Recently，Notice of the State Food and Drug Administration on issuing and issuing the research requirements of natural drug new drug research (Note [2013] No. 17)，The full text of the "Requirements for Research on Natural Drug New Drugs" is as follows:
Technical Requirements for Research on Natural Drug New Drugs
1. Overview
The natural drug referred to this technical requirements refers。The source includes plants、Animals and minerals，Generally does not include substances from genetic modification animals and plants、Materials fermented by microbial or chemistry。
The research and development of natural drugs should be paid attention to the following points: First, the design and evaluation of clinical trial solutions guided by modern pharmaceutical theory; second, the determination of active ingredients should have a sufficient basis; third, the full test data should be reasonable and reasonable. sex、Non -clinical and clinical effectiveness and safety; fourth is to ensure the sustainable use of resources。
R & D and registration of natural drugs shall follow the registration classification and relevant requirements of Annex 1 of the "Registration Management Measures of Drug Registration"。
This technical requirements are explained around the characteristics of the natural drug itself，The specific content and design method of the research can refer to the relevant Chinese medicine、Principles of technical guidance principles of natural drugs or chemical drug research。
2. General principles
The development of natural drugs should meet the theory of modern pharmaceuticals，Pay attention to test research evidence，Reflecting clinical application value，Ensure that the safety, effectiveness and quality of the drug are uniform。
To ensure the sustainable use of resources and protect the ecological environment，Natural drugs should not be used as raw materials with wild animals and plants，If it is necessary to use non -key protection wild animals and plants as raw materials，Research data should be provided to prove that the production of the corresponding variety will not have adverse effects on the resources and ecological environment，If it can be used, it does not affect its growth、The medicinal parts of the breeding are raw materials, etc.。
Study on the chemical composition of natural drugs for systemic drugs，Determine the structure type and main ingredients of the large category ingredients，should be studied determined by active ingredients。
Pharmacology toxicology test、Samples for early clinical trials should be prepared after fixed process，If the sample of the test sample is not guaranteed to be the same as the sample of the production scale，Samples of production scale should be used for the above research。Phase III clinical trials shall use samples of production scale。The preparation of the test objects used in the pharmacological toxicology test should be provided in the application information、Quality inspection and storage related information。
Natural Drug Compound Preparation is a preparation of multiple extracts，Each extract should be the raw medicine for the listed unilateral preparation。The rationality of the group should be adopted by the main drug test or toxicology research，If necessary, it should be explained to the interaction between the prescription composition。
Natural drug new drug non -clinical safety research shall follow the quality management specifications of drug non -clinical research (GLP)，and undergo a non -clinical safety evaluation research institution certified by the State Food and Drug Administration。
Natural drugs should conduct exploration and research in the body process，Main active ingredients performed in the body absorption、distribution、metabolism and excretion research，Understand the basic characteristics of its pharmacokinetics。
Natural drugs should provide sufficient non -clinical effectiveness and safety research information，Perform mechanism research。The clinical effectiveness of natural drugs should be evaluated with modern medical methods and standards，Adaptive symptoms should be described by modern medical scientific terms。Natural drug clinical trials shall follow the quality management specifications of drug clinical trials (GCP)，and the institution that has passed the qualification certification of the national drug clinical trial institution。Clinical trial design and evaluation standards need to refer to the principles of technical guidance related technical guidance of chemical drugs。
The applicant can apply for clinical trials for clinical trials for clinical trials of natural drugs and provide clinical trials that support clinical trials，You can also apply for phased (III、Iss II、III) Clinical Test，and can provide non -clinical safety test materials and pharmaceutical information that supports corresponding clinical trials in stages。Pharmaceutical clinical trials are completed，You can apply for clinical trials of the next stage according to the application of supplementary applications。
3, Pharmacy Research
To ensure the stability of the quality of natural drugs after listing，The quality control of the production of natural drugs。It should be studied clearly that the active ingredients contained in natural drugs，Create standards that comprehensively reflect the quality of natural drugs。
(1) Raw material
& ldquo; raw materials Stake Sports Betting& stake betting apprdquo; refers to the starting raw materials used in the extract of the preparation of the preparation preparation。
1. The base of the plant -based raw materials should be clear、Medicinal parts、Place of origin、Harvest period、Contains a variety of bases。Contains a variety of bases，One of the bases should be used。
