications.
For example, there are 3 drugs for the treatment of non-small cell lung cancer.
They are anlotinib hydrochloride and aletin hydrochloride.
There are two drugs for treating melanoma, and they are teriprizumab and pembrolizumab
.

It is worth mentioning that Tereprizumab is China's first domestically produced PD-1 antibody developed by Junshi Biologics.

The remaining new drugs approved include the advanced colorectal cancer drug fruquintinib, the breast cancer drug pirotinib maleate and the Hodgkin's lymphoma drug anti-PD-1 monoclonal antibody sintilimab
.

Fruquintinib is a targeted anticancer drug developed by Hutchison Whampoa for 13 years

2019 year

2019 year

Accepted 302 types of category 1 innovative drug IND, an increase of 26.
4% compared with 2018; accepted 17 types of category 1 innovative drug NDA, a decrease of 8 varieties compared with 2018
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Among the innovative drugs approved by the IND by the Center for Drug Evaluation, there are still more anti-tumor drugs, digestive system disease drugs, anti-infective drugs, and neurological disease drugs, accounting for 70% of all innovative drugs approved in clinical trials

Let's look at the 17 new drugs approved in 2019
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There are still the most anti-tumor drugs, with a total of seven, and two biosimilar drugs, rituximab and bevacizumab

In addition, Nirapali tosylate is an innovative PARP inhibitor for the treatment of adult patients with recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer
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PARP inhibitors are becoming popular in China

In 2019, there are 4 other approved anti-infective drugs, 1 circulatory system drug, and 2 rheumatic diseases and immune drugs
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Among them, belyumumab is the world's first new drug marketed for the treatment of systemic lupus erythematosus (SLE) in the past 60 years
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The nervous system drug midazolam is the first oral and buccal mucosal solution for the treatment of acute episodes of convulsions in children in China
.
With the introduction of the guidelines for the clinical development of children's drugs by the Center for Drug Evaluation, the enthusiasm of China's children's drug R&D enterprises may be activated
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The skin and ENT treatment drug Benvimod is also a blockbuster.
This drug has a new structure and a new mechanism of action, and is suitable for the treatment of mild to moderate stable psoriasis vulgaris in adults
.
The main inventor of the drug, Dr.
Chen Genghui, said that it was not easy to go through 20 years from discovery to market
.

In addition, in 2019, the Center for Drug Evaluation has 4 rare disease drugs approved through the clinically urgently needed overseas new drug list and China’s first batch of rare disease catalogs.
They are elosulfatase α, agalsidase for injection β, and Nosi Nasheng sodium and edaravone sodium chloride solve the problem that there is no effective treatment in the field of corresponding disease treatment
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2020 year

2020 year

For the first time, the Center for Drug Evaluation has incorporated the technical guidelines issued in 2020, the review and approval status of new drugs that are urgently needed for clinical trials overseas, the status of approved drugs, the status of drugs that have been included in the breakthrough treatment channel in the clinical trial phase, the innovative drugs that have passed the review, and the review The approved overseas-produced original research drugs and approved listing drugs included in the accelerated listing procedures were sorted out
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A total of 597 applications for the registration of category 1 innovative drugs were accepted, an increase of 51.
71% over 2019
.
Among them, 559 varieties of IND applications were accepted, an increase of 49.
78% over 2019; 38 varieties of NDA were accepted, an increase of 100.
00% over 2019
.
In terms of drug category statistics, the number of Class 1 innovative drugs accepted for traditional Chinese medicine, chemical medicine, and biological products were 14, 752, and 296 respectively
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In terms of the approval of innovative drugs, there will be 3 new coronavirus vaccines and new coronavirus pneumonia treatment drugs approved by the Center for Drug Evaluation in 2020
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Approved drugs in the anti-tumor field include Ametinib, anti-angiogenic oral small molecule tyrosine kinase inhibitor Sofantinib, the world's first CD30 target, and the first domestic ADC drug injection vitamin for patients with malignant lymphoma Butuximab, the world's first bispecific antibody targeting CD3 and CD19, is the first bispecific antibody for acute lymphoblastic leukemia in China, and the first in China for radioactive iodine Lenvatinib, a small molecule drug tyrosine kinase inhibitor for refractory differentiated thyroid cancer
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In addition, 2 anti-infective drugs, 2 circulatory system drugs, 2 respiratory system drugs, 2 neurological drugs, and 2 rare disease drugs have been approved
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Although 2020 has experienced the new crown epidemic, the number of new drug research and development reviews has not decreased, the review time limit has not been compressed, and the number of approved listings is significantly greater than the level of the same period in the past three years, and has reached the highest level in recent years
.
Many domestic companies including Hengrui Pharmaceuticals, BeiGene, Hutchison Pharmaceuticals, Zai Lab, Chia Tai Tianqing, CSPC, and Dongyang Sunshine have achieved remarkable results in their declarations.
Both Chia Tai Tianqing and Dongyang Sunshine have more than 5 varieties for the first time.
Declare the IND
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It can be seen from the figure above that after the introduction of the new "Administrative Measures for Drug Registration", there has also been an increase in the number of applications for Class 5.
1 original research drugs that have been listed overseas and have not been listed in the country
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In addition to category 1 innovative drugs, in 2018, the Center for Drug Evaluation accepted 75 applications for the registration of imported original research drugs for category 5.
1 chemical drugs, and by 2020, there are 160 applications for category 5.
1 chemical drugs
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For the first-time declaration of category 5.
1 new drugs that have been marketed abroad and have not been marketed in China, based on the ICH guidelines, the benefit and risk assessment of the Chinese population is considered as a whole by analyzing ethnic differences and bridging the test evidence chain
.
This will attract overseas drugs for rare diseases or serious life-threatening diseases without effective treatments to enter China with conditional approval
.
Class 5.
1 drugs are also ushering in new opportunities for declaration and clinical research in China
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As Yang Zhimin, director of the Department of Clinical Medicine of the Center for Drug Evaluation, recently concluded at the CSCO conference, the number of IND registration applications increased year by year from 2018 to 2020, especially the implied license for the implementation of IND review on July 27, 2018 (60 jobs).
After Japan), the increase was significant
.
Among them, the number of oncology drug IND applications accounted for about half of the overall IND applications
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Judging from the approval of new drugs in the above three years, chemical drugs are still the main way for drug R&D and production in China
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As of the end of 2020, China's chemical pharmaceutical preparation production enterprises reached 1,123
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Biological products have also grown rapidly in recent years, from 971 applications in 2018 to 1,410.
Taking antineoplastic drugs as an example, according to Yang Zhimin’s introduction at the CSCO conference, China’s anti-tumor drug R&D activity has increased in proportion to the global proportion.
Joining the increase in the number of global early research and key research, the number of MRCTs carried out by Chinese pharmaceutical companies is also increasing, and finally, the number of new anti-tumor drugs approved in the past two years has increased
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In the first half of 2021, the number of oncology drugs approved still dominates.
According to the latest statistics from CDE, as of September 10, 2021, a total of 45 new oncology indications have been approved
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Source|The 24th National Conference on Clinical Oncology and Online Conference of CSCO Annual Conference 2021

Source|The 24th National Conference on Clinical Oncology and Online Conference of CSCO Annual Conference 2021

The increase in applications for large molecules was significantly higher than that for small molecule compounds, with monoclonal antibodies, double antibodies, polyclonal antibodies, ADCs, therapeutic vaccines, oncolytic viruses, and cell therapy as the main application directions
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All this is closely related to the changes in China's drug approval and review system and the construction of the industry's ecological environment
.
Kong Fanpu, director of the Drug Evaluation Center of the State Drug Administration, said in an interview with the Pharmaceutical Economic News that in recent years, limited review resources have been used in drug review and approval for innovative drugs with obvious clinical value and urgently needed drugs.
With the practice and optimization of the year, these reform measures have gradually become effective
.

2 .
   Review of quality changes

2 Review quality changes

In 2018, the Center for Drug Evaluation realized that the time limit review and approval rate of various registration applications for Chinese medicines, chemical drugs, and biological products exceeded 90%, and basically completed the State Council's "Opinions on Reforming the Review and Approval System for Drugs and Medical Devices" (Document 44) Determine the work goal of achieving approval within the time limit in 2018
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2018

At the end of 2018, the number of registration applications waiting for review and approval dropped from nearly 22.
000 at the peak of September 2015 to 3,440, which resolved the backlog of registration applications
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The completion rate of approvals within the time limit throughout the year was 84%
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In 2019, the Center for Drug Evaluation has achieved a time-bound review and approval rate of over 99.
8% of various registration applications for Chinese medicines, chemical drugs, and biological products, and completed the work objectives set in Document 44
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2019 year

In 2020, the drug approval center's annual application task completion rate was 94.
48%, of which the completion rate of clinically urgently needed overseas new drug registration application review tasks was 100%, and the completion rate of tasks within the time limit under the implied license was 99.
87%
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The overall NDA completion rate within the time limit in 2020 has increased significantly.
For example: the NDA completion rate within the time limit exceeded 80% in December 2020 and increased to 87.
5%; the completion rate of the applications included in the priority review process reached more than 90% within the time limit.
Break through
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2020 year

From 2018 to 2020, the Center for Drug Evaluation has expanded its review capabilities, improved review efficiency and speed by increasing review channels, strengthening project management, and recruiting personnel, so that the backlog of drug registration applications can be resolved
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R&D customers have learned that in the past few years, the Center for Drug Evaluation has established an evaluation management process with clinical efficacy as the core, standard guidelines prior to guidance, communication during the review process, and finally review decision-making, such as review items Assigned according to profession and indication; after the review of the acceptance form, it enters the stage of participating in the review and the main review professional review, and finally the three professional comprehensive reviews.
The responsibilities of the reviewers at all levels are clear, and the cross-professional review teams cooperate with each other
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The staffing of the Drug Evaluation Center has increased from 190 in 2015 to 648 in July 2021, of which 435 are reviewers
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In particular, the participation of many talents with R&D backgrounds in the industry has brought the perspective of pharmaceutical personnel and promoted the exchange between the drug review center and the applicant
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In the application process, the Center for Drug Evaluation guides applicants to apply for projects from a clinical perspective in a scientific, standardized, and rational manner, and fully prepare application materials until the project is established and clinical trials are carried out, saving unnecessary communication and issuing supplements
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In particular, it is worth mentioning that the Center for Drug Evaluation issued the "Administrative Measures for the Disclosure of Drug Review and Approval Information" in early 2021.
The purpose is to improve the transparency of drug review and approval work.
It can be seen that the drug regulatory department has improved the quality of review and approval work.
Effort and attitude
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3.
Communicate and optimize the review process

