Guideline ID: [Z] GPT1-1
Technical Guidelines for General Pharmacological Studies of Traditional Chinese Medicines and Natural Drugs
(Draft 2)
March 18, 2004
Technical Guidelines for General Pharmacological Studies of Traditional Chinese Medicine and Natural Drugs
1. Overview
Pharmacology research is categorized into three types: primary pharmacodynamics, secondary pharmacodynamics, and safety pharmacology. Additional or supplemental safety pharmacology studies may be required based on experimental needs. General pharmacology refers to broad pharmacological investigations beyond primary pharmacodynamic effects, encompassing both secondary pharmacodynamics and safety pharmacology.
General pharmacology studies identify unintended pharmacological effects of the test article that may impact human safety, evaluate adverse drug reactions and/or pathophysiological effects observed in toxicology and/or clinical studies, and investigate the mechanisms underlying observed or suspected adverse drug reactions.
General pharmacology studies provide reference for designing long-term toxicity trials, inform clinical research and safe medication use, and support the development of new indications.
Currently, the general pharmacology studies for new traditional Chinese medicine (TCM) and natural drugs are referenced against the 2009 "Guidelines for Research on New TCM Drugs" and the 2005 "Technical Requirements for Pharmacology and Toxicology Studies of New TCM Drugs," both issued by the People's Republic of China. These guidelines have helped standardize research methodologies to a certain extent. However, as global understanding of general pharmacology deepens, research methods for TCM and natural drugs continue to evolve, and our knowledge of these substances expands, these requirements increasingly reveal their limitations.
This guideline was developed based on the characteristics of traditional Chinese medicines and natural drugs, in alignment with international requirements for drug safety evaluation and the current status of drug safety research in China.
This technical guideline applies to general pharmacology studies of traditional Chinese medicines and natural drugs.
Research on new Traditional Chinese Medicine (TCM) and natural drug candidates is complex. The content discussed herein cannot cover all aspects of general pharmacology studies for TCM and natural drugs. When conducting such studies, the principle of "analyzing specific problems in a specific manner" should be followed.
II. Basic Principles of General Pharmacological Studies
(1) Test Management
Safety pharmacology studies in general pharmacological research should generally be conducted in accordance with the Good Laboratory Practice (GLP) regulations.
(II) Experimental Design
Experimental design must adhere to the core principles of randomization, control, and replication.
III. Basic Content of General Pharmacology Studies
(I) Investigational Product
Test substances for general pharmacology studies should adequately represent those used in clinical trials and marketed drugs. Therefore, test substances should be samples prepared using a stable manufacturing process that meet the quality standards for clinical use. Pilot-scale samples are generally recommended; if not used, adequate justification must be provided. The name, source, batch number, potency (or specification), storage conditions, and preparation method of the test substance shall be documented. If dosing volume or administration route limitations preclude the use of pilot-scale samples, active pharmaceutical ingredients (APIs) or extracts may be used instead. Any solvents or excipients employed in the study must include their batch number, specification, and manufacturer.
(II) Test System
To obtain scientifically valid general pharmacology data, the most appropriate animal or other test system should be selected. Selection criteria include the pharmacodynamic response of the test system, the pharmacokinetic characteristics of the test article, the species, strain, sex, and age of the test animals, as well as the sensitivity, responsiveness, and reproducibility of the test system, along with background information on the test article. The rationale for selecting a specific animal/model and test system must be provided.
1. Commonly Used Laboratory Animals
Common laboratory animals include mice, rats, and dogs. Awake animals are typically used for testing. Mice and rats must meet or exceed National Standard Class II requirements for laboratory animals; dogs must meet or exceed Class I. If anesthetized animals are used, carefully select the anesthetic agent and depth of anesthesia.
2. Common In Vitro Test Systems
In vitro systems are used for supportive research (e.g., to characterize the activity profile of a test article and to elucidate the mechanisms underlying pharmacological effects observed in vivo). Commonly used in vitro models include isolated organs and tissues, cells, subcellular organelles, receptors, ion channels, and enzymes.
