The research and development of new drugs of traditional Chinese medicine is a systematic project, involving upstream basic research, applied basic research and downstream applied research, which needs to integrate multidisciplinary knowledge for overall design. . Therefore, for the key bottle in the process of innovative research and development of traditional Chinese medicine and achievement transformationIt is of great strategic significance to meet the needs of clinical medication, improve the original innovation ability of China's traditional Chinese medicine industry and promote industrial development to carry out theoretical, model research and key technology research, and build the theory, scientific model and generic technology system of innovative research and development of traditional Chinese medicine.

1 General idea

1.1 Facing major national strategic needs

1.1.1 Major common diseases Common major diseases have always been the key direction supported and encouraged by the national new drug creation. Since the "Eleventh Five Year Plan", major scientific and technological projects such as the national "major new drug creation" and "key research and development plan" have listed major diseases such as cardiovascular disease, malignant tumor, metabolic disease, respiratory system disease and immune disease as key support areas. More attention should be paid to these fields in the research and development of new drugs of traditional Chinese medicine.

1.1.2  Refractory disease  Refractory diseases also pose a great threat to human health. Developing effective therapeutic drugs to solve the treatment problems of refractory diseases is in line with the major strategic needs of the country, and is an important direction for the research and development of new drugs of traditional Chinese medicine.

1.1.3 Major health events The prevention and control of major health events is an important part of the national system of disease prevention and control. In recent years, infectious diseases have occurred frequently and have become a major threat to human health. Especially since this year, the global outbreak of the new coronavirus epidemic has formed a new model of global joint anti epidemic. Moreover, the important role played by traditional Chinese medicine during the anti epidemic period has also provided new opportunities for the development of new traditional Chinese medicine and the market path under the "double circulation" pattern in the future.

1.2  Adhere to the principle of taking clinical needs as the core^[1]

1.2.1  Meet clinical needs The purpose of new drug research of traditional Chinese medicine is to meet the clinical drug demand, and the new drug research based on this purpose must be oriented by the clinical demand. Clinical needs are mainly reflected in the following aspects:① The incidence and epidemiological characteristics of the disease; ② Aiming at the problems existing in the current intervention methods and clinical programs; ③ ; ④ Reflect the comparative advantages with similar drugs. Through the development of new drugs of traditional Chinese medicine, we can solve the above problems and provide effective therapeutic drugs for the clinic.

1.2.2  Reflect clinical value Applying the principles and methods of evidence-based medicine to affirm that the core value of new drugs is clinical value. Drugs are the main tools used by human beings for disease prevention and treatment. Different intervention means and therapeutic drugs are adopted for specific diseases. Fundamentally speaking, all drugs are used to treat diseases, but different drugs will assume different roles and play different roles. Combination drugs are also commonly seen in clinical programs. For example, the toxicity reduction and efficiency enhancement of traditional Chinese medicine in tumor radiotherapy and chemotherapy, and the glucocorticoid of anti asthma drugs＋βThe synergism of receptor agonists, as well as the traditional Chinese medicine program in China's fight against the new coronavirus epidemic. No matter any new drug, it must meet and reflect the unique clinical value of new drugs in existing therapies and drugs.

1.2.3  For medication habits and methods It is undeniable that there are inherent understandings and medication habits in clinical medication and clinical protocols. These medication principles and methods are embodied in clinical protocols, such as tumor"Three step therapy", chemoradiotherapy and adjuvant Chinese medicine, anti-inflammatory andβ. In fact, for specific diseases, traditional Chinese medicine and chemical drugs have different characteristics and advantages, and play different roles. To a certain extent, based on clinical experience, inherent clinical cognition and medication habits have been formed. Therefore, in the process of new drug research and development, we should pay high attention to the existing clinical programs and medication habits.

