Question 1: Issues related to special safety tests

Special safety test, or "irritation, allergy, hemolytic test", "preparation safety test" or "No. 21 data"; involving a variety of dosage forms, such as injections, patches, sprays, inhalants, drops Eye drops, ointments, etc. The following common issues only apply to chemical drugs.

1, irritation test

①Route of administration: only the proposed clinical route can be used

②The number of doses: should include single and multiple doses

③Dosing volume for vascular irritation test: Whether using intravenous drip or bolus injection, the volume should not be too small. It is common to convert the amount of drug used in the human body based on the equivalent dose, and the resulting dose volume may be too small to reflect the actual situation of clinical drug use. At this time, attention should be paid to the local exposure volume of vascular administration, not just the dose.

④Drug concentration: If a drug includes multiple strengths (concentrations), at least the highest concentration planned for clinical use should be used for testing;

If the formulation is different, it should be done under normal circumstances.

⑤Skin irritation test: Generally, it should include intact skin and broken skin.

2, allergy test

Chemical drug injection, usually only active systemic allergy test is performed.

Certain antibiotics, macromolecules or injections containing special excipients, depending on the specific circumstances, consider whether to add other allergy tests.

3. Is it necessary to set up original research/marketed reference products for imitation products?

If a result that is significantly different from the original research/marketed product is found, it is necessary to set up a comparison between the original research/marketed product to analyze the cause of the resulting product.

4, GLP requirements

For situations where only special safety tests are required, the country has no regulations requiring tests in GLP laboratories. However, judging from the actual situation of the current review, some tests conducted under non-GLP conditions cannot guarantee the quality of the test, and supplementary information is often caused because of this. It is recommended to conduct the test in the certified GLP test.

5. Requirements for imported products

For imported products, if standardized animal specific safety tests and/or standardized clinical trials have been conducted to study the local safety of imported products when they are marketed overseas, the above-mentioned animal data or clinical data can be provided as a substitute.

6. Which products do not require special safety tests?

Water for injection, glucose injection, sodium chloride injection, glucose sodium chloride injection, mannitol injection do not need to provide special safety test data.

Question 2: Are biological products necessarily conducted in GLP trials?

According to national regulations, all safety tests of biological products need to be carried out in GLP laboratories.

Question 3: Requirements for submitting relevant supporting documents for non-clinical trials completed overseas

At present, there is an increasing number of cases in which pharmacological and toxicological research data conducted abroad support domestic applicants for drug registration and application. The following consensus has been reached after the meeting between the Drug Registration Department of the National Administration of China and the Center for Drug Evaluation:

Using pharmacological and toxicological research materials that have been completed overseas to support the chemical drug application of domestic applicants, it should:

1. Provide evidence of the consistency of the material basis between the test substance used for overseas research and the domestic application.

2. Provide certification materials of overseas research institutions, such as institution licenses, business scope, etc.

3. Safety research should be carried out in a research institution that complies with GLP specifications, and a GLP Compliance Statement must be provided, as well as the recent GLP inspection records and conclusions of the institution by overseas regulatory authorities.

The above-mentioned supporting documents such as 2 and 3 need to be notarized.

The above requirements do not apply to imported products/international multi-center clinical trial products, but the applicant may be required to provide relevant information based on the needs of the review.

Question 4: Carcinogenicity test

According to the relevant provisions of the "Administrative Measures for Drug Registration", carcinogenicity trials or literature should be provided for drugs that are clinically expected to be used continuously for more than 6 months (including 6 months) or that require frequent intermittent use for the treatment of chronic recurrent diseases. According to the general rules of new drug development, the applicant can complete the animal carcinogenicity test during the clinical research period and provide the information when submitting the marketing application.

Special Note:

1. For products that meet the above conditions, the clinical research approval document may not specify the relevant requirements for carcinogenicity tests, but the carcinogenicity test data should also be submitted in accordance with the above requirements.

2. Natural products derived from Chinese medicine are also suitable for the above requirements.

3. Welcome to communicate with CDE on issues related to animal carcinogenicity tests.

Question 5: Requirements for pharmacodynamic test of 3 types of antibiotics

The sensitivity of bacteria to antibacterial drugs has time and regional characteristics. Compared with the literature, or compared with the current foreign strains, there may be big differences between the existing clinical isolates in China. Differences in the use of antimicrobial drugs in the treatment of infections may bring about differences in the degree of cross-resistance. Therefore, it is necessary to use representative domestic recent clinically isolated pathogenic bacteria for in vitro and in vivo pharmacodynamic tests, and to use the current domestic clinical The main application of similar drugs is used as a reference drug.

Question 6: Non-clinical pharmacokinetics such as sustained and controlled release oral preparations

1. For non-innovative sustained and controlled-release oral preparations (category 3, 5), etc., it is usually necessary to conduct a single non-clinical pharmacokinetic comparison study with the original product/marketed product.

2. For the five types of oral preparations modified from oral administration to sustained release, single and multiple administration pharmacokinetic studies should be considered.

Question 7: Special issues

1. If the indication only involves single-sex patients, is it possible to use single-sex animals for testing?

From the perspective of fully understanding the safety characteristics of compounds, it is usually necessary to use bi-sex animals for testing, even if the indications only involve single-sex patients, such as ED, endometriosis, etc.

2. For some special population indications, is it possible not to provide reproductive toxicity test data?

For indications involving elderly patients such as Alzheimer's disease and Parkinson's disease, and indications involving children patients such as childhood attention deficit syndrome, from the perspective of fully understanding the safety characteristics of the compound, it is usually necessary to provide reproductive toxicity test data , But its submission time can be considered flexibly.