(3) Sample Size and Controls
To ensure scientific and meaningful interpretation of experimental data, adequate sample sizes are essential. Generally, each group should include no fewer than 10 mice or rats, and no fewer than 6 dogs.
Experimental design should include appropriate blanks and negative controls, and positive controls where necessary.
(IV) Route of Administration
The route of administration should match the intended clinical route. If a different route is used, provide a justification.
(V) Dosage or Concentration
In Vivo Study: In vivo general pharmacology studies should, to the extent possible, establish the dose-response and time-course relationships of adverse effects (e.g., onset and duration of adverse reactions). At least three dosage groups must be included. The low-dose group should correspond to the effective dose identified in primary pharmacodynamics studies, while the high-dose group should be limited to the level that does not produce severe toxic reactions.
In vitro studies: In vitro studies should aim to establish the dose-response relationship of the test substance. The upper concentration limit of the test substance should not affect the physicochemical properties of the test system or other special factors influencing the evaluation.
(VI) Dosing Frequency and Measurement Timing
Single-dose administration is generally recommended. If the pharmacological effects of the test drug manifest only after a period of treatment, or if repeated-dose nonclinical and clinical studies reveal safety concerns, the number of doses for general pharmacology studies should be rationally designed based on these findings. The timing for assessing general pharmacology parameters should be selected according to the pharmacodynamic and pharmacokinetic properties of the test substance.
(7) Observation Indicators
Based on the importance of organ systems and vital functions, relevant systems may be selected for general pharmacology studies. The objective of general pharmacology is to assess the effects of the test substance on vital functions. The cardiovascular, respiratory, and central nervous systems are critical for sustaining life; therefore, preclinical general pharmacology studies must include initial observations of these systems. If adverse reactions potentially affecting humans or animals are observed or suspected during other nonclinical or clinical trials, further in-depth evaluations of these key systems or additional organ systems should be conducted and completed prior to submitting a marketing authorization application.
1: Essential Observation Indicators for General Pharmacology – General Pharmacological Studies on Vital Life Function Systems
Assess the effects of the test substance on the central nervous, cardiovascular, and respiratory systems based on their importance to life functions.
1. 1 Central Nervous System Observe animals' general behavior, posture, gait, and signs such as salivation, muscle tremors, and pupil changes immediately after dosing. Qualitatively and quantitatively evaluate spontaneous activity and motor coordination post-dosing. Assess whether the test substance exhibits synergistic effects with pentobarbital sodium at both sedative threshold and sub-threshold doses. If marked CNS excitation, depression, or other CNS responses occur, conduct further in vivo or in vitro studies accordingly.
1. 2 Cardiovascular System Assess and record changes in blood pressure (including systolic, diastolic, and mean values), electrocardiogram parameters (including QT interval, PR interval, QRS complex, ST segment, etc.), and heart rate before and after drug administration. If significant blood pressure or ECG changes occur at therapeutic doses, further in vivo or in vitro studies should be conducted.
1. 3 Respiratory System Monitor and record respiratory rate, rhythm, and depth before and after drug administration. If the therapeutic dose causes marked respiratory stimulation or depression, further in vivo or in vitro studies should be conducted.
2 Other Observational Indicators in General Pharmacology Studies — Additional or Supplemental Safety Pharmacology Studies
Based on general observations and clinical studies of the central nervous, cardiovascular, and respiratory systems, as well as in vitro and in vivo tests or literature, if potential adverse effects of the test article are anticipated, appropriately select additional or supplementary general pharmacology studies to further elucidate the possible causes of these adverse reactions.
These studies do not need to be conducted individually. Instead, select the appropriate studies based on a comprehensive review of nonclinical and clinical data, tailored to specific practical needs.
2. 1 Additional safety pharmacology studies
Central Nervous System: Assess effects on behavioral pharmacology, learning and memory, neurochemistry, vision, hearing, and/or electrophysiology.
