Differences in the requirements of Chinese pharmacology and toxicology data for registration application

CFDA basic requirements for non-clinical pharmacology/toxicology content

Study on primary and secondary pharmacodynamics and mechanism of action

● First determine the registration classification. The newer the registration classification and the newer the target, the more research on drug efficacy is needed, and different animal models should be used to illustrate the clinical and mechanism feasibility of the drug;

● Determine the clinical indications based on the biological activity of the drug. There will be many primary and secondary targets for a drug in the early screening, and the sponsor should locate it according to the structure and characteristics of the drug;

● Conduct different drug efficacy tests (in vivo, in vitro) according to the indications, and pay more attention to the effectiveness of pathological model animals;

● If it is a class of drugs, necessary mechanism research must be conducted;

● The type of registration will affect the amount and depth of efficacy trials (minor efficacy);

● The drug effect test must obtain the time-effect relationship, the dose-effect relationship, etc. The CFDA hopes to make the relationship between the time-effect and the dose-effect on the data of the drug effect, especially the data of the drug effect in the body.

● Pay more attention to the verification of the experimental system and the results of animal experiments;

● It is best to set a positive drug control in the test to be a recognized effective drug with the same target and the same mechanism;

● Repeatability problems, especially in vitro tests should be carried out appropriately repeated tests;

● Pay attention to the problem of secondary targets in mechanism research. Sometimes secondary targets can cause toxicity. Therefore, in early drug efficacy and target screening, not only should be the primary target, but also the secondary target. At present, China still lacks in this part.

Comprehensive non-clinical pharmacokinetic research

First, determine the registration classification. The non-clinical pharmacokinetic studies required for different registration classifications are also different. The following are considered from two aspects of large molecules and small molecules.

Macromolecular pharmacology ranges from protein drugs to antibodies and double antibodies. The practice of each drug cannot be defined by uniform guidelines, but basically the drug absorption and distribution must be done, and the accompanying immunogenicity must be done.

Special reminder of the following points:

●Immunogenicity issues: The US FDA pays more attention to human immunogenicity and is drafting guidelines for clinical immunological research, which are mainly the requirements for immunogenicity research in clinical trials.

● Significance of the study: It is not terrible to have immunogens before the clinic, and it is scientific to use immunogen data to explain toxicogen exposure and toxicological results. For example, the pre-clinical animal experiment of humanized protein is unscientific, because the immunogenicity seen in animals affects the progress of clinical experiments. It needs to be analyzed in detail according to the specific situation. Sometimes the immunogenicity is caused by the substance itself or the immunogenicity problem caused by glycosylation during the preparation of the entire macromolecular drug. This is also clinically impossible. Avoided.

● Current actual situation: For immunogenicity research, single-dose preclinical studies on immunogenicity and pharmacokinetics are often done, and immunogenicity studies accompanying drug toxicity studies are also currently required. Of course, the results will be required. The final conclusion is based on a comprehensive review of the entire chain of evidence. The immunogenicity in the clinical stage, including the establishment and testing of immune methods, is very demanding.

Small molecules need to do a full set of DMPK research

The current guidelines combine the requirements of small molecule medicines with traditional Chinese medicines and natural medicines, requiring plasma concentration-time curves, absorption, distribution, excretion, plasma protein binding, biotransformation, and effects on drug metabolism enzyme activities and transporters. For non-clinical ADME research of innovative drugs, the existence of gene polymorphisms of drug metabolizing enzymes and transporters, the interaction between metabolic enzymes and transporters, the clearance mechanism and potential interactions of major metabolites, and human specificity should also be considered. Evaluation of metabolites, etc.

Special reminder of the following points:

● CFDA requires complete biological sample analysis methods

Including accuracy, precision, specificity, sensitivity, reproducibility, and stability.

● For special preparations, CFDA may require pre-clinical isotope drug substitution

For example, a prodrug is very much distributed in animal organs in pre-clinical research, and cannot be detected by conventional methods, so it may require pre-clinical analysis using isotope methods.

● CFDA generally does not recommend the use of TK instead of pharmacokinetics for repeated administration

Unless the drug safety window is very small and the third-level dose of pharmacokinetics is very similar to the third-level toxicological dose, toxicological TK can be used to replace the pharmacokinetics for repeated administration, otherwise it will be required to be repeated for small animals Drug administration.

● CFDA requires absolute bioavailability

For new drugs that are not administered intravascularly, whole animal tests should be carried out, and intravascular administration tests should be carried out at the same time as possible to provide absolute bioavailability. If necessary, in vitro cell test, in vivo or in vitro intestinal absorption test can be performed to illustrate the drug absorption characteristics. Drugs made abroad often do not have absolute bioavailability, and this experiment may need to be supplemented when reporting in China.

Non-clinical safety evaluation study (toxicology)

● Toxicology research mainly includes research in these areas:

● Safe pharmacology

● Single-dose toxicity test

● Repeated administration toxicity test (including toxicokinetics study)

● Allergy test (local, systemic and photosensitive toxicity)

● Hemolysis test

● Local irritation (vascular, skin, mucous membrane, muscle, etc.)

● Mutagenicity test (genotoxicity): Ames, chromosome aberration test, micronucleus test, MLA or comet and pigA as required by ICH

● Reproductive toxicity test: 1, 2, 3

● Drug dependence test

● Carcinogenicity test

The above are all experiments that support NDA.

These experiments are based on the sponsor’s application strategy and application plan, especially the requirements of different stages of clinical trials, and different trials are selected to support the clinical stage.

Special reminder of the following points:

● Safety pharmacology experiment

China’s safety pharmacological experiments require all research to comply with GLP standards, such as the HERG experiment.

● Additional and supplementary safety pharmacological tests

The additional and supplementary safety pharmacological tests do not need to be completed in the GLP laboratory, because each drug is different, and the additional and supplementary safety pharmacological tests cannot be controlled; the three channels of potassium, sodium and calcium, the central nervous system, and the respiratory system test design It must be done under the GLP standard; for ion channels and action potentials that can be used as GLP, do GLP, try to avoid obstacles in the acceptance process; if the technical guidelines of CFDA are absent, accept the research conducted in accordance with the guidelines of ICH. When the ICH requirements are higher than the current CFDA requirements, it is also acceptable to follow the CFDA requirements. This requires companies to follow their own reporting strategies, which can be high or low, or they can follow the minimum standards.

● Monitoring of toxicity-related indicators related to drug efficacy

Currently doing pre-clinical safety test evaluations in China, and now more and more attention is paid to mechanism research.

● Allergy test

At present, CFDA requires systemic active allergy test (PCA) and systemic passive skin allergy test (PCA), but the United States does not require it.

● Local allergies

For some locally administered drugs, such as skin dosage forms, local allergy tests are required. Including the Guinea-Pig Maximization Test (GPMT) and Buehler test (BT), which are required by the CFDA.

● Hemolysis test

All injections and other pharmaceutical preparations that may cause immune hemolysis or non-immune hemolysis reactions should be tested for hemolysis; applicants need to pay attention to whether the excipients are positive for hemolysis, pay attention to the issue of osmotic pressure, and consider the clinical administration concentration and preclinical toxicity Management of the difference in the concentration of administration.

Frequently Asked Questions in Chinese Registration Application for Research Completed Abroad

Focusing on the aspects of non-clinical pharmacodynamics, non-clinical pharmacokinetics and non-clinical toxicology, some common problems in Chinese registration applications for studies completed abroad are summarized.

Non-clinical efficacy

● There is no positive control group for the efficacy study;

● Focus on mechanism research and light on effectiveness of model animals;

● The comprehensive consideration of innovative models and classic models is lacking. For example, only the zebrafish model used to evaluate the efficacy of tumor drugs cannot be accepted by the review agency temporarily;

● China’s disease diagnosis and treatment routines are not considered in the study of combination medication, which usually appears in the international multicenter combined drug treatment plan;

● In vitro drug efficacy and mechanism studies are not repeated enough. Drugs for tumors require three repetitions. Other drugs are temporarily not required.

Non-clinical pharmacokinetic studies

Absolute bioavailability research is lacking. At present, CFDA will require absolute bioavailability research. In addition, insufficient PK method verification is also a common problem.

Non-clinical toxicology research related issues

● The application period of the declared clinical trial is longer than the completed toxicology study of repeated dosing;

● Sensitive drug efficacy indicators lack observation in toxicological research;

● Lack of research on immunotoxicity and immunogenicity;

● Insufficient attention has been paid to the timeliness of the PK study, and the time point is inappropriate, such as ECG monitoring 24 hours after the administration;

● There are differences in understanding of NOAEL (such as diarrhea without pathological changes, slow weight gain, etc.). The current CFDA requirements are stricter, while the United States is relatively loose;

● At the time of IND registration, there is no single-dose toxicology study under the condition of GLP, and genetic toxicity is lacking. Except for antibody drugs and cell therapy drugs, CFDA originally required that reproductive toxicity needs to be the second generation of rats. At present, the conditions have been relaxed after China joined ICH. Drugs that do not have long-term risks to the reproductive system, or drugs that do not act on the reproductive system, apply for clinical trials to phase 2, and the scale does not exceed 150 people. It is acceptable not to do reproductive toxicity before IND.

Co-administration problem

● Fixed clinical plan

The effect of the drug needs to be compared with the split formula: A (the declared varieties, three doses of L, M, and H), B, A+B (2-3 doses); pharmacokinetics need to provide reference materials for mutual research, investigation Changes in pharmacokinetics of combined and single administration; a separate full set of toxicological studies of the declared drug, it is best to add a combined drug effect to be compared with the separate prescriptions in the toxicological study of a most suitable animal repeated administration Research: A (the declared varieties, three doses of L, M, and H), B, A+B (2-3 doses).

● Combined dosing regimen to be confirmed by clinical trial results

The efficacy of the drug should be compared with the possible combination of drugs; a separate full set of toxicological studies of the toxicological declaration drug should fully consider the toxicological target organs that have been discovered and the toxicological target organs that may be co-administered. Plus, it may require further toxicological studies of target organs.