[field view] Zhang Zhefeng: analysis of the basis of drug research and development from the perspective of technical review

Since 2015, the consistency evaluation policy of generic drugs has been implemented A large number of well-known enterprises began to distribute products with large market capacity, such as amlodipine besylate tablets, Amoxicillin Capsules, metformin hydrochloride tablets, etc Then, with the transformation of bidding and purchasing mode in recent years, the drugs that have been evaluated are indeed favored by all provinces, such as directly linked to the Internet, preferentially used, etc At that time, the domestic generic pharmaceutical enterprises entered the stage of fierce competition However, with the rapid rise of bidding price linkage mechanism, the "advantage" of over evaluated drugs in price is not large, which makes domestic enterprises realize that the golden period of profit in generic drug market is gradually disappearing, and innovative drugs are the core chips for enterprises to seize the market Therefore, drug R & D has become the primary investment project of major pharmaceutical enterprises, and the basic ideas and Strategies of R & D, the basis for setting up the topic and other elements directly determine the key to the economic value and technical value of drugs In view of this, as the scientific director and chief consultant of Beijing Peiyou innovative Pharmaceutical Biotechnology Co., Ltd., Professor Zhang Zhefeng analyzed the basis of drug R & D from the perspective of technical review at the 2019 China Pharmaceutical Health Industry Development Conference and the fourth China Pharmaceutical R & D Innovation Summit, and made a specific analysis of the current R & D status of improved innovative drugs 01 the basic idea and strategy of drug research and development the reform plan of chemical drug registration and classification issued in 2015 This plan can be said to be the regulatory guidance document for drug research and development and drug evaluation In this document, the innovative drugs, improved drugs and generic drugs are actually redefined This new definition is more in line with the international standards in terms of connotation and extension For example, for new drugs, it must be a global one There is no new compound on the market at home and abroad More importantly, in terms of clinical treatment, new drugs should solve the problem of new indication treatment For example, improved new drugs emphasize clinical advantages and changes of improvement The generic drugs can be substituted for the original drugs in clinical treatment Therefore, for drug research and development, the key elements are four words: new, same, excellent and practical There are three basic types of drug R & D and drug registration declaration: innovation, improvement and imitation Different types of R & D have different objectives, R & D characteristics, and R & D basic ideas are also different For example, the R & D goal of innovative drugs must be to solve the clinical needs that have not been solved yet, and it must be based on clinical needs Under this goal, we need to consider issues, such as R & D ideas and R & D strategies? It is clear that there is an unmet need for an indication in the current treatment How large dose and how long course of treatment can the product be developed? These studies need to be explored step by step Do animal experiments and animal models prompt such information? At the same time, a new compound, the first time into the human body, can bring a certain therapeutic effect But it will inevitably bring some side effects and toxic reactions What kind of people and measures are available to avoid this toxic reaction at what dose? These studies are also achieved through gradual clinical research For example, what is the performance of R & D products in terms of efficacy? Is it better than the existing treatment methods? What is the appearance of adverse reactions? What are the expected, unexpected and potential adverse reactions that have not been found? These considerations need to be further explored or closely observed after listing In addition, the comprehensive evaluation of these benefits and risks will determine whether the product can be approved for marketing and what the market benefits are In contrast, in the case of generic drugs, it is a completely different situation For a long time, the cost of the original research is very high in clinical practice, and the patients' sense of access is not strong Therefore, it is the requirement of every country to push a large number of generic drugs with the same curative effect and lower price to the clinic The goal of generic drug research and development is to replace the original product and use it in clinic The idea and strategy of research and development of generic drugs should be a comparative research idea To replace the original research products, we should compare the material basis and quality characteristics with the original research products Only with the same material basis and quality characteristics can we replace the original research products in clinical So, in the comparative study of generic drugs and the original research, such as what kind of principle to follow, what kind of indication, what kind of dose, what kind of course of treatment in the process of treatment, which information is very important, but for generic drugs, which content does not need to be re studied, it can directly refer to some research information of the original research drug So the essence of generic research strategy is bridging and comparing Innovative drugs are different Innovative drugs are exploratory and gradually advancing research ideas, and comprehensive weighing strategies are necessary to evaluate its listing Let's talk about improvers The improvement is also based on the clinical needs, on the basis of the existing drugs to improve, improve and upgrade, in order to solve some problems in the clinical use of the drug This kind of R & D is an improvement based on the above market products Some research information does not need to be re studied by the enterprise, such as active ingredients, safety, effectiveness, etc At the same time, the original research data can be used for improvement research and development Therefore, the improved drugs have some advantages in the research process No matter which stage of research and development, the success rate of preclinical and clinical trials is much higher than that of innovative