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    Status and Development Trend of Evaluation of Post-Marketing Traditional Chinese Medicines in China

    2020-12-29 06:51:39WEIRuili魏瑞麗WANGZhifei王志飛XIEYanming謝雁鳴
    關(guān)鍵詞:雁鳴瑞麗

    WEI Rui-li (魏瑞麗), WANG Zhi-fei (王志飛), XIE Yan-ming (謝雁鳴)

    ( Institute of Basic Research on Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China)

    ABSTRACT Evaluation of traditional Chinese medicines after the market has achieved fruitful results after years of development. The real-world research concept has been first proposed by Chief Researcher Xie Yanming in 2010 and to 2020 with the approval of the National Medical Products Administration to use real-world evidence to support drug development and review in 2020. Real-world data application and transformation continue to cause heated discussions in the industry. Real-world research concepts have been added new motivation into the evaluation of Chinese medicines after they are marketed. The development of the Chinese patent medicine industry is facing unprecedented opportunities and challenges.

    KEYWORDS Evaluation of traditional Chinese medicines after marketing; Real world research; Clinical safety evaluation; Pharmacovigilance

    Post-marketing evaluation is an important part of the drug life cycle and can make up for the limitations of pre-marketing evaluation. The scope of evaluation of traditional Chinese medicines after marketing is similar to that of chemical drugs,which is to evaluate the safety, effectiveness,pharmacoeconomics, etc. of a wide range of people in the actual clinical application of Chinese medicines that have been approved for marketing in accordance with relevant national regulations and promote the clinical rationality of traditional Chinese medicines. The use of drugs provides a basis for the risk and benefit assessment of traditional Chinese medicine and the national drug supervision work.

    STATUS AND DEVELOPMENT IN THE PAST 10 YEARS IN CHINA

    1. Evaluation of traditional Chinese medicines after they have been on the market has developed rapidly in the past 10 years and has been highly valued in China.

    1.1 At the national level, relevant policies and regulations are constantly improving

    China's post-marketing evaluation work stipulated that "evaluate drugs that have been approved for production" in the "Drug Administration Law of the People's Republic of China" (hereinafter referred to as "Drug Administration Law") issued in 2001; in 2007, The "Administrative Measures for Drug Registration" issued by the National Food and Drug Administration (SFDA) also stipulates that phase IV clinical trials are not carried out as required, and adverse drug reaction monitoring or evaluation, drugs will not be re-registered;On September 29, 2010, the SFDA issued the"Notice on Printing and Distributing 7 Technical Guidelines for Re-evaluation of the Production Process Evaluation of the Safety of Traditional Chinese Medicine Injections", including production process, quality control, non-clinical research,clinical research, risk control, The seven aspects of risk benefit evaluation and risk management provide guidance on how to carry out post-marketing evaluation, which greatly promotes the standardized and orderly development of post-market evaluation in China. At present, the evaluation of etraditional Chinese medicines after the market has become a scale, and the varieties with great development potential, large sales volume and better profit will be re-evaluated after the market; the "Adverse Drug Reaction Report and Monitoring Management Measures" issued by the Ministry of Health in 2011.It is stipulated that drug manufacturers must set up full-time institutions and full-time personnel to monitor adverse drug reactions, submit periodic safety update reports, fail to establish adverse drug reaction reports and monitoring management systems in accordance with regulations, and have no specialized agencies or full-time personnel responsible for adverse drug reaction reports in their units and monitoring work, failing to submit regular safety update reports in accordance with the requirements, will be given a warning, ordered to correct within a time limit, and fined. Since then,the National Adverse Drug Reaction Monitoring Center has issued the "Guidelines for Key Drug Monitoring" and "Guidelines for the Inspection of Adverse Drug Reaction Reports and Monitoring of Manufacturers" to guide enterprises to play the main role of normalized monitoring[1]. In June 2018,the Center for Drug Evaluation of the National Medical Products Administration (NMPA) publicly solicited opinions on the "General Considerations for the Clinical Research of Syndrome-based TCM New Drugs". In November of the same year, the National Medical Products Administration issued the "Technical Guidelines for Clinical Research of Syndrome-based TCM Drugs" "For the development,effectiveness, and safety evaluation of clinical trials of new Chinese medicines based on syndromes, the principled requirements are put forward with regard to the special considerations of traditional Chinese medicine, and the technical evaluation system of the characteristics of traditional Chinese medicine is continuously improved and promoted[2]. In 2019, the Twelfth Session of the Standing Committee of the 13th National People's Congress voted and passed the newly revised "Drug Administration Law", which specifically sets up Chapter 3 "Drug Marketing Authorization Holders", and the conditions,rights, obligations, and responsibilities have been comprehensively and systematically stipulated,and the main responsibility for the entire life cycle of the drug is assumed; Chapter 7 "Post-marketing Management of Drugs" puts forward specific requirements for post-marketing research and risk management of drugs[3]. On July 30, 2020, NMPA issued the "Opinions on Further Strengthening the Adverse Drug Reaction Monitoring and Evaluation System and Capacity Building", requesting to further strengthen the construction of adverse drug reaction monitoring and evaluation institutions and speed up the improvement of the adverse drug reaction monitoring and evaluation system, create a highef ficiency national adverse drug reaction monitoring information system, research and explore new methods of post-marketing drug safety monitoring and evaluation, guide and urge holders to implement the main responsibility for drug safety, and adhere to and consolidate the work mechanism of adverse drug reaction reporting in medical institutions[4].

