In March 2010, Health Canada adopted guidelines entitled Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs[1] pertaining to the approval of subsequent entry biological products (now known as biolosimilars). The guidelines lacked particulars with respect to the nature of the quality of non-clinical and clinical data necessary for the determination of similarity. The revised guidelines attempt to clarify these points.

Health Canada Revises its Guidance for the Approval of Biosimilars

The revised guidelines primarily address the approval process for a "biosimilar" which is defined by Health Canada as a subsequent entry biological product which is similar to a previously approved innovator biological product (known as the reference product).[2] The similarity allows the subsequent manufacturer to present a reduced clinical and non-clinical package as part of its submission[3] which in turn presumably allows it to file a submission and obtain its approval more rapidly.

Health Canada felt the need for the clarifications to the approval process given that the expiration of patents and/or data protection for some biologic drugs is creating opportunities for subsequent entry versions.[4] The revised guidelines apply to biologic drugs that contain well-characterized proteins derived through biotechnological methods such as use of recombinant DNA and/or cell structure.[5]

Demonstration of similarity

The revised guidelines specify that a determination of similarity is based, among other things, on data derived from comparative structural, functional, non-clinical and clinical studies.[6] In addition to a complete chemistry and manufacturing package, the submission should include characterization studies conducted in a side-by-side format.[7] Characterization includes the determination of physicochemical properties, biological activity, immunochemical properties (if any), purity, impurities, contaminants and quantity.[8] Differences in the manufacturing process are also taken into account.

According to Health Canada, if the biosimilar and the reference product are highly similar in terms of quality attributes, then this can support a possible conclusion that any differences in these attributes should have no adverse impact upon the safety and efficacy of the biosimilar. Non-clinical and clinical data previously generated with respect to the reference product may be thus become relevant to the biosimilar.[9] If similarity has not been established, then reduced data cannot be justified and the product cannot be considered a biosimilar.[10]

Non-clinical and clinical studies

The revised guidelines state that the degree of similarity at the quality level will determine the scope and the breadth of the required non-clinical and clinical data.[11] Where similarity is well established by structural and functional studies, and where extensive in vitro mechanistic studies are indicative of similarity, in vivo non-clinical studies may not be necessary.[12] Specialized toxicological studies are not generally required for a biosimilar submission.[13]

Insofar as clinical studies are concerned, Health Canada specifies that the program should begin with pharmacokinetic/pharmacodynamic studies.[14] A comparative clinical efficacy trial is also important to rule out clinically meaningful differences in efficacy and safety between the biosimilar and the reference biologic drug, although it may not always be necessary, for example where there is a clinically relevant pharmacodynamic endpoint.[15] As well, the nature, severity and frequency of adverse events should be compared and a comparative immunogenicity study carried out.[16] Where similarity has been established, the biosimilar may be approved for the same indications as the reference product even if clinical studies are not conducted with respect to each indication.[17]

Other

The revised guidelines also contain labelling requirements and the need for a risk management plan.[18] Insofar as post-market requirements are concerned, these relate to adverse drug reaction reporting and post-notice of compliance changes.[19]

Conclusion

The Biologics and Genetic Therapies Directorate is undergoing a 3 year pilot to explore a stepwise review approach that would be complementary to the biosimilar development process. Those who wish to participate in the pilot or who want obtain further details on the approval of biosimilars should refer to the revised guidelines.[20]