Thinking on the development of new drugs of traditional Chinese medicine in medical institutions under the new requirements of drug regulation
; Chenxinshu
Guangdong Provincial Hospital of traditional Chinese Medicine
Objective: to provide suggestions for promoting the development of new drugs of traditional Chinese medicine in medical institutions. Methods: a series of relevant measures and guiding principles of new drugs of traditional Chinese Medicine issued by the state in recent years were summarized, the current situation of research and development of new drugs of traditional Chinese medicine was analyzed, and the existing problems were discussed. Results: medical institutions have certain advantages in the development of new drugs of traditional Chinese medicine, but they are lack of clinical value evaluation and collection of empirical evidence for human use. Conclusion: we should improve the index evaluation system of clinical efficacy, establish the application mode of human experience of traditional Chinese medicine preparations in medical institutions, effectively use the real world evidence, and design the overall method of quality control of new Chinese medicine research and development, so as to speed up the development of new Chinese medicine in medical institutions and promote the innovative development of traditional Chinese medicine.
In recent years, the state has attached great importance to the development of traditional Chinese medicine. Following the law of the People'sRepublic ofChina on traditional Chinese medicine, the drug administration law of the People'sRepublic ofChina, and the opinions on promoting the inheritance, innovation and development of traditional Chinese medicine, the state has issued a series of measures and guiding principles (see Table 1) to encourage and support the development of traditional Chinese medicine[1,2,3]In April 2020, the special provisions on the registration and administration of traditional Chinese medicine (Draft for comments), drafted by the State Drug Administration, solicited opinions from the public to reflect the characteristics of traditional Chinese medicine, inherit the essence, maintain integrity and innovation[4,5]To promote the high-quality development of the traditional Chinese medicine industry.
Table 1 relevant guiding principles for the research and development of new traditional Chinese medicine from 2020 to 2021
The above-mentioned measures have been fully reflected in clinical value, registration classification, quality control and human experience. The measures for the administration of drug registration requires adhering to the clinical value orientation and points out the direction for the development of new drugs. In terms of drug registration classification, from the original drug registration classification of 11 categories (2002 version of the drug registration management measures) to 9 categories (2007 version of the drug registration management measures), and then simplified to the latest 4 categories (2020 version of the drug registration management measures); . For the quality control of drugs, the "drug registration management measures" introduces the concept of full life cycle management of drug quality, requiring the overall control step by step from the source of medicinal materials to the final product quality delivery process[6]In addition, it is also proposed to build a review evidence system of "Three Combinations" of traditional Chinese medicine theory, human experience and clinical trials, and attach importance to human experience evidence. These are milestone progress in the research and development and evaluation of new drugs of traditional Chinese medicine in China, provide normative guidance documents for the development of new drugs of traditional Chinese medicine, and help accelerate the development of new drugs of traditional Chinese medicine, so that safe and effective products can be listed as soon as possible and benefit the people.
1 current situation of research and development of new drugs of traditional Chinese Medicine
Medical institutions are the cradle of the development and application of new drugs of traditional Chinese medicine. They are rich in clinical resources. The projects of new drugs of traditional Chinese medicine are mostly from the experienced prescriptions of famous traditional Chinese medicine and the preparations of medical institutions, which have unparalleled advantages. .
From the 2012-2020 drug review report, it can be seen that only a handful of new traditional Chinese medicine drugs have passed the marketing license (see Figure 1). The ultimate goal of the research and development of new drugs of traditional Chinese medicine is to apply and transform them into listed drugs. Due to the long research and development cycle and large investment, many varieties of new drugs of traditional Chinese medicine often fail in the midway from project approval to becoming listed drugs. In the early stage, the preparation process and quality standards of medical institutions were rough, the pilot study was not suitable for the scale-up production of pharmaceutical enterprises, and the independent intellectual property rights were lacking. The varieties of new Chinese medicine approved by medical institutions were disconnected from the market of pharmaceutical enterprises. .
Figure 1 number of new Chinese medicine drugs approved in 2012-2020
2. Problems in the research and development of new drugs of traditional Chinese Medicine
The supporting measures and systems for the development of new drugs of traditional Chinese medicine are still being continuously improved. Up to now, in order to speed up the establishment and improvement of the technical evaluation system in line with the characteristics of traditional Chinese medicine, the drug examination center of the State Drug Administration has drafted and formulated 12 technical guidelines related to traditional Chinese medicine, of which 10 have been published[7]The content is centered on deepening the reform of the drug evaluation and approval system[8,9]In order to meet the needs of drug research and development, the principle of encouraging innovation is formulated, step by step and linked, providing a strong theoretical system guarantee for the research and development of new drugs of traditional Chinese medicine. On this basis, the research teams and research platforms of new Chinese medicine in medical institutions should further explore in the practice of new Chinese medicine research and development, and face the current problems in the development of new Chinese medicine.
