Health Canada recently released the final version of its guidance document "Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs)." The document provides guidance to sponsors on how to satisfy the information and regulatory requirements under the Food and Drugs Act and regulations for approval of SEBs in Canada. At the same time, Health Canada also updated the Data Protection and Patented Medicines (Notice of Compliance) (PM(NOC)) guidelines to address certain issues specific to SEBs.
The significance of the new and updated guidelines is that they:
- provide for a somewhat abbreviated submission package for SEBs, by accepting a reduced non-clinical and clinical data package;
- state that SEBs will not qualify as an "innovative drug" for data protection;
- state that SEBs will be subject to the submission filing and approval restrictions of the data protection provisions if their submissions rely on another innovative product that has been afforded data protection, as per regulations; and
- state that SEBs will be subject to section 5 of the PM(NOC) Regulations if they make "a direct or indirect comparison with, or reference to, another drug."
Biologics (or biological medicines) are manufactured from or through the use of animals or microorganisms, unlike pharmaceutical drugs which are synthesized by traditional chemical methods. Biologics are drugs listed in Schedule D to the Food and Drugs Act and include products such as immunizing agents and drugs obtained by recombinant DNA procedures.
An SEB, known as a "biosimilar" in Europe and "follow-on biologic" in the US, is defined by Health Canada as a "biologic drug that enters the market subsequent to a version previously authorized in Canada, and with demonstrated similarity to a reference biologic drug."
In the guidelines, Health Canada affirms that the authorization of an SEB is not a declaration of pharmaceutical and/or therapeutic equivalence to the reference biologic drug. An SEB is not a "generic" biologic.
The demonstration of "similarity" means that:
- the existing knowledge of both products is sufficient to predict that any differences in quality attributes should have no impact upon safety or efficacy of the SEB; and
- non-clinical and clinical data previously generated with the reference biologic drug can be used for the SEB.
This implies that the SEB and the reference biologic drug product are not necessarily substitutable or interchangeable.
While the guidelines provide for an abbreviated approval process for SEBs, the sponsor will still need to file a new drug submission (NDS) for market approval. In the NDS, the sponsor must clearly identify, and demonstrate similarity to, a previously Canadian-approved innovative biologic drug. Similarity is determined on the basis of analytical testing, biological assays and, to a lesser degree, non-clinical and clinical data. In certain circumstances, a manufacturer may be able to use a foreign reference product not authorized for sale in Canada to demonstrate similarity. The submission in that case must clearly explain the link between the reference product and the innovator product approved in Canada.
The guidelines set out the requirements for clinical trial applications and post-marketing. They also indicate that an SEB cannot be used as a reference biologic drug for future SEB submissions.
Sponsors of an SEB will not be able to utilize the product monograph (PM) of the reference biologic drug in its entirety as that of its own product. However, the PM for SEBs will include tables showing the results of the comparisons between the SEB and reference biologic drug.
SEBs will also be subject to the PM(NOC) Regulations and the data protection provisions of the Food and Drug Regulations, as well as their respective guidance documents, "Guidance Document: Patented Medicines (Notice of Compliance) Regulations" and "Guidance Document: Data Protection under C.08.004.1 of the Food and Drug Regulations." These guidance documents were amended concurrently with the SEB guidelines.
Under the PM(NOC) Regulations, SEBs that made "a direct or indirect comparison with, or reference to" a previously approved drug in its drug submission will be subject to section 5 of those regulations. Accordingly, a manufacturer of such an SEB will be required to either accept that market approval for the SEB will be delayed until the patents on the Patent Register expire or file a notice of allegation. Thus, if a first drug has a patent listed on the Health Canada Patent Register, the SEB will not receive market approval until the patents have expired, or the SEB manufacturer can show the patent is invalid, improperly listed or not infringed.
Under the Food and Drug Regulations data protection provisions, SEBs will not qualify as an "innovative drug" for data protection. Thus manufacturers of SEBs cannot benefit from data protection. On the other hand, SEBs will be subject to the drug submission filing and approval restrictions of those provisions, if their submissions rely on another innovative product that has been afforded data protection. That is, sponsors will not be able to file a drug submission for an SEB on the basis of a direct or indirect comparison to an "innovative drug" until six years after the notice of compliance (NOC) for the innovative drug was issued. Furthermore, sponsors will not be granted an NOC until eight years from the date of the issuance of the first NOC for the innovative drug. This way, independent of any patent protection, the innovator gets eight years of exclusivity. Note these time lines can be extended by six months if pediatric studies are conducted in accordance with the prescribed requirements.
McCarthy Tétrault Notes
Before the guidelines were finalized, Health Canada approved the first-ever SEB. Following similar actions taken by the European Medical Agency and the US Food and Drug Administration, Sandoz Canada received an NOC for its drug product Omnitrope™, based on comparison with Genotropin®, a previously approved recombinant biotechnology drug product indicated for the treatment of growth hormone deficiency.