Clinical application of innovative drug Phase I needs to study pharmacological science content

Theinnovative drugs, in the process of determining the candidate drug, whether pre-test, or formal testing, need to be timely support of pharmacological data, to judge how to proceed with the next stage of development work, or to terminate the development ..In recent years, with the extensive spread of new drug development in China, Phase I clinical application needs to do pharmacological toxicology and other safety evaluation work, no longer mysterious, has formed a systematic SOPBut after all, interlaced as a mountain, small partners in the synthetic/quality/preparation sector often have difficulty obtaining feedback on pharmacological data, and then it is difficult to systematically understand the overall progress of the projectBased on this, the author summarizes the main pharmacological information required for the application of the innovative drug Phase I clinical trial for common study1The technical requirements for Phase I clinical trial applicationsthe Researcher's Handbookthe Researcher's Handbook, which is a summary of the pharmacological, non-clinical and clinical studies (if any) available in the study of the experimental drug in human studies, with the aim of providing the clinical researcherwith with information on the drug under study to ensure the safety of the subjectPS: It is important to stress that the pharmaceutical data for the development of new drugs is very important, which is the foundation of the project development, if there is a problem with pharmacy, product quality problems are difficult to say, and then the next GLP-related work is difficult to further corroboratenon-clinical clinical resultspharmacology, should include completed non-clinical trial results used to indicate efficacytoxicology, it is necessary to list in items the reasons and grounds for safety pharmacological tests, single-drug toxicity tests, repetitive toxicity tests, genetic toxicity tests, reproductive toxicity tests, carcinogenic tests and other toxicity tests;non-clinical pharmacokinetics studies: ADME of the drug must be introduced;PS: Efficacy is the main pharmacodynamics researchToxicology, attention must be paid to the sensitivity of test animals to the candidate drug, reasonable application of rodents and non-rodents, in the event of unplanned animal death, must be carefully recorded and collated the cause of death in order to reasonably determine whether to continue the development of the project; And ADME, whether pre-trial or formal testing, in addition to special varieties, the highest degree of attention for metabolismclinical studies or use data (if any) this section, including all clinical trial information and literature available at home or abroad Such as "human drug metabolic dynamics," "effectiveness," "safety," "marketing situation", if there is no new drug use information, should be based on the summary of existing non-clinical and clinical research results, the applicant should provide relevant information: may include special population, safety information, warnings and precautions, risk control plan, drug interaction, drug overdose, etc PS: Most of the new drugs currently developed in China are me-too, domestic and foreign clinical information and literature is relatively large, so it is necessary to have the clinical results of listed drugs to summarize, in support of their own products, but also can further reflect the advantages of their own varieties 2 Clinical Trial Programme
Clinical Trial Programme should cover "research background (e.g indications, effective/safety information)," "trial purposes," "expected number of subjects expected to participate," "Description of selection criteria and exclusion criteria," "Description of the drug plan (time, dose, etc.)," "test indicators (e.g vital signs of the subject and necessary blood biochemical monitoring)," "toxicity determination principles and test suspension criteria for discontinuation of research" PS: This section needs to be discussed with colleagues in the clinical trialdepartment.. In the drug development process, the initial project targeted for the indications, with the project, as well as the clinical statistics of similar varieties, indications are very likely to be adjusted! Discussions with clinical partners are more conducive to the future direction of the product Single administration, continuous administration, single-drug kinetics for the main three parts of the experimental program design And the setting of the dose group, climbing to how high, will be one of the key content of discussion 3 Pharmacological toxicology information pharmacological information should include a review of non-clinical studies, a summary report on pharmacological effects, a summary report on toxicology studies, a pharmacokinetic summary report and various studies Applicants should submit all completed non-clinical trials, including exploratory non-clinical pharmacological and toxicology studies of the drug, so that the review department can make an overall evaluation at this stage non-clinical study review