    1.2 At the academic level, evaluation of Chinese medicines after the market has established a standardized method and technical system for the evaluation of Chinese medicines.

    With the expansion of the clinical application of traditional Chinese medicine injections and the increase in sales, based on the design,measurement and evaluation methods, the introduction of foreign advanced research concepts and technical methods has formulated the "Guidelines for Clinical Safety Evaluation of Chinese Medicine Injections"[5]. With reference to the pharmacoeconomics guidelines of various countries,combined with the particularity of traditional Chinese medicines, the "Technical Specifications for Post-Marketing Pharmacoeconomic Evaluation of Chinese Medicines"[6]was formulated to make the pharmacoeconomic evaluation process and results of Chinese patent medicines more scienti fic and reasonable. For the centralized monitoring of hospitals, the "Technical Speci fications for Centralized Monitoring of Traditional Chinese Medicines after the Market" and related reporting specifications[7]guide the large-sample, observational hospital centralized monitoring program and the use of nested casecontrol design on the characteristics and mechanisms of allergic reactions conduct in-depth research design, implementation, and reporting. In addition,post-market safety signal detection methods have also been explored and practiced, such as early warning technology for spontaneous reporting of adverse reactions and data analysis methods based on propensity scores.

    1.3 At present, there are still some problems in evaluation after the market of Chinese medicine

    The evaluation of Chinese medicines after the market is based on the combination of activity and passivity, scienti fic and feasibility, representativeness and authenticity, avoiding repeated evaluations,following the principles of medical ethics and embodying the characteristics of traditional Chinese medicine, and focusing on the safety evaluation of traditional Chinese medicine, evaluation of effectiveness of traditional Chinese medicine,economic evaluation of traditional Chinese medicine,and evaluation of combined use of traditional Chinese and western medicine[8]. At the same time,there are still some problems: (1) The enterprise is not very active. Companies are advancing under the impetus of policies, focusing on immediate bene fits and ignoring long-term plans. Some companies carry out post-marketing research in order to apply for entry into the medical insurance, basic medicine or China Insurance catalog, and the research stops once the application is completed. This approach is undoubtedly wrong. Enterprises must establish a long-term early warning mechanism,set up a special organization, assign a dedicated person to be responsible, and carry out normalized monitoring. (2) The credibility of the evaluation evidence is insufficient, and a market mechanism must be introduced and a third-party evaluation system established. The evaluation of traditional Chinese medicine after the market is in the process of subject differentiation and development towards professionalism. The evidence of evaluation is gradually accepted by the government, enterprises,medical staff and patients, and it has gradually become an important basis for decision-making.Whether the evidence of evaluation is true, objective and affects all aspects of medical and health. A team of high-level evaluation talents and professional evaluation agencies build a third-party evaluation system in accordance with market operating rules to improve the quality of re-evaluation evidence.(3) The effectiveness lacks high-quality evidencebased evidence, and the research on the mechanism of adverse reactions is not clear. The re-evaluation is based on human biological samples to study the ef ficacy and adverse reaction mechanism of human medication in the real world. Mechanism research needs to go further to clarify the mechanism and target of its clinical efficacy or adverse reactions,especially to study the mechanism of efficacy and adverse reactions of drugs in different populations,different comorbidities and combination medications.This is different from animal experiments conducted before the market. (4) The bene fit or risk reduction of the combination medication for patients is not clear. With the changes in the disease spectrum,more and more complex diseases such as coronary heart disease and tumors. In the actual medical environment, it is difficult to use one drug to block the multiple targets of the disease and achieve all therapeutic purposes. Therefore, combination drugs are widely available, especially the combined application of Chinese and Western medicine is becoming more common. However, whether the combination medication can really bring bene fits to patients or reduce the risk, will it "enhance ef ficiency and reduce toxicity" as predicted by theory, and further, if it can increase efficiency and reduce toxicity, what is the mechanism? Post-marketing research is to focus on this major and universal clinical problem and conduct research to produce scienti fic, evidence-based clinical evidence.