2. It should be explained that the method of ensuring the quality of the raw materials used in the guarantee。The medicinal part of the cultivated plant is used for medicine，Requirements should be referred to the relevant requirements of the Quality Management Specification (GAP) of Chinese medicinal materials，Explain methods and conditions to ensure stable quality of raw materials。Pharmaceuticals using wild animals and plants，Measures that should be used to ensure the sustainable resource，Provide drug production to medicinal materials、Evaluation Report for Ecological Environment and other influences。
3. Appraisal certificate of raw materials issued by a qualified unit shall be provided，and related research materials。
4. The quality standard of raw materials should be established。Quality control projects in quality standards should reflect the quality of raw materials，and reflect its characteristics。For might be doped、Poinized medicinal materials should be studied，and establish the corresponding quality control project in the quality standard。
5. The packaging material or container of raw materials should be clear、Storage conditions and storage period。
6. The raw materials are the medicinal parts or minerals of animals，You can refer to the relevant requirements of the above plant raw materials。The medicines of animal raw materials，Research on the activation of related pathogenic microorganisms。
(2) Extract
& ldquo in this technical requirements Stake Sports Betting& rdquo; refers to the raw medicine for direct supply preparations in the prescription of natural drug preparations。
1. It should be clearly clearing the pre -processing methods and conditions of the raw material for the extraction object。Research materials for the abroad and foreign -based harmful substances should be provided，Including heavy metals and other harmful elements、Pesticide、fungal toxin, etc.。
2. It should be studied and determined a reasonable preparation process。For the production process route with activity ingredients、Methods and parameters，Keep active ingredients as much as possible，Reduce impurities。Research clarify the method of production of the entire process of production，Determine production process that meets the requirements of large -scale production。
3. On the basis of in -depth and systematic chemical composition research，Establishing quality standards for natural drug extracts。Quality control items that should be established in addition to establishing activated ingredients，and stipulate that the reasonable content range，Multi -ingredient natural drug extraction material quantity standards should also be used to comprehensively reflect the information contained in the ingredients。
4. It should be studied to determine the packaging material or container of the extract、Storage conditions、Validity period, etc.。
5. The quality standards for the materials used in the production process (such as large holes adsorbing resin) should be established，Clear treatment methods and conditions, etc.; The working principle of the key equipment used should be clear、Key parameters, etc.。
(3) Preparation
1. The quality standard of the auxiliary materials used should be clear、Source、Quality condition; if you need to refine，The refined method should be clear、Conditions and standards。
2. Natural drug preparation should be cast with extraction。Measures and methods of ensuring the quality of the preparations between the batch and the batch should be clearly guaranteed。The physical and chemical nature of the activity ingredients should be、Features of in vitro release and pharmaceutical research data，Research on preparation prescription and molding process，Determine a reasonable type of accessories、Dosage and preparation molding process。Research clarify the method of production of the entire process of production，Determine production process that meets the requirements of large -scale production。
3. should be based on full research，Study the quality standard of the establishment of natural drug preparations。Testing items that reflect the quality of preparations should be established，Reflecting the stability of the quality of the preparation between different batches。Quality Control Projects that should be established in the quality standard，and stipulate that the reasonable content range，Multi -ingredient natural drug preparation quality standards should also be used to comprehensively reflect the information contained in the ingredients。The determination of the relevant requirements in the quality standard shall be based on the quality of the phase III clinical trial sample as the main basis。If necessary, you should also use biological methods that can reflect the quality of the preparation。
4. The packaging of determining the preparation should be studied、Storage conditions、Validity period, etc.。The quality standards and selection of the quality standards and selection of the packaging materials or containers of the drug，Study on compatibility of packaging materials and drugs if necessary。
5. The quality standards of the materials used in the production process should be clarified、Treatment methods and conditions, etc.; Clarify the working principle of the key equipment used、Key parameters, etc.。
(4) Pharmacy requirements for clinical trials in stages
Research on new drugs of natural drugs can be applied for clinical trials in stages according to the needs of exploratory research，and refer to the requirements of the following stages to complete the corresponding pharmaceutical research。One -time application for all clinical trials，Requirements for phase III clinical trials can be referred to。
