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New veterinary drug development process and safety evaluation

2016-10-17
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With the development of the veterinary drug industry, the research and development of new veterinary drugs has gradually attracted the attention of many companies. At the same time, due to the improvement of people’s living standards, food safety has also received more and more attention. People are paying more attention to the safety of new veterinary drugs. Therefore, relevant departments require new veterinary drugs. Safety evaluations are required before veterinary drugs are marketed.
Safety evaluation is the traditional acute, subchronic, chronic, mutagenic, teratogenic, and carcinogenic (“three causes”) evaluations of new veterinary drugs before they are marketed in the traditional sense. The toxic effects of doses and multiple doses are found through in vivo and in vitro experimental models to discover the “three causes” effects of new veterinary drugs, thereby discovering the most sensitive target animal species and the lowest non-effect dose.
 Veterinary drug consistency evaluation

  1. New veterinary drug development process and safety evaluation
    The first stage is the invention (discovery) stage. In this stage, exploratory research is generally carried out on new compounds discovered, including research on the structure and properties of the compound, small-scale trial production under experimental conditions, and pilot tests. Carry out dose response (pharmacodynamics), toxicity and pharmacokinetic studies in experimental animals and target animals. Market research and development decisions are made based on the new research results of the guide, mainly to see whether it meets the clinical needs, the economic benefits, the feasibility of development, and whether there is a need for research and development. Generally, patent registration applications are started at this stage.
    The second stage is the non-clinical (pre-clinical) research stage. Generally, this stage is mainly to answer development feasibility questions to determine whether to invest in further research and development. At this stage, experimental animals are generally used for related experimental research, including the main pharmacodynamics, general pharmacodynamics, pharmacokinetics and mechanism of action of the drugs in pharmacological research to prove the validity problem, as well as toxicological research Acute toxicity, long-term toxicity and special toxicity studies are carried out, and toxicokinetic studies should be carried out when necessary to prove safety issues. In addition, according to the results of pharmacological research, relevant pharmaceutical research, selection and determination of dosage forms, inspections of product stability, formulation of corresponding quality standards, and further pilot production of APIs and preparations should be carried out, and experimental animals should be used at this stage. test.
    The third stage is the clinical research stage. Generally, at this stage, it is mainly to determine whether the new veterinary drug product has the significance of further research and development. In this stage, the research generally needs to be tested with target animals, which can be carried out in three phases. Phase 1 clinical (laboratory) Test: Under controllable conditions in the laboratory, including target animal tolerance test, find effective dose and poisoning dose range, determine the effectiveness and safety of target animal; conduct pharmacokinetic and bioavailability test of target animal , To provide the basis for the next recommended clinical dosage; Phase 2 clinical (laboratory) trials: including drug efficacy evaluation trials (randomized controlled treatment trials), which use healthy target animals to conduct drug efficacy controlled trials under controlled conditions, if necessary Carrying out animal pharmacokinetic tests to determine the preliminary effective dose, so it is also called a dose determination experiment. According to the determined effective dose, carry out the residue elimination test in healthy animals to determine the drug withdrawal period after use; the phase 3 clinical trial is also called the dose verification test abroad, mainly to verify whether the results of phases 1 and 2 are feasible. This test is natural Under production conditions, conduct randomized controlled trials of target animals in designated areas to further verify the clinical trial dose (also known as dose confirmation test). At the same time, conduct safety trials on target animals based on clinical doses to investigate the increase in clinical doses Toxic side effects.
    Generally, after completing the trials at this stage, you can start to prepare the new veterinary drug application materials, submit the new veterinary drug registration application, and conduct the new veterinary drug registration.
    The fourth stage is the post-marketing stage. After the new veterinary drug is approved for marketing, the manufacturing process and quality control standards should be further improved, and necessary pharmacological and toxicological data should be supplemented, and post-marketing adverse reaction testing (for animals and Everyone needs to be monitored) to observe whether the new veterinary drugs on the market lack efficacy? What is the toxicity of animals under the prescribed conditions of use? What are the toxic and side effects on people (producers and users)? If used off-label, what toxic side effects will occur? After the use of food animals, the residues are tested to determine whether the drug withdrawal period is sufficient and whether there is any impact on food safety? What is the impact on the ecological environment after medication? The development of antimicrobial resistance should also be tested.

