The "patent dance" in the U.S. has received a great deal of attention in the last few years, with pharmaceutical companies, their counsel and the courts struggling to determine the scope and meaning of the Biologics Price Competition and Innovation Act (BPCIA). Fortunately, the law is much more settled north of the border.
Canada has a linkage regime (the Patented Medicines (Notice of Compliance) Regulations),1 which encompasses any drug, whether a small molecule pharmaceutical or a biologic. This has been the case since the enactment of the PM(NOC) Regulations in 1993, which was well before biosimilars, or subsequent entry biologics (SEBs) as they are known in Canada, could even be approved by way of an abridged pathway before Health Canada.
The SEB Pathway to Approval
The Food and Drugs Act and related Food and Drug Regulations govern the approval of all drugs, including biologics. For generic drugs, an abbreviated new drug submission (ANDS) can be filed, which does not require clinical trials, but only a showing that the drug is "bioequivalent" to an earlier approved "Canadian reference product". This pathway is not available to SEBs, as the active medicinal ingredient is not identical to that of the reference biologic drug, and there is no unique regulatory pathway for SEB approval. Rather, Health Canada will accept a SEB submission as a new drug submission (NDS), based on a reduced data package. Typically an NDS would include complete clinical and non-clinical data.
The first SEB that was approved in Canada was Sandoz's OMNITROPE (somatropin). This was in 2009, and before Health Canada published its Guidance for SEB approval in 2010.2
According to the Guidance, for an SEB to be approved, there must be a suitable reference biologic drug (i.e., one approved based on a complete data package with significant safety and efficacy data accumulated); the SEB must be well characterized; and the SEB must be "similar" to the reference biologic in terms of its quality attributes making relevant safety and efficacy data from the reference biologic drug. The reference biologic drug used for comparison purposes may be a non-Canadian reference biologic, which is a suitable proxy to the approved Canadian reference biologic drug. The SEB sponsor may seek one or more indications approved for the reference biologic drug, and may seek indications that are not approved for the reference biologic drug, if there is supporting data.
The 2010 Guidance is presently under review. A draft amended Guidance was published on December 7, 2015, and the public comment period expired on February 15, 2016. The proposed amendments seek to clarify the information and regulatory requirements for SEB approval, such as: the selection of a reference biologic drug; considerations when performing non-clinical and clinical studies for SEBs; and post-market requirements, including periodic safety reporting.
In order to further assist SEB sponsors, Health Canada has also launched a 3-year pilot program commencing on September 14, 2015, which will permit an SEB sponsor to request a scientific advice meeting with Health Canada on its comparability package early in the SEB development process.
There have been four SEBs approved since OMNITROPE: REMSIMA/INFLECTRA (infliximab) was approved in 2014, and BASAGLAR (insulin glargine) and GRASTOFIL (filgrastim) were approved in 2015. Of these products, filgrastrim and infliximab have been the subject of litigation under the PM(NOC) Regulations.
A subsequent entry manufacturer (SEM) filing an SEB NDS that makes reference or comparison to a biologic reference drug for which there are patents listed on the "Patent Register" must await patent expiry, or make an allegation that, for instance, its product will not infringe the listed patents, or the listed patents are invalid, in order for Health Canada to approve the SEB. The manufacturer of the biologic reference drug has the option of challenging the allegations in court, which proceeding can last up to 24 months. During this time period, Health Canada cannot approve the SEB. The court will ultimately make a finding that the allegations are justified or unjustified, and if unjustified, the SEM can launch its product at risk once Health Canada has approved the SEB. There is no final finding of non-infringement or invalidity in a proceeding under the PM(NOC)Regulations. Thus, all listed patents can be asserted in a patent infringement action once the SEB is approved, as well as any patents that were not listed. This same process applies to generic drugs.3
The first judicial decision under the PM(NOC) Regulations relating to an SEB was released on November 10, 2015. The Federal Court dismissed Amgen's application for an order prohibiting the issuance of a NOC4 to Apotex for its proposed filgrastim product (GRASTOFIL), which relied on a comparison to Amgen's NEUPOGEN. Apotex was successful in its patent validity challenge (based on an allegation of obviousness), and received its NOC on December 7. Amgen has sued Apotex for patent infringement.
There was no litigation for the first indications approved for INFLECTRA (rheumatoid-arthritis or "RA" indications), since there were no patents listed on the Patent Register when Celltrion filed its NDS. A patent was subsequently listed prior to Celltrion's submission to expand its indications to irritable bowel disease (IBD), which engaged the PM(NOC) Regulations. However, Janssen's application was summarily dismissed on the basis that the patent claims did not encompass IBD, and as such Celltrion's further indication would not be infringing. There is a separate infringement action pending.
Further litigation of SEBs under the PM(NOC) Regulations is pending relating to versions of Amgen's recombinant antibody etanercept (ENBREL) by Samsung Bioepsis and by Sandoz.
As with other countries, one of the reasons for the focus on SEBs is the expectation that pricing pressures facing generic drugs will not be extended to biologics.
Most of Canada's provincial drug plans, and some of the other public plans, turn to the Canadian Agency for Drugs and Technologies in Health (CADTH) for guidance on reimbursement, including whether the drug should be listed on the formularies that govern reimbursement, and pricing.
The first SEB to be considered by CADTH was INFLECTRA. The recommendation was to "list" INFLECTRA on the formularies in accordance with the Health Canada-approved indications (treatment of rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis), provided: (i) it is used in patients for whom infliximab is considered to be the most appropriate treatment option and (ii) it is listed in a manner similar to REMICADE. The costs considered were: INFLECTRA at $650 per 100 mg vial and REMICADE (under the Ontario Exceptional Access Program) at $987.56 per 100 mg vial.
The price of an SEB may be further limited if there are any patent(s) owned or licensed by the SEM relating to the SEB. Where a patent pertains to a medicine, then the Patent Medicines Prices Review Board (PMPRB) may have jurisdiction over the price at which the medicine can be sold. Thus, far we have not seen any information from the PMPRB regarding patented SEBs and pricing.
In 2014, CADTH also published an Environmental Scan, which provided an overview of the SEB landscape, designed to assist in developing approaches to the review and reimbursement of SEBs. The report includes information on SEBs in development, as well as expected patent expiry dates.
Other Aspects Related to Market Entry
No discussion of exclusivities would be complete without a reference to data protection. Canada provides eight years of market exclusivity (8.5 years if the pediatric extension applies) from the first NOC for an "innovative drug", which includes a biologic. Thus, if a reference biologic drug is an "innovative drug" an SEB cannot be approved until after this period of market exclusivity expires. An SEB sponsor is also not able to file its NDS for 6-years after the first NOC for the innovative drug. According to Health Canada, an SEB would not be entitled to its own data protection term.
While we expect to see much more activity in the courts relating to SEBs, and further guidance on issues such as pricing, we can count on the fact that there is clarity in the SEB litigation landscape in Canada. This is one instance where being a wallflower is not such a bad thing.
- The PM(NOC) Regulations, SOR/93-133, as amended.
- "Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs)": http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/seb-pbu/seb-pbu_2010-eng.php.
- If Canada and Europe sign the Comprehensive Economic and Trade Agreement (CETA), then this regime may change to end the possibility of "dual litigation" of the same patents in respect of the same product and as between the same parties under the PM(NOC) Regulations and the Patent Act.
- Notice of Compliance; the Canadian marketing authorization.
- "Subsequent Entry Biologics – Emerging Trends in Regulatory and Health Technology Assessment Frameworks": https://www.cadth.ca/subsequent-entry-biologics-emerging-trends-regulatory-and-health-technology-assessment-frameworks