Five guiding principles of CFDA: comparison of new and old rules, what benefits enterprises enjoy

Source: medical economic news 2017-05-23 On May 18, CFDA issued five official drafts of guiding principles, which belong to two major announcements: "Circular of the General Administration on the technical guiding principles for the release of adult drug use data extrapolation to pediatric population (No 79 in 2017)" and "Circular of the General Administration on the release of guiding principles for the on-site verification of generic drug quality and efficacy consistency evaluation development" (No 77 in 2017) " Pediatric clinical free opportunity: good for products listed in East Asian countries The official draft of "technical guidelines for extrapolation of adult medication data to pediatric population" envisages the difficulties existing in clinical trials of pediatric patients - specific ethical challenges (such as the use of placebo), practical operation difficulties (such as efficacy evaluation, special protection for children in the study), significant differences in growth / development, etc., and clarifies that data extrapolation is aimed at the effectiveness and safety Comprehensive data In general, data extrapolation focuses on validity data to obtain a clear dose However, in some cases, when considering the safety of drugs for different age groups, especially the long-term safety related to growth and development, we should pay attention to the safety data In addition, it is officially defined that the application scope is only applicable to the extrapolation of products with Chinese adult data to Chinese pediatric population, and the extrapolation of products without Chinese adult data is not within the application scope of this guiding principle The main principle of data extrapolation has also been adjusted According to the draft, "the main principle of data extrapolation used in clinical trials of pediatric population is to avoid unnecessary research in the target population due to ethical and efficiency considerations, so as to reduce ethical concerns and allocate resources to the areas where research is most needed" In the "official draft", it said, "through scientific research methods, the research information and conclusions of known Chinese adults will be extended to the unknown pediatric population (target population), so as to reduce unnecessary research in the unknown pediatric population" This means that the principle of data extrapolation has nothing to do with ethics In view of the fact that the higher the similarity between the predicted population and the higher the prediction accuracy, the greater the possibility of extrapolation, and the lower the need for additional research data, the "official draft" has a new improvement on data sources, evaluation methods, etc.: "in terms of the sources of known data", the official draft has added "diagnostic research, pharmacokinetic (PK) and pharmacokinetic (PD) research"“ "Similarity" evaluation increases the evaluation of the relationship between drug exposure and drug effect; when performing extrapolation analysis, if the hypothesis is not verified, add "re collection of data if necessary or consideration of segmented use of data" In terms of methodology, no matter "official draft" or "consultation draft", according to the similarity degree of known data in the extrapolation hypothesis between the known population and the target population, the extrapolation mode can be divided into three types: complete extrapolation, partial extrapolation and no extrapolation The "complete extrapolation" model is that the target population is highly similar to the known population, and the hypothesis (prediction) is highly accurate The "partial extrapolation" model refers to the similarity between the target population and the known population, and / or the uncertainty of the hypothesis (prediction) The "no extrapolation" model is that there is no similarity between the target population and the known population, and / or the hypothesis (prediction) is highly inaccurate The "official draft" is based on whether the pediatric population indication has been approved in foreign countries, whether there are references (or other supporting data) of pediatric population application at home and abroad, It can be divided into three situations: "data use of Chinese adult data and approved pediatric population indications abroad", "data use of Chinese adult data and available pediatric population references at home and abroad" and "extrapolation of only Chinese adult data" According to the data sources, "draft" is divided into "extrapolation of Chinese adult data", "extrapolation of foreign pediatric population data" and "extrapolation of existing literature or other supporting data" The "data usage of Chinese adult data and foreign approved pediatric population indications" in the "official draft" is basically the same as the "extrapolation of foreign pediatric population data" in the draft, only adding the existing Chinese adult data There are no differences in disease epidemiology, etiology, pathogenesis and disease progression prognosis in different countries or regions with the approval of Chinese adult data and foreign pediatric population indications; there are no significant ethnic differences in the test data of adult patients at home and abroad, including clinical pharmacology (pharmacokinetics, pharmacodynamics) and therapeutics (medical practice, safety) The data of clinical