2.1 it is difficult to evaluate the clinical value
. According to the measures for the administration of drug registration, we should adhere to the clinical value orientation and attach importance to the evaluation of clinical value. However, how to balance the risk / benefit of clinical trials and evaluate its clinical value in combination with traditional Chinese medicine theory, human experience and clinical trials, medical institutions still lack corresponding evaluation methods and systems, and many clinical key specialties are still in the exploratory stage when carrying out clinical trials of traditional Chinese medicine compound.
2.2 lack of human experience in applying relevant models
According to the requirements for registration classification and application data of traditional Chinese medicine, human experience, as an integral part of the drug registration and application data, plays a role of connecting the past and the future in the evidence system of the "Three Combinations" of traditional Chinese medicine theory, human experience and clinical trials. According to the adequacy of human experience evidence, pharmacodynamics and phase II clinical trials can be exempted, which can effectively shorten the R & D cycle and reduce the development cost. Through the analysis of empirical evidence for human use, it is helpful to reasonably determine the clinical positioning, dosage and course of treatment of new Chinese medicine, reduce the risk of new Chinese medicine research and development, and provide a basis for the design of clinical trials of new Chinese medicine. However, there is no mature application mode at home and abroad on how to apply human experience evidence in medical institutions[10,11]。
In addition, real-world research as one of the methods of collecting human experience data[12]It has unique advantages. Clinicians in China have high diagnosis and treatment efficiency, rich clinical case resources, and can obtain a large number of clinical research samples in a short time. However, real world research has been proposed in China for many years and is still in the exploratory stage. Medical institutions lack technological innovation, control of data quality and institutional improvement.
2.3 lack of overall design mode of quality control
The difficulty and key problem of pharmaceutical research is the quality standard control, which has been the key content of traditional Chinese medicine preparation experts' research and discussion[13,14]At present, the drug evaluation center of the State Drug Administration has issued a number of technical guiding principles for traditional Chinese medicine, which are also the first special guiding principles for the research of new Chinese medicine decoction pieces, quality standards and biological effect detection[15]On this basis, researchers of traditional Chinese medicine preparations began to study the influencing factors related to the quality in the formation process of traditional Chinese medicine preparations and control them, but the research and development is often limited to the exclusive research on the quality standards of traditional Chinese medicine pieces used in traditional Chinese medicine preparations. In the practice process of research and development, how to integrate the guiding principles, and the medical institutions lack the overall research and design mode.
In order to promote the inheritance, innovation and development of traditional Chinese medicine and better carry out the research and development of new drugs of traditional Chinese medicine, the measures for the administration of drug registration proposed to establish and improve the registration management system and technical evaluation system in line with the characteristics of traditional Chinese medicine, and encouraged the use of modern science and technology and traditional research methods to develop traditional Chinese medicine[16,17]The R & D teams of traditional Chinese medicine new drugs in medical institutions, traditional Chinese medicine innovation enterprises and experts in traditional Chinese medicine industry should combine with the current practice of traditional Chinese medicine new drug research and development, continue to explore and strengthen the transformation and application development of traditional Chinese medicine new drugs. According to the current problems, the following suggestions are put forward:
3.1 improve the index evaluation system of clinical efficacy of traditional Chinese medicine compound
At present, the index system of clinical efficacy evaluation of traditional Chinese medicine compound in medical institutions is not comprehensive and perfect, and it complies with the theory of traditional Chinese medicine in clinical application; . Therefore, according to the clinical efficacy evaluation index system of chemical drugs only, it is difficult to evaluate the clinical value of traditional Chinese medicine compound, and it is impossible to find out the advantages of traditional Chinese medicine compound compared with chemical drugs or biological drugs. Establishing and improving the evaluation system suitable for traditional Chinese medicine is the key technical problem of clinical evaluation of the curative effect of traditional Chinese medicine, and it is also the necessity of the development and transformation of new drugs of traditional Chinese medicine. Therefore, it is particularly important for medical institutions to improve the evaluation index system for traditional Chinese medicine compound, which is the basic problem to improve the clinical value of traditional Chinese medicine compound and avoid blind project approval.
