Health Canada recently released its new guidance document for Subsequent-Entry Biologics (SEBs). In addition, a final guidance document was released for Data Protection under the Food and Drug Regulations, as well as proposed amendments to the guidance documents under the Data Protection Regulations and the Patented Medicines (Notice of Compliance) Regulations (PM(NOC) Regulations) to reflect the new SEB guidelines.

The Data Protection Regulations and the PM(NOC) Regulations are critical aspects of the SEB regulatory system both for existing biologic therapies and for IP strategies on biotechnology products going forward in Canada.

The guidance documents define an SEB as a biologic drug that would enter the market subsequent to, and 'similar' to an innovator product authorized for sale in Canada. The new regulations apply to all biologic drug submissions where the sponsor seeks authorization for sale based on demonstrated similarity to a biologic drug that was authorized for sale in Canada and relies, in part, on prior information regarding the authorized innovative biologic drug in order to present a reduced clinical and non-clinical package as part of the submission.

The policy statements included in the new guidance document specifically state that SEBs are not "generic biologics" and many characteristics associated with the authorization process and marketed use for generic pharmaceutical drugs do not apply. Authorization of an SEB is not a declaration of pharmaceutical and/or therapeutic equivalence to the reference biologic drug.

An SEB will only be authorized if a submission demonstrates similarity based on a direct or indirect comparison to such an authorized innovative biologic drug. The concept of what an indirect comparison may constitute will no doubt create discussion amongst sponsors looking for approval of SEBs. The basis for a product being authorized as an SEB hinges on the ability to demonstrate similarity to a suitable reference biologic drug.

In order to provide flexibility to sponsors, Health Canada has provided a mechanism to be used in appropriate and special circumstances, to permit the use of a reference biologic drug that is not authorized for sale in Canada which can still be used in the demonstration of similarity between the SEB and the product authorized for sale in Canada. However, where a non-Canadian reference product is used, the submission must explicitly and clearly explain the link between the reference product and the product authorized for sale in Canada.

If a non-Canadian reference biologic product is considered, the new guidance documents state that non-Canadian product should be widely marketed in a jurisdiction that formally adopts International Conference on Harmonization (ICH) guidelines and has regulatory standards and principles for evaluation of medicines, post-market surveillance activities, and approaches to comparability that are similar to Canada.

Finally, in order for a sponsor to sufficiently explain the link between the non-Canadian reference biologic drug and the version of the product authorized for use in Canada, it must document in its submission that the non-Canadian reference biologic drug is marketed by the same innovator company or corporate entity which is approved to market the medicinal ingredient in the same dosage form in Canada, or that it is marketed through a licensing arrangement with the innovator company or corporate entity which currently markets the version of the product approved in Canada.

Once a notice of compliance (NOC) is granted, the SEB is a new biologic drug and regulated like any other new biologic drug. Therefore, an SEB cannot be used as a reference biologic drug.

Detailed and comprehensive product characterization will need to be provided by a sponsor in order to demonstrate similarity. The following additional criteria will be used to determine the scope of eligible products:

  • a suitable reference biologic drug exists that: a) was originally authorized for sale based on a complete data package and b) has significant safety and efficacy data accumulated such that the demonstration of similarity will bring into relevance a substantial body of reliable data;
  • the product can be well characterized by a set of modern analytical methods; and
  • the biologic drug, through extensive characterization and analysis, can be judged similar to the reference biologic drug by meeting an appropriate set of pre-determined criteria  

In addition to the requirements which need to be included in the chemistry and manufacturing (C&M) data package for an SEB the regulations also set out the amount and type of data required to demonstrate similarity with the reference biologic drug, including extensive side-by-side characterization of the SEB and the chosen reference biologic drug. A number of quality considerations and characterizations of physical properties for submissions are also outlined in the new guidance documents.

For more information, please see: http://www.hc-sc.gc.ca/dhp-mps/consultation/biolog/2009-03-seb-pbu-eng.php