On December 2, 2016, Health Canada released the revised Guidance Document Information and Submission Requirements for Biosimilar Biologic Drugs. The Guidance is intended to assist biosimilar companies to navigate the information and regulatory requirements for Health Canada’s market authorization process.
Some highlights of the long-awaited revisions include changes to terminology, as well as clarifications to the scientific basis for biosimilar authorization, criteria for reference biologic products, clinical and non-clinical data requirements, authorization of indications, and labelling requirements. Health Canada also provided its position on interchangeability and announced that it is still considering biologic naming.
The updated Guidance is the culmination of a substantial review process by Health Canada’s Biosimilar Working Group, which considered the concerns of various stakeholders provided in February 2016 in response to the original proposed revisions, released for comment in December 2015. It updates the 2010 Guidance Document: Information and Submission Requirements for Subsequent Entry Biologics (SEBs). Some updates are discussed below.
Change to terminology
The term “biosimilar biologic drug”, abbreviated as “biosimilar”, will replace the term “subsequent entry biologic”, or “SEB”, previously used by Health Canada. This is in line with the practice of the U.S. Food & Drug Administration (FDA) and European Medicines Agency (EMA).
Moreover, the term “comparability exercise” has been replaced with “studies to demonstrate similarity” to distinguish studies comparing the biosimilar with the reference biologic drug from studies addressing intra-product comparability.
Clarification on the scientific basis for biosimilar authorization
Health Canada has indicated that it will accept a reduced non-clinical and clinical data package for a biosimilar based on demonstrated similarity between the biosimilar and the suitable reference biologic drug (see Policy statement 1.3.4). The entire submission, including data derived from comparative structural, functional, non-clinical, human pharmacokinetic/pharmacodynamic and clinical studies, will be reviewed for determining similarity.
Reference biologic drug
Further information was provided on the requirements that must be met for demonstrating the relationship between a non-Canadian reference biologic drug and the Canadian version (see sections 2.1.2 Patents, intellectual property, and data protection and 2.1.3 Reference biologic drug) and to provide clarity on the data requirements when more than one reference biologic drug is used in clinical studies (section 2.1.3 Reference biologic drug).
Clinical and non-clinical data requirements
Under section 184.108.40.206 Clinical studies, Health Canada has included additional considerations/factors for designing adequately sensitive studies to be able to rule out clinically meaningful differences between the reference and biosimilar, including a new subsection on immunogenicity.
Health Canada has also indicated that an in vivo study may not be considered necessary prior to biosimilar clinical trials if comparative structural, functional and non-clinical in vitro studies are considered satisfactory and no issues are identified that would preclude administration of the biosimilar into humans, as set out in sections 2.2 Information requirements for clinical trial applications (CTA) and 220.127.116.11 Non-clinical studies.
Authorization of indications
Health Canada made an extensive revision to section 2.3.4 Authorization of indications (previously 18.104.22.168 Extrapolation) indicating that the decision to authorize indications is based on similarity between the biosimilar and reference biologic drug demonstrated by comparative structural, functional, non-clinical, human pharmacokinetic/pharmacodynamic and clinical studies along with a detailed rationale that scientifically justifies authorization in each indication. The revisions remove the term “extrapolation” from the guidance document to clarify that clinical data are not extrapolated from one indication to another but that Health Canada extrapolates the overall conclusion of similarity between biosimilar and reference biologic drug when authorizing indications.
Revisions were made to section 2.3.5 Labelling requirements — Product Monograph to clarify that biosimilar sponsors should present comparative data generated in the product monograph in a summarized tabular format and that the biosimilar product monograph may now include relevant safety and efficacy information from the product monograph of the reference biologic drug authorized in Canada.
In a Notice to Stakeholders accompanying the release of the guidance, Health Canada has indicated that market authorization of a biosimilar is not a declaration of equivalence to the reference biologic drug; the designation of a drug as interchangeable is under the purview of the provinces and territories.
Health Canada is currently “evaluating the most appropriate naming convention for biosimilars and biologic drugs, including the World Health Organization Biologic Qualifier (BQ) proposal, while taking into account Canadian pharmacovigilance and prescribing/dispensing needs and international approaches to biologic drug and biosimilar naming”. In the interim, Health Canada’s Notice to Stakeholders advises that biologic drugs and biosimilars should continue to be identified by brand name, common (non-proprietary) name and Drug Identification Number (DIN).