Safety pharmacology is mainly to observe the adverse effects of the drug on the central nervous system, cardiovascular system and respiratory system when the drug is in the treatment range or above the treatment range. Additional and/or supplementary safety pharmacology studies that may be carried out as needed should also include observations of the urinary system, autonomic nervous system, digestive system and other organs and tissues. The purpose and significance of safety pharmacology research is to discover undesirable pharmacological effects that may be related to clinical safety, evaluate adverse reactions or pathological effects observed in toxicological tests or clinical studies, and explore the mechanism of adverse reactions.
| Test type | Animal species | Type of drug | Route of administration | Research content |
| Safe pharmacology | Mouse Rat Guinea pig Rabbit Beagles | Small molecule biological Natural products vaccine traditional Chinese medicine | Oral: gavage, capsule Parenteral: intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, subcutaneous injection, continuous infusion, intravitreal injection Other: nasal feeding, nasal cavity, eyes, rectum, vagina, implant | Cardiovascular system (anaesthetized animals/awake animals) Central nervous system: spontaneous activity test in mice, runner test in mice, prolonged sleep time test of pentobarbital sodium in mice, subthreshold hypnotic dose test in mice Cardiovascular system: blood pressure, electrocardiogram, heart rate, etc. before and after administration Respiratory system: respiration rate and depth of respiration before and after administration Supplementary test |
Effects of the test substance on the central nervous system should be assessed appropriately. Motor activity, behavioral changes, coordination, sensory/motor reflex responses and body temperature should be evaluated.
Effects of the test substance on the cardiovascular system should be assessed appropriately. Blood pressure, heart rate, and the electrocardiogram should be evaluated. In vivo, in vitro and/or ex vivo evaluations, including methods for repolarization and conductance abnormalities, should also be considered.
Effects of the test substance on the respiratory system should be assessed appropriately. Respiratory rate and other measures of respiratory function (e.g., tidal volume or hemoglobin oxygen saturation) should be evaluated. Clinical observation of animals is generally not adequate to assess respiratory function, and thus these parameters should be quantified by using appropriate methodologies.
Safety pharmacology studies may not be required for topically applied agents (e.g., dermal or ocular) where the pharmacological profile of the test substance has been adequately characterized and systemic exposure or distribution to other organs or tissues has been demonstrated to be low.
For biotechnology-derived products that achieve highly specific receptor targeting, it is often sufficient to assess safety pharmacological endpoints as part of toxicology or pharmacodynamic studies, thus reducing or eliminating safety pharmacology studies for these products.
In addition, new salts with similar pharmacokinetics and pharmacodynamics and cytotoxic agents do not need to be tested for the treatment of patients with end-stage cancer.
However, extensive safety pharmacology studies should be considered for cytotoxic agents and biotechnology-derived products that represent new therapeutic classes or mechanisms of action or that do not achieve high receptor-specific targeting(Quoted from the Encyclopedia of Toxicology).
The research objectives of safety pharmacology include the following aspects: determine the undesired pharmacological effects of drugs that may be related to human safety; evaluate the adverse drug reactions and/or pathophysiological effects of drugs observed in toxicological and/or clinical studies ; The mechanism of adverse drug reactions observed and/or speculated in the research.
The trial design should be rationally based on the characteristics of the drug and the purpose of clinical use. Choose appropriate and validated methods, including scientific and effective new technologies and new methods. Certain safety pharmacology studies can select test methods based on the model of pharmacodynamic response, the characteristics of pharmacokinetics, and the species of experimental animals. The test can use in vivo and/or in vitro methods.
Safety pharmacology research runs through the entire process of new drug research and can be carried out in stages. Before the drug enters the clinical trial, the study of the core battery (Core Battery) test for the effects on the central nervous system, cardiovascular system and respiratory system should be completed. Additional and/or supplementary safety pharmacology studies can be completed before application for clinical or production, depending on the specific circumstances.
Drug safety evaluation research must implement the “Non-clinical Drug Research Quality Management Practice” (GLP). In principle, safety pharmacology studies must perform GLP. For some special cases that are difficult to meet GLP requirements, proper test management and data storage must also be ensured. The core combination test shall perform GLP. Supplementary or/and supplementary safety pharmacology studies should follow GLP specifications as much as possible.
Traditional Chinese medicine and natural medicine: The test substance should be a sample that can fully represent the quality and safety of the samples to be used in clinical trials and/or the samples on the market. The process should be prepared after the process route and key process parameters are determined. Generally, it should be a sample of a pilot scale or above, otherwise there should be sufficient reasons. The name, source, batch number, content (or specification), storage conditions, expiration date and preparation method of the test substance should be indicated, and a quality inspection report should be provided. Due to the particularity of traditional Chinese medicines, it is recommended to use them now, otherwise data should be provided to support the quality stability and uniformity of the test substance after preparation. When the administration time is longer, it should be investigated whether the volume after preparation is swelled with the prolonged storage time, causing the final concentration to be inaccurate. If the volume or method of administration is limited, the drug substance can be used for testing. The solvent and/or auxiliary materials used in the test should be marked with the name, standard, batch number, expiration date, specification and production unit.
Chemical drugs: The test substance should be a sample with relatively stable technology, purity and impurity content that can reflect the quality and safety of the samples to be used in clinical trials and/or the samples on the market. The test substance should be marked with the name, source, batch number, content (or specification), storage conditions, expiration date and preparation method, etc., and a quality inspection report should be provided. The solvent and/or auxiliary materials used in the test should be marked with the name, standard, batch number, expiration date, specifications and production unit, etc., and meet the test requirements.
In the process of drug development, if the process of the test substance changes that may affect its safety, corresponding safety studies should be carried out.
During the chemical drug test, the test substance sample should be analyzed, and the sample analysis report should be provided. Traditional Chinese medicines and natural medicines with basically clear ingredients should also be analyzed for test substance samples.
1. Preclinical Toxicological Safety Evaluation of Biological Drugs
Different from small-molecule chemical drugs, macromolecular biopharmaceuticals have unique species specificity, immunogenicity, and multiple tissue affinity, etc. The toxicological evaluation of biopharmaceuticals emphasizes the principle of specific analysis of specific problems and evaluates them. Security.
2. The United States Exempts the IND's BA/BE Safety Report Requirements
US IND clinical trials report SUSAR in accordance with the requirements of ICH E2A. 21 CFR 312.32 clearly stipulates the reporting time limit and requirements:
3. Efficacy and safety evaluation of tocilizumab in adult systemic sclerosis
Systemic sclerosis is a rare disabling autoimmune disease with few treatment options. Recently, Khanna D of the University of Michigan in the United States conducted a phase II randomized double-blind placebo-controlled trial (faSScinate) to evaluate tocilizumab (IL-6 receptor alpha inhibitor) in patients with systemic sclerosis (SSc) In the efficacy and safety.
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