1.2.4 Highlight the clinical advantages of traditional Chinese Medicine Compared with chemical medicine, traditional Chinese medicine has unique advantages in some aspects. Similarly, there are also weaknesses and deficiencies in other aspects. The research and development of new drugs of traditional Chinese medicine should always highlight the characteristics of traditional Chinese medicine. The principles that must be followed in the research and development of new drugs of traditional Chinese medicine are syndrome differentiation and treatment, developing strengths and avoiding weaknesses, and highlighting advantages. First of all, we should select the clinical dominant diseases of traditional Chinese medicine for new drug development; Second, highlight the clinical characteristics and comparative advantages of traditional Chinese medicine; Finally, the clinical positioning, prescription selection and scientific research design were carried out based on the understanding of the disease and the principles of drug intervention (therapeutic principles) in the theory of traditional Chinese medicine.

1.2.5 Focus on clinical evidence . Clinical evidence is crucial in the development of new drugs. In particular, compound traditional Chinese medicine is mainly derived from classical ancient prescriptions, modern clinical empirical prescriptions (including hospital preparations) and folk proven prescriptions. The following factors should be considered in the selection of compound new drugs:① Clinical dominant diseases of traditional Chinese medicine; ② ; ③ Medical schools, tendencies and specialties of physicians; ④ The herbal origin of the medicinal flavor used in the prescription has the characteristics of succession, evolution and change; ⑤ The physical characteristics of modern people and their laws of onset, transmission and prognosis; ⑥ The pharmacological action characteristics of prescription and medicine flavor; ⑦ Compatibility principle; ⑧ Modern clinical application data.

1.2.6 Clinical oriented research design

（1）Preparation process design of expression based on clinical efficacy: extraction, purification and preparation process are important contents of the research and development of new Chinese medicine. Its process design should be based on the expression of clinical efficacy, that is, the efficacy expression path of the prescription. At present, there are many misunderstandings in the research and development of new drugs of traditional Chinese medicine, which often pay more attention to the chemical components of the drug taste and ignore the integrity of the prescription; It only sees the pharmacodynamic material basis of the medicine taste and ignores the role of "nature, taste" and its material basis in prescription compatibility and clinical efficacy, thus departing from the theory and formula of traditional Chinese Medicine-. Therefore, the process design of new drug research and development of traditional Chinese medicine should be based on the understanding of disease in traditional Chinese medicine theory-card-square-drug-work-From the perspective of obtaining the effectiveness of the prescription, scientific and reasonable extraction and purification, preparation process design, process route screening and process parameter optimization were carried out, and finally the reasonable extraction and purification and preparation process were determined.

（2）Based on clinical disease-To establish pharmacodynamic model and evaluation index based on syndrome differentiation: "syndrome differentiation and treatment" is the essence of traditional Chinese medicine theory and the characteristics of clinical application of traditional Chinese medicine, "disease-The combination of "syndrome" is the clinical orientation of the research and development of new drugs of traditional Chinese medicine, while "function + indications" is the general expression of the role of traditional Chinese medicine. Therefore, the pharmacodynamic evaluation method of new drugs of traditional Chinese medicine should reflect the above3Characteristics of. Based on the understanding of TCM on diseases, the establishment of animal models should not only conform to the characteristics of diseases, but also reflect the characteristics of TCM syndromes; ; At the same time, starting from the compatibility theory of traditional Chinese medicine, we should try to explore the synergy of multi-component complex system of traditional Chinese medicine in different targets, pathways and efficacy networks, so as to reflect the action characteristics and comparative advantages of the components, and provide sufficient experimental basis for new drug research and development.

