Phase I clinical application of innovative drugs needs to study the content of pharmacology and Toxicology

Wen Qiang Johnson Innovative drugs, in the process of identifying candidate drugs, whether pre-test or formal test, need the timely support of pharmacological and toxicological data to judge how to carry out the next stage of development work, or terminate the development.. In recent years, with the extensive development of new drugs in China, the safety evaluation work of pharmacological and toxicology required for phase I clinical application is no longer mysterious A systematic SOP has been formed But after all, it is difficult for small partners in synthesis / quality / preparation departments to get the feedback of pharmacotoxicology data, and then it is difficult to systematically understand the overall progress of the project Based on this, the author summarizes the main pharmacological and toxicological information needed for the application of phase I clinical trials of innovative drugs for everyone to learn The investigator's manual is a summary of the existing pharmaceutical, non clinical and clinical studies (if any) of the experimental drugs in the human body study, aiming to provide the clinical researchers with the information of the studied drugs to ensure the safety of the subjects PS: it should be emphasized that the pharmaceutical information of new drug development is very important, which is the foundation of project development If there is any problem in pharmacy, it is difficult to make clear the product quality problem, and then the GLP related work done next is difficult to be further proved Pharmacology, which should include the results of completed non clinical trials to indicate efficacy Toxicology: safety pharmacology test, single dose toxicity test, repeated dose toxicity test, genetic toxicity test, reproductive toxicity test, carcinogenicity test and other toxicity tests shall be listed separately; if some studies have not been conducted or are not required to be conducted, reasons and basis shall be explained Non clinical pharmacokinetic study: ADME of the drug must be introduced; if some studies have not been carried out or do not need to be carried out, reasons and basis need to be explained PS: pharmacodynamics is the main pharmacodynamic study Toxicology, we should pay attention to the sensitivity of the test animals to the candidate drugs, and reasonably use rodents and non rodents If there is any animal death beyond the plan, we should record and sort out the cause of death in detail to reasonably judge whether to continue the development of the project At the same time, according to the current evaluation requirements, Ames test can be pre tested in advance But ADME, whether in the pre test or the formal test, except for the special varieties, the metabolism is the most concerned The content of this part should include all existing clinical trial information and literature at home or abroad For example, "human pharmacokinetics", "effectiveness", "safety" and "listing situation"; if there is no new drug use information, the applicant shall provide relevant information based on the summary of existing non clinical and clinical research results: may include special population, safety information, warnings and precautions, risk control plan, drug interaction, drugs Overdose PS: Currently, most of the new drugs developed in China are me too There are relatively many clinical information and literature at home and abroad Therefore, it is necessary to summarize the clinical results of the existing drugs on the market, which can further reflect the advantages of their own varieties while supporting their own products It should cover "research background (such as indications, effective / safety data)", "test purpose", "number of subjects expected to participate", "description of inclusion criteria and exclusion criteria", "description of drug administration plan (time, dose, etc.)," test indicators (such as vital signs of subjects and necessary blood biochemical monitoring) "," toxicity determination principles and Test suspension criteria " PS: the content of this part needs to be communicated and discussed with colleagues of clinical trial department.. In the process of drug development, the indications targeted at the beginning of the project are likely to be adjusted with the progress of the project and the clinical statistics of similar varieties! Discussion with clinical partners is more conducive to the future trend of the product Single administration, continuous administration and single pharmacokinetics are the three main parts of the experimental scheme design The setting of dose group and how high to climb will be one of the key points discussed The information of pharmacology and toxicology should include non clinical research review, pharmacological action summary report, toxicology research summary report, pharmacokinetics summary report and various research reports The applicant shall submit all completed non clinical trials, including exploratory non clinical pharmacological and toxicological studies of the drug, so that the review department can make an overall evaluation at this stage The summary of non clinical studies should provide the summary information of completed non clinical studies, and each trial can be listed in turn 1 Summarize the trial strategy and implementation date of non clinical trial study 2 Compliance information of non clinical study design and deviation from the design 3 Analysis results of quality comparability of test substance with pharmaceutical research and clinical trial samples 4 List the overall research items and numbers, research institutions and research sites of non clinical trials, and the non clinical study review shall be signed and dated 5 Systematically present the results of animal toxicology research and toxicokinetics, and pay special attention to the information that may endanger human safety 6 The results of non clinical research have supporting basis for clinical trials 7 Statement of compliance with GLP In case that the above regulations are not fully followed, the reasons shall be explained and explanations that may affect the test results shall be provided In this paper, the pharmacological action in vivo and in vitro, the mechanism of action, and the secondary pharmacodynamic information were summarized The pharmacodynamic study of new drugs should be carried out with recognized in vitro and in vivo test system and indicators, and try to use updated in vivo model to carry out the effectiveness study related to the mechanism of action, and provide research information on the relationship between pharmacodynamics and exposure Pharmacodynamic study should indicate the correlation and efficacy potential between new drugs and clinical disease treatment Validity information is usually not the main reason for delay in clinical trials However, it shall be submitted at the time of application for phase I clinical trial PS: the main research content is the main pharmacodynamic information! The main task of pharmacodynamic research is to evaluate the main pharmacological effects of new drugs in clinical prevention, diagnosis and treatment The research process involves the general guiding principles and requirements of methods, indicators, administration methods and controls, but there are many main pharmacodynamic research problems reflected in the specific new drug evaluation, including animals, models, indicators, doses, designs, statistics and other issues The degree, severity, duration, dose correlation, reversibility, species and gender differences of toxicity should be described Special attention should be paid to the information of repeated toxicity, animal death, pathological examination, local tolerance and other problems that need special explanation The evaluation of toxicological research results should pay attention to the logical evaluation of the correlation of toxic reactions, and explain the extrapolation of human risk prediction The evaluation factors include animal species, number of animals, dosage, administration period, exposure and its correlation with the maximum exposure of human body The toxicity test results should clearly state NOAEL, MTD and / or std10, hnstd dosage and exposure information PS: NOAEL, MTD, LD50 and other values are usually in the stage of determining candidate compounds, that is, preliminary understanding through pre experiments to confirm the safety of candidate drugs to be developed The toxicology test of new drugs (including acute, long and local toxicity) should be carried out in the laboratory meeting the GLP specification, and the principle of "specific problem specific analysis" should be followed According to the drug characteristics and human research stages, special research information may be needed, such as in-depth study of immunogenicity and immunotoxicity of macromolecular drugs The feasibility of the analytical method, pharmacokinetic / toxicokinetic parameters, absorption and tissue distribution, metabolism and excretion, as well as physiological changes caused by pharmacodynamics and toxicity issues, such as the impact of disease status, antibody generation, cross reactivity, etc., should be described If there are human studies, the metabolism and exposure of animals and human body in non clinical studies should be compared, and the prediction effect of non clinical research results on potential adverse reactions in human body should be expounded PS: the feasibility of the analytical method Currently, "GC-MS" and "high performance capillary electrophoresis" are widely used The pharmacokinetic parameters mainly include F, brpp, T1 / 2, VD, AUC, Cl, Cmax, Tmax, etc It is necessary to provide the obtained reports on pharmacological action, toxicological research and pharmacokinetics The comprehensive summary report of all test results shall be accurate and consistent with the test results, and shall fully reflect the test situation and data results, and make a comprehensive technical evaluation based on this If the final toxicology report of each study is not obtained at the time of submitting the phase I clinical trial application, the audited draft report and the summary report based on the draft report can be submitted The final report of each toxicology study shall be submitted within 120 days after the first clinical trial application The final report shall include the description of all changes and necessary analysis to indicate whether it will affect the original safety evaluation.