drugs and biological drugs Moreover, in terms of clinical value, improvement and innovation should have more obvious clinical advantages, which is what developers value in economic benefits Moreover, from the perspective of global R & D background, it is very difficult to develop new molecules, new mechanisms and new targets, while the success rate is very low, the rate of return and the duration are very long Therefore, compared with the innovation of new molecules, this kind of improved innovation is more and more popular Especially in the domestic pharmaceutical enterprises, it is a potential direction to change the benign innovation The research ideas and Strategies of improved innovation are actually the comprehensive application of exploratory research and comparative research Through comparative research, we can verify the functions of improved products and improved drugs Generally, different dosage forms will lead to different distribution and absorption of blood concentration and active ingredients in the body Therefore, when improving drugs, we need to evaluate the establishment of benign innovation, research and development ideas from these aspects, that is, what is the goal of improvement? What are the risks of improvement and improvement? Is this risk controlled? How to control? What limit and scope should be controlled? This is a basic idea and strategy for improvement and innovation 02 discussion on the purpose and basis of research and development the purpose and basis of research and development is based on a clear understanding of the basic ideas and Strategies of drug research and development The pharmaceutical enterprises should understand that the foothold and starting point of innovative drugs must be based on clinical needs Innovation must be aimed at a certain purpose Innovation is not a goal, but a means to achieve this goal Before research and development, we need to have an understanding of disease and treatment status For example, what are the characteristics of target indications? What are the characteristics of epidemiology? What is the effect of standard treatment for a disease? What is the status quo of clinical treatment? What are the shortcomings of the existing treatment methods? In addition, the function mechanism, safety and effectiveness of the product development are evaluated to determine the purpose and basis of the establishment In the above considerations, clinical needs are the key to the purpose and basis of research and development However, which specific conditions can be understood as meeting the clinical needs for effective solutions, for example, for rare diseases without treatment means or effective treatment means, there must be clinical needs; for drugs without effective treatment for general diseases, or with unsatisfactory treatment effect and safety problems, there is also room for development There are also some newly discovered diseases, as well as serious problems in drug efficacy or safety, which need to be solved in clinical needs All these are important factors for research and development Next, after determining the clinical needs, how to judge it? What are the criteria for evaluation? This is an important issue to consider For example, the existing drug efficacy is not good, clinical urgent need for better efficacy of drugs to meet clinical needs In view of this situation, the development of more effective products, or innovative drugs based on new theories, has a high degree of recognition to meet clinical needs In addition, for rare diseases, serious life-threatening, difficult to treat diseases As long as the product developed by the enterprise is effective and better than placebo, the patient has considerable income after using the product, which can also be considered to meet the clinical needs In the research and development of products, non clinical information is also very important For example, in the non clinical safety study, the reference factors for the evaluation of the topic include the lowest dose of toxic reaction, the highest dose without toxic reaction, and the lowest dose But at the same time, because of the diversity of the body, the information from the comprehensive evaluation of animal experiments can not support the human experiments The research and development goal of generic drugs is clinical substitutability Its establishment must refer to its listing basis, listing time, listing country, disease spectrum and other specific conditions There are also benefit risk tradeoffs associated with product launch, because the early benefit tradeoffs may not have the same value as the actual ones In addition, considering from the prescription characteristics of the product, whether the project approval, technology and characteristics can realize the replacement of the original research product is also a problem worthy of attention For the improved and innovative products, does the improved basic reliability, time to market, region, etc., and the advantages after improvement solve the current clinical deficiencies of the products? The answer is that it has advantages for the original research and improved drugs But compared with the current standard treatment of diseases, is it still advantageous? It's worth thinking about Although it has advantages over the improved products, the improved products are not the mainstream treatment, and the treatment effect is far from the mainstream treatment effect This improvement may also face a problem Therefore, the risk of improvement and risk control is also a problem to be considered in the improvement stage The improvement category is generally carried out for the same indication Molecular improvement and molecular optimization are the development of prodrugs of improved compounds, or the change of the characteristics of prodrugs, and also the basis for the division of improvement and innovation For example, there was a very typical case earlier, that is, the physical and chemical properties of TDR to TAF were improved after subsequent improvement Most of the drugs that originally stayed in the blood gradually entered the liver, and then played a pharmacological role in the liver, reducing toxic and side effects Therefore, such improved drugs not only maintain the same therapeutic effect, but also greatly reduce adverse reactions In terms of mechanism, it is an excellent case to meet the clinical needs In addition, in terms of compliance, for example, the slow speed of repeated long-term and multiple administration