    STATUS ON THE EVALUATION IN RELEVENT FIELDS IN EUROPE AND AMERICA

    2. The evaluation of relevant policies,regulations and methods of drug after the market are basically mature in foreign countries, but the development is slow

    Developed countries represented by European countries, Japan, and the United States have conducted sufficient research on the effectiveness of drugs before they are marketed, and expand the population of drug users after they are marketed.Therefore, special attention is paid to re-evaluation of drug safety.

    The post-marketing evaluation work in the EU has been at the forefront. In July 2012, the EU implemented new pharmacovigilance regulations. In order to better promote the speci fic implementation of the new regulations, the European Medicines Agency has formulated the Good Pharmacovigilance Practices (GVP) as a new guideline for pharmacovigilance work in the European Union,replacing Volume 9A of the European Medicines Administration Act Part of "Pharmaceutical Police Ring South of Pharmaceutical Products for Human Use"[9]. The EU's pharmacovigilance consists of a series of interconnected processes, and the main pharmacovigilance processes are presented in the form of independent "modules" in the guidelines.GVP includes a total of 16 modules, covering the main aspects of pharmacovigilance, and has been formulated.

    In December 2016, the US Congress promulgated the "21st Century Cure Act", requiring the U.S. Food and Drug Administration (FDA) to include Real-World Evidence (RWE) in medical product review and supervision procedures. Since then, the FDA has successively issued statements and issued guidelines explaining the definition and characteristics of RWE, regulating the generation and application of RWE, and taking "giving full play to the role of RWE in review and regulatory decisionmaking" as its primary strategic focus. On December 6, 2018, the FDA announced the "Framework for FDA's Real-World Evidence Program" (Framework for FDA's Real-World Evidence Program), which provides a relatively clear roadmap for achieving RWE's goal of supporting review decisions.

    ON THE REAL WORLD RESARCH

    3. Introduce foreign advanced technology and methods, and continuously improve the technical system of evaluation methods for traditional Chinese medicines with traditional Chinese medicine characteristics.

    Traditional Chinese medicine is different from chemical medicine. Most proprietary Chinese medicines are compound prescriptions. Syndrome type Chinese medicines are very common.Syndrome differentiation and treatment and holistic view are the core of Chinese medicine theory.The particularity of Chinese medicines determines that the evaluation of Chinese medicines after the market cannot be copied abroad, and the market of Chinese medicines is constantly improved. Then evaluate the method and technical system to make it conform to the characteristics of traditional Chinese medicine. Real-world research is in line with the basic characteristics of the overall concept of TCM and syndrome differentiation and treatment. It will play an important role in the field of TCM clinical research and will occupy an important position in drug development and approval; the clinical effect and safety evaluation of drugs after the market will play a major role.

