Expect More "Biosimilars" On The Market In Canada

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By Louisa Pontrelli and Noel Courage

SEB Approval Process
As more innovator patents for biologics approach expiry, the interest in developing “generic versions” or “copies” of these biologics, known as “biosimilars” will increase. Health Canada approved its first subsequent entry biologic (“SEB”) for Omnitrope (growth hormone) back in April 2009. It was approved despite the absence of a specific regulatory pathway for SEB approval. It is also now clear that no amendments to the Food and Drug Regulations are on the horizon. Health Canada’s position is that the existing regulatory frameworks provide a sufficient basis for approval of SEBs. In these circumstances, industry will have to pay careful attention to Health Canada’s revised draft Guidance Document on SEB’s (dated March 27, 2009).

The Challenges of Evaluating SEB’s
Biologic drugs, which are derived from living organisms, are large and structurally complex. They are inherently more variable than chemically synthesized drugs. Chemically synthesized drugs are generally small molecules and are easier to reproduce. A drug may be approved in Canada under the Food and Drug Regulations by filing a new drug submission (“NDS)”, which involves the submission of a complete data package (including quality, non-clinical and clinical data). The NDS is generally the route taken by innovators for both biologic and chemically synthesized drugs. In contrast, a generic manufacturer seeking to make a copy of a chemically synthesized drug files an abbreviated new drug submission (“ANDS”), which involves the submission of a truncated data package that relies on the clinical data generated at the innovator’s time and expense. In both cases, once safety and efficacy requirements are met, marketing authorization, called a Notice of Compliance (“NOC”), is issued by Health Canada.

Approval Under the Current Pathway
The approval pathway for generic versions of chemically synthesized drugs is based on the demonstration of pharmaceutical bioequivalence to a Canadian reference product. This involves providing data comparing the generic product and innovator formulations, such as comparing concentration of the innovator drug and generic drug in the blood at different time points. Due to the complexity and heterogeneity of biologic drugs, it is not possible for SEB sponsors to make identical copies of innovator biologic drugs. These differences are partly due to different cell lines, manufacturing processes, culture conditions, materials, and purification methods, etc.

As indicated in the revised draft Guidance Document, approval of an SEB does not declare pharmaceutical and/or therapeutic equivalence to the reference biologic drug. Rather, approval of an SEB stems from a submission demonstrating similarity of the SEB based on a direct or indirect comparison to an innovator biologic product authorized for sale in Canada. A reduced non-clinical and clinical data package is permitted for SEBs. A non-Canadian or foreign reference product may be used to establish similarity (i.e. data that originated outside of Canada) provided that there is a sufficient link between the non-Canadian reference biologic drug used in comparative studies and the version of the innovator product approved in Canada. The revised draft Guidance Document sets out information on the type of data required for an SEB submission. A demonstration of similarity means “any differences in quality attributes should have no adverse impact upon safety or efficacy of the SEB…”.

Final determination of similarity is based on a “combination of analytical testing, biological assays, and non-clinical and clinical data”, which includes immunogenicity studies.

The revised draft Guidance Document distinctly states that SEBs are not ‘generic’ versions of reference biologic products, rather, SEBs are considered to be ‘stand alone’ products.

An SEB will have its own product monograph and will not be automatically substitutable with reference biologic products. Clinical indications will be granted based on data provided by an SEB sponsor, and thus SEBs may not be granted all indications of reference biologic products. However, it may be possible to obtain additional indications based on extrapolation to other indications approved for the reference biologic where justified, for example, on the basis of mechanism of action. An SEB sponsor may also obtain an indication that has not been granted to the reference biologic product provided that full clinical trial data is filed.

Patent & Data Protection
The regulatory pathway for SEB marketing authorization based on safety and efficacy interfaces with a larger regulatory environment involving patents and clinical data protection.

