Clinical research and development of children's medicines, classic prescriptions, and traditional Chinese medicines will accept real-world data

On January 7, the State Food and Drug Administration officially released the guiding principles of real world evidence supporting drug development and review (Trial) Among them, it mainly includes six parts: definition of real world research, source and applicability of real world data, real world evidence supporting drug regulatory decision-making, basic design of real world research, evaluation of real world evidence, communication and exchange with review agencies, with relevant glossary, examples, common statistical analysis methods and comparison of Chinese and English vocabulary Enclosure In the 21st century cure Act approved by the U.S Congress on December 7, 2016, "real world evidence (RWE) is clearly defined as" data on the way of use, potential benefits or safety of drugs obtained from sources other than randomized clinical trials (RCT) " The fundamental difference between real-world evidence and clinical trial evidence is that the scene of data acquisition is different: the former comes from the real scene such as the actual medical site or family community, while the latter comes from the strictly controlled scientific research scene In order to avoid misunderstanding of the new concept, FDA experts stressed that "the difference between the two should not be based on whether there are planned intervention experiments and whether randomized experiment design is adopted" In other words, real-world evidence can still involve intervention experiments and randomized trial design The data obtained by researchers through real world research is called "real world data" (RWD) As early as the beginning of 2000, China has realized that RWD and RWE are beneficial supplements and promoters for the clinical evaluation system of traditional new drug research and development In 2010, the real world research first appeared in the intervention experiment design of traditional Chinese medicine In the past two years, the Chinese government has been actively committed to building a regulatory and technical level system, making many efforts to improve China's drug active alert system and build a health technology assessment framework In order to further standardize the relevant work and promote the improvement of the quality and efficiency of drug research and development, the relevant departments of the State Food and Drug Administration organized a research group composed of representatives from academia, pharmaceutical industry and relevant institutions, and launched the drafting of the guiding principles in November 2018 Based on the work framework and technical requirements of foreign drug regulatory agencies, combined with domestic R & D practice, the general principles and basic technical requirements of using real world evidence to support drug R & D and evaluation are combed, studied and refined, and the draft guiding principles are formed After several discussions, the basic consideration of real world evidence supporting drug research and development (Draft for comments) was formed, and opinions were widely sought from May to August 2019 CDE organized the summary and analysis of relevant opinions, further listened to the opinions of the industry, clinical experts and other interested parties, and organized the expert finalization meeting and internal discussion again, finally forming the guiding principles of real world evidence supporting drug research and development and review (Trial) Definition of real world research CDE defines real world research as the research process of collecting health-related data (real world data) or aggregate data derived from the data in real world environment for preset clinical problems, and obtaining clinical evidence (real world evidence) of drug use and potential benefit risk through analysis Among them, all kinds of data related to patients' health status and / or diagnosis and treatment and health care collected daily are real world data Not all real world data can become real world evidence after analysis Only real world data that meets the applicability can produce real world evidence The scope of application of real world evidence to support drug research and development real world evidence is used to support drug regulatory decision-making, including pre market clinical research and development and post market re evaluation For example, provide evidence of effectiveness or safety for the approval of new products for marketing; provide evidence for the modification of approved product instructions, including adding or modifying indications, changing dose, drug delivery scheme or route, adding new applicable population, increasing effectiveness comparison information, increasing safety information, etc.; provide evidence to support regulatory decision-making as part of post marketing requirements, etc 1 To provide evidence of effectiveness and safety for the registration and listing of new drugs According to the characteristics of different diseases, the accessibility of treatment means, target population, treatment effect and other factors related to clinical research, we can obtain the effect and safety information of drugs through real world research, and provide supporting evidence for the registration and listing of new drugs Common real-world studies that provide evidence of effectiveness and safety for new drug registration and marketing include: randomized clinical trials using outcomes or safety data obtained from real-world data, including PCT design, etc.; and single arm clinical trials based on real-world evidence as external control for some rare and life-threatening diseases that lack effective treatment measures Proven 2 To provide evidence for changes in the specifications of marketed drugs For marketed drugs, new indications usually need RCT support However, when RCT is not feasible or the research