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The importance of toxicological data to clinical trial design

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Toxicological research is an important part of the non-clinical safety evaluation process of drugs. The purpose is to clarify the toxic reaction, dose correlation, toxicity and drug exposure of target organs before developing new drugs for humans and during clinical research. The reversibility of toxic reactions. This information is helpful for estimating the safe starting dose and dose range for the first human trial, selecting indicators for monitoring clinical adverse reactions, and providing important scientific basis for ensuring the safety of clinical subjects. Toxicological data is a bridge between preclinical and clinical. A comprehensive understanding of toxicological data is of great significance to clinical trial design.

Toxicological research
Toxicological research

The routine toxicology tests that need to be done before the clinic are as follows:

General toxicity test: 1) Acute toxicity test 2) Repeated administration toxicity test
Safety pharmacology test: 1) Cardiovascular telemetry test 2) Rat nerve function combination observation test 3) Rat respiratory safety Pharmacology test Genetic toxicology test: 1) Bacterial reverse mutation test 2) Chromosome aberration test 3) Micronucleus test Reproductive Toxicology Test: 1) Section I 2) Section 2) Section 3)
Allergy test: 1) Active systemic allergy 2) Passive skin allergy

Hemolysis test: 1) In vivo 2) In vitro

Local stimulation test

For acute toxicity tests, the FDA does not require it, because the data provided by so many animals is of little reference value. But currently CFDA is required to do so, if this article is missing, it may not be accepted. Safety pharmacology test. If the drug finds cardiotoxicity problems, supplementary research on the cardiotoxicity mechanism may be required. If the drug has a primary target and a secondary target, the secondary target is very active, then secondary pharmacodynamics or supplementation is required Safety pharmacology research. For injections, allergy tests (including active systemic allergy and passive skin allergy tests) and hemolysis tests (in vivo and in vitro hemolysis) are required.

Regarding genetic toxicology trials, there is no problem that anti-tumor drugs can be carried out in Phase II clinical trials after IND. The guidelines for biological drugs do not require genotoxicity tests. The reason is that most biological drugs act on the surface of cells and do not enter the cells. Therefore, the possibility of genetic toxicity of biological drugs is small (if macromolecular drugs act on the target and grow Factor correlation, may be done).

Reproductive toxicology tests, as a member of ICH, do not need to do reproductive toxicology before IND, but the following requirements must be met: the number of test cases applying for clinical trials does not exceed 150, and there is no toxicity in the reproductive organs in the chronic toxicity test.

Repeated dosing toxicity test is an important part of drug non-clinical safety research. It is a toxicology test with the strongest comprehensiveness, the most information, and the greatest significance for clinical guidance. The test results can determine the toxicity target of the test substance. Organs, predict the clinical adverse reactions that the test substance may cause, and determine the dose level (NOAEL) that no toxic reaction is observed, so as to estimate the starting dose of the first clinical trial (FIH) based on the NOAEL.

The formula for converting the adult equivalent dose (HED) from NOAEL is as follows: HED=Animal dose*Animal Km/Human Km,

converting the adult equivalent dose (HED) from NOAEL

To give an example: For example, in the repeated administration toxicity test for beagle dogs, NOAEL is 5 mg/kg, HED=5 mg/kg20/37=2.7mg/kg. Choose the human safety factor (between 1/10 and 1/1000), if 1/10 is used as the starting dose to calculate the safety factor, 1/102.7mg/kg*50kg=13.5mg, 13.5mg can be the first Reference for the initial dose of FIH. In addition, there is a derivation method based on biological exposure that is close to the pharmacological mechanism of action. The maximum initial dose that the researcher finally uses should be the lower dose obtained by various calculation methods.

At the same time, animal toxicology tests should match the clinical cycle:

The longest clinical trial periodThe shortest period of repeated administration toxicity test: RodentsNon-rodents
<=2 weeks2 weeks2 weeks
2 weeks – 6 monthsSame as clinical trialSame as clinical trial
>6 months6 months6 months

In some cases, such as antitumor drugs, patients who may benefit from phase I clinical trials cannot be discontinued from an ethical point of view. One-month long-term toxicity trials may not support long-term clinical trials. Many domestic clinical hospitals fail to pass the ethics problem because of this problem, but rarely in foreign countries. In this case, you can report to the IND first, and the Food and Drug Administration will not prevent you from going to the clinic because of the four-week toxicology test. If the human metabolism is not clear, it is meaningless to do a long toxicology test before IND. After the human pharmacokinetic data of clinical phase I patients is released, evaluate the data, and the future metabolism in the human body will help the drug move forward, and start a 3-month toxicology test as soon as possible to ensure that patients who may benefit from the clinic When the medication was continued, the toxicological tests used for support had already been done. The longer the IND phase toxicology test is done, the lower the NOAEL and the lower the starting dose of clinical climbing, which will cause a larger clinical loss.