    Real-world research based on big data is suitable for post-market evaluation of Chinese medicines, and the concepts of the two are similar.The research of traditional Chinese medicine is fundamentally real world research. Traditional Chinese medicine rarely conducts randomized controlled trials under "ideal" conditions under strict conditions. It emphasizes that theories come from the clinic to the clinic, and more methods of induction are used to discover patterns in practice, and in practice verify the law, improve awareness and raise awareness. Real-world research originated from practical randomized controlled trials, emphasizing compliance with the reality of clinical medical treatment, non-random selection of treatment measures based on the actual condition and willingness of patients, and long-term, large-sample clinical observations to evaluate the clinical value of diagnosis and treatment measures and discover medicine laws, gain new knowledge. In addition, the characteristics of TCM syndrome differentiation and treatment and individual diagnosis and treatment emphasize the consideration of personal physique,psychology, social status, religious beliefs, personal wishes and other information, which can be fully implemented and exerted only under real-world conditions.

    Post-marketing evaluation involves a wide range of areas, and different evaluation methods are often used according to different evaluation purposes. No matter which evaluation method has its advantages and limitations. Therefore,integrate drug epidemiology, phase IV clinical trial data, passive monitoring data, active monitoring data, medical data and literature data, and use big data thinking to fully consider the timing and complementarity between the data, and carry out multiple perspectives, multi-level and comprehensive analysis.

    4. The development trend of evaluation after the market of Chinese medicine

    In recent years, national drug research and development policies and regulations have been continuously improved. Post-marketing evaluation research of traditional Chinese medicines revolves around clinical epidemiology and evidencebased medicine methodology, clinical research of syndrome-type new Chinese medicines,formulation of clinical practice guidelines and expert consensus, and real-world research design and data analysis paths, traditional Chinese medicine pharmacovigilance and risk and bene fit assessment of traditional Chinese medicine, implementation of scienti fic and traditional Chinese medicine evidence transformation, national medical decision-making,etc. continue to develop.

    4.1 Real-world research design and data analysis

    From the publication of the first domestic realworld research paper "Real-World Research: New Ideas for the Evaluation of the Effect of Traditional Chinese Medicine Interventions"[10]in 2010 to 2020,the National Medical Products Administration issued the "Guidelines for Real-World Evidence Supporting Drug Development and Evaluation" Principles(Trial)"[11], the research design, data analysis and application of real-world research continue to deepen.

    Real-world research belongs to the category of effect research, and has certain characteristics in common with other effect research. However,real-world research is used in the selection of the research population, the size of the sample, the application of randomness and control, the time point of evaluation and the determination of indicators,Data collection and statistical analysis have their own characteristics, which can complement RCT[12].In many cases, real-world research based on big data cannot control the quality of the data from the source, and can only achieve the data requirements of the research through data processing. For example, in large-scale prospective observational studies, data can be carried out through clinical research data management methods such as timely filling in a large amount of research data, accurate entry, computer-assisted manual review and proofreading, question and answer correction, and data blind review and lock-in, quality control. Realworld research based on the hospital information system (HIS) data, as an observational clinical trial,its data is essentially forward-looking data, and data quality control runs through the entire research including the research planning stage, the research process and the research end stage, including multiple data quality. The control link can greatly improve the quality of the HIS data through data quality control measures and the HIS optimization,thereby increasing the scientific nature of the research results.

    It is foreseeable that the application of realworld research is indispensable, but it also faces many challenges, such as the timeliness of data collection, data collection costs, data quality,handling of missing data and any bias in the data. In China, the volume of real-world data is large but the degree of standardization is low. The HIS of medical service institutions operates independently, and there is no national disease database. In addition,industry standards have not been established in real-world research methodology, and research is uneven. It is urgent for stakeholders to improve their understanding and investment in realworld research. A good project supervision and management mechanism will play a key role in research quality[13].

    4.2 Chinese medicine pharmacovigilance and risk and bene fit assessment of Chinese medicine

    Traditional Chinese medicine pharmacovigilance thought (compatibility, dose and treatment control,toxicity classification and poisoning rescue, etc.)attaches great importance to the safe use of Chinese medicine. With the changes of the times, it incorporates new connotations. Chinese medicine pharmacovigilance includes the theory of clinical safe use of traditional Chinese medicine and traditional Chinese medicine. Adverse reaction theory, traditional Chinese medicine toxicology and other academic content, safety monitoring and evaluation of traditional Chinese medicine before and after marketing, basic research on traditional Chinese medicine safety, discovery, evaluation,awareness and prevention of clinical safety issues of traditional Chinese medicine, and rational use of medicine guidance and publicity activities.

