The purpose of drug safety pharmacology research is to discover unexpected pharmacodynamic properties of the test substance that may be related to the clinical safety of humans, and to evaluate the adverse reactions and/or pathology of the test substance observed in toxicological tests and/or clinical studies The purpose of the QT interval study is mainly useful non-clinical research strategies to assess the potential effect of the test substance in delaying ventricular remodeling, as well as the analysis of non-clinical research information and comprehensive risk assessment. The International Coordination of Technical Requirements for the Registration of Human Drugs (ICH) has issued corresponding guidelines for the evaluation of safety pharmacology trials, which are formulated by the corresponding ICH expert group according to the ICH procedures, and therefore are adopted by the European Union, Japan and the United States regulatory agencies.
Therefore, this article gradually compares the domestic guidelines with ICHS7A and S7B, lists the main similarities and differences, and provides references for the revision of domestic guidelines.
1.1 The name and introduction of ICH guidelines [1-2]
At present, ICH’s non-clinical research evaluation and risk assessment of drug safety pharmacology mainly include “ICH S7A: Human Drug Safety Pharmacology Research Guidelines” (ICHS7A) and “ICHS7B: Human Drug Use to Relieve Ventricular Duplication Mutation (QT Interval Extension)” Two Guiding Principles for the Non-clinical Evaluation of Potential Role (ICH S7B).
ICHS7A is currently in the fourth stage of ICH progress and provides definitions, general principles and recommendations for safety pharmacology research. This principle generally applies to new chemical compounds for human use and biotechnology products. In some cases (such as when clinical adverse reactions occur, new drug users or new target routes cause new safety targets), it can also be applied to marketed drugs.
ICHS7B is a supplement and extension to ICH S7A. The main content is a non-clinical research strategy to evaluate the potential effect of test substances in delaying ventricular repetitive transitions. This guideline applies to new compounds for human use, as well as drugs already on the market (such as the occurrence of clinical adverse events, new drug users, or the addition of new routes of occurrence that have not been used before).
1.2 Relevant guiding principles corresponding to China (domestic guiding principles) [3-4]
In order to guide the safety pharmacology and QT interval prolongation risk non-clinical research and risk assessment of conventional Chinese medicines, natural medicines and chemical medicines, the “Drug Safety Pharmacology” Research Technical Guidance Principles (referred to as ” Guidelines for Safety Pharmacology), and “Technical Guidelines for Non-clinical Research on Potential Effects of Drug QT Interval Extension” (referred to as “Guidelines for QT Interval Extension”). The current two guiding principles also apply to the research of biological products.
The main content of the “Guiding Principles of Safety Pharmacology” includes non-clinical research strategies for evaluating the effects of drugs on the central nervous system, cardiovascular system and respiratory system, and suggests additional and/or supplementary safety pharmacology studies as needed. In order to determine the undesired pharmacological effects of the drug that may be related to human safety, evaluate the drug’s adverse drug reactions and/or pathophysiological effects observed in toxicological and/or clinical research, and the research observed and/or considered The purpose of the adverse drug reaction mechanism.
The main content of the “Guiding Principles for QT Interval Extension” includes non-clinical research strategies to evaluate the potential effects of test substances in delaying ventricular remodeling, as well as the analysis of non-clinical research information and comprehensive risk assessment. The guiding principles suggest that the results of the QT interval study can be integrated with other information to correct the mechanism of drug action, replace the human body’s continuous ventricular repetitive mutations and prolong the risk assessment of the QT interval.
2.1 Overall differences
2.1.1 Overall evaluation of content integrity differences The two guiding principles of “Safety Pharmacology Guiding Principles” and “QT Interval Extension Guiding Principles” are comprehensive in content, both of which provide guidance and suggestions for non-clinical research strategies, and basically cover the ICH guidance The core technical requirements in the principles.
The basic principle part puts forward guidance and suggestions on the test methods, phases, GLP requirements and test substances; the basic content part puts forward basic requirements on the experimental design and research content; the result analysis and evaluation part proposes to combine the efficacy, toxicology, Comprehensive evaluation of pharmacokinetics and other research data to make recommendations for clinical research design.
In contrast to the ICH guidelines and indicators, the conventional guidelines are more detailed and in-depth in some details, such as basic requirements for sample size and number of dose groups, more specific definitions of certain terms, and further guidance and reference through supplements And so on (see the content under 2.2 for details).
2.1.2 Overall evaluation of differences in technical requirements The two guiding principles of “Guiding Principles of Safety Pharmacology” and “Guiding Principles of QT Interval Extension” are based on the basic principles. The core technical standards are consistent with the requirements of the ICH guiding principles, but some detailed requirements are different.
Among them, the main differences between the “Guiding Principles of Safety Pharmacology” and ICH S7A are shown in (see Section 2.3 for details): alternative design requirements; studies of metabolites, multiple organisms and preparations; additional and/or supplementary safety pharmacology The phase and time of the experiment.
The main differences between “QT Interval Extension Guidelines” and ICH S7B are shown in (for details, see the content under 2.3): the significance and essence of research at different functional levels in the domestic and foreign guidelines; test implementation specifications; additional research content; In vitro electrophysiological research.
2.2 Content contradiction
Comparing the conventional guiding principles and the ICH guiding principles, we can see that the conventional guiding principles are more in-depth and detailed in some details, which are specifically reflected as follows:
2.2.1 Requirements for sample size and dose group The “Guiding Principles of Safety Pharmacology” requires that there are generally more than 10 small animals in each group, and generally more than 6 large animals in each group; in general, safety pharmacology trials should be designed 3 doses. The “Guidelines for QT Interval Extension” require that in vitro tests generally consist of 3 to 5 groups, each with more than 4 parallel samples; for in vivo tests, there are generally more than 10 small animals in each group, and large animals are generally redundant in each group. In 6 animals, generally half male and female.