3.
Communicate and optimize the review process

In recent years, the Center for Drug Evaluation has continued to strengthen communication with companies
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According to relevant teachers of CDE, all communication and exchanges are free of charge in China
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From 2018 to 2020, the Center for Drug Appraisal has maintained growth in terms of receiving, handling or consulting on technical issues, and the total number of consulting on general technical issues of enterprises has increased from 15.
219 to 20.
285
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The close communication between the applicant and the drug review center can not only help pharmaceutical companies solve scientific-related problems in the application, but also enable CDE to optimize the review process in local feedback, correct the unreasonable areas of review, and promote the common growth of the company and the drug review center
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Achievements and challenges of new drug review

Achievements and challenges of new drug review

In the past three years, the Center for Drug Evaluation has accelerated the review of new drugs that are urgently needed in clinical trials overseas, implemented the implicit approval system for clinical trials, further refined the priority review, communication, and file review systems, and promoted the reform of clinical trial management and other measures.
Drug review work is done more meticulously and professionally
.
After joining the ICH, the State Food and Drug Administration has been continuously transforming and implementing various guidelines
.

The drug review center has not stopped in its pursuit of innovation
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It is understood that in 2020, the Center for Drug Evaluation has drafted 119 technical guidelines and officially issued 71
.
On this basis, 37 technical guidelines were issued in the first half of 2021
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For the year of 2021, 102 plans will be formulated, covering multiple fields such as new coronary pneumonia prevention and treatment drugs, traditional Chinese medicine, chemical drugs, biological products, and children’s drugs.
12 have been submitted to the State Food and Drug Administration for review, and 2 will be released soon after review and approval by the State Food and Drug Administration
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Now, what challenges will China's new drug review face?

The author once saw on the wall of the lobby on the first floor of the Beijing Drug Evaluation Center at 128 Jianguo Road, Chaoyang District, Beijing, and saw that the mission of the Drug Evaluation Center is to protect and promote public health, which is the same as the mission of the US FDA.
Same thing
.
Let us not forget that the core responsibility of CDE is to be responsible for the acceptance and technical review of drug clinical trials and drug marketing authorization applications, and to undertake the publicity and implementation of ICH-related technical work by the State Food and Drug Administration
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In the era of rapid iteration of innovative drug research and development in China, in the face of a huge number of application tasks, the center must first weigh the quality and speed of drug review
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According to the annual report of the Center for Drug Evaluation, 2020 is after the implementation of the "Administrative Measures for Drug Registration", 43 new drugs were accepted in one month in July, of which a total of 21 types of chemical drugs were used
.
This reflects the high speed and efficiency of innovative drug research and development, which has never been seen in the history of Chinese pharmaceuticals
.
Behind the fast and good review of good drugs is the embodiment of the team's accumulated review ability of the Drug Review Center, and it is also the support of the mechanism that encourages innovation
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What needs to be vigilant is that too much emphasis on the speed of new drug approval and ignoring the necessary links and steps in the approval process will undoubtedly lead to poor quality drugs entering the market; however, if the review process tends to be conservative, it is likely to lead to new drug review.
Severely lags behind
.
Drug safety and innovative efficacy go hand in hand, constantly gambling
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How to reduce the time spent on drug registration and approval without reducing the quality? This is a dilemma for global drug regulatory agencies
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How should we respond? In my opinion, the drug review center still needs to focus on the needs of patients, keep in mind the protection and promotion of public health as its own responsibility, carry out scientific and standardized reviews (Good Review Practice), and concentrate limited review resources On the "knife edge", to meet the urgent clinical needs of patients, comprehensively provide opinions from multiple perspectives, provide effective guidance to pharmaceutical companies, and generate scientific review wisdom in exchanges is the way to break the situation
.
In addition, how to formulate all regulations and technical guidelines in a scientific, standardized, and orderly manner, with the purpose of scientific supervision, to make them predictable, sustainable and stable, is also a topic that the State Food and Drug Administration and CDE need to think about
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We sincerely hope that China's biopharmaceutical companies can continue to maintain their motivation for innovation, and that the Center for Drug Evaluation will give full play to its technical review capabilities in the future to conduct timely and effective reviews of good drugs
.
Finally, I borrowed a sentence once said by Ms.
Zhang Xianglin, director of the original drug review center and dean of Shenyang Yihong Business School-believe in the China Drug Administration, believe in the China Drug Review Center, because the drug review center is the future of the China Drug Administration
.