Health Canada released a draft guidance this week which would allow approval of “subsequent entry biologics” (SEB) based on an abbreviated complement of clinical data, provided the SEB is shown to be “similar” to a reference, approved biologic product.[1] While the U.S. continues to heatedly debate legislation which would create a pathway for abbreviated approval of biosimilars, or follow-on biologics, by the U.S. Food and Drug Administration (FDA), Canada is advancing its implementation of such a pathway with the release of the SEB draft guidance. The European Union has permitted approval of biosimilar products since 2005.
Like FDA guidance documents in the U.S., Health Canada guidance documents do not have the force of law in Canada. However, the draft guidance indicates that the Canadian Food and Drug Regulations will be amended to provide “a comprehensive legal basis” for the regulation of SEBs and that in the interim, the draft guidance will provide a flexible SEB regulatory framework. The Canadian Minister of Health also plans to publish additional guidance documents that will further elaborate information and data requirements for specific classes of SEBs. Public comments on the SEB draft guidance are due April 16.
Requirements for SEB Approval Under the Draft Guidance
The draft guidance provides for approval of SEBs based on a showing of “similarity” to a reference approved biological product. Notably, the reference biological product may, but need not, be approved in Canada. Upon request, the Minister of Health may consider use of a reference product approved in a jurisdiction outside of Canada. While approved SEBs are considered “new” biological products subject to all regulatory requirements for approved biologics, an SEB may not be used a reference product.
Critical provisions relating to approval of an SEB are as follows:
- Definition of Similar. The SEB must be “similar” to the reference product in terms of quality, safety, and efficacy.
- Comparative studies are needed to show similarity, including a full chemistry and manufacturing data package to show similarity in manufacturing processes, as well as studies to show comparable physicochemical and immunochemical properties, biological activity, and purity.
- The final decision on similarity should be largely based on analytical and biological characterizations to show that the existing knowledge of both products is sufficient to: 1) predict that any differences in quality will have no adverse impact on safety or efficacy; and 2) demonstrate that non-clinical and clinical data for the reference product are relevant to the SEB.
- An SEB will not be granted approval for all indications for the reference product, approval will only be granted for indications for which data is provided.
- Clinical Trials. Clinical trials are required to show quality, safety, and efficacy of the SEB, however, the “level and extent” of required clinical data will depend on the level of demonstrated similarity between the SEB and the reference product. At a minimum, the draft guidance requires PK/PD studies, as well as comparative clinical trials to show similarity in efficacy and safety profiles, including immunogenicity.
- Interchangeability. The draft guidance explicitly states that SEBs are not generic biologics, and that approval of an SEB does not indicate that the SEB may be automatically substituted with the reference product, though a substitutability decision may be made on the “basis of science.”
- Postmarket Requirements. The draft guidance document strongly recommends that a post-market safety plan be presented as part of the SEB approval application, and that such plan be implemented post-approval. Adverse drug reaction reporting is required for SEBs.
- Patent Protection and Market Exclusivity. The draft guidance does not discuss intellectual property concerns or market exclusivity related to SEBs or innovator products. However, the draft guidance does state that “all the laws, patent and intellectual property principles” outlined within the Patent Act, Food and Drug Regulations (Data Protection) and Patented Medicines Notice of Compliance Regulations are applicable to SEBs.
Comparison to Pending U.S. Legislation
Canada’s approach to biosimilar or follow-on biologic approvals appears similar to legislation introduced by U.S. Senators Kennedy, Enzi, Clinton and Hatch. Like the Health Canada draft guidance, S. 1695, the Biologics Price Competition and Innovation Act, does not require product-specific guidance to be issued before approval of an FOB. However, the Senate legislation is dissimilar in that it does not require the FOB to be approved for each indication of use for the reference product. Canadian SEBs will not be granted approval for all indications for the reference product and is therefore more similar to the provision in legislation introduced in the U.S House of Representatives by Representatives Eshoo and Barton, which requires product specific guidance before approval of an FOB as well as approval of the FOB for each indication for use for the reference product.
All three proposals require the FOB/SEB to be “similar” to the reference product and require clinical trials, including immunogenicity studies. One key difference is that Canada does not require a determination on interchangeability at the time of the SEB approval, while both the U.S. Senate and House bills do require such a determination (whether positive or negative). In addition, both U.S. bills require strict post-market surveillance, while Health Canada only strongly recommends such attention.
Finally, the U.S. legislation addresses patent and market exclusivity concerns for both the SEB and FOB to strike a balance between protecting and fostering innovation and stimulating competition.
The Canadian draft guidance includes a statement that the regulatory framework for SEBs is “not intended to be a disincentive to innovation nor to become unduly burdensome for SEB sponsors,” and applies current patent law to approved SEBs. However, the draft guidance does not specifically address market exclusivity or other protections for innovator products.
Conclusion
The circulation of the SEB draft guidance is a major step towards a well-defined approval pathway for biosimilar approvals in Canada. Whether the U.S. follows before a new Administration takes shape in Washington D.C. during 2009 remains to be seen.
1. Draft Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs), Canada, Minister of Health, available at http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/brgtherap/003-2008-seb-pbu_e.pdf.