Not yet approved! Guidelines for clinical trials of thorades mono-injectable biosimilar synopsis released

On May 20, CDE issued the Guidelines for Clinical Trials of Tocojud Anti-Injection BiosimilarS (Draft for Comments), which makes recommendations on the design, endpoint selection and equivalent boundary values of tocotrotized anti-injection biosimilarstocodone injection (Tocilizumab) developed by Roche, using mammalian cells (CHO) expression of anti-human interleukin 6 receptor monoclonal antibody preparation, by blocking the binding of leukin 6 and soluble and membrane binding of the leukone 6 receptor, inhibits the signal transduction of leukin 6, thereby reducing pathological inflammatory reactionThe name of the product is: Yamero/Actemratozhu monoresist has been approved in the European Union, the United States, Japan and other countries and regions since February 2009, approved indications include: adult rheumatoid arthritis (RA), multi-joint type of juvenile iade (pJIA), systemic juvenile isoarthritis (sJIA), cytoblastic arteritis (GCA) and cytokine release syndrome (CRS)At present, the indications approved in China include RA and sJIAtozhu single anti-injection original research product sequence patent has expired, there is no tozhu mono-anti-biosimilars have been approved for listing at home and abroad, many pharmaceutical companies have joined its biosimilar drug research and development process, according to incomplete statistics, there are currently 5 pharmaceutical enterprises in the country to carry out relevant clinical trials:At this stage, it is necessary to clarify and unify the domestic tozhu mono-biosimilar drug clinical trial requirements in order to better promote the development of the species of biosimilar drugsTocilizumab was developed by Roche to use the anti-human leukin 6 receptor monoclonal antibody preparation expressed in mammalian cells (CHO) under the name: Yamero ®/Actemra ®By blocking the binding of leukin 6 and the aclegentic and membrane binding of the leukin 6 receptor, the signal transduction of leukin 6 is inhibited, thereby reducing the pathological inflammatory responseTozhu monoresist has been approved for listing in the European Union, the United States, Japan and other countries and regions since February 2009, and has been approved for indications including: adult rheumatoid arthritis (RA), multi-joint infant iade (pJIA), systemic juvenile isoarthritis (sJIA), cytomegaloe arteritis (GCA) and cytokine release syndrome (CRS)At present, the indications approved in China include RA and sJIAtozhu single anti-injection original research product sequence patent has expired, many pharmaceutical companies at home and abroad have joined the development process of their biosimilar drugsIn order to better promote the development of biosimilar drugs, in the former State Food and Drug Administration issued the "biosimilar drug research and development and evaluation technology guidelines (trial)" on the basis of the "3" , we combined with the characteristics of the species and research and development enterprises related issues of communication and communication, the discussion formed a tozhu mono-biosimilar drug clinical trial research and design points, with a view to providing reference for the industryprinciple, pharmacokinetic ratio requires a single bioequivalence study of pharmacokinetics in healthy subjects to verify the similarity of the candidate drug and the PK characteristics of the original drugThe clinical comparison study suggested that the original research import approved RA indication synopathy population, with the original research drug to carry out a "head-to-head" comparison of clinical equivalence study to support its registration as a biosimilar drug market the clinical comparison of biosimilar drugs should be designed scientifically and reasonably with the aim of proving the similarity between the candidate drug and the original drug (1) The study of the pharmacokinetic ratio of healthy subjects the experimental design: with reference to the design of the general bioequivalence study, combined with the tobeak monobiotic similar drug has a longer half-life (at steady-state concentration, once every four weeks, 11 days at 4 mg/kg, 13 days at 8 mg/kg), with the characteristics of immunogenicity, it is recommended to use randomized, double-blind, parallel control, single-injection design test study population: Healthy volunteers are the ideal homogenous subject sedatives, which better reflect the PK difference between the candidate drug and the original study drug The main objective of the PK comparison study was to look at similarity, and healthy male subjects could usually be selected only Note the equalization of parallel groups dose and method of administration: Clinical studies of the original drug showed that 4 mg/kg of elimination was mixed with nonlinear removal and linear removal, while 8 mg/kg was linear elimination, with more variability factors between individuals in the case of nonlinear elimination, but from the perspective of protecting the subjects and comparing the PK similarity between the two preparations, it was recommended that the PK ratio was 4 mg/kg The route of administration is consistent with the original drug Intravenous administration should pay attention to control the speed of infusion, the duration of administration should be as consistent as possible end indicators and boundary values: the original drug in patients with rheumatoid arthritis (RA) t1/2 concentration dependence The PK ratio of biosimilars uses an equivalence design for the study, and it is controversial to choose Whether AUC0-t or AUC0-thumas is the end point We believe that AUC0-t is obtained by actual measurements, and recommend AUC0-t and Cmax as the main end indicators of the study AUC0-to-a comparative analysis as an important secondary research endpoint The equivalence boundary value is set to 80%-125% according to the general recommendation It is suggested that the blood collection point should be reasonably set according to the pharmacokinetic characteristics