trials of paediatrics in foreign countries can be used The "use of data available from Chinese adult data and references of pediatric population at home and abroad" in the official draft mainly corresponds to the "extrapolation of existing literature or other supporting data" in the draft The formal draft mainly advocates systematic evaluation method System evaluation can be divided into quantitative and qualitative two categories: quantitative system evaluation is to use meta analysis method to quantitatively combine the original research data; if there is heterogeneity among the included studies, which cannot be quantitatively combined, qualitative description can be used to complete Compared with the draft for comments, it pays more attention to meta analysis method, and the formal draft methodology is more comprehensive For the existing Chinese adult data, the indications of pediatric population at home and abroad have not been approved, but there is evidence of clinical use of pediatric population at home and abroad, through the systematic evaluation method, the existing research evidence will be used as the main basis for revising and improving the pediatric population medication information in the manual, which is expected to be clinical free The "extrapolation of only Chinese adult data" in the official draft corresponds to the "extrapolation of Chinese adult data" in the exposure draft Based on the existing knowledge, most of the extrapolation of adult clinical trial data to pediatric population is limited to efficacy data However, the acquisition of pediatric population safety data usually needs to be tested in pediatric population, and the clinical trial of pediatric population safety must be done In terms of the flow of effectiveness clinical trials, CFDA draws on the flow chart of FDA's pediatric population research design and extrapolation decision (see Figure 1) According to the results of PK and PD trials of the same or similar mechanism drugs in adults and pediatric population under different circumstances, it extrapolates the dose to be used in pediatric population from adult dose Figure 1 flow chart of pediatric population research design and extrapolation decision to sum up, "technical guidelines for extrapolation of adult medication data to pediatric population" is good for the products with pediatric indications that have been added when the chemical drugs that have been listed in China are listed in East Asian countries, and the above products hardly need to carry out ethnic research and are directly clinical free "Minor changes" in conformity evaluation: in order to promote enterprises to implement the four principles of conformity evaluation of quality and efficacy of generic drugs, the "guiding principle of research site verification" is changed to "guiding principle of research site verification" However, the change is not big, such as requiring only mechanical verification of drug dissolution meter, without performance verification test, etc In terms of "guidelines for on-site inspection", the inspection points include the consistency between the new application materials and bioequivalence research and clinical research on the source of raw materials and internal packaging materials, the prescription of finished products, production process and production batch The production process of drugs used for bioequivalence, clinical research and in vitro evaluation shall be consistent with the dynamic production process of production site inspection and the content of application materials The scope and key points of quality risk management add new risk management activities within the company The adjustment of the above content fully shows the concept of drug life cycle management The "production site inspection guidelines" delete the inconsistency between the production batch and the declared batch, and the inconsistency between the production process and the declared data needs further research and verification, indicating that the process and data must be consistent during the inspection, and the research and verification do not belong to the field inspection of conformity assessment "Guidelines for clinical trial data verification" refers to "relevant policies on encouraging innovation and reform of clinical trial management of pharmaceutical and medical devices" (Draft for comments), "the qualification of hospitals undertaking clinical trial projects of generic drug consistency evaluation to be clarified by the General Administration" is deleted In accordance with the provisions of "guidance on further standardizing the quality and efficacy consistency evaluation of generic drugs, selection of reference preparations and other related matters (Draft for comments)" and other provisions on reference preparations, "the legal source certification of reference preparations is drug test report, drug specification, etc." is deleted There is no change in the "guidelines for causal inspection" To sum up, the changes between the official draft and the draft of the four guiding principles of consistency evaluation are not big, and the four guiding principles are more to promote the process of consistency evaluation It is expected that the process of conformity evaluation and certification will be accelerated after the issuance of the guiding principles for the production of the drugs listed in the same production line and approved for listing in the European Union, the United States or Japan and the indigenous drugs.