Q4: Consideration in immunogenicity assessment

A4: Sponsors are encouraged to collect immunogenicity data in any clinical study, including human PK or PD studies.

The timing and duration of follow-up evaluation should be determined according to the immunogenic characteristics of different products. Factors such as the length of administration of the product, pharmacokinetics of the product, and the time course for the generation of immune responses should also be considered. It is recommended to discuss with CDE before initiating the study.

Sponsor should pay attention to any differences in human immune responses between proposed products and reference products, and evaluate the effect of the differences on effectiveness and safety.

Q5: How to determine the equivalence margins of a comparative clinical study for a biosimilar?

A5: In the comparative clinical study of biosimilars, it is necessary to select the rational ratio or difference as the effect size of primary study endpoints. The equivalence margin is generally estimated based on the confidence interval of the efficacy of the originator product, and is determined in combination with clinical significance. The efficacy of the originator product is usually based on the meta-analysis of the randomized control superiority study of the originator product and the standard treatment (or placebo). The selection of meta-analytical literature, the use of analytical results need to consider factors such as clinical practice, ethnic differences, and sample size feasibility of the target indications.

Q6: Consideration in extrapolation of clinical data across indications

A6: If comparative study demonstrates the proposed product is clinically similar to reference product, the applicant may seek licensure of the proposed product for one or more additional conditions of use for which the reference product is licensed. The extrapolation of indications needs to be considered on the basis of the characteristics of the products and the sufficiency of similarity research data.

The following issues should be addressed:

• clinically relevant pathological mechanisms and/or related receptors, and the function and target are the same;
• in the clinical comparison study, appropriate indications are selected, and the safety and immunogenicity are fully assessed.

The applicant would need to provide sufficient scientific justification for extrapolating clinical data to support a determination of biosimilarity for each condition of use for which licensure is sought.

Q7: Recommendations on package insert of biosimilar product

A7: The general principles for writing of biosimilar product package insert should be “not affect clinical use” and “facilitate post-marketing safety monitoring”.

It is recommended to add the header on the front page like ” [BIOSIMILAR PRODUCT’S PROPRIETARY NAME (XYZ mAb)] is biosimilar to [REFERENCE PRODUCT’S PROPRIETARY NAME (XYZ mAb)]”; and add the definition of a biosimilar product in the front page footer as: ” Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an NMPA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. The package insert of this product is consistent with the one of originator product.”

Clinical trial data in the package insert of biosimilar product should demonstrate effectiveness and safety rather than the similarities with reference product. in the package insert, the difference between the proprietary name of reference drug, the proprietary name of similar product and the proper name. When clinical studies of reference product is described, the reference product’s proper name instead of proprietary name should be used.

Q1: The scope of ‘biosimilars’

A1: ‘Biosimilars’ applies to the therapeutic recombinant protein products with a definite structure and function. The amino acid sequence of the proposed product should in principle be the same as the reference product. Host cells and expression systems similar to the reference product are recommended because different cell types can affect patterns of post-translational modifications, such as glycosylation.

If a different expression system comparing to the reference product is used, a sufficient CMC study is required to demonstrate that the expressed protein of proposed product has the same amino acid sequence, comparable higher order structure and post-translational modification, and biological activity; after comparison, if the degree and type of post-translational modification between the proposed product and reference product are found to be different, the potential impact on safety and efficacy must be demonstrated. If a new expression system is adopted for proposed product, it usually increases the difference in glycosylation patterns and new process-related impurities, and the impact on clinical immunogenicity should also be considered.

Q2: Approaches to developing a biosimilar

A2: The general idea of ​​similar product development is to demonstrate similarity based on data directly comparing the proposed product with the reference product, and further to support its safety, efficacy and quality. A stepwise approach include the CMC, non-clinical, and clinical comparison studies.

After the CMC and non-clinical comparison studies finished, it is recommended that the sponsor have a pre-IND communication and with CDE to confirm the follow-up research content and research design. It is suggested that the PK study should be carried out in the clinical research stage. After completing the PK study, the communication with CDE is recommended. If PK study supports a demonstration of biosimilarity after preliminary assessment, the head-to-head comparative trial can be continued to prove the efficacy and safety.

Q3: How to choose reference product and the origin

A3: The originator biological product approved in China should be selected as the reference product. The reference product used in each stage of the whole development program should from the same origin.

Other suitable pathways may be considered for those that are not commercially available in China, but bridging comparison studies of reference products from different origins or comparative evidence for reference products from different origins should be provided, with a focus on the source of the drug substance.

Sponsor should, as far as practicable, select the originator biological product that has been approved for importation or clinical trial in China as a reference for clinical trials of biosimilars. For the safety of the subjects consideration, if the sponsor intends to select the originator product of the same enterprise but from the different origins as the reference, before the start of the clinical trial, the comparative data between the original products of different origins should be provided to CDE first, otherwise comparative research on the originator products of different origins should be carried out in accordance with the relevant technical guidelines published by China NMPA and information should be submitted to CDE as supplement application. After review and approval by CDE, the sponsor may use the reference product from a different origin for clinical trial use. However, the comparison research at various stages of development program should be conducted with the originator product from the same origin.