design is not optimal, the real world evidence generated by PCT or observational research may be more feasible and reasonable to support the new indications In the field of children's drug use, the use of real world evidence to support the expansion of the population with indications is also one of the possible situations for drug regulatory decision-making In general, the real world evidence supports the change of the specification of the marketed drugs, which mainly includes the following situations: 1 Increase or modify the indications; 2 Change the dosage, dosage scheme or route of administration; 3 Increase the new applicable population; 4 Add the results of the comparative study of effectiveness; 5 Increase the safety information; 6 Other modifications of the specification On April 4 last year, Pfizer's breast cancer drug, ibrance, was approved by the US FDA for male breast cancer This approval does not depend on clinical research, but on the electronic health records (EHRs) detailing the actual use of the drug and the real world data obtained in the post marketing report This example illustrates the potential of real world data to support the expansion of indications 3 Provide evidence for post marketing requests or re evaluations The drugs approved based on RCT evidence are usually limited in safety information, uncertain in extrapolation of efficacy conclusion, not necessarily optimal in medication plan, and lack of economic benefits due to the reasons of fewer cases, shorter research time, strict in group conditions and standardized intervention It is necessary to use real world data for the effect and safety of drugs in real medical practice , use, and economic benefits, etc to conduct a more comprehensive assessment, and constantly make decision-making adjustments based on real world evidence 4 On the basis of prescription fixation and production process, we can try to combine real world research with randomized clinical trials to explore a new path of clinical research and development There are many kinds of clinical R & D strategies to support the existing human experience with real world evidence Different R & D strategies should be selected according to the characteristics of products, clinical application and data applicability For example, we can explore to replace the observation research (including retrospective and prospective) with the routine phase I and / or phase II clinical trials in clinical research and development for preliminary exploration of clinical efficacy and safety; on the basis of the observation research, we can further confirm the effectiveness of the tested traditional Chinese medicine by RCT or PCT to provide supporting evidence for the registration and listing of the product If there is applicable high-quality real world data after evaluation, and the real world evidence formed through well-designed observational research is scientific and sufficient, it can also communicate with the drug regulatory department, and apply for direct support for product listing There are two main strategies to explore and apply real world evidence to support clinical research and development of traditional Chinese medicine One is the combination of observational research and RCT research The second is the combination of observational research and PCT research 5 To guide the clinical research design of real world evidence, including the natural history of disease, the prevalence of disease in the target population, the efficacy and effectiveness of standardized treatment, as well as the distribution and change of key covariates related to efficacy and effectiveness in the target population, etc., which provides the basis for the next stage of research design 6 Accurate targeting of target population using real-world data such as group data, public gene database information, and relevant clinical data in the population queue, real-world evidence can be obtained through target analysis technology of various machine learning classes, which can support accurate population targeting of targeted therapeutic drugs Conclusion: real world research is a scientific research model guided by clinical needs It will become an inevitable trend of scientific research development in the future to provide strategies for pharmaceutical enterprises, improve medical services and maximize the service for patients On the basis of scientific understanding of its value, it is necessary to further explore the construction of scientific decision-making system of medical products and health policies based on real world evidence, promote the improvement of regulatory departments and industry ideas, legislation and technology, so as to better ensure the accessibility, safety, effectiveness and economy of medical services Real world research has many advantages and uses: for example, it can link data from different sources in the industry, and determine the results based on a large number of data samples, which is more valuable for reference; it can reduce development costs and improve the efficiency of clinical trials; it can prevent errors and accelerate the time to market; it can explore new indications of existing therapeutic drugs; it can determine new markets and patients who are eager to be treated 。 It is helpful for medical staff and medical institutions to improve the level of individualized treatment of drugs and to deal with adverse reactions more quickly For adequate health care institutions, it is helpful to analyze the cost-effectiveness of drugs; it is a choice of expensive new therapies Naturally, the public can also get useful information from it The role of real world evidence in promoting future health care cannot be underestimated In the future, real world evidence will not only play an increasingly important role in the change of new drug development mode, approval and regulatory system, but also play an important role in the further development and improvement of precision medicine.