In the context of conventional generic pharmaceuticals, an innovator may list eligible patents on the Health Canada Patent Register. A generic manufacturer (i.e. second person) seeking to make copies of the innovator drug must then address all the patents on the Register before it gets marketing authorization.

The innovator is provided with notice that the generic manufacturer has applied for marketing authorization. The innovator then has an opportunity to apply to the Federal Court to attempt to block the genetic competitor from entering the market. An SEB manufacturer will be in a similar position as a generic manufacturer under these rules when the SEB relies on a direct or indirect comparison to an innovator biologic for which a patent is listed on the Register. It remains to be seen as to whether the existing language in the regulations is sufficient to adequately capture SEB submissions, so that patent protection will be obtained prior to SEB market entry.

Data protection refers to the period of time during which a competitor is precluded from relying on an innovator’s data to show evidence of safety and effectiveness. This effectively prevents the SEB from obtaining approval since its manufacturers will not generate their own complete data set. There is an 8-year data protection period starting from the innovator’s first NOC for the drug (extended by 6 months if the drug has been the subject of pediatric clinical trials).

An innovator is eligible for data protection if its marketed drug meets Health Canada’s definition of an ‘innovative drug’. There is also a 6-year no filing period within the 8-year term, where a second person will not be permitted to even file a submission seeking approval to market a copy of an innovative drug. The 6-year no filing period will be triggered when a submission for a SEB makes a direct or indirect comparison to a previously authorized innovative reference biologic product for the purpose of demonstrating similarity.

It is unclear how the definition of ‘innovative drug’ will apply to biologics. In addition, given the time and investment it takes to develop biologics as compared to chemically synthesized drugs, it is debatable whether an 8-year prohibition of SEB approval is adequate.

Biosimilars in Other Jurisdictions
Approval of biosimilars has been extensively considered in other jurisdictions. The European Commission (“EC”) has had established legislation and guidelines on similar biological medicinal products in place as early as 2005, and has approved several biosimilars thus far including human growth hormone, epoetin alfa, epoetin zeta, and filgrastim. The EC guidelines stipulate that comparability data is needed to demonstrate the similar nature of the new similar biological medicinal product and the chosen reference medicinal product with respect to quality, safety and efficacy. The EC’s European Medicines Agency (EMEA) also has guidelines directed to quality, non-clinical, and clinical aspects for similar biological medicinal products. Overall, studies must be conducted which demonstrate that the biosimilar product is similar to and is as safe and effective as the reference biological product. The EMEA also has product specific guidelines in place. In the United States, several draft bills have been proposed by the US Senate or House and died. Legislative efforts have been renewed, but it is not clear when legislation will be implemented. The US FDA has approved a human growth hormone biosimilar, however the FDA noted that this did not create a pathway that could be routinely followed for other biosimilars.

Conclusion
The revised draft Guidance Document establishing the SEB approval pathway has attempted to address concerns from innovators and SEB sponsors. However, the fact that no amendments to existing legislation and regulations are proposed creates a level of uncertainty in the approval of SEBs. Competition from entry of SEBs in the Canadian marketplace will become more and more evident as patents for innovator biologics expire. The approval frameworks for SEBs need to achieve a balance between competition, patient safety, and continued incentives for innovative biologics, for example, by providing clear protection of patent rights and data.

Louisa Pontrelli, B.Sc., M.Sc. (Clin. Biochem.), LL.B. is an associate with Bereskin & Parr LLP. Her practice focuses on biotechnology and pharmaceutical matters, including patents, licensing, and related litigation. She is also a member of the firm’s Litigation Practice and is involved in cases relating to life sciences. She can be reached in Toronto at 416.957.1656 or lpontrelli@bereskinparr.com

Noel Courage, B.Sc. (Biochem.), LL.B. is a partner in Bereskin & Parr LLP and a registered Canadian and U.S. Patent Agent. His practice focuses on the patenting and licensing of chemical, biotechnological and pharmaceutical inventions. He can be reached in Toronto at 416.957.1655 or ncourage@bereskinparr.com