（3）Establishment of quality control method based on the effectiveness expression characteristics of traditional Chinese Medicine^[2-5]. The expression of the effectiveness of traditional Chinese medicine is very complex, and the quality control method of a single index is obviously unsatisfactory. Academician liuchangxiao^[2]According to the characteristics of its own medical system, such as biological properties, manufacturing process and compatibility theory of traditional Chinese medicine, integrating multidisciplinary knowledge, the core quality concept of "quality marker of traditional Chinese medicine" is proposed to guide the quality research of traditional Chinese medicine and further strengthen the effectiveness of traditional Chinese medicine-material basis-. The proposal of quality marker of traditional Chinese medicine is conducive to the establishment of the whole process quality control and quality traceability system of traditional Chinese medicine. Quality research and the formulation of quality standards are important contents of the research and development of new drugs of traditional Chinese medicine. The theory and methods of quality marker of traditional Chinese medicine are consistent with the principles and objectives of the formulation of quality standards of new drugs of traditional Chinese medicine. Under the guidance of the concept of quality marker of traditional Chinese medicine, it is conducive to the scientific and effective control of the safety and effectiveness of new drugs of traditional Chinese medicine, improve the quality control level, and establish a quality control system based on "consistency".

（4）Clinical trial scheme design based on the clinical intervention methods and characteristics of traditional Chinese medicine: new traditional Chinese medicine originates from the clinic, and finally returns to the clinic. The clinic has always been the core link of the research and development of new traditional Chinese medicine. At the same time, new drugs of traditional Chinese medicine are different from chemical drugs. According to their own characteristics and for the purpose of seeking comparative advantages, the clinical positioning of new drugs of traditional Chinese medicine and the design of experimental scheme are very important. Evidence based research on traditional Chinese Medicine20With the development of the past five years, learning from and using for reference the existing successful clinical research design concepts and experience of new traditional Chinese medicine will certainly be conducive to improving the quality and efficiency of clinical research. Therefore, the criteria for selected cases, the criteria for judging the efficacy and objective indicators of clinical scheme design should reflect the treatment characteristics of traditional Chinese medicine as much as possible. At the same time, based on the clinical value and action characteristics of new drugsAnd clinical application mode to achieve clinical experience-Non clinical pharmacodynamic study-The linkage of clinical scheme design and clinical research, through "transformation" and "reverse transformation" research, discover the clinical characteristics of new drugs and focus on clinical positioning.

1.3 Oriented by enterprise demand and market

Traditional Chinese medicine and new drugs have been industrialized in pharmaceutical enterprises. Pharmaceutical enterprises are the main body of new drug project selection and scientific research investment, and the value driver of new drug research and developmentMotive force of motion. The research and development of new drugs should be guided by the needs of enterprises and the market. The scale of enterprises, business philosophy, product structure, product pipeline, market brand, commercial channels, etc. are important factors that determine the options of new drugs. R & D institutions should form a consensus with enterprises on R & D concepts. At the same time, they should implement the smooth connection of upstream R & D achievements to downstream transformation, and continue to provide continuous technical support after listing. .

1.4 Scientific research and design based on the whole process of new drug research and development and the whole life cycle of drugs

2  R & D strategy

2.1 Research and Development Countermeasures of innovative traditional Chinese Medicine

2.1.1  Innovative traditional Chinese medicine derived from natural plant, animal and mineral extracts  According to the new registration classification of new traditional Chinese medicine drugs, these new drugs belong to new traditional Chinese medicine drugs1.2Class, compared with the previous registration classification, should belong to the original new drug registration classification1Class and5Class I refers to the category of new drugs with active ingredients and active parts. The research and development of such new drugs need to focus on the "innovative" characteristics.

（1）Subject source: whether it is the natural products derived from traditional Chinese medicine, ethnic medicine or folk medicine, traditional medicine experience is an important clue and basis; Secondly, because the biosynthesis of natural products has a specific law, plant populations and their relationships, the geography and ecological dependence of secondary metabolites are important clues for the discovery and selection of new drugs; . Finally, because this kind of innovative drugs has no advantage of compatibility of traditional Chinese medicine, we must face chemical drugs directly and reflect the comparative advantage and clinical value. Such new drugs have long R & D cycles, large investment and high requirements for innovation. Enterprises should reasonably position themselves according to their own development requirements.