Cardiovascular System: Evaluate the effects of drugs on cardiac output, myocardial contractility, and vascular resistance, and investigate their mechanisms of action.
Respiratory System: Monitor effects on airway resistance, pulmonary artery pressure, blood gas analysis, and blood pH.
2. 2 Supplementary Safety Pharmacology Study
Urinary System: Assess the impact of drugs on renal function by monitoring indicators such as urine volume, specific gravity, osmolarity, pH, electrolyte balance, protein levels, cellular components, and blood biochemistry markers (e.g., blood urea nitrogen, creatinine, and total protein).
Autonomic Nervous System: Assess the effects of drugs on the autonomic nervous system, including binding to receptors associated with this system, functional responses to agonists or antagonists in vivo or in vitro, direct stimulation of the autonomic nervous system, and impacts on cardiovascular responses, baroreflexes, and heart rate.
Gastrointestinal System: Assess the effects of drugs on the GI system, including gastric acid secretion volume and pH, GI injury, bile secretion, in vivo transit time, and in vitro ileal contraction.
Other Organ Systems: If safety concerns arise and the effects of the drug on other organ systems—such as potential dependence, skeletal muscle function, immune function, and endocrine function—have not been investigated in relevant studies, these aspects should be evaluated.
(VIII) Results and Analysis
Conduct quantitative and qualitative statistical analysis of results based on detailed experimental records. Specify the statistical methods used and justify their selection, while also evaluating individual trial outcomes. Based on the statistical findings, analyze the general pharmacological effects of the test substance. Weigh the benefits and risks by integrating data from other safety, efficacy, and quality control studies to assess the development potential of the test substance.
IV. General Requirements for Pharmacological Studies in Different Scenarios
For active components extracted from traditional Chinese medicine or natural drugs and their preparations that have not yet been marketed in China, general pharmacological studies should generally be conducted progressively according to the requirements outlined above.
For drug preparations made from medicinal substances derived from plants, animals, or minerals that are not yet marketed in China; preparations made from new medicinal parts of Chinese medicines not yet marketed in China; preparations made from active components extracted from Chinese medicines or natural drugs not yet marketed in China; compound preparations made from Chinese medicines or natural drugs containing medicinal substances without established standards and not yet marketed in China; and injectable preparations made from Chinese medicines or natural drugs not yet marketed in China, general pharmacological studies on major organ systems should generally be conducted. Depending on the specific characteristics of the test article and other study results, additional general pharmacological studies may be required. In such cases, relevant study items should be selected based on a comprehensive evaluation of nonclinical and clinical data, taking into account actual conditions.
If the above requirements are not followed for relevant research, a justification must be provided.
Traditional Chinese medicine and natural drugs are complex; select appropriate testing methods and study components based on the characteristics of the test article.
V. Terminology Definitions
Primary Pharmacodynamic Studies: Research on the activity and/or effect models related to the intended therapeutic purpose of the test article.
Secondary Pharmacology: Studies of activities and/or effects unrelated to the intended therapeutic purpose of the test article. These studies are sometimes considered part of general pharmacology.
Safety Pharmacology Studies: Evaluation of potential adverse effects on physiological functions when the test substance is administered at doses within or above the therapeutic range.
Supplementary Safety Pharmacology Studies: Based on the drug's pharmacological properties and chemical class, estimate potential adverse reactions. If existing animal and clinical trial results raise concerns that could affect human safety, additional supplementary safety pharmacology studies should be conducted, including in-depth investigations of the central nervous system, cardiovascular system, and respiratory system.
Supplementary Safety Pharmacology Studies: These evaluate the effects of the test drug on organ systems other than the central nervous system, cardiovascular system, and respiratory system, including the urinary (renal), autonomic, gastrointestinal systems, and other organs/tissues. Supplementary safety pharmacology studies should be conducted when primary safety pharmacology studies do not adequately demonstrate the effects of the drug's efficacy on organ system function, or when significant safety issues arise during long-term toxicity studies.
