2021 Annual Drug Evaluation Report Released - These issues are worth paying attention to


Release time:2023-02-02

On June 1, 2022, the State Food and Drug Administration issued the 2021 Annual Drug Evaluation Report (hereinafter referred to as the "Report"). The "Report" shows that China's drug review work in 2021 has achieved outstanding results, including the review of 47 innovative drugs throughout the year, setting a new record high; The overall time-bound completion rate increased to 98.93% throughout the year, and the time-bound completion rate of many projects made historic breakthroughs, including a number of new coronavirus vaccines, therapeutic drugs and innovative drugs, new drugs urgently needed overseas in clinical practice, and the launch of drugs for children.

At the same time, the 183 FDA daily problems encountered by the "Report" in terms of review and approval cannot be ignored, among which there are many products that are denied and recommended not approved, most of which have problems in the feasibility of project establishment, and there are also compliance and quality problems prominent.

In 2021, the Center for Drug Review accepted 11,658 registration applications, and after technical review, the review concluded that 542 registration applications were not approved/recommended for disapproval, accounting for 4.6%. Among them, 359 cases were due to the applicant's failure to supplement information within the prescribed time limit, accounting for 66.3% of the total number of non-approvals/recommended disapprovals throughout the year, including 9 cases of traditional Chinese medicines, 349 cases of chemical drugs and 1 case of biological products; The 183 registration applications mainly had defects such as the safety, efficacy or quality controllability of the drugs applied for registration because the application materials could not prove the safety, efficacy or quality controllability of the drugs applied for registration, including 14 traditional Chinese medicines, 126 chemical drugs and 43 biological products.

In view of the above unapproved registration documents, the Center for Drug Review summarized the common problems and gave corresponding guidance and suggestions. It is not difficult to see the attitude of the drug review center, encourage new drug research and development to start from clinical value, encourage enterprises to strengthen exchanges with drug review center, and do a good job in the preliminary basic research of innovative drug research and development, etc., so as to save costs for all parties and improve the success rate of research and development.

(1) Main issues

1. R&D proposals

This problem mainly exists in the early development of varieties (IND stage) and the development stage of certain generic drugs and supplementary applications. Specifically, it includes: unclear clinical positioning of drug research and development, unreasonable selection of indications; Improper selection of dosage form or route of administration; The existing research data suggest that the pharmacodynamic effect is not obvious, the target and mechanism are not clear, and the druggability risk is high. The combination of drugs violates the principles of clinical diagnosis and treatment, or lacks the support of efficacy and safety research data; The existing research data does not support the improvement and development of marketed varieties; The reference preparation developed by generic drugs has been withdrawn from the market due to safety and efficacy issues; The supplementary application for changes lacks scientificity and reasonableness.

2. Effectiveness aspect

This aspect is more common in listing applications. Specifically, these include: the available clinical research data cannot prove the effectiveness of the variety; The clinical studies that have been carried out have trial protocol or study quality control problems, and cannot evaluate the effectiveness of the tested varieties; The results of the human bioequivalence test of generic drugs showed that they were not equivalent to the reference preparation; The application for marketing registration in Class 3 of the Chemical Drug Registration Classification lacks clinical data on domestic validity.

3. Security aspects

Drug safety issues exist at all stages of drug development. Specifically, early (IND phase) studies suggest significant toxicity or a narrow safety window that is difficult to enter clinical development or suggests that the overall benefit of clinical application is very limited; preclinical safety study methods or study quality control issues, or insufficient study data to support subsequent clinical development; The existing clinical research data show that there are serious adverse reactions, and the benefit and risk ratio of clinical application is unreasonable; The application for registration of Class 3 of the Chemical Drug Registration Classification lacks domestic safety clinical data.

4. Quality controllability

This problem is common in the development of generic drugs. Specifically, there are serious defects in pharmaceutical research that cannot prove the quality controllability of the product; The declaration materials cannot prove the consistency of the quality of the generic drug and the reference preparation; Inconsistent study samples at different stages of development; The results of sample stability research results and the selection of starting materials of APIs do not meet the technical requirements for the listing of generic drugs; generic drugs do not use APIs of legal origin as required; The sample review inspection does not comply with the regulations or the inspection method has serious defects.