non-clinical study review should provide a summary of completed non-clinical studies, and the trials can be listed in turn 1 Outline the pilot strategy for non-clinical trial studies and the date of implementation of the trial 2 Compliance information and deviations from design in non-clinical research designs 3 Results of quality comparability of subjects and pharmaceutical research and clinical trial samples 4 The list indicates the overall research project and number of non-clinical trials, research institutions, research sites, and non-clinical research reviews should be signed and dated 5 The results of animal toxicology studies and toxicdynamics should be presented systematically, with special attention to information that could endanger human safety 6 Non-clinical study results are supportive of clinical trials 7 Follow the statement of the Drug Non-Clinical Research Quality Management Practice (GLP) In cases where the above regulations are not fully followed, the reasons should be explained and explanations may affect the results of the test Summary of Pharmacology Research an overview of the role of the internal and external pharmacology and its mechanism, as well as secondary pharmacological information The pharmacodynamics research of new drugs should be carried out using recognized in vivo and invivy experimental systems and indicators, and updated in vivo models should be used to carry out the effectiveness of the mechanism of action, and the research information on the relationship between efficacy and exposure should be provided Pharmacomyamic research should indicate the relevance and effectiveness potential of new drugs to the treatment of clinical diseases Effectiveness information is usually not the main reason for delays in clinical trials However, it should be submitted at the time of application for Phase I clinical trials PS: The most important research content is the main pharmaceutical information! The mission of the main pharmacological research is to evaluate the main pharmacological effects of new drugs for clinical prevention, diagnosis and treatment The research process involves the general guiding principles and requirements of methods, indicators, administration methods, controls, etc., but there are many major pharmacological research issues reflected in the evaluation of specific new drugs, including animals, models, indicators, dosage, design, statistics and other issues summary of toxicology studies
need to explain the extent, severity and duration of toxic reactions, dose correlation, reversibility, species and gender differences Particular attention is paid to information on repetitive toxicreactions, animal deaths, pathological examinations, local tolerance, and other specific problems The evaluation of toxicological research results should pay attention to the logical evaluation of the correlation of toxicity reactions and explain the risk prediction of the extrapolation of human body The evaluation factors include animal genus, animal population, dose of administration, duration of administration, exposure and its correlation with maximum exposure in human se, and the toxicity test results should clearly state NOAEL, MTD and/or STD10, HNSTD dose and its exposure information PS: NOAEL, MTD, LD50 and other values, usually in the determination of the candidate compound stage, i.e through pre-experiments to preliminary understanding to confirm the safety of the drug to be developed The toxicology tests of new drugs (including acute, long, local, etc.) should be conducted in the laboratory that conforms to the GLP specifications, while adhering to the principle of "specific analysis of specific problems" Depending on drug characteristics and human research phases, special research information may be required, such as macromolecule drugs that require in-depth studies that increase immunity and immunotoxicity Summary of pharmacokinetics should describe the feasibility of analytical methods, pharmacokinetic/toxic kinesidynamics parameters, absorption and tissue distribution, metabolism, excretion, as well as physiological changes caused by pharmacodynamic and toxic problems, such as the effects of disease status, antibody generation, cross-reactive If there are already human studies should also compare the metabolism and exposure of animals and humans in non-clinical studies, and explain the predictive effects of non-clinical research results on potential adverse reactions to human body PS: the feasibility of the analysis method, the current frequency of use for "chromatography-mass spectrometry" and "high-efficiency capillary electrophoresis", pharmacology involved in the parameters of F, BRPP, t1/2, Vd, AUC, CL, Cmax, Tmax and so on studies should provide studies on obtained pharmacological effects, toxicology studies and pharmacokinetics other summary reports a comprehensive summary report on the results of all trials should be accurate and consistent with the results of the tests, should fully reflect the test and data results, and be able to make a comprehensive technical evaluation based on this If the final toxicology report of each study is not received at the time of submission of the Phase I clinical trial application, the draft audited report and the summary report based on the draft report may be submitted Final reports of each toxicology study should be submitted within 120 days of the initial submission of the clinical trial application The final report should include a description of all changes and the necessary analysis on whether the original security evaluation would be affected 4 The most critical is safety the pharmacological content required for clinical applications for the innovative drug Phase I! In the premise of security, to reflect the true effectiveness! And the main premise of safety and effectiveness, but also the quality of test products can be controlled! Before formally entering the variety development, it is necessary to go ahead with some pre-tests to understand the initial pharmacological background, and the selection of pre-tests, as well as the acquisition of important parameters, is based on the developer's depth of understanding of the product background information! Variety in the whole process of development, need the full cooperation of various disciplinedepartments, before entering each node to hold a full meeting, from the perspective of each discipline to obtain the next development of recommendations, to prevent communication is not timely caused by various contradictions, and even the death of the project! references
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Original title: First Knowledge: Innovative Drug Phase I Clinical Application must be studied "Pharmacology - Toxicology" content!