VI. References
1. ICH S7A: Safety Pharmacology Studies for Human Pharmaceuticals. 2001
2. ICH S7B: Safety Pharmacology Studies for Assessing the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals. 2002
VII. Drafting Explanation
(I) Scope of General Pharmacology
In "General Pharmacological Studies for New Traditional Chinese Medicine Drugs" published in 1993, general pharmacology was primarily defined as pharmacological effects beyond therapeutic efficacy, with no mention of potential new effects or adverse reactions. During this revision of the guidance principle, general pharmacology was incorporated into the scope of safety evaluation for the first time, mainly because international standards now recognize it as an integral component of drug safety assessment.
General pharmacology originally referred to the study of effects of test substances beyond their primary pharmacodynamic actions, with a focus on identifying potential adverse effects on physiological functions. It encompasses both secondary pharmacodynamics and safety pharmacology. Safety pharmacology investigates potential undesirable effects on physiological functions at therapeutic doses or above. The concept of safety pharmacology first appeared in 1997 in the ICH guidelines for the timing of nonclinical safety studies required for new drug clinical trials (M3) and preclinical safety evaluation of biotechnology-derived pharmaceuticals (S6), which mandate safety pharmacology studies as part of nonclinical safety assessments to support human clinical trials. Prior to the adoption of the safety pharmacology concept, general pharmacology was widely used. In Japan, the Ministry of Health, Labour and Welfare issued its general pharmacology study guidelines in 1991, defining the purpose of general pharmacology as discovering unanticipated effects on organ function and identifying other pharmacological activities, whereas safety pharmacology focuses specifically on detecting adverse reactions to new drugs. As required by ICH M3 and S6, the objective and significance of safety pharmacology are to identify unwanted pharmacological effects potentially related to clinical safety, evaluate adverse reactions or pathological effects observed in toxicology studies or clinical trials, and investigate the mechanisms underlying these adverse reactions. This ensures that, to the greatest extent possible, any adverse effects beyond therapeutic benefits are identified before a new drug enters clinical trials or after it is marketed.
The ICH convened in 2001 to establish the safety pharmacology guideline, S7A Safety Pharmacology Studies for Human Pharmaceuticals, emphasizing drug safety evaluation and its clinical relevance. To align with international standards, this revised guideline incorporates references to 1993's "General Pharmacological Studies of New Chinese Medicines," the ICH guidelines, and accounts for China's specific context as well as the unique characteristics of traditional Chinese medicines and natural drugs.
(II) Requirements for Trial Management, Investigational Products, and Test Animals
This guideline incorporates general pharmacology into the scope of safety evaluation. The Guangzhou Research Group discussion concluded that general pharmacology studies should meet safety evaluation requirements, including adherence to GLP, use of pilot-scale test articles, and animals meeting specific qualification levels; this should be the direction for future development. ICH S7A recommends that essential system-specific general pharmacology studies comply with GLP, while additional or supplementary general pharmacology studies should adhere to GLP as much as possible. However, given the broad scope of general pharmacology and the complex, variable testing conditions required (e.g., multiple instruments, various animal models, and in vitro assays), the feasibility under current conditions warrants extensive discussion.
(III) Regarding the Setup of the Control Group
The original guidelines did not specify requirements for control groups; this updated guideline clarifies them. Generally, a blank control group should be established. Depending on the drug's characteristics and trial design, a positive control group may also be included as necessary.
(4) Use of Anesthetized Animals
While many studies on the circulatory and respiratory systems currently use anesthetized animals, anesthesia can introduce multiple confounding factors. We therefore recommend using awake animals whenever possible. If anesthetized animals must be used, careful selection of both the animal model and anesthetic depth is essential.
8. Authors
Research Group for the "Technical Guidelines on General Pharmacological Studies of Traditional Chinese Medicine and Natural Drugs"