5. Compliance aspect

This aspect is common in applications for registration that have undergone registration verification and registration inspection. Specifically, it includes: the authenticity of the research data found in the registration verification; Other major defects affecting product quality are found during the registration verification; Registration verification sampling inspection failed.

6. Other aspects

Specifically, this includes: failure to provide research data or supplement research projects in accordance with the requirements and standards set by the regulator at the time of communication; During the evaluation, it was found that the research content was missing and could not support the registration application; The application for revision and supplementation of drug instructions does not comply with the requirements for writing instructions and management practices; Insufficient documentary evidence or research data to support the application for change supplementation.

(2) Comparison with previous years

Generally speaking, the main problems existing in the registration application in 2021 are quite similar to previous years in terms of classification and specific performance. But there have also been some changes, mainly including:

1. New problems that arise

The applicant failed to submit the research data in accordance with the supplementary information requirements proposed by the regulator during the pre-clinical trial application, resulting in the absence of IND research content during the review process. According to Article 88 of the current Measures for the Administration of Drug Registration, the applicant shall not supplement new technical information during the review of the drug clinical trial application, resulting in the review not passing.

The above situation is mainly due to the fact that the applicant did not pay attention to the fact that no new technical information should be added during the review period according to the current Measures for the Administration of Drug Registration, and ignored the research materials that should be submitted in the communication when submitting the registration application materials. This is rare in the past for reasons that have led to non-approval.

2. Changes in the number of varieties that are not approved based on certain problems

First, in 2021, there were no registration applications that were not approved due to lack of communication; Second, the number of applications for the registration of Class 3 of chemical drug registration classification that has not been approved due to the lack of domestic efficacy and safety clinical data has increased significantly compared with previous years; Third, the number of unapproved registration applications due to compliance issues has decreased compared with previous years; Fourth, the number of unapproved registration applications has increased significantly.

The above situation is related to the management requirements for communication and exchange in the registration application process, as well as the adjustment of the management requirements for the review conclusion of the Class 3 marketing registration application of the chemical drug registration classification after the implementation of the current "Measures for the Administration of Drug Registration".

(3) Enlightenment and suggestions

The main problems existing in recent registration applications can be analyzed to enlighten them, and provide reference suggestions for all parties involved in drug research and development, registration and supervision.

1. Pay full attention to the basis of drug development

Drug development should be based on clinical needs, with particular emphasis on addressing unmet clinical needs; It should be guided by clinical value, pay full attention to the advantages of the development of similar innovative drugs, and avoid group, low-level and repetitive innovation; The clinical value and advantages of new modified drugs should be fully evaluated; The application for change and supplement shall follow the principles of necessity and reasonableness.

2. Make good use of the communication mechanism

Under the existing communication mechanism, in addition to submitting communication and exchange applications at key nodes in the drug development process, applicants can also strengthen communication in other aspects of R&D and the review and approval process; Communication should be based on problems, solve problems, reach consensus on issues of concern, eliminate information asymmetry, and should not equate communication and administrative approval procedures; All parties should fully follow the consensus reached through communication.

3. Strengthen the preliminary basic research of innovative drug development

Some new mechanisms and new targets should be fully evaluated for druggability, and as many proof-of-concept studies as possible should be carried out to reduce the risk of subsequent development and avoid waste of research resources; The commercial development strategy of innovative drugs should be based on scientific nature, and pay attention to the integrity of the evidence chain of druggability; The scientific logic of drug development should be followed, step by step, and the interference of non-scientific factors on the development process should be minimized.

The R&D of new drugs is obstructed and long, from project establishment, pre-clinical, phase I/II/III clinical trials to post-marketing monitoring, multiple links are closely interlinked, one wrong step, full of losses. Therefore, the head of enterprise R&D needs to have a big-picture view, understand the common problems of rejection of new drug registration and the official guidance and suggestions, which often represent reference answers, so as to lead the team away from dangerous areas and improve the success rate of drug research and development efficiently and labor-saving.

Relevant attachment: https://www.nmpa.gov.cn/xxgk/fgwj/gzwj/gzwjyp/20220601110541120.html full text of the 2021 Drug Evaluation Report

key words: 2021 Annual Drug Evaluation Report Released - These issues are worth paying attention to