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

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) 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 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 Provide evidence of effectiveness and safety for new drug registration 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 information of drug effect and safety 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 Provide evidence for the change of the specification of the marketed drugs For drugs already on the market, 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 following changes in the specifications of the marketed drugs: 1 Add or modify indications; 2 Change dosage, administration plan or route of administration; 3 Add new applicable population; 4 Add the results of comparative study on actual effect; 5 Add safety information; 6 Other modifications of the manual 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 Experience summary and clinical research and development of famous and old TCM prescriptions and preparations of TCM medical institutions For the clinical research and development of famous and old traditional Chinese medicine empirical formula, traditional Chinese medicine medical institution preparation and other existing human experience drugs, on the basis of fixed prescription and basic formation of 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 5 Guide clinical research design Real world evidence, including the natural history of the disease, the prevalence of the disease in the target population, the efficacy and effectiveness of standardized treatment, and the distribution and change of key covariates related to efficacy and effectiveness in the target population, provides the basis for the next stage of research design 6 Targeted population Using the real world data such as the group data, the public gene database information, and the related clinical data in the population queue, the real world evidence can be obtained through the target targeting analysis technology of various machine learning classes, which can support the accurate population positioning of targeted therapeutic drugs.