（2）New drug screening: the screening method combining target and phenotype should be the screening method of this kind of new drugs. According to the needs of indications, purity and different research and development stages, selective emphasis can be given.

（3）Drug likeness evaluation: drug likeness evaluation is a key link in the development of innovative drugs. A good candidate drug must meet the requirements of drug likeness before it can be developed into a new Chinese medicine. For a long time, due to insufficient attention to the evaluation of drug likeness, the upstream basic research can not be effectively transformed into the downstream application development, resulting in the premature death of a large number of phased achievements in new drug research and development. Therefore, it is necessary to strengthen the research of drug likeness and evaluate drug likeness for clinical value and industrialization implementation.

（4）Effectiveness and safety: drug likeness evaluation should be based on clinical value and comparison with existing drugs. Generally, the overall animal model related to the disease should be adopted to“Gold index”Its clinical advantages and action characteristics were deduced.

（5）Realizability of the preparation process: the preparation process should be targeted at the industrial process and realize small-scale test-Pilot test-Consistency of material transfer and release of process parameters in the whole process of large-scale production. At the same time, resources, costs, environmental protection and other factors should be considered to ensure the industrialization of the project.

（6）Feasibility of pharmaceutics realization: according to the in vivo process of drugs and the proposed drug delivery route, carry out physical pharmaceutics and Biopharmaceutics research, solve relevant technical problems, and implement the feasibility of pharmaceutics.

2.1.2 New compound Chinese Medicine  Compound prescription is the main form of clinical application of traditional Chinese medicine, which can best reflect the compatibility theory and synergy advantage of traditional Chinese medicine. Therefore, the new compound Chinese medicine is the main content of innovative Chinese medicine. .

In terms of topic selection, we should select the clinical dominant diseases of traditional Chinese medicine, put forward the clinical treatment problems according to the clinical treatment needs, existing therapies and existing drugs, and focus on the treatment field and topic selection direction.

The prescription sources of compound traditional Chinese medicine and new drugs generally include ancient prescriptions, clinical experience prescriptions (including in-hospital preparations), and folk prescriptions. The following advantages and requirements shall be reflected:①; ② Clinical evidence; ③ The feasibility of drug likeness (such as the amount of drug flavor, prescription dose, raw material compliance, process feasibility, industrialization), etc.

2.2 Improved new drugs

Improved new drugs refer to the preparations that change the administration route and dosage form of traditional Chinese medicine after marketing, and have clinical advantages and characteristics, or increase the main functions. Improved new drugs should have "necessary" and "reasonable" basis.

Many existing drugs have more or less problems, which need to be improved from the aspects of changing the dosage form, route of administration, changing the preparation process and adding new indications, in order to improve the efficacy, reduce toxicity and improve the clinical value.

2.3  Classic famous prescription new drug

The new drugs of classical famous prescriptions are classified according to the registration of new drugs of traditional Chinese Medicine3.1According to the requirements of new drug registration, "consistency" is the most important requirement. That is, the "consistency" of the material benchmark of the use of new classical prescriptions and ancient prescriptions is essentially the consistency of the effectiveness of classical prescriptions and ancient classical prescriptions. The following key links should be grasped in the development of classic famous prescriptions.

（1）Textual research on key information of ancient Chinese Medicine^[10-12]: traditional medical experience is the basis and cornerstone of the research and development of classical famous prescriptions. It is based on the prescription flavor, processing method, dosage, decoction method and dosage of classic famous prescriptions. The textual research of the key information of ancient prescriptions should pay particular attention to the changes of the original varieties of medicinal materials, medication habits, processing methods and weights and measures of ancient prescriptions at that time, and reflect the regional characteristics of doctors engaged in medical activities and the physical characteristics of the disease population. At the same time, it is also necessary to clarify the evolution process of the evolution and application of ancient prescriptions from the perspective of development. Clarify the core basis of new drug research and development.

