The content of "pharmacology-toxicology" that needs to be studied in the Phase I clinical application of innovative drugs!

01Technical requirements for phase I clinical trial application

1.Researcher’s Handbook

The Investigator’s Handbook is a summary of the pharmacy, non-clinical and clinical research (if any) data available when the trial drug is being studied in the human body. It aims to provide clinical investigators with information on the research drug to ensure the safety of the subjects.

PS: I still have to emphasize that the pharmaceutical information for new drug development is very important. This is the foundation of project development. If there is a problem in pharmacy, it is difficult to tell the quality of the product. The subsequent GLP-related work will hardly be further corroborated. .

2.Non-clinical research findings

Pharmacology, should include the results of non-clinical trials that have been completed to indicate the efficacy of the drug.

Toxicology, the safety pharmacology test, single-dose toxicity test, repeated-dose toxicity test, genotoxicity test, reproductive toxicity test, carcinogenicity test and other toxicity tests must be listed separately; if some studies have not been carried out or are not needed To proceed, the reasons and basis need to be explained.

Non-clinical pharmacokinetic studies: The ADME of the drug must be introduced; if some studies have not been conducted or do not need to be conducted, the reasons and basis need to be explained.

PS: Pharmacodynamics is the main pharmacodynamic study. Toxicology, attention should be paid to the sensitivity of test animals to candidate drugs, rodents and non-rodents should be used rationally. If an unplanned animal died, the cause of death should be recorded in detail to make a reasonable judgment on whether to continue the development of the project; At the same time, according to the current review requirements, the Ames test can be pre-tested in advance. Regardless of whether it is a pre-test or a formal test, ADME, except for special varieties, is the metabolism that attracts the most attention.

3.Existing clinical research or use data (if any)

This part of the content should include all existing clinical trial information and literature materials at home or abroad. Such as “human pharmacokinetics“, “effectiveness”, “safety”, “marketing situation”; if there is no new drug use information, it should be based on the summary of the existing non-clinical and clinical research results, and provide the applicant’s opinion Relevant information: may include special populations, safety information, warnings and precautions, risk control plans, drug interactions, drug overdose, etc.

PS: At present, most of the new drugs developed in China are me-too. There are relatively more existing clinical information and literature at home and abroad. Therefore, it is necessary to summarize and summarize the clinical results of existing marketed drugs. It can further reflect the advantages of its own varieties.

02 clinical trial protocol

Should cover “research background (such as indications, effective/safe data)”, “test purpose”, “expected number of participants”, “inclusion criteria and exclusion criteria description”, “dosing plan description (time, dose) Etc.)”, “Testing indicators (such as subject’s vital signs and necessary blood biochemical monitoring)”, “Toxicity determination principles and test suspension criteria for suspension of studies”.

PS: This part of the content needs to be discussed with colleagues in the clinical trial department… In the drug development process, the indications targeted at the beginning of the project, as the project progresses, and the clinical statistics of similar products, the indications are very May be adjusted! Discussion with clinical partners is more conducive to the future direction of the product. Single administration, continuous administration, and single pharmacokinetics are the main three parts of the experimental program design. The setting of the dose group and how high the climb is will be one of the key points of discussion.

03 Pharmacology and Toxicology Information

Pharmacology and toxicology information should include non-clinical research summary, pharmacological action summary report, toxicology research summary report, pharmacokinetic summary report and various research reports. The applicant should 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.

1.Non-clinical research review

The non-clinical research review should provide summary information of the completed non-clinical research, and each trial can be listed in sequence.

1. Summarize the trial strategy of non-clinical trial research and the date of trial implementation.

2. Compliance information and deviations from the design of non-clinical research.

3. The quality comparability analysis results of the test substance and the samples of pharmaceutical research and clinical trials.

4. The list describes the overall research project and number, research institution, and research location of the non-clinical trial. The non-clinical research summary should be signed and dated.

5. The system presents the results of animal toxicology studies and toxicokinetics, and special attention should be paid to information that may harm human safety.

6. The results of non-clinical research have a supporting basis for clinical trials.

7. A statement of compliance with the GLP for non-clinical drug research. For cases where the above regulations are not fully complied with, the reasons should be explained and explanations that may affect the test results should be provided.

2.Summary of pharmacological research

Summarize the pharmacological effects in vivo and in vitro and their mechanism of action, as well as secondary pharmacodynamic information. The pharmacodynamic research of new drugs should be carried out using recognized in vivo and in vitro test systems and indicators, and updated in vivo models should be used as far as possible to carry out effectiveness studies related to the mechanism of action, and to provide research information on the relationship between drug efficacy and exposure. Pharmacodynamic studies should indicate the relevance and effectiveness potential of new drugs and clinical disease treatment. Effectiveness information is usually not the main reason for delaying clinical trials. However, it should be submitted when applying for a 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 for clinical prevention, diagnosis, and treatment. The research process involves general guiding principles and requirements such as methods, indicators, administration methods, and controls. However, there are many major pharmacodynamic research issues reflected in the evaluation of specific new drugs, including animals, models, indicators, dosages, design, Statistics and other issues.

3.Summary of Toxicology Research

Need to explain the degree, severity and duration of the toxic reaction, dose correlation, reversibility, species and gender differences. Pay special attention to repeated administration toxicity information, animal death, pathological examination, local tolerance, and other issues that need special explanation. The evaluation of toxicological research results should pay attention to the logical evaluation of the relevance of toxic reactions, and explain the extrapolation of human risk prediction. Evaluation factors include animal species, number of animals, dose, period of administration, exposure, and its correlation with the maximum exposure of the human body. The results of the toxicity test should clearly indicate the NOAEL, MTD and/or STD10, HNSTD dose and its exposure.

PS: NOAEL, MTD, LD50 and other values, usually in the stage of determining the candidate compound, that is, preliminary understanding through preliminary experiments to confirm the safety of the candidate drug to be developed. Toxicological tests of new drugs (including acute, chronic, local, etc.) should be carried out in laboratories that comply with GLP specifications, and follow the principle of “specific analysis of specific problems”. According to the characteristics of the drug and the stage of human research, special research information may be required, such as in-depth research on the increase of immunogenicity and immunotoxicity of macromolecular drugs.

4.Summary of pharmacokinetics

The feasibility of the analytical method, pharmacokinetic/toxicokinetic parameters, absorption and tissue distribution, metabolism, excretion, and physiological changes caused by pharmacodynamic and toxicity issues should be explained, such as the impact of disease states, antibody production, and cross-reactions Sex and so on. If there are human studies, the metabolism and exposure of animals and humans in non-clinical studies should be compared, and the predictive effect of non-clinical research results on human potential adverse reactions should be explained.

PS: The feasibility of the analytical method. The most frequently used ones are “Chromatography-Mass Spectrometry” and “High Performance Capillary Electrophoresis”; the parameters involved in pharmacokinetics mainly include F, BRPP, t1/2, Vd, AUC, CL , Cmax, Tmax, etc.

5.Various research reports

Various research reports on pharmacological effects, toxicological studies and pharmacokinetics that have been obtained should be provided.

6.Other summary reports

The comprehensive summary report of all test results should be accurate and consistent with the test results, should fully reflect the test conditions 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 obtained when the phase I clinical trial application is submitted, the audited draft report and the summary report based on the draft report can be submitted. The final report of each toxicology study should be submitted within 120 days after submitting the clinical trial application for the first time. The final report should include a description of all changes and the necessary analysis, stating whether it will affect the original safety evaluation.

04 summary

1. The most important part of the pharmacology and toxicology content required for the Phase I clinical application of an innovative drug is safety! On the premise of safety, to reflect the real effectiveness! The major prerequisite for safety and effectiveness is that the quality of the test product is controllable!

2. Before entering the product development formally, it is necessary to go through some pre-tests in advance to understand the preliminary pharmacological and toxicological background; and the selection of pre-tests and the acquisition of important parameters are based on the developer’s depth of understanding of the product background information!

3. The whole process of variety development requires the full cooperation of various disciplines and departments. Before entering each node, a meeting must be fully held to obtain suggestions for the next development from the perspective of each discipline, so as to prevent delays due to untimely communication. The various contradictions caused, and even the death of the project!

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