3.2 establish the mode of human experience application of traditional Chinese medicine preparations in medical institutions
Human experience evidence is the key to the implementation of the "Three Combinations" evidence system for the registration and evaluation of traditional Chinese medicine, and the quality of human experience evidence depends on the quality of human experience data. It is necessary to collect, sort out and statistically analyze the data of human experience, and summarize to form the human experience verification data. At present, traditional Chinese medicine (TCM) new drugs from clinical experience, famous traditional Chinese medicine (TCM) prescriptions, and traditional Chinese medicine (TCM) preparations in medical institutions have a history of clinical use. Among them, TCM preparations in medical institutions are clear and fixed in terms of prescription composition, preparation technology, quality standards, usage and dosage, functions and indications, and can be used in the medical institutions or medical consortia, medical group alliance, with the advantages of wide application scope, standardized clinical use, and easy data collection.
Therefore, for the evidence of human experience, it is suggested to start with the evidence of human experience of traditional Chinese medicine preparations in medical institutions. On the one hand, it is necessary to strengthen the training and supervision of clinicians, including the standardized filling of electronic medical record system, and mastering the traditional Chinese medicine preparations of various specialties in the hospital; . To establish the mode of human experience application of traditional Chinese medicine preparations in medical institutions, and provide references for the mode of human experience application of clinical experience prescriptions and famous traditional Chinese medicine prescriptions.
3.3 improve the system, method, evaluation system and technological innovation of real world research
Real world research is a research conducted in the process of clinical practice. Clinical and research are combined into one, which is the research closest to the clinical real medical environment. However, the record requirements of real world research are different from clinical medical records, which need to be more rigorous and complete. At present, clinicians in China receive more patients every day and have a large workload. If they want to carry out real-world research while carrying out clinical work, but do not increase the workload of clinicians, they need to reduce the time input of clinicians in collecting patient data and improve the work efficiency of doctors. It is necessary to rely on modern information innovation technology and artificial intelligence to assist in the recording and video collection of clinical case data. At the same time, the clinical electronic medical record system of medical institutions should be upgraded to facilitate follow-up, retrieval and sorting. In the past two years, pharmaceutical enterprises and internet medical and health service institutions have tried to actively promote the application of digitalization, in order to achieve a more efficient medical work mode, and use their respective advantages to explore technical means to help clinicians improve the quality of diagnosis and treatment from multiple angles. Through the establishment of online case management platforms for various diseases and the introduction of certain incentives, such as the development of platform permissions according to the number of included cases, the degree of standardization of medical history filling, etc., we can attract data sharing between different medical institutions and scientific research institutions, integrate and connect the scientific research platform of medical institutions with the big data platform of health care, and overcome the incompleteness and non shareability of data.
In addition, since medical institutions have more than 5 years of use history before the registration of traditional Chinese medicine preparations is approved, only 60 cases of clinical trials or other specific conditions need to be done, provinces and cities can promote the establishment of standardized reevaluation centers for traditional Chinese medicine preparations in medical institutions, reevaluate famous old traditional Chinese medicine prescriptions, traditional Chinese medicine preparations in medical institutions and other varieties with clear clinical efficacy, clear property rights and potential for the development of new Chinese medicine, and combine the use of outpatient and inpatient services in medical institutions, screen and export the data of the case system, establish an information-based database, so as to play a certain auxiliary role in real-world research.
3.4 create an overall design method for quality control
The quality research of traditional Chinese medicine preparations should follow the guidance of traditional Chinese medicine theory, and pay attention to the overall research design and production process control of traditional Chinese medicine preparations. . This requires the research work based on the research and design of new traditional Chinese medicine, the interdisciplinary integration, the strengthening of the research on the quality standards of the source medicinal materials, decoction pieces processing and intermediates, and the correlation with clinical safety and effectiveness, so as to reflect the transmission process of traditional Chinese medicine substances from the source to the preparation in the production process of traditional Chinese medicine preparations, create the overall quality control system of traditional Chinese medicine preparations, and improve the quality of new traditional Chinese medicine.
There has been no ready-made research and development model for reference in the research and development of new drugs of traditional Chinese medicine. After a long-term exploration, relevant measures and guiding principles in line with the characteristics of traditional Chinese medicine have been introduced, and they are in continuous improvement. In the current new situation, all disciplines and platforms of new Chinese medicine research and development in medical institutions should grasp the development opportunities of traditional Chinese medicine, strictly control the research and development risks, reduce the research and development costs, shorten the research and development cycle, effectively carry out the research and development of new Chinese medicine, and promote the innovative development of traditional Chinese medicine.
The article comes fromChina Pharmaceutical 2022,36 (03)；