（2）Refining of key quality attributes: unlike innovative and improved new drugs, classical famous prescription new drugs do not emphasize "excellent effect", but require "consistency", that is, the consistency of safety and effectiveness between classical famous prescription "new drug preparation" and ancient classical famous prescription "Decoction". The "key quality attributes" can best reflect the essential connotation of safety and effectiveness, and it is also the most effective starting point for the "consistency" evaluation in the process of new drug research and development. Attaching importance to the refining of key quality attributes is the key to ensure "consistency". The extraction of key quality attributes should be based on the theory of traditional Chinese medicine, starting from the etiology and pathogenesis of the disease, and according to the prescription group method of physicians.

（3）Production of high-quality products based on consistency and the whole manufacturing process^[13-15]: traditionalThere is a natural gap between the "Decoction" obtained by the preparation method and the granules prepared by modern industrial mass production. Only through scientific and careful research on the process route, process parameters and equipment conditions can we build a bridge between them and meet the "consistency" requirements of classical famous new drugs. At the same time, classic famous new drugs require the production of high-quality products, so it is necessary to establish the whole process of high-quality product manufacturing and quality control system.

3 Technology path

3.1 Discovery technology of new lead compounds in traditional Chinese medicine based on traditional medicine experience and systematic and Evolutionary Botany theory

  Traditional Chinese medicine and natural drugs are mainly derived from the secondary metabolites of plants. According to the theory of systematic and Evolutionary Botany, the formation of botanical drugs is not only closely related to their individual development process, but also the types of their chemical components can be traced back to their phylogenetic process, such as germline occurrence, origin and evolution, distribution and dissemination pathways, common ancestral proximity, evolution rate, geological history, ecological history, etc. And the following rules exist:① . ② The differences among members of the genus are all marked by geological and ecological processes. ③ The taxa closely related to the ancestral species contain the original chemical components of the genus and are distributed at the beginning of the genusSource center or original species preservation site; The taxa far away from the ancestral species contain the nascent (evolutionary) chemical components of the genus and are distributed in the evolutionary center or diversity center of the genus or at the edge of the distribution area.④ .

3.2  base on“Holographic fingerprint technology”Extraction and purification technology of traditional Chinese Medicine

3.3 Preparation technology based on clinical needs and drug in vivo process

3.4 Based on quality marker of traditional Chinese Medicine（Q-Marker）Quality evaluation technology of^[16-20]

3.5 Effectiveness and safety evaluation technology

3.6 Industrial chemical engineering technology

The industrialization of new Chinese medicine is the ultimate symbol of the transformation of scientific research achievements. In the clinical and industrialized research stage, when the dosage form is basically determined, in order to meet the requirements of large-scale production, it also needs an engineering research, which is the key step for the laboratory test to move towards large-scale.

Through the research on the key technologies of the engineering transformation of new drug varieties, especially for the key contents of industrialization such as parameter transmission, quality consistency, online monitoring of the manufacturing process and process control, a pilot test has been formed-Pilot test-The engineering technology mode of mass production has established a systematic and complete technical system from new drug research and development to industrialization implementation.

4  Prospect -- meet the new era of innovation and development of traditional Chinese Medicine

5  epilogue

At the same time, the research and development of new drugs of traditional Chinese medicine is a systematic project, which requires multidisciplinary knowledge integration and multidisciplinary cooperation, involving new drug discovery-Drug likeness evaluation-Preclinical studies-Clinical research and industrial production cover the whole industrial chain of traditional Chinese medicine production. Only through overall design and sequential research can we successfully develop and industrialize new drugs.

Conflict of interest 

References (omitted)   Source: zhangtiejun, liuchangxiao. Ideas and strategies for the research and development of new traditional Chinese medicine under the new situation   [J] . Chinese herbal medicine, 2021, 52 (1): 1-8