Key points and Judgment principles for Drug Registration verification

(Pharmacological and toxicological research)

(Trial)

To ensure the quality of drug registration verification, unify the scope of verification and judgment standards, in accordance with the "Drug Administration Law of the People's Republic of China", the "Measures for the Administration of Drug Registration" and other laws, regulations and relevant guiding principles, the "Key Points and Judgment Principles of Drug Registration Verification (Pharmacological and Toxicological Research) (Trial)" is specially formulated.

I. Purpose

The main purpose of on-site verification for pharmacological and toxicological research is to verify the data reliability of the original materials of pharmacological and toxicological research and/or conduct on-site confirmation, to check the compliance of pharmacological and toxicological research, and to verify the authenticity and consistency of the relevant declared materials.

Ii. Scope

(1) It is applicable to the on-site verification of pharmacological and toxicological research in the on-site verification of drug registration and development initiated by the Center for Drug Evaluation of the National Medical Products Administration and organized and implemented by the Center for Food and Drug Control of the National Medical Products Administration.

(2) On-site verification of pharmacological and toxicological research mainly involves checking the research situation of pharmacological and toxicological studies, including research conditions, implementation of protocols, data recording, and result reporting, etc. Based on the registration requirements and the principle of risk, only part of the contents of some pharmacological and toxicological test items can be verified.

Iii. Key Points of On-site Verification

(1) Research institutions and personnel

The name of the research institution, the address of the research site and the research content carried out should be consistent with the application materials. In multi-site research, all the institutions involved in the research and their responsibilities should be fully and accurately reflected in the application materials.

2. Institutions conducting non-clinical safety evaluation research on drugs should have obtained the Good Clinical Practice (GLP) certification from the national Medical Products regulatory department, and the research content should fall within the scope of the trial projects that have passed the GLP certification of the institution.

3. When the research involves radioactive and biohazardous substances, it should comply with relevant national regulations and provide corresponding supporting documents.

4. For commissioned research, there should be proof materials of the commission.

5. Establish standard operating procedures (Sops) or other test operation documents that are commensurate with the research;

6. Participants in the research should possess the professional knowledge and qualifications, work experience and training experience required for the research, and the files of the main researchers should be fully retained. The personnel involved in the research should be consistent with the declared materials.

(II) Facilities

1. Facilities necessary for conducting research should be available, with a reasonable layout and normal operation.

2. For research involving experimental animals, there should be animal facilities that meet the research requirements and corresponding licenses for the use of experimental animals. Records of environmental control data of animal facilities and handling of abnormal situations during the research period should be completely preserved.

3. The storage and preservation conditions of the test substances/reference substances, their prepared preparations, biological samples, research archives and specimens, etc., should comply with the requirements of the test protocol, the institution's SOP or other test operation documents. The corresponding environmental control data and records of handling abnormal situations during the research period should be completely preserved.

(3) Instruments and Equipment

The necessary instruments and equipment for the research should be available and their performance should meet the research requirements.

2. Records of the use, cleaning, maintenance, testing, calibration, confirmation or verification, repair, handling of abnormal situations, and scrapping of the instruments and equipment used during the research period should be completely retained. The time and content of the usage records of the instruments and equipment should be consistent with the research.

3. Computerized systems (or equipment and instruments containing computer systems) used for researching data collection, transmission, storage, processing, archiving, etc. shall be verified, and the corresponding verification plans, records and reports shall be retained; After the hardware or software of the system is replaced, or the system is upgraded and patches are installed, a system assessment should be conducted and relevant assessment reports should be retained. If the assessment results need to be verified, the corresponding verification plans, records and reports should be retained.

4. Computerized systems with inspection trajectory functions should enable the inspection trajectory function. The electronic data generated should retain complete inspection trajectories and electronic signatures to ensure the authenticity and traceability of the electronic data. The operation permission Settings of the computerized system are reasonable.

5. Research data generated by computerized systems should be backed up in a timely manner and properly preserved to ensure data integrity and traceability.

(4) Test substance/reference substance

The receipt, storage, distribution, use, sample retention, return or disposal of the test substance/reference substance should have complete records and the quantities should match.

2. The storage conditions of the test substance/reference substance should comply with the requirements of the test protocol or relevant supporting documents (such as user manuals, quality inspection reports, etc.). The monitoring records of the storage conditions of the test substances/reference substances and their preparations during the study period, as well as the handling records of abnormal situations, should be completely retained.

3. Complete records should be kept for the preparation of the test substance/reference substance, its storage after preparation, usage, and the handling of the remaining substances after use. The amount taken each time should be consistent with the record of the test substance being taken. The preparation amount, the usage amount, and the remaining disposal amount after use should conform to the material balance.

4. Records of the preparation, storage, use, return or disposal of toxic and narcotic drugs, mold-making reagents (drugs), etc. required for the research should be completely retained.

(V) Experimental System

Experimental animals serve as the experimental system

(1) The source of the experimental animals required for the research should be clear and compliant. Suppliers of experimental animals should have the corresponding qualification certificates; The certificates of conformity of experimental animals and other relevant supporting documents should be completely retained.