2.2.2 Definitions of terms The “Guidelines for QT Interval Extension” require that in vitro ion channels and action potential time-course tests should use the sub-maximum effective concentration. Here, the definition of the sub-maximum effective concentration is changed, that is, the effect of the drug on the channel The concentration at which the inhibition rate reaches 70% to 80%.
2.2.3 The appendix in the “Guiding Principles of QT Interval Extension” provides more detailed guidance and suggestions for in vitro tests, overall research and additional research.
2.3 Differences in technical requirements
2.3.1 Differences in technical requirements between ICHS7A and the domestic “Guiding Principles of Safety Pharmacology”
(1) Different budget design requirements
ICHS7A: In the part of the trial design, it is recommended that “appropriate positive and negative substitutions should be included in the trial design. In the in vivo test system with clear characteristics, it is not necessary to set the correct substitutions, but the rationality of not providing substitutions should be explained.”
Domestic “Guiding Principles of Safety Pharmacology”: In the control content of the trial design, it is recommended that “Vehicles and/or excipients can generally be used for opposite control. For example, to illustrate the similarities and differences between the characteristics of the test substance and the known drugs, it can also be used Positive control drug.”
(2) The domestic guidelines do not provide requirements and recommendations for the research of metabolites, multi-components and preparations
In ICHS7A “2.6 Metabolites, Complexes and Preparations”, the requirements and recommendations for the safety pharmacological assessment of metabolites, substitutes and preparations are put forward. However, the “Internal “Guiding Principles of Safety Pharmacology” does not make corresponding requirements and recommendations for part of the content.
(3) Domestic guidelines do not provide requirements and recommendations for additional and/or supplementary safety pharmacology tests
In the “2.10.3 Pre-market Approval Tests” section of ICHS7A, requirements and recommendations are put forward for the completion stage and content of additional and/or supplementary safety pharmacology test studies. The content makes corresponding requirements and suggestions.
2.3.2 Differences in technical requirements between ICH S7B and the domestic “Guiding Principles for QT Interval Extension”
(1) The essence and significance of the research content of the 4 functional levels in ICH and domestic guidelines are different
1) The research content of 4 functional levels includes: b. Using isolated animal or human cardiomyocytes, cultured cardiomyocyte cell line or cloned human ion channel heterogeneous expression system to measure ion current. c. Conduct conduction potential measurement on isolated heart specimens, or conduct electrical and physiological parameter testing of energy conduction action potential time course in anesthetized animals. The arrhythmia-causing effects are measured on isolated heart specimens or animals.
2) ICHS7B pointed out: The results of the three studies a, b, and c are useful and complementary.
3) The national “Guiding Principles for QT Interval Extension” points out: the research on a and b can be carried out first, and then the research on c and d. The four researches a, b, c, and d are combined and complementary.
(2) ICH and national guidelines have different requirements for test execution specifications
1) ICHS7B: In vitro tests and in vivo QT interval studies should perform GLP.
2) The national “Guiding Principles for QT Interval Extension” only recommends the implementation of in vitro tests: “GLP specifications are recommended for in vitro tests, GLP for in vivo tests, and additional studies should comply with GLP within the maximum feasible limit.”
(3) The national guidelines did not mention “repetitive reconstruction experiments” in the additional research content
The domestic “Guiding Principles for QT Interval Extension” no longer clearly states “repetitive substitution trials” in the “additional studies” section, but replaces it with “if the drug is accumulated and long-term clinical use, multiple substitution observations need to be considered”.
(4) The national guidelines do not specify and limit the factors that may interfere with or limit the interpretation of in vitro electrophysiological studies
ICH S7B mentions possible alternatives or factors that limit the interpretation of in vitro electrophysiological studies in the section “3.1.2. In vitro electrophysiological studies”.
3.1 Existing technical difficulties
The domestic guidelines are comprehensive in content, covering the core technical requirements in the ICH guidelines, and are more in-depth and detailed in some details, and corresponding content has been added or revised according to certain specific circumstances. The conditions, there are no technical difficulties, can be implemented immediately.
3.2 Legal barriers
For ICH S7B mentioned in vitro tests and in vivo QT interval studies, the GLP requirements should be implemented. Although the internal guidelines only recommend the implementation of GLP requirements for in vitro tests, they must conflict with the current conventional regulations or guidelines, and the current domestic The research platform has developed rapidly and has been able to meet GLP requirements. Therefore, there are no obstacles in terms of GLP implementation conditions or the policies and regulations, and they can be implemented immediately.
There are differences in the details of the technical requirements between the ICH and the domestic guidelines, especially the study of metabolites, substitutes and preparations, which may replace or limit the two parts of in vitro electrophysiological research. The domestic guidelines do not propose changes to the relevant content. For detailed requirements and suggestions. Although domestic enterprises are currently in the R&D stage, when encountering such problems, they may add corresponding research content or explain and explain related issues according to the characteristics of the drug. However, due to the existence of systematic and directional guidance and suggestions, the research results There may be problems in the preliminary or scientific aspects.
Through systematic comparison with ICH S7A / S7B related guidelines, these two guidelines basically cover the core technical requirements in the ICH guidelines in terms of basic content, and are more in-depth and detailed in some details. In terms of basic principles, the core technology standards are also consistent with the ICH guidelines. Although some detailed requirements are different, the current core technology requirements or the internal regulatory framework have implemented the ICH S7A / S7B conditions, so you can immediately Implement.
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