Technical requirements for Phase I clinical trial application

（1） Data format and content

The application materials for Phase I clinical trial application shall be submitted in the form of paper materials and electronic materials, and the electronic materials can be submitted in the form of CD. The format and content can be sorted and submitted according to the requirements of the General Technical Document (CTD) of the International Coordinating Committee (ICH) on Technical Requirements for Registration of Human Drugs.

（2） INTRODUCTION AND OVERALL STUDY PLAN

The introduction shall include the name of the new drug, all active ingredients, pharmacological action categories, structural formula (if known), dosage form, formulation, route of administration, clinical trial purpose, etc. If there is experience in clinical use of the investigational drug, a brief overview should be provided, including experience in research and marketing in other countries; If not, write "None" under the title.

The overall research plan shall summarize the design basis for applying for clinical trial scheme, mainly including the proposed indications, subject population, number of subjects, administration scheme (dose, administration interval, administration duration, etc.), drug safety evaluation methods, risk control plan, etc., and risk demonstration of any safety (important identified risks, important potential risks, important missing data, etc.) expected based on existing information.

（3） Investigator's Handbook

The Investigator's Manual is a summary of the existing pharmaceutical, non clinical and clinical studies (if any) of the investigational drug during human research, aiming to provide the clinical researchers with information about the investigational drug to ensure the safety of the subject.

When there is new important information, the applicant shall timely update the investigator's manual to include a summary of all important research information of the study drug. The updated investigator manual shall be submitted to the Drug Approval Center in a timely manner. The format and content of the researcher's manual can refer to the relevant chapters of ICH E6.

The investigator's manual shall include the following contents:

1. Cover page: including the name of the drug, the name of the registration applicant, the date of completion or update and the version number;

2. Contents: list all the first level titles, second level titles and corresponding page numbers;

3. Confidentiality statement;

4. Overview: introduce the types of drugs, formulate the indications and pharmacological characteristics;

5. Name and physical and chemical properties of new drug: briefly describe the name, chemical name (if any), molecular weight, molecular formula, structural formula (if any), physical and chemical properties, dosage form, temporary validity period, storage conditions, and precautions for use based on existing stability data of the drug;

6. Results of non clinical studies

6.1 Pharmacological effect: it shall include the results of the completed non clinical trials used to indicate the efficacy.

6.2 Toxicological study: safety pharmacology test, single dose toxicity test, repeated dose toxicity test, genetic toxicity test, reproductive toxicity test, carcinogenic test and other toxicity tests are itemized. If some studies have not been carried out or do not need to be carried out, reasons and basis shall be stated.

6.3 Non clinical pharmacokinetic study: it shall include the absorption, distribution, metabolism and excretion (ADME) of drugs. If some studies have not been carried out or do not need to be carried out, reasons and basis shall be stated.

7. Existing clinical research or use data (if any): should include all existing clinical trial information and literature data at home or abroad.

7.1 Pharmacokinetics of human body

7.2 Effectiveness

7.3 Safety

7.4 Listing

8. Others

If there is no information on the use of new drugs, the applicant should provide information that the applicant considers relevant based on the summary of existing non clinical and clinical research results: may include special population, safety information, warnings and precautions, risk control plan, drug interaction, drug overdose, etc.

9. References

Clinical trial protocol

The clinical trial protocol shall include the following information:

1. Research background, briefly describe the indications of the drug, and briefly describe the existing clinical effectiveness and safety data of the drug (if any);

2. Test purpose;

3. Estimated number of subjects to participate;

4. Description of inclusion criteria and exclusion criteria;

5. Description of the administration plan, including duration, starting dose, dose increasing scheme and termination conditions, administration scheme, and description of the basis and method for determining the first dose;

6. Test indicators, detailed information of relevant tests that are critical to the safety evaluation of the subject, such as vital signs of the subject and necessary blood biochemical monitoring;

7. Toxicity judgment principle and test suspension standard for study suspension.

Pharmaceutical Research Information

With the development of drug research, the pharmaceutical research of new drugs has different research purposes in different research stages. For the pharmaceutical research data of the new drug application for Phase I clinical study, the laws of drug development should be followed, and the focus should be on the pharmaceutical research information related to the safety of the subjects in the planned study (such as the analysis of impurity mass spectrometry based on the existing knowledge, the methodological verification of the specificity and sensitivity of related substances, the analysis and control of potential genotoxic impurities, the immunogenicity and immunotoxicity of new biological drugs, etc.).

