Notice to Stakeholders

Release of the Revised Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs

Health Canada is pleased to announce the release of the revised Guidance Document, Information and Submission Requirements for Biosimilar Biologic Drugs.

Health Canada's 2010 Guidance Document: Information and Submission Requirements for Subsequent Entry Biologics (SEBs) was updated based on experience gained as well as international developments in the regulation of biosimilars. A draft revised version was published on the Health Canada website from December 7, 2015 to February 15, 2016 for stakeholder consultation. Comments were received from over 20 stakeholders representing individual drug companies, industry associations, patient, healthcare, scientific and clinical research organizations, law firms and provincial ministries of health. All comments were reviewed and considered in the finalization of the Guidance. Key revisions to the Guidance Document are outlined.

Change in terminology:

• The term subsequent entry biologic (SEB) has been replaced with biosimilar biologic drug and its internationally accepted abbreviation biosimilar.
• The term comparability exercise has been replaced with studies to demonstrate similarity to distinguish studies comparing the biosimilar and the reference biologic drug from studies addressing intra-product comparability.

Clarification on the scientific basis for biosimilar authorization:

• Policy statement 1.3.4 has been expanded to state that the basis for accepting a reduced non-clinical and clinical data package for a biosimilar hinges on demonstrated similarity between the biosimilar and the suitable reference biologic drug. A final determination of similarity will be based on the entire submission, including data derived from comparative structural, functional, non-clinical, human PK/PD and clinical studies.

Reference biologic drug:

• Additional clarity is provided in sections 2.1.2 Patents, intellectual property, and data protection and 2.1.3 Reference biologic drug on the information required to demonstrate the relationship between the non-Canadian reference biologic drug and the Canadian version.
• Section 2.1.3 Reference biologic drug has been updated to provide clarity on the data requirements when more than one reference biologic drug (e.g. versions of the reference biologic drug sourced from more than one jurisdiction) is used in clinical studies.

Non-clinical data requirements:

• Sections 2.2 Information requirements for clinical trial applications (CTA) and 2.3.3.2 Non-clinical studies have been revised to communicate 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.

Clinical data requirements (2.3.3.3 Clinical studies):

• Additional considerations/factors are included for designing adequately sensitive studies to be able to rule out clinically meaningful differences between the reference and biosimilar.
• Clarification that a clinical efficacy trial may not always be needed (e.g. if there is a clinically relevant PD endpoint).
• A new subsection on immunogenicity has been included based on Health Canada guidance provided to sponsors at the pre-submission meeting stage.

Extrapolation/Authorization of Indications:

• Section 2.3.4 Authorization of indications (previously 2.3.3.4 Extrapolation) has been extensively revised to provide clarity on Health Canada's approach. The decision to authorize indications is based on similarity between the biosimilar and reference biologic drug demonstrated by comparative structural, functional, non-clinical, human PK/PD and clinical studies along with a detailed rationale that scientifically justifies authorization in each indication. When authorizing indications, Health Canada extrapolates the overall conclusion of similarity between biosimilar and reference biologic drug where scientifically justified; clinical data are not extrapolated from one indication to another. Due to stakeholder confusion regarding use of extrapolation for biosimilars and to better communicate the basis for Health Canada's authorization of indications, the term extrapolation was removed from the guidance document. It should be noted that the updated guidance reflects a change to how Health Canada communicates the basis for authorization of indications but does not change the supporting data requirements.

Labelling Requirements (2.3.5 Labelling requirements - Product Monograph):

• The statement in the product monograph indicating that the product is a biosimilar has been expanded to indicate that similarity between the biosimilar and the reference biologic drug has been established based on comparative structural and functional, non-clinical and human PK/PD studies, and clinical safety and efficacy trials, as applicable.
• Addition of a statement that indications have been granted on the basis of similarity between the biosimilar and the reference biologic drug.
• Clarification that comparative data generated by the biosimilar sponsor on which the decision for market authorization was made should be presented in the product monograph in a summarized tabular format.
• Revisions were made such 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.

Health Canada intends to release a Biosimilars Product Monograph template which will provide guidance to sponsors on information to be presented in the product monograph.

Post-notice of compliance (NOC) changes:

• Section 2.4.2 Post-notice of compliance (NOC) changes was revised to clarify that there may be situations following receipt of a notice of compliance, where a biosimilar sponsor seeks authorization of additional indications held by the reference biologic drug in Canada (e.g. the biosimilar sponsor did not originally file for all indications held by the reference biologic drug in Canada). A Supplemental New Drug Submission (SNDS) for a biosimilar that relies on the previously demonstrated similarity provided in the original biosimilar New Drug Submission may be considered by Health Canada on a case by case basis. Biosimilar sponsors should consult with BGTD for regulatory guidance for their specific SNDS.

Health Canada will review the Guidance Document on an ongoing basis based on new scientific knowledge, best practices and/or experience gained by the Department.

Some of the comments received during the stakeholder consultation pointed to issues that fall outside the scope of the Guidance. Two common issues - biologics naming and interchangeability - that were raised by stakeholders are addressed below:

What is Health Canada's position on non-proprietary naming of biologic drugs, including biosimilars?

Health Canada is 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. While a decision is being made, biologic drugs and biosimilars continue to be identified by brand name, common (non-proprietary) name and Drug Identification Number (DIN).

Does Health Canada designate a biosimilar as interchangeable?

A market authorization (Notice of Compliance) of a biosimilar is not a declaration of equivalence to the reference biologic drug. Designation of a drug as interchangeable is under the purview of the provinces and territories, and is thus outside the scope of this guidance document.

Contact Information

Office of Policy and International Collaboration
Biologics and Genetic Therapies Directorate
Health Products and Food Branch
Health Canada
Building #6, 100 Eglantine Driveway
Tunney's Pasture
Ottawa, ON K1A 0K9
Address Locator: 0601B
Fax number: (613) 952-5364
BGTD.OPIC@hc-sc.gc.ca