of the reference drug and the general principle of pharmacokinetic research, so as to fully characterize the PK similarity of the candidate drug and the reference drug sample size: The required sample size needs to be fully estimated prior to the test, usually alpha take two-sided 0.1 (double-sided 0.05), the test efficiency is 80% Sample size estimation should take full account of individual variation and evaluation index of the differences between preparations (2) Patientclinical effectiveness ratio experimental design: the patient clinical effectiveness ratio study aims to prove that similar drugs and reference drugs are similar to the clinical efficacy, should be used as a reference drug for control, random, parallel control equivalent design study population: Guidelines recommend the selection of the most sensitive patient groups and clinical endpoints to facilitate sensitive detection of the consistent clinical efficacy of biosimilars and reference stodgies The first approved indication of the original drug was RA, and the clinical trial data available for reference in the population of the disease were more adequate It is recommended that the clinical comparison of the subjects in the study choose RA patients who have a poor response to methotrexate administration plan/dose: The original drug is recommended in different indications of roughly the same dose, but there are differences in the initial dose of different countries or regions (4 mg/kg in the United States, 8 mg/kg in the European Union and China), it is recommended that the clinical comparison of the study dose should be consistent with the reference drug domestic approved dosage program, allowing the necessary dose adjustment according to the specification the end of the study: the percentage of subjects who reached ACR20 is a common lyse index of RA indications, can objectively reflect the efficacy, and is easy to detect and evaluate, has been used in the clinical comparison of many biosimilars such as Inflexi mono-resistance, Adamu mono-resistance, and recommended that the clinical comparison study of tocothethan antibiotic similartotins also reached A20 in the 24th week as the main therapeutic similarity index equivalence boundary values: There is still controversy over the difference between the use of candidate drug groups and the reference drug group study endpoints (RiskDifference, RD) or ratio (RiskRatio, RR) when setting boundary values in the international academic community RR and RD are also equivalent in most cases Based on the meta-analysis results of three clinical studies, including THE original drug LITHE, OPTION and ASI, and combined with other clinical studies of biosimilar drugs of the same species, it is recommended that the equivalent boundary of the 95% confidence interval of RD be set to a of 13.7% other issues of concern
1 Safety and immunoogenics research immunoogenic sinology research should run through the whole research and development process of biomolecular drugs Immunoogenicity is evaluated primarily by detecting the incidence of anti-drug antibodies (anti-drugantibodies, ADA) and neutralized antibodies (neutralization antibodies) Clinical research results of original drug showed that in a six-month controlled clinical trial, a total of 2,876 patients were tested against anti-tobean antibodies Forty-six patients (1.6%) were positive for anti-tobean anti-antibodies and 30 (1.1%) were present with neutralizing antibodies The results of the immuno-primarity test are highly correlated with the sensitivity, specificity and drug tolerance of the test method, and may be influenced by several factors: blood sample treatment, sampling time, combined drug use, and combined diseases Typically, clinical immunoogenic study (including ADA and Nab) is conducted in the same clinical trial as clinical effectiveness compared to the study It is recommended that all subjects should be immunogenicized, sampling point-in-time settings should include at least the first before administration, 4 weeks or / and 12 weeks, and one month after the last administration, and then confirm that the candidate drug in antibody positive rate, antibody titer, antibody appearance time and the incidence of neutralizing antibodies are not higher than the original drug At the same time, the research involved should prove that biosimilar drugs and primary drugs should not have clinical significance in terms of immunogenicity 2 Patient pharmacokinetics research patients multiple dose PK ratio studies can indirectly reflect the tozhu mono-drug dose dependence and time dependence-related immunogenicity, as well as enzyme-mediated, targeted-mediated, FcRn-mediated and other related drug removal It is suggested that the PK characteristics of multiple administrations should be examined at the same time in the clinical effectiveness ratio study, in order to support the similarity evaluation of torbead monobiosimilars the study of clinical similarity of biosimilar drugs should follow the general requirements of clinical similarity evaluation of biosimilar drugs, combined with product characteristics, targeted clinical comparison of research design, so as to support the candidate drug by biosimilar drug approved for market The views described in this article only represent the current review understanding, sincerely look forward to the industry to put forward valuable comments and suggestions, in order to follow up It is also expected that with the further research of biosimilar drugs, the understanding of the clinical development of biosimilar drugs will become clearer .1.The National Drug Administration.http://
[2] Mulard A Cannext-generationantibodies offset biosimilars? NatRevDrugDiscov.2012Jun1;11 (6):426-8.
The National Drug Administration Guidelines for The Development and Evaluation of Biosimilar Drugs (trial) http://
The National Drug Administration technical guidelines for the study of bioequivalence of chemical drug generics with pharmacodynamic parameters as the end-of-term evaluation indicators http://
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