1. Application for Phase I clinical trials: Bichams that should be fixed for raw materials、Place of origin、harvesting period, etc.，Fixed key parameters; provide the basis for the choice of dosage form; complete the test research; establish raw materials、Extract、Draft quality standard for preparations。If the toxic ingredients contain, the quality control method should be established。
2. Application for phase II clinical trial: The stake betting appStake Sports Bettingpreliminary entire process quality control system should be established，It can basically ensure that the quality of samples for different batches of clinical trials is uniform。Except for the needs of large -scale production, the molding process can be adjusted、In order to meet the needs of clinical trials, the specifications are studied outside，The rest of the process should be fixed。Raw materials should be established、Extract、Quality Standards for Preparation，and auxiliary materials、Materials used in the production process、Quality standards for the packaging materials of the drug directly contacting the drug; the preliminary stability inspection of the extract and the preparation of the preparation，Validity meets the needs of clinical trials。
3. Application for phase III clinical trial: The quality control system of the entire process should be established。Establish a relatively complete raw material quality control method; stable production technology of extracts and preparations，and meet the needs of large -scale production，Clear and detailed extract and preparations & ldquo; production process & rdquo; build a relatively complete quality standard system，Can use appropriate indicators and methods to comprehensively reflect raw materials、The quality of the extract and preparation。It should be guaranteed that the auxiliary materials used、Materials used in the production process、The quality stability of the packaging materials of the drug directly contact the drug; the validity period of the preparation meets the needs of clinical trials。
(5) Pharmaceutical requirements before listing
1. The complete process quality control system should be established，Basically guarantee the stability of the quality of different batches of drugs after listing。
It should be established to establish a sound raw material quality control method。Ensure the relative stability of the quality of raw materials and the sustainable use of resources。
The production process of extracts and preparations is mature、Stable，Related quality control method、Requirements and key equipment, etc.。Clear detailed extract and preparations & ldquo; production process & rdquo;。
The complete quality standard system should be established，In raw materials、Establishment of active ingredients in the quality standards of extracts and preparations，Use appropriate indicators and methods to comprehensively reflect the raw materials、The quality of the extract and preparation。It should be guaranteed that the auxiliary materials used、Materials used in the production process、The quality stability of the packaging materials of the drug directly contact the drug。
2. Clear raw material、Packaging materials for extracts and preparations、Storage conditions and validity period (storage period)。
3. Research and analysis of the quality comparative comparative comparative comparative comparative research and analysis of clinical trial samples and planned products，It can ensure that the quality of the medicine after listing is consistent with the samples for clinical trials。
4. Research on Pharmacology toxicology
Pharmacological and toxicology declaration materials of natural drugs new drugs include the main pharmacology、Toxicology、Pharmacokinetics research information。In addition，It also includes the screening of activity ingredients、Confirmation of pharmacological and toxic research materials supporting the basis of supporting questions。
(1) Non -clinical effectiveness research
Should pay attention to the screening of natural drug activity ingredients、Pharmacy research in the confirmation stage，Provide support basis for natural drugs。
Dose exploration of non -clinical effectiveness research on natural drugs。The dosage used by the test of the test objects should be determined on the basis of the pre -test。Key indicators for the main drug test，Study on the relationship of quantitative effects。When necessary，A comparative study of quantitative effects with positive control drugs。
Study on the mechanism and characteristics of natural drugs should be carried out，Provide necessary information for the reasonable design of clinical trials。
(2) Non -clinical safety research
Projects and content for non -clinical safety evaluation shall meet the requirements of the principles of relevant safety research technical guidance。
The non -clinical safety evaluation of natural drugs mainly includes acute toxicity、Long -term toxicity、Safety Pharmaceutical、Reproductive toxicity、Genetic toxicity test，Test research such as carcinogenicity is needed if necessary;、Preparation Features, etc.，The corresponding preparation safety test may be performed (allergic test、Hemo -dissolving test、Local irritating test)、Dependence Test, etc.。
Natural drugs made of single effective ingredients，It should provide a full set of toxicology research materials，And accompanied by poisonous dynamics research in the poisonous science test。Natural drugs made of multi -ingredients made of ingredients with relatively clear ingredients，Encourage the research on poisonous dynamics exploration。When necessary，Natural drugs should also conduct exploration research on toxic mechanisms。
Under normal circumstances，Safety Pharmaceutical、Acute toxicity、Long -term toxic and genetic toxic test materials or literature materials shall be provided when applying for clinical trials。Two kinds of mammals (one of them are non -rodent) should be used before clinical trials for long -term toxic test。Reproductive toxicity test data can be provided in clinical or when applying for clinical trials in clinical trials.。
Determination of animal administration time limit in the toxicology test shall consider the indication of the proposed application、The proposed clinical treatment and the actual medication after listing (such as long -term or repeated medication)。Under normal circumstances，The way to administer the administration should be consistent with the clinical administration pathway。If it is a special way to give it，You can also consider using other ways of administration that can be more fully toxic。
(3) Research on non -clinical pharmacokinetics
Natural drugs made of effective ingredients should be conducted in non -clinical pharmacokinetics research。For reference "Principles of the Technical Guidance Principles of Drug Non -clinical Pharmacodynamics Research"。At the same time，Some pharmacokinetic characteristics of natural drugs are different from chemical drugs，Appropriate evaluation of natural drugs in the process of natural drugs shall be fully combined with the characteristics of the Stake Sports Bettingdrug，Tracking research Stake Sports Bettingon active metabolic products。Encourage the evaluation and research on the early body process in the development of natural drugs，Provide reference data for the determination of the administration and subsequent research and development。
Multi -ingredients natural medicine，Based on the degree of exposure to the ingredients contained in the body as much as possible，Encourage the selection of the main active ingredients that can reflect the main efficacy for non -clinical pharmacokinetic exploration research。
When conducting non -clinical pharmacokinetics research，The exposure of the body of the main active ingredients of natural drugs should be examined at different dosage doses，Research dose and exposure correlation，To explain the results of the test of pharmacology and toxicology。The preferred animal of non -clinical pharmacokinetic research should be consistent with the animals used in the animals used by the drug and/or toxic science test，and test as much as possible in a sober state，It is best。Under normal circumstances，Test animals should be half of each of the male and female，If there is a significant gender difference if it is found that the dynamic characteristics are obvious，The number of animals should be increased to identify gender differences。
If the clinical trial involves the test content of natural drugs intended to be combined with other drugs，Study on the interaction of the available drugs that are intended to be used for combined medicine，Including the interaction that may exist between drugs through in vitro and in vivo drug metabolism。
(4) Compound preparation
Natural drug compound preparations except the above non -clinical effectiveness、Safety research and other contents, in addition to research，It should also be paid attention to the component rationality research at the project stage，Provide sufficient test data，The reasonableness of supporting its compound questions。
Under normal circumstances，Natural drug compound preparations should be clearly defined in the pharmacological role of the extraction of each extraction of each extraction，Explain its efficacy function in this compound preparation。Study on compatibility validity should be carried out，Prove the scientific nature of the compatibility、Reasonableness;，Prove the best ratio of compatibility。Compatibility of natural drug compound preparations，The target should be based on exploring and determining its drug characteristics and clinical advantages，For the purpose of its group (such as increasing efficiency、drug reduction, etc.)，Combined with the application to apply for indications，Select the right main medicinal model for research。When necessary，It also needs to provide the research basis for the pharmacokinetics that support its prescription composition。Select the right main medicinal model for research，Long -term toxic test information compared with the extract of toxic ingredients，Possible mechanism to explore drug reduction，or choose other suitable toxic tests for comparison research，Provide support basis for its prescribedness。
(5) Application of non -clinical safety requirements for clinical trials at different stages
To reduce R & D risk，Applicants can apply for clinical trials at different stages。Variety of early clinical trials for applications，It has different requirements for its non -clinical safety evaluation data。
The dating period for long -term toxicity tests is usually and the deadline for clinical trials to be applied for、Clinical indications related。Applying for the long -term toxic test period required for different clinical stages is different，For the specific period, please refer to "Principles of Drug Repeated Research Technology Guidance Principles"。Natural drugs that need to be performed for genetic toxicity test，Generally, the genetic toxicity test of the standard combination should be completed before clinical trials。If the standard combination test occurs suspicious or positive test results，Other related tests should be taken in addition to additional，and determine the content required for the test and the time to complete according to the specific situation。
Natural drugs that need to be performed by reproductive toxicity test，Natural medicines made of effective ingredients，Generally, fertility and early embryo development toxicity tests should be completed before clinical trials (section Ⅰ reproductive toxicity test)、Embryo-fetal naphthain development toxicity test (segment reproductive toxicity test) and perinatal toxicity test (Section III reproductive toxicity test)。According to the specific situation，Section Ⅱ reproductive toxicity tests of the second animal and the III reproductive toxicity test can also be considered before the clinical stage or listing application。Natural drugs used for certain special indications，If the clinical trials are clearly not used for people for childcare、Special groups such as pregnancy or lactation，According to the specific situation，Reproductive toxicity tests can also be completed during clinical trials or before listing.。
In addition，Natural drugs below should also be considered for reproductive toxicity tests，For the fertility regulatory drugs used for people for childbearing age (such as contraceptive pills、Sperm -promoting sperm -generated medicine and therapeutic dysfunctional drugs, etc.)、Tire -keeping medicine、Drugs that may affect the reproductive system (such as sex hormone or drugs with hormone -like activity)、Genetic toxic -based drugs and cytotoxic drugs、Drugs that have obvious effects on reproductive systems in the long poison test，The corresponding reproductive toxicity test information should be provided according to the specific situation，Such natural drugs should complete the corresponding reproductive toxicity test before applying for clinical trials。
Natural drugs that require carcinogenic tests can generally be completed during clinical trials or before listing。Whether natural drugs should conduct carcinogenic tests and the time arrangement of carcinogenic tests，You can refer to "Technical Guidance Principles of the Necessity of Drug Carcanogy Test"。
V. Clinical Studies
(1) General requirements
1. Doctors and other related personnel who stake sports betting appconduct clinical trials of natural drugs should stake online sports bettingreceive clinical research training，With corresponding qualifications and abilities。
2. The clinical trial of natural drugs should be scientifically and reasonably designed，Should follow random、The design principles of blind method and control。Under the premise of ethical principles，Plazons should be adopted; when the comfort agent control design does not meet the ethical principles，You can use a positive medicine control with exact treatment effect。For placebo control，Researchers can have multiple design methods，If you use & ldquo; load (add-on) & rdquo; design、Dose-Effect Design, etc.，When necessary，It is recommended to add a positive control (such as a three -arm test) at the same time as the placebo control (such as the three -arm test)。
3. Effective evaluation of clinical trials of natural drugs，Including the subject of the subject、Main efficacy indicators and secondary efficacy indicators、Drug plan、Evaluation standards and methods, etc.，It is necessary to refer to the technical guidance principles of the clinical trial of chemical drugs。
4. The clinical trial of natural drugs should pay special attention to safety evaluation，Safety index design should be as perfect as possible、Reasonable，For the adverse reactions of known，Including literature、Clinical application experience and security reminder in the research of toxicology，All should be reflected in the clinical trial design。For chronic diseases or the need for long -term repeated medication，We should continue to observe after the validity test is over，Safety data for long -term medication。
5. The clinical trials of natural drugs must take appropriate measures to protect the subject，The characteristics of the test drugs should be clearly explained in the consent of informed consent。
(2) Clinical trial installment and requirements
Natural drug new drugs should be carried out before listing Ⅰ、Ⅱ、Phase III clinical trial。
Phase I clinical trial: Preliminary clinical pharmacology and human safety evaluation test。Observe the degree of tolerance of the human body and pharmacokinetics for new drugs，Provide a basis for formulating a dosing plan。Based on the research of animal agency research，Perform human pharmacokinetics test，The results they have obtained are the basis for the formulation of subsequent clinical trials。Tolerance test aims to observe the reaction and dose tolerance relationship of natural drugs for the first time in human test。
Phase II clinical trial: Preliminary evaluation phase of therapeutic effect。Its purpose is to preliminary evaluation of the treatment and safety of drugs for patients with target adaptive patients。The research design at this stage should be based on specific research purposes，Design multiple clinical trials，Use a reasonable design method to study。Study of dose effects in Phase II clinical trials，and the applicable population、Drug plan、treatment、Drug interactions, etc. Exploration research，Plan design for phase III clinical trials and the determination of dose schemes provides a basis for，Provide information for accurate writing instructions。
Phase III clinical trial: The treatment effect is confirmed。The purpose is to further verify the treatment and safety of drugs for patients with target adaptive patients，Evaluation benefit and risk relationship，Finally provides a sufficient basis for the review of drug registration applications。Natural Drug Phase III clinical trial should be a random control test with sufficient sample amount。Generally, two confirmed test data should be adopted to illustrate its effectiveness。Drugs used for long -term treatment of life diseases (such as continuous treatment for 6 months or more，or the cumulative time of intermittent treatment is more than 6 months)，It needs to provide long -term safety data，300 to 600 subjects who exposed 6 months and 100 cases of the subject who exposed at least one year。The exposure test of the extension of the drug can start with the phase III clinical trial。