    At present, China's pharmacovigilance system highlights some problems: (1) The organizational system is not perfect, such as the large gaps in ADR monitoring institutions at all levels in information construction, expert teams, operating mechanisms,and funding guarantees; some cities and counties with poor drugs response agencies are attached to drug control institutes, information centers, etc., which are prone to unclear division of labor or overlapping functions; (2) The awareness of ADR reports is insufficient, such as poor initiative awareness, low quality of reports, low information utilization, and poor professional background of pharmacovigilance personnel; (3) Information transmission is not smooth, such as the uneven development level of pharmacovigilance in various regions and lack of communication; (4) The characteristics of traditional Chinese medicine are insufficient, such as the lack of pharmacological effects, adverse reactions,contraindications and other modern research content in many Chinese patent medicine instructions.

    Therefore, it is necessary to improve the traditional Chinese medicine pharmacovigilance system, form a pharmacovigilance system that meets the national conditions and has traditional Chinese medicine characteristics, enhance the concept of pharmacovigilance, formulate complete laws and regulations, improve organizational structure, strengthen the main body status of enterprises, give play to the role of medical institutions, and strengthen publicity training and education, increase supervision and punishment,establish a systematic and standard Chinese medicine application and evaluation system, and carry out post-marketing safety evaluation and risk management research of Chinese medicine[14].

    4.3 Implement scienti fic and traditional Chinese medicine evidence transformation

    From evidence to practice, there is a gap between ideal and reality. Ideally, medical information can be transformed into high-quality evidence, and high-quality evidence will be transformed into safe and effective clinical practice.Clinical professionals at all levels understand and master the use of high-quality evidence in the shortest possible time. The reality is that only a small part of medical information is converted into high-quality evidence, and high-quality evidence will be restricted by various factors in the process of converting it into clinical practice (including the available medical conditions, the level of professional and technical personnel, and the completeness of supporting services), clinical professionals may experience diminishing information at each lower level, and the wider the spread, the longer the cycle.In this context, the implementation of science came into being. The National Institutes of Health (NIH)defines implementation science as the study of methods used to integrate scientific findings and evidence into health service policies and practices.The core of implementing science is to fill the gaps in scientific research and clinical practice, and to introduce effective medical care interventions into clinical practice.

    The implementation of the scienti fic evaluation framework includes population coverage,intervention effects, institutional application,practical implementation and effect maintenance. To implement scienti fic common research designs, you can choose the intervention to be implemented, and select the corresponding design in combination with the scenario to be implemented, such as stepped mosaic cluster randomized controlled experiments,adaptive design, and a combination of qualitative and quantitative hybrid methods[15].

    Based on the current status quo that there is a large amount of clinical evidence in the field of Chinese medicine, and the national policy strongly supports the development of Chinese medicine to play a role in the health of the people, it is necessary to implement science in the field of Chinese medicine. Using evidence-based methodology,develop a set of strategies to promote the implementation of evidence-based practice, evaluate the effects before and after the implementation of the strategy, and finally realize the transformation of scienti fic research evidence into clinical practice[16].

    4.4 Pharmacoeconomic evaluation of traditional Chinese medicine and evidence-based medical decision-making

    Pharmacoeconomics evaluation can seek the best balance between drug resources and consumption and the improvement of health conditions, including disease burden, drug prescription management, drug pricing, national drug policies, and essential drug lists. The new version of the National Drug Insurance Catalogue released in 2019 accounted for half of the number of Chinese medicines, and 101 Chinese patent medicines were newly transferred[17]. The state vigorously supports the development of traditional Chinese medicine, continuously deepens the reform of the medical security system, establishes a dynamic adjustment mechanism for the drug catalog, and advances the reform of procurement methods, price negotiations, third-party payments,and centralized procurement. The success or failure of the re-evaluation of traditional Chinese medicine after the market is directly related to the value of the product and indirectly related to the company's product portfolio strategy and future development.Therefore, pharmaceutical companies need to make overall planning for the re-evaluation of products after the launch of the product from a strategic perspective, in order to achieve the maximization of corporate and social bene fits and the optimization of resource allocation.

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