  2. The content and purpose of safety evaluation
    (1) Contents of safety evaluation

  3. Single-dose toxicity test stage, also known as the acute toxicity test stage, which mainly evaluates the toxic effects of new veterinary drugs on organisms after exposure through different routes under the condition of one exposure, including systemic toxicity and local toxicity.
    Oral L50 determination: It is mainly to investigate the systemic toxicity caused by single-dose oral route. Generally speaking, all APIs must be tested.
    The determination of injection route L50: mainly to investigate the systemic toxicity of new veterinary drugs through various injection routes (including intramuscular injection, subcutaneous injection, intraperitoneal injection) in the case of single-dose poisoning. Generally, the physical and chemical properties of the drug should be combined to select future clinical trials. The route of administration, according to the determined clinical route of administration, select the corresponding route of injection for exposure. APIs for injection must be tested, and other APIs can be determined according to the clinical route of administration.
    The determination of transdermal L50 is mainly to investigate the systemic toxicity of new veterinary drugs in the case of single dose exposure through the skin administration route (smear, transdermal, etc.).
    Skin irritation test: To investigate the irritation of the new veterinary drug through skin injection or transdermal administration to the local skin, such as redness, swelling, heat, pain, etc. This test is generally required for preparations for injection and transdermal absorption.
    Muscle irritation test: To investigate the irritation response of new veterinary drugs to local muscles by intramuscular injection. Generally, this test is required for preparations for intramuscular injection.
    Eye conjunctival irritation test: To investigate the local irritation of the new veterinary drug to the eye conjunctiva through the administration of the eye conjunctiva, and to understand the protection required for veterinary drug manufacturers and users. General ophthalmology direct medication, spray and volatile preparations must be tested.
    Mucosal irritation test: To investigate the local irritation of new veterinary drugs to the vagina and uterine mucosa produced by vaginal or uterine injection. Generally, only uterine injections must be tested.
    Hemolysis test: To investigate the toxic effects of new veterinary drugs on blood cells after intravenous injection. Generally, the test must be carried out for preparations for intravenous injection, and there are strict regulations on the selection of the solvent for such preparations.

  4. Subchronic toxicity test phase
    30/90-day subchronic toxicity test: To investigate the systemic toxicity of the new veterinary drug in multiple doses of experimental animals. Rats are generally administered by gavage. All raw materials must be tested.
    Accumulative toxicity determination: This test must be performed for multiple-dose preparations.

  5. Mutagenicity test phase
    Ames test, also known as Salmonella typhimurium recovery mutation test, is used to detect whether new veterinary drugs have gene mutations. According to statistics, the coincidence rate of genetically mutagenic compounds detected in this test can reach 75% or even higher. If the drug is mutagenic, it cannot be used as a veterinary drug, and it cannot be developed.
    In addition, the micronucleus test of small tree bone marrow cells, mouse sperm abnormality test or testicular spermatogonia chromosome aberration analysis test, mouse bone marrow cell chromosome aberration analysis test and dominant lethal test are also performed.
    It should be noted that the API must be tested at this stage, and various preparations are not required.

  6. Reproductive and developmental toxicity (teratogenicity) test stage
    Traditional teratogenic test: all APIs must be carried out;
    Reproductive toxicity test: optional. If this test is done, the traditional teratogenic test is not required. It is worth noting that the API must be tested at this stage, and various preparations are not required.
    In the teratogenic test, for general veterinary drugs, the traditional teratogenic test is mandatory; for feed drug additives, feeding teratogenic test and feeding reproductive toxicity test should also be added. Feeding reproductive toxicity tests generally only do the first generation of reproductive toxicity, and the second generation of reproductive toxicity should be done when the first generation is positive.

  7. Chronic toxicity test (including carcinogenic test) stage
    Chronic toxicity test: APIs used as pharmaceutical feed additives must be tested.
    Carcinogenicity test: According to the results of 90-day toxicity test and mutagenicity test, it is generally not required. But the mutagenicity test has a positive result, is suspected of carcinogenic effects, hormones or hormones, and raw materials used as immunomodulators must be tested.

(2) Evaluation of safety evaluation results
After safety evaluation studies, to determine whether a compound can be used as a veterinary drug, the choice is generally based on the following results.
Acute toxicology test results: if the oral LD50 is less than 10 mg/kg body weight of the raw material drug, or the drug feed additive that is less than 10 times the possible intake of the target animal, generally abandon its use as a veterinary drug and no longer continue other toxicology tests.
Subchronic toxicity test results: various APIs with a toxic dose less than 2 to 3 times the recommended dose can generally not be used as veterinary drugs, and APIs with accumulation coefficients less than 3 generally cannot be used as pharmaceutical feed additives.
Mutagenicity test results: one of the three tests is an API with a positive result, and generally cannot be used in food animals. If the API is particularly important, one or two other toxicological tests must be done, and the carcinogenic test must be used for confirmation .
Reproductive toxicity test results: drugs with a minimum teratogenic dose less than 3 times the recommended dose cannot be used in pregnant animals; drugs with obvious reproductive toxicity generally cannot be used in breeding animals.
Chronic toxicity results: APIs with positive or suspicious carcinogenic test results should generally not be used in food animals.

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