Release of technical requirements for the consistency evaluation of the quality and efficacy of generic chemical injections

On November 5, CDE issued technical requirements for consistency evaluation of quality and efficacy of special injection (Draft for comments) Attachment: technical requirements for conformity evaluation of quality and efficacy of generic drugs (special injection) for chemical injection (Draft for comments) Special injection means that compared with ordinary injection, the quality of special injection and the in vivo behavior of its active ingredients are greatly affected by the prescription and process, which may further affect the safety and effectiveness of the preparation in vivo, such as liposome, intravenous milk, microspheres, suspension injection, etc In principle, the chemical generic drugs for special injections shall meet the requirements of technical requirements for evaluation of consistency of quality and efficacy of generic drugs for chemical injections This document is a supplement on this basis, aiming to put forward the overall thinking and general principles for the research and development of generic drugs for special injections and provide technical guidance for the research and development of generic drugs for special injections 1、 Overall consideration for special injection, due to the complexity of preparation characteristics, we should take a step-by-step comparative research strategy based on the preparation characteristics and product characteristics First, we should carry out the pharmaceutical and non clinical comparative research of the test preparation and the reference preparation, and then carry out the bioequivalence research of human body, and carry out further clinical research if necessary If the results of pharmaceutical research and / or non clinical research indicate that the test preparation is inconsistent with the reference preparation, the applicant shall carry out the research again after further optimization of the prescription process of the test preparation 2、 In pharmaceutical research, according to the technical requirements for quality and efficacy consistency evaluation of generic drugs for chemical injection, the consistency evaluation of special injection should be carried out in accordance with the above technical requirements, and at the same time, according to the characteristics of special injection, refer to the relevant technical requirements of special preparation issued by FDA and EMA, and design the test scientifically It is suggested to pay attention to the following problems: (1) in principle, the prescription process should be consistent with the reference preparation It is suggested to study the type of excipients and CQA of excipients that may affect the behavior of the injection The production process of special injections may affect the behavior of the drug in vivo, which needs to be further studied; for special injections produced by aseptic process, special attention should be paid to the aseptic assurance measures and verification of each production step In principle, the production process and batch size of registered batch and commercial batch shall be consistent The batch of registered batch samples shall be implemented in accordance with the general requirements for the production scale of registered batch of chemical generic drugs (Trial) （2） The key quality attributes investigated in quality research may include but are not limited to the following: physical and chemical properties (such as properties, viscosity, osmotic pressure molar concentration, pH value / pH value, etc.), zeta potential, particle shape, particle size and distribution (such as D10, D50, D90, etc.), dissolution / release behavior in vitro, free and combined drugs, drug crystal form and crystal form In principle, the quality comparison and inspection data of at least three batches of reference preparation samples shall be provided （3） The consideration of human bioequivalence study / clinical trial should use commercial batch of samples for human bioequivalence study and / or clinical trial For specific injection varieties for which FDA or EMA has published guidelines, it is recommended to carry out a comparative study with the reference preparation according to its technical requirements 3、 Non clinical study Different from ordinary injections, special injections usually have factors such as drug release process and absorption of body fluid components after entering the body Therefore, differences in the formulation and process of the test preparation and the reference preparation may lead to changes in pharmacokinetic behavior in the body, resulting in changes in effectiveness and toxicity However, the in vitro comparative study of pharmacy alone is not enough to fully reflect the test preparation The difference of behavior between the preparation and the reference preparation Based on the above considerations, before carrying out human bioequivalence study or clinical trial, appropriate animal species and genera should be selected for non clinical pharmacokinetic comparative study, so as to fully indicate the consistency of pharmacokinetic behavior in vivo and / or distribution in pharmacodynamic / toxic targets of the test preparation and the reference preparation In view of the fact that only the drug released from the preparation can play an active role in the body, it is recommended to determine the concentration of the loaded drug and the released drug respectively when determining the blood drug concentration 4、 Clinical research can only be carried out on the basis of the consistency between the test preparation and the reference preparation in pharmaceutical and non clinical aspects In clinical research, we should adopt the step-by-step research strategy We should first study the bioequivalence of human body and carry out further clinical research if necessary （1） The bioequivalence of human body is studied by establishing a bioequivalence research method with differentiated force General requirements and test design can refer to the technical guidelines for bioequivalence research of chemical generic drugs in human body with pharmacokinetic parameters as the end point evaluation index and the statistical guidelines for bioequivalence research and other relevant guidelines Specific research suggestions are as follows: Research Design: randomized, single dose, cross study design is usually adopted Under special circumstances, a reasonable research design should be selected based on the characteristics of drugs and the population with indications Subjects: usually healthy subjects When the selected healthy subjects may face safety risks when participating in the trial, it is recommended to select the patients with the proposed indications of the trial drug Sample size: the number of selected subjects should make the bioequivalence evaluation have enough statistical effect Test substance: if the active substance of a special injection has multiple forms at the same time in vivo, the bioequivalence research should fully consider the influence of various forms of drugs on the safety and effectiveness, and select a scientific and reasonable test substance based on the characteristics of drugs The detection method needs to be fully validated, and has enough discrimination for the target detection substance, and has enough sensitivity for the difference between the test preparation and the reference preparation Bioequivalence evaluation index: auc0-t, auc0 - ∞, Cmax geometric mean, geometric mean ratio and 90% confidence interval of the test preparation and reference preparation shall be provided Under special circumstances (such as microspheres, etc.), it may be necessary to add some exposure indicators to observe the early exposure or the exposure in a specific period Acceptance criteria of bioequivalence: generally, for the main endpoint index, the 90% confidence interval value of the ratio of geometric mean of the above parameters shall not be less than 80.00% and not more than 125.00% Pre test: before the formal test, the pre test can be carried out in a few subjects to verify the analytical method (including the partition force of the test substance), evaluate the degree of variation, optimize the sampling time, and obtain other relevant information The data from the pre-test cannot be included in the final statistical analysis Others: in addition to meeting the current requirements of relevant application materials, the registration application shall fully demonstrate the scientific rationality of relevant key issues based on product characteristics, including but not limited to test design, subject selection, sample size, test substance, bioequivalence evaluation index, etc The study on bioequivalence of human body with pharmacodynamic index as the end point evaluation index shall be carried out according to relevant guidelines In case of special circumstances, it can communicate with the regulatory authority in advance （2） Whether a randomized controlled clinical trial is needed or not should be determined based on the characteristics of the drug and the results of previous studies on pharmacy, non clinical and human bioequivalence If the results of bioequivalence study show that the test preparation is not equivalent to the reference preparation, the applicant shall further optimize the formulation process of the test preparation and carry out a comparative study again For the following cases (not limited to), it is suggested to carry out randomized controlled clinical trial to prove the equivalence of the test preparation and the reference preparation: (1) there is no accurate and reliable biological sample determination method to evaluate the bioequivalence of the test preparation and the reference preparation through the bioequivalence study (2) The results of bioequivalence study showed that there was a difference between the test preparation and the reference preparation, and it was not sure whether the difference would have a significant impact on the safety and effectiveness of the drug (3) The correlation between the drug concentration in the systemic circulation and the efficacy or safety is poor, and the study of human bioequivalence is not enough to evaluate the efficacy and safety of the test preparation and the reference preparation It is recommended to communicate with the regulatory authorities in advance about the implementation of clinical trials.