Canada: Subsequent Entry Biologics: A New Paradigm

There are several biologic drugs approved for use in Canada comprising an estimated 14-16 per cent of the prescription pharmaceutical market. Health Canada defines such drugs as those derived through the metabolic activity of living organisms and are therefore variable and structurally complex. It is this complexity that is introducing a new paradigm of drug development with regards to R&D investment, manufacturing costs and adequate patent protection.

Biologics are typically manufactured from animals, microorganisms, or through the use of animals or microorganisms. They comprise a wide range of therapeutic indications and include products such as vaccines, hormones, enzymes, cytokines and antibodies. Biologic drugs can have a very powerful clinical impact on the management of a wide variety of diseases. For example, the use of biologic medications has revolutionized the treatment of rheumatoid arthritis thereby providing patients with very effective treatment options where few existed in the past.

The complexity of developing a biologic drug as compared to a traditional chemically synthesized drug, requires considerable R&D investment. The U.S. recognizes this investment through extended data protection for biologic drugs. In Canada, while biologic drugs are granted standard data protection, there is no additional recognition for this particular drug class. Since biologics are highly dependent on complex manufacturing processes, follow-on biologics (known in Canada as subsequent entry biologics and biosimilars in the U.S.), pose a number of particular challenges.

Subsequent Entry Biologics (SEBs) are similar, but not identical, to the innovator reference product. These differences raise additional safety and efficacy concerns. For example, SEBs may exhibit a higher immune response in certain patients, thereby leading to unacceptable levels of side effects that may not exist with the innovative product. For these reasons, Health Canada stated that subsequent entry biologics are not generic biologics and it does not support the automatic substitution of an SEB for its reference biologic drug. In other words, SEBs are not interchangeable with the innovator reference product.

SEB applicants must therefore undergo an analogous approval process as innovator biologic drugs by completing a New Drug Submission (NDS). Applications are assessed on a case by-case basis. Although it is preferable for an SEB sponsor to compare its product to a biologic drug authorized in Canada, in certain circumstances, a sponsor may be permitted to seek approval using a non-Canadian reference biologic drug. When this happens, the SEB sponsor is responsible for showing that the non-Canadian reference biologic drug is a suitable proxy for the version of the product approved in Canada.

Comparative studies (both chemical and manufacturing) between the SEB and the innovator product as well as characterization studies are required to establish similarity. According to Health Canada, the extent of the comparability studies depends on the nature of the product, the analytical techniques available to determine product differences and "the relationship between quality attributes and safety and efficacy, based on overall non-clinical and clinical experience." The clinical data required for SEB approval depends on the application, and in theory, may not be as exhaustive as that required of the innovator product. This will depend on the choice of comparable innovator drug, the design of the comparability studies, biological assays and the clinical data that is submitted. For example, Health Canada says an SEB may rely in part on "prior information regarding safety and efficacy that is deemed relevant due to the demonstration of similarity to the reference biologic drug which influences the amount and type of original data required." However, due to the fact that Health Canada considers SEBs to be new stand alone drugs that are not bio-equivalent to their reference product, extensive original testing ought to be required regardless of the initial similarity.

After Health Canada has issued approval for the SEB to be considered a new stand-alone biologic drug, a Notice of Compliance (NOC) and Drug Identification Number (DIN) are issued. SEBs are regulated and monitored in the same fashion as innovator biologics in regards to post-market surveillance. As previous noted, an approved SEB is not considered a bio equivalent of the innovator biologic to Health Canada; however, provinces individually govern whether an SEB can be substituted or interchanged for its reference drug. Consequently, the current system allows provinces to regulate the distribution of SEBs according to their individual healthcare systems.

Members of the medical community have expressed concern over potential SEB interchangeability at the provincial level. In a recent review article published in Clinical Rheumatology, several rheumatologists expressed concerns over the lack of a clear policy from provincial drug plans, stating:

Doctors and patients should remain free to select the most appropriate biologic therapy based on the patients' needs and its history of safe use and clinical response. Decisions to substitute one similar product with another should only be made at a physician's discretion. (Russell et al. Subsequent entry biologic/biosimilars; a viewpoint from Canada, Clin Rheumatol, 26 August 2012)

The review also noted that costs must not override safