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Editor's note
After the NMPA joined ICH in 2018, Dr. Zhang Xingyi, the senior chief reviewer of the Drug Evaluation Center of the NMPA at that time, wrote "On the Cultivation of Reviewers" with nearly 20 years of accumulation and unique perspective, discussing how to write technical review reports with the high standards of "Xindaya" under the framework of drug administration and regulations, the craftsmanship, technical expertise and project management capabilities that reviewers should have, and predicting the challenges of ICH to the core strength of CDE.
If you want to wear a crown, you must bear its weight. In June 2024, the NMPA was elected as a member of the ICH Management Committee for the third time in a row, highlighting the size advantage and technical foundation of the mainland in the international pharmaceutical market and drug supervision, and also putting forward more arduous requirements for the high level and sustainability of the mainland's drug supervision. Dr. Zhang Xingyi once again wrote an analysis of the meaning of drug technology review, the innovation in the logical paradigm and how CDE can carry out the review work efficiently and efficiently in the context of big data AI and the ever-changing R&D environment, clarifying the underlying scientific and philosophical logic, consolidating the regulatory and technical foundation, and assisting the pharmaceutical industry to move towards new quality and high-end productivity in the pharmaceutical industry, which is the world's second largest pharmaceutical market and moving towards almost all high-end therapeutic fields.
He hopes to combine the experience of global regulations and from the overall and objective perspective of the overall situation that has passed, and pass on the philosophical thinking of the mainland review cause to the pharmaceutical industry, academia and regulatory industry, so that the R&D customers can understand the unpredictable road to application and approval from the bottom of science and philosophy, and also share the in-depth thinking and understanding of the internal logic of the review career they are engaged in. It enables review practitioners to shuttle between major disciplines such as pharmacy, clinical medicine, pharmacology and statistics, and enjoy the joy of world-class scientific thinking and philosophical thinking. Stay curious and discerning in an ever-changing regulatory environment to better meet your mission of safeguarding and promoting global public health.
Written by Zhang Xingyi
Review is also known as Evaluation, and is called "Review" in Japanese. Drug review is a professional and administrative act based on scientific and medical knowledge to conduct detailed technical review of drug clinical trials or marketing applications submitted in accordance with pharmaceutical regulatory regulations.
Ability and inability of the review
The cornerstone of drug evaluation is mainly based on the Drug Administration Law. The review process comprehensively covers the entire process of drug design, production, quality control, distribution, storage, and distribution, as well as an in-depth evaluation of all clinical trials and data on the pharmacological safety and human efficacy of the chemical and biological components contained in the drug, as well as its excipients and packaging materials.
Due to the significant gap between the scale of clinical trials and the broad patient population faced by the drug after it is officially launched, and the production scale of the new drug in the trial production stage and the commercial production stage is also significantly different, the technical data on which the drug evaluation is based cannot fully include and predict all the effects and subtle differences that may occur in a large number of patients after the drug is marketed when reflecting the safety and efficacy information of the drug. Therefore, the review process is mainly based on the limited results of clinical trials designed with certain specifications. The trial was designed and operated in accordance with the common clinical trial norms and guidelines identified by the ICH, but even then, it was not possible to cover all adverse reactions and rare side effects.
Therefore, drug evaluation is a scientific intellectual activity based on scientific norms and regulatory requirements. It uses standardized new methods, new means and new tools to make a preliminary judgment on the safety and efficacy of drugs. The Evaluation Body is not omnipotent, sharp-eyed, and its conclusions are not absolutely authoritative and always correct. The findings of the review will also be adjusted and refined over time, with the deepening of scientific understanding and the increasing number of drug users.
Philosophy of Science for Review
Evaluation is a rigorous science, which requires reviewers to be proficient in existing scientific knowledge and experimental methods, and conduct a comprehensive and detailed assessment of the scientificity and feasibility of the application materials in accordance with the law based on scientific and medical rigorous judgments.
Review, always standing at the forefront of science and cognition, based on existing knowledge and reasonable inferences, to make accurate predictions and predictions about the quality, safety and effectiveness of drugs, appropriate scientific foresight is necessary.
The evaluation is always faced with the dialectical relationship between the correctness of the details and the correctness of the overall situation. A drug application dossier, including a lot of technical details, is checked item by item during the review to identify whether it is compliant. However, all the details are in accordance with the regulations, which does not mean that the drug must be in line with the national policy guidance at that time, nor does it mean that there will be no safety or use problems after the drug is marketed. Conversely, those drugs that have been approved for marketing and have been successful may not be perfect in retrospective back to their application materials. Looking back at the application materials and approval procedures ten years ago, it is easy to feel the tremendous progress in technical requirements.
Review, often need to be fully sufficient data and evidence to carry out close to correct prediction and validation, which is like a scientific expedition, but also a kind of exploration in the face of unknown areas, it undertakes the mission of curing diseases and saving people, protecting and promoting public health, and exploring the frontier of medicine.
Logical paradigm for evaluation
The paradigm of the evaluation is generally as follows:
1) The drug research data should be complete, the indications should be clear, the research protocol should be clear, and the requirements of the regulatory authorities for the application materials must be met, and the verification of the production data should also be feasible. This declaration usually applies to all types of common generic drugs. For such products, CDE can formulate specific review technical points and procedural specifications, and improve the work efficiency of reviewers through full-time training and assembly line operation mode. As a basic project to protect people's livelihood, the focus of its work should be to improve the efficiency of review to ensure that the public can obtain safe and effective drugs in a timely manner. There is a possibility that this part of the work will be intervened, assisted or even partially replaced by artificial intelligence (AI) in the future.
2) For innovative drugs with innovative mechanisms and components, structures or indications that are all completely new fields, the existing pathological models and quality control methods may not be able to fully cover all the risk points and risk sources that CDE is concerned about. At the same time, there are blind spots and blind spots in the design and scale, operation, data statistics and model analysis of clinical trial protocols, which pose great challenges to reviewers. In the face of the fact that the conventional review work paradigm cannot make full use of the internal resources and past experience of CDE to completely, scientifically and accurately evaluate such declared varieties, it is necessary to activate the external expert consultation mechanism, and even invite foreign experts to give lectures to explain the relevant technical difficulties and the latest global drug research and development trends.
At the same time, combined with the clinical practice, production and quality control practice experience of domestic experts, as well as mature supervision methods, etc., comprehensive collection of multi-faceted information to form a phased review conclusion. During the evaluation process, the applicant should be encouraged to grow and improve the supplementary information. During the clinical research period, applicants are encouraged to continue to carry out relevant research, and even conditional approval and other means and gradual methods can be considered to achieve a balance and mutual promotion between the timely acquisition of patient treatment methods and the prudent review and supervision.
This kind of innovative project does face a lot of challenges in the review process, but it is a project that has attracted high attention from the scientific community, the pharmaceutical industry and the investment and finance community, and also reflects the professionalism, ability and efficiency of the country's drug R&D and evaluation institutions, and has a significant role in stimulating and improving the reputation of a country's pharmaceutical industry.
This part of the capability is the core competence of the drug regulatory agency, and it is also the main sector that competes with the world's major regulatory agencies. The leading approval of innovative drugs and the ability to withstand scientific and time-tested examinations are the basis for the evaluation agency to establish a global reputation. At the same time, the first approval of innovative drugs will also attract the world's pharmaceutical innovation achievements to China, and adopt the strategy of applying for registration in China first, thus interfering with the real success of the mainland in the world's pharmaceutical innovation.
3) Innovative dosage forms, innovative routes of administration, innovative packaging and excipients can often be repurposed for old drugs, or by changing the mode of administration, as well as using the latest scientific and technological innovations in materials science to significantly improve the delivery and absorption efficiency of drugs. These projects not only reflect a country's long-term accumulation in the field of basic science and applied technology, but also reflect a country's biomedical innovation capabilities.
Although the drug itself may be a mature drug that has been validated, with corresponding safety and efficacy data and clinical feedback accumulation, the difficulty of review is relatively more reflected in the understanding of new technologies and the establishment and compliance of innovation evaluation systems. In addition, the review of such drugs also needs to mobilize multidisciplinary forces such as materials science and industrial design to improve and expand small innovations such as clinical evaluation methods and safety pathological models. These innovations involve a wide range of complex points, so when coordinating the review progress, there are many speed limit control points, and the control speed of the review is no less difficult than the review of new innovative drugs.
In the past few decades, the mainland has excelled in the digestion and absorption of existing technologies and the reduction of costs in large-scale mass production, and the achievements of basic scientific research such as materials science have not yet been highlighted. In the future, the development of new quality productive forces must rely more on the innovation of basic science, so as to get out of the low-cost depression and guide the country to climb in the world's industrial niche. In this regard, the timely and effective combination of basic science and pharmaceutical application can open up new drug delivery systems, expand the duration and accuracy of drug administration, bring subversive innovation to the pharmaceutical market structure, and also pose new challenges for drug technical review.
4) For the fields of integrated traditional Chinese and Western medicine, chemical and biological drugs, modernization of traditional Chinese medicine, and innovative dosage forms of biological drugs, it belongs to the scope of cross-departmental and multi-professional collaboration within CDE. They involve the differences and integration of traditional theories of traditional Chinese medicine and the scientific evaluation system of chemical medicine, so they require a high degree of coordination and co-development between various departments. For example, ADC or xDC drugs, which can achieve targeted and precise localization and release of anti-tumor drugs in the body through various combinations such as antibodies or isotope nuclear drugs, thereby enhancing efficacy and reducing side effects. However, ADC itself integrates three parts: antibody biologics, toxic chemicals, and linkers, which not only maintain their own characteristics in the process, but also need to be connected and fused with each other. Therefore, the complexity and difficulty of the review of such drugs have reached a new level, requiring reviewers not only to have professional competence in chemical and biological drugs, but also to have interdisciplinary understanding and coordination skills. It is indeed a huge challenge to get this type of drug right.
5) Innovation review mechanism: The mainland's imitation capacity has been perfected, and interdisciplinary integration is one of the main directions of pharmaceutical innovation in the coming period. Since the CDE is organized according to the classification of disciplines, the interdisciplinary review has put forward new requirements for the organizational form, the knowledge reserve of personnel, and the logical paradigm of the review. If the new treatment methods proposed based on the new pathological theory are still attached to the original scientific system for evaluation, it will inevitably be biased and delayed. With the addition of AI and big data regulation, the review has become more diverse and real-time, and the CDE, which is on the front line of innovation, has an unprecedented thirst for knowledge and talent.
How to do a good job in the review
To sum up, in the ever-changing environment of new drug research and development, how should CDE do a good job of review? The author has the following thoughts for reference only.
First of all, the reviewers need to have a solid professional foundation, including pharmacy, clinical medicine, pharmacology, and statistics. Due to the large number of sub-disciplines within these majors, many people usually concentrate their professional strengths in a narrower field after graduating with a master's or doctoral degree. Therefore, it is particularly important to constantly broaden the scope of knowledge in the work and accumulate the knowledge of other brother majors. Of course, this requires a long process, and the reviewers will improve their comprehensive quality and professional ability through continuous learning, communication and practice. At the same time, the review body should also create conditions to encourage the reviewers to participate in various academic exchange activities to promote the expansion and improvement of their capabilities.
Second, evaluators need to demonstrate interdisciplinary understanding. Pharmacy belongs to the branch of science or engineering, while clinical medicine belongs to medicine. There is naturally a huge difference between the two majors in terms of professional content and judgment criteria. In order to effectively understand each other across these two disciplines, and at the same time examine the problems of the profession from the perspective of the other party, this process is like a dialogue between the top of two mountains, which requires in-depth exchanges and empathy with each other, which requires the reviewers to have a high degree of understanding and continuous cultivation. After completing their master's and doctoral studies, many people's thinking has been solidified, and the joy of studying may make them reluctant to give up their existing experience and open their minds to new ways of thinking. Evaluators need to keep an open mind and actively seek interdisciplinary knowledge and perspectives to improve their comprehensive evaluation capabilities.
Third, it is necessary to have a balanced professional knowledge and a grasp of the dynamics and timeliness of regulations. Expertise is the foundation, and understanding cross-departmental collaboration is a prerequisite. The key is to be able to integrate the knowledge of various disciplines to form a consistent, actionable conclusion. This requires trade-offs and prioritization. Without experience in the industry and in-depth experience of the regulatory system, I am afraid it will be difficult to find this balance. Only in this way can the findings of the review be accepted by all parties and be practicable, ensuring the successful completion of the regulatory tasks assigned by the State.
Fourth, we must be aware of the mission of protecting and promoting public health. If the Xinhua News Agency is the mouthpiece of the Party Central Committee, then the Food and Drug Administration is the party's leader in the field of drug supervision and health. While promoting policy development, we must not deviate from the implementation of the underlying scientific logic. Therefore, drug review and approval and supervision work is a discipline that tests the artistry and technical skills of leaders, and those who are not skilled cannot be competent.
Continue to accumulate innovative experience
According to customs data from January ~ December 2023, the mainland's annual pharmaceutical trade deficit is 204.8 billion yuan, far exceeding that of bulk commodities such as crude oil and natural gas, which confirms the reality that the mainland's pharmaceutical industry is large but not strong. Different from high-end chips, new energy vehicles and other competitive and open fields, the pharmaceutical industry has high barriers, strong supervision, large investment and high uncertainty, which is a major event that can be done efficiently by simply concentrating manpower and material resources. Cultivate the healthy development ecology of the pharmaceutical industry, wait for the flowers to bloom, and use patience, capital and tolerance mentality, modesty and low-key to break the wall in ten years.
As the pinnacle industry of capital and talent accumulation, the pharmaceutical industry is a high-end pillar industry in the G7 countries alongside finance, information and military industry. Although the mainland has entered the threshold of ICH and is on the table, it will take time to play a leading role in ICH with its strength and convince people with virtue.
In the past 30 years, when the mainland's economy has made rapid progress, it has shifted to a new stage of still water and deep flow, and has continued to advance into fields with high experience accumulation and high knowledge intensity, and has continuously reaped brilliant achievements in one industrial field after another. Innovative medicine, as a never-ending development field, is different from other industrial pearls, it needs to be picked up in continuous improvement, because once one step ahead, it is expected to occupy most of the profits in this field, just as Apple once accounted for more than half of the net profit in the global mobile phone industry.
We expect CDE to firmly defend our achievements in the field of medicine with its increasingly strong professional strength, actively participate in international high-level competition, and escort the international development of the mainland pharmaceutical industry in the process of expanding its influence in the world.
About the Author
Dr. Zhang Xingyi has served as a CMC review expert for innovative drugs, generic drugs and imported pharmaceuticals at the Center for Drug Evaluation of the National Medical Products Administration for more than 20 years, and has more than 10 years of experience in drug R&D/CMC technical evaluation and regulatory science, and is familiar with the drug regulatory policies and technical requirements of China, the EU/the United States and Japan. He is also an EWG Specialist for the ICH Quality Control Working Group, Leader of the ICH Q1 Stability Group, and a Scientific Lead for CDE in the Evaluation of Complex Generic Drugs. He has obtained a postdoctoral degree in pharmacokinetics from the Faculty of Pharmacy of Kyoto University, Japan, and was selected for the public study abroad program of Kyoto University organized by the Sasakawa Foundation and the Ministry of Health of the People's Republic of China. Contact email: [email protected]
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