On July 31st, China CDE has published 7 Questions and Answers on biosimilar development to industry on its website. It mentioned that these Q&As respond to the most-commonly-asked-questions from applicants, and these Q&As also describe CDE’s considerations and requirements.
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.
