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.
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.