According to the information provided by the pharmacy department, when there are concerns about safety issues or the data is insufficient for safety evaluation, the clinical trial should be postponed. Reasons for concern may include but are not limited to the following:

(1) The chemical structure of the new drug or the excipients of the preparation have known toxicity or are highly likely to have toxicity;

(2) During the whole phase I clinical trial project planned to be implemented, the new drug cannot maintain stability;

(3) The impurity characteristics of the new drug indicate potential toxicity, or the impurities in the new drug with content above the identification limit are not fully identified and their potential toxicity is not evaluated;

(4) There are biosafety problems of animal derived ingredients;

(5) The main cell bank or working cell bank has not been fully identified.

The applicant shall analyze whether the existing pharmaceutical research information shows potential human risk, discuss these potential risks, and elaborate the measures planned to control or monitor the risk.

For new drugs with biological toxicity, radionuclides, etc., or involving biological safety risks, relevant research data, research plans and risk control measures shall be provided in accordance with the relevant international technical guidelines.

1. Pharmaceutical research information of chemicals

The applicant for new drugs shall analyze and compare the samples for animal research and the samples for human test (can be described in a list). If there are differences, it is necessary to discuss the possible impact of the differences on clinical safety, so as to provide safety support for the subsequent human test.

For chemicals applying for Phase I clinical study, the following pharmaceutical research data shall be provided. At the same time, the summary form of pharmaceutical research information applied for Phase I clinical trial of chemicals shall be summarized and provided according to the attached form and submitted electronically.

1.1 API information

1.1.1 Manufacturer

The complete address of the API manufacturer (including production and inspection) shall be submitted.

1.1.2 Preparation process

The data of API preparation process shall be provided, including the reaction flow chart, indicating the reagents, solvents and catalysts used in the process. For fermentation process, extraction process preparation, polypeptide and small molecule nucleic acid drugs, more information on preparation process is required. Sterilization/sterilization process and sterility assurance measures shall be provided for sterile APIs.

1.1.3 Structure confirmation

The method, atlas and brief structure analysis summary used for structure confirmation shall be provided.

1.1.4 Physical and chemical properties

The crystal form, solubility, permeability, particle size and other key physical and chemical properties of the drug substance that may be related to the performance of the preparation should be listed.

If possible, list the specific solubility data in different media (such as different pH).

1.1.5 Quality control

Preliminary quality standards shall be provided, indicating inspection items, acceptable limits, analysis methods, and representative maps. At the initial stage of drug development, it is not necessary to submit comprehensive and complete validation data of analytical methods, but at least key validation information such as specificity and sensitivity of methods should be provided.

Sample inspection report shall be provided. Provide batch analysis data of key research batches (such as those used for safety studies, stability studies, clinical studies, etc.).

Preliminary impurity spectrum analysis results, potential genotoxic impurity control strategies and analysis information shall be provided. Refer to ICH M7 guidelines to study and submit reports.

1.1.6 Stability

The stability study data of API shall be provided, the analysis method adopted shall be listed, the preliminary data of representative samples and other supporting stability study data can be submitted in tabular form, and the representative atlas of key items shall be provided. The stability data should support that the physicochemical parameters of the new drug meet the requirements during the planned clinical study. If the planned test cycle is extremely short, limited supportive stability data can be provided. On the basis of ensuring the stability of the drug during the clinical trial, gradually accumulate stability data to support further clinical development.

1.1.7 Packaging and storage

Direct contact packaging materials and storage conditions shall be listed.

1.2 Preparation information

1.2.1 Dosage form and product composition

The prescription composition and dosage of the preparation shall be described in a list, and the components used in the preparation process but finally removed shall also be listed. The excipients in the preparation shall meet the pharmaceutical requirements; For new excipients that have not been used in domestic and foreign preparations, related declaration shall be made.

1.2.2 Name and address of manufacturer

The complete address of the manufacturer (including production, packaging and inspection) of the preparation for clinical trial shall be submitted.

1.2.3 Production process and process control

Production process information, including process flow diagram, shall be provided. Sterilization process and sterility assurance measures shall be provided for sterile preparations; More detailed process description shall be provided for unconventional process preparation.

1.2.4 Quality control

Preliminary quality standards shall be provided. Explain the acceptable limit, analysis method and representative map of the inspection items. The impurity reporting method can refer to ICH Q3A and Q3B. Appropriate quality control items and analysis methods shall be set according to the dosage form and product characteristics. The test items that are intended to accumulate data but not used as conditions for release of preparations shall be indicated.

At the initial stage of drug development, it is not necessary to submit comprehensive and complete validation data of analytical methods, but at least the validation information of key items such as specificity and sensitivity of methods should be provided.

Provide inspection reports of key research batches (such as those used for safety research, stability research, clinical research, etc.). The preliminary research results of the degradation pathway and degradation products of the preparation shall be provided. Refer to ICH Q3B.

1.2.5 Stability

The preparation stability research data shall be provided, the analysis method adopted shall be listed, the preliminary data of representative samples (such as animal pharmacological toxicology research samples, samples proposed for clinical trials) and other supporting stability research data shall be submitted in tabular form, and the representative atlas of key items shall be provided. The stability data should support that the physicochemical parameters of the preparation meet the requirements during the planned clinical study. If the planned test cycle is extremely short, limited supportive stability data can be provided.

1.2.6 Packaging and storage conditions

The information and storage conditions directly contacting the packaging materials shall be listed.

For drug packaging materials with new materials, new structures and new uses, information shall be provided and related declaration shall be made as required.

1.2.7 Others

Relevant stability test results shall be provided for the preparations that need to be used in clinical compatibility and have special requirements for use.

1.3 Placebo information

If a placebo is required in the clinical trial plan, the prescription, production process, relevant information of the manufacturer, quality control, inspection results and other research data of the placebo shall be provided.

2. Pharmaceutical research information of biological products

Provide summary data of pharmaceutical research results, and explain the quality control items in the proposed quality standard that are lower than the basic requirements of the Pharmacopoeia or the requirements of the general technical guidelines; Focus on the difficult problems found in pharmaceutical research that need special attention in the review.

2.1 Raw materials for production

2.1.1

The name, source, quality standard, safety and other information of the starting materials for production shall be provided. The starting materials for production shall comply with the relevant requirements of the current version of the Pharmacopoeia of the People's Republic of China or the third part of the Pharmacopoeia of the People's Republic of China "Quality Control Procedures for Raw Materials and Excipients for Biological Products Production". According to the risk level, the corresponding supporting documents and/or quality control test reports shall be provided.

2.1.2 Establishment and identification of engineering cells (bacteria)

For the protein expressed by gene recombination technology, the amino acid sequence shall be provided. If the target gene is modified or mutated, the applicant can make a preliminary description based on the impact on the product structure and function. Provide the name, source, structure and genetic characteristics of the expression vector, and determine the structure of the recombinant expression vector. Provide the name, source, safety, culture characteristics, biological characteristics (genotype and phenotype), generation history (including domestication process), verification results, etc. of host cells (bacteria) and engineered cells (bacteria) constructed, and indicate whether gene manipulation has been performed to introduce foreign gene sequences.

2.1.3 Establishment, verification, preservation and generation stability of seed bank

Research data on the establishment, verification, preservation and stability of seed bank shall be provided.

The seed bank shall be verified according to the Chinese Pharmacopoeia, European Pharmacopoeia, American Pharmacopoeia and other international general pharmacopoeias, the relevant requirements of international general use or other international general standards, and the verification report of the seed bank shall be provided to ensure that there is no risk of internal and external source factor pollution. The seed bank established shall be able to support subsequent research and development.

2.1.4 Sources and quality standards of other raw materials for production

The name, source, quality standard, use steps, etc. of other raw materials used in production shall be listed in table form according to the process flow. Other raw materials for production shall also comply with the relevant requirements of the current version of the Pharmacopoeia of the People's Republic of China or the third part of the Pharmacopoeia of the People's Republic of China "Quality Control Procedures for Raw Materials and Excipients for Biological Products Production", be graded according to the risk level, and provide the corresponding certification documents and/or quality control test reports.

2.2 Stock solution

2.2.1 Manufacturer

The complete address of the original solution manufacturer (including production and inspection) shall be provided.

2.2.2 Raw solution preparation process and process control

Flow chart shall be provided according to process steps, indicating process parameters, production scale, important production equipment, and technical conditions and parameters of key process steps. For purification process, coupling process and other special treatment steps, the technical conditions and parameters adopted shall be specified; Verify the key process steps of virus inactivation/removal. Research data on optimization of key process parameters shall be provided.

2.2.3 Summary of development of stock solution preparation process

The batch size, production time, production location of each batch of stock solution in process development, as well as the corresponding production process, production scale and sample use (such as quality study, pharmacological and toxicological study, process stability, stability study, reference substance/reference substance, etc.) shall be listed, and the verification results shall be provided. Conduct quality comparability analysis on animal pharmacological and toxicological research samples and samples to be used in Phase I clinical trials, so as to provide safety support for subsequent human trials.

2.3 Preparations

2.3.1 Manufacturer

The name and address of the manufacturer of the sample preparation for clinical trial shall be provided.

2.3.2 Dosage form and formulation

The specific dosage form shall be described, and the prescription composition of the unit dose product shall be listed, the role of each ingredient in the prescription and the standards to be implemented shall be described. If there is excessive addition, it shall be explained. If special solvent is attached, the prescription of special solvent shall be listed according to the above table. For new excipients that have not been used in domestic and foreign preparations, related declaration shall be made