(2) Information such as the species, strain, quantity, age, gender, weight range and grade of the experimental animals should be consistent with the declared materials.

(3) Experimental animals should have appropriate individual identifiers to ensure the traceability of individual animals during the research period.

(4) Complete records should be kept for the reception, quarantine, use and handling of experimental animals, with the quantities matching and consistent with the declared materials.

(5) The names, sources, batch numbers (if applicable), expiration dates and main control indicators of experimental animal feed, bedding and drinking water, etc., should be consistent with the declared materials and the test results in the original records.

2. Other experimental systems except for laboratory animals

(1) The source of the experimental system required for the research institute should be clear and compliant. Relevant supporting documents such as the purchase (transfer) and quality appraisal of the experimental system should be completely preserved. The applicability assessment materials should be completely retained.

(2) Complete records should be kept for the preservation, access, and passaging of the experimental system, and the time, quantity, and other information recorded should be consistent with the application materials.

(VI) Biological samples

All relevant records of biological sample collection, identification, transportation, storage, handover, processing, analysis and testing should be completely preserved and be traceable.

(VII) Original Records

Verify the consistency of the application materials with the test plan, original data and summary report;

2. All original records should be true, timely, accurate, complete and traceable, and the results should be consistent with the declared materials. Record modifications must not overwrite the original data traces and should be marked with the modifier, modification date and modification reason.

3. Data retesting should follow the data retesting SOP or the corresponding test operation documents, record the reasons for retesting, retain the results of each measurement, and provide the reasons for including the selected results in the test report.

4. In accordance with the requirements of the verification task, conduct on-site spot checks on the original data of various types of experiments to verify their consistency with the declared materials. The types of on-site spot check data generally include but are not limited to:

(1) All traceable records of the experimental system, including reception, grouping, dosing, testing and disposal, should be completely preserved and ensured to be consistent with the declared materials. For example:

The animal weight records are complete.

The records of the animals' food intake and water intake are complete.

The records of animal observation and administration, as well as the detection records of physiological and biochemical indicators, are complete.

The records of animal anesthesia, execution and dissection are complete.

Complete records of resuscitation, passage, culture, sample addition and drug administration of non-animal experimental systems such as cells, etc.

(2) Complete and traceable records of the acceptance, preparation, analysis (such as homogeneity, concentration, stability, etc.), use, and return of the test substances and reference substances should be kept, and they should be consistent with the declared materials. For example:

The stability, batch number, purity content, specification, quantity, physical and chemical characteristics, storage conditions, and validity period of the test substance and the reference substance are all recorded completely.

The preparation records, distribution and return records, etc. are complete;

(3) Records of the collection (time, etc.), identification, processing, transportation, handover, testing and preservation of traceable biological samples (blood, urine, tissues, etc.) should be completely preserved and consistent with the declared materials. For example:

The handover records of biological samples and the transportation temperature records are complete.

The relevant records for the establishment and confirmation of analytical methods for the test substances and reference substances in solvent and blood samples are complete.

Spot-check the biological sample analysis data of drug (drug) pharmacokinetics, including whether the paper spectra submitted in the application materials are consistent with the original spectra and whether the analysis data submitted in the application materials are consistent with the original analysis data.

The relevant records of pathological examination are complete (such as: anatomy, tissue collection, pathological slide preparation and reading records, etc.);

5. Deviations from the test protocol, SOP or other test operation documents should be recorded, evaluated in a timely manner and truthfully reflected in the summary report.

(VIII) Others

During the on-site verification period, the applicant and the verified research institution should ensure that the original research materials are kept intact and can be provided and accepted for verification in a timely manner, including the original of the trial protocol, original data, specimens, relevant test reports, retained samples of test substances and reference substances, the original of the summary report, and various documents related to the research.

During the on-site verification period, the applicant and the verified research institution should actively cooperate with the verification work and must not obstruct or interfere with the on-site verification work.

Iv. Principles for Determining Verification Results

(1) Verify and on-site confirm the original records and data during the research process. If any of the following situations are found after verification and confirmation, the verification shall determine it as "not passed" :

1. Fabricating or modifying the information of the experimental system, as well as the test data, test records, information of the test substances and reference substances without reasonable explanation;

2. Using false test substances or reference substances;

3. Concealing test data, discarding test data without reasonable explanation, or selectively using test data in other ways in violation of the test protocol;

4. Intentionally damaging or concealing test data or data storage media;

5. Key research activities and data cannot be traced.

6. The application materials are inconsistent with the original records and affect the evaluation of the results;

7. Other serious data reliability issues;

8. Refusing or not cooperating with the verification, resulting in the inability to proceed with the on-site verification.

9. Other circumstances where approval is not allowed as stipulated by laws and regulations.

(2) Verify and on-site confirm the original records and data during the research process. If no problems are found or the problems found do not constitute the above-mentioned non-pass circumstances, the verification and determination will be "passed". Among them, the problems discovered that may have an impact on data quality and reliability need to be given key attention during the review.

药品注册核查要点与判定原则（药理毒理学研究）（试行）.pdf

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