The selection of test animals should be noted that the sensitivity of different target organ animals is different, such as the gastrointestinal sensitivity of beagle dogs. If the drug has gastrointestinal toxicity, dogs are the appropriate species. If it is a drug that acts on the coagulation system, the coagulation system of dogs and humans is the closest. Especially for macromolecular drugs, it is necessary to select related species for testing. If you select unrelated species, it may cause misunderstanding of the test data.

When analyzing the results of toxicity tests, the meaning of mean data and individual data should be correctly understood. When analyzing the results of repeated dosing toxicity tests, the statistical significance and biological significance of the data should be considered. It should be considered that the statistical significance does not necessarily mean the biological significance; the dose of the parameter change should be considered when judging the biological significance- Factors such as reaction relationship, changes in other related parameters, and comparison with historical background data. When analyzing toxicological data, we must pay attention to physiological fluctuations. There are physiological fluctuations in blood pressure, heart rhythm, and endocrine. Another point is that you should not use animal individual differences to explain abnormal data easily. Even if there are individual differences in 1/100 animals and there is a dose-effect relationship, it cannot be ruled out that it is caused by drugs.

When extrapolating the results of long-term toxicity studies to humans, you need to pay attention: there are differences in the toxicity of the test substance between different species or individuals. For example: 1) Rodents do not have a gallbladder. When cholestatic liver injury or thickening of the bile ducts, they are prone to pancreatic injury, while human dogs and monkeys will never occur. This is related to the physiological structure. So don’t open your eyes just because you see a lot of pancreatic diseases in mice, you can design clinically the adverse pancreatic reaction indicators. 2) The teeth of rodents continue to grow, and the inhibitors that act on the EGFR target will cause the rats to break their teeth and cannot push them to humans. 3) Dogs are particularly prone to allergic or allergic reactions. For example, hypersensitivity to Tween 80 is prone to degranulation of mast cells. If the preparation contains Tween 80, it is not suitable to select dogs for toxicology test. 4) The distribution of drug targets in different species and humans is different. For example, the PCSK9 target, the long-toxic NOAEL dose used in the reproductive toxicity test is the lethal dose, and the cause of death is liver toxicity. Through literature review and additional experiments, it was found that the PCSK9 target is highly expressed in the liver of pregnant rodents. 5) Some targets have different sensitivity between humans and animals. Like many molecularly targeted drugs, especially anti-tumor drugs, they have common characteristics: Compared with humans, animals have poor tolerance and sensitivity, and humans are the opposite. Therefore, the safety window of this type of drug is often different from preclinical and clinical, such as apatinib. 6) Immunogenicity. China currently prefers preclinical immunogenicity research. Preclinical animal immunogenicity results are of little reference value for humans. Many large foreign companies do not do preclinical immunogenicity. What we do in China is to use it to explain toxicological data. 7) In toxicology studies, the dosage is relatively high, and the test product may exhibit a non-linear kinetic metabolic process in the animal body, resulting in toxicity that has nothing to do with the human body. 8) Toxic reactions caused by different metabolites between humans and animals. For example, the toxicity caused by metabolites, drugs can detect metabolites in humans, but can not be detected in animals, it is unable to provide clinical data support.

A good clinical designer, based on the toxicological reactions and the suggested target organs, should be certain of these. However, a principle is that humans must be assumed to be the most sensitive in clinical design. Animals in long-term toxicity studies The toxic reaction may be reproduced in clinical trials. Designing experiments based on this principle can ensure the safety of human experiments to the greatest extent.

For drugs for the treatment of general diseases, the safety window is very important for a large population of clinical drugs. It is necessary to analyze the toxicological NOAEL, find the death dose as much as possible, and understand the cause of death; for “non-toxic” drugs, first consider whether it is exposed in the body; pay special attention to the target organ toxicity that leads to sudden death: heart, central nervous system, anaphylactic shock Etc.; it is necessary to consider the amplification of the toxicity of the clinical patient to the target organ under the pathological state, and the drugs that are positive for genotoxicity in the early stage should be cautious; the drugs that affect the ion channel should be cautious.

In short, toxicology studies provide clinical basis for the design of the first dose and maximum tolerated dose, provide observation indicators for clinical adverse reactions, and provide support for clinical design to fully consider species differences and pay attention to the toxicity of important target organs. It is necessary to assume that humans are the most sensitive to toxic reactions in the design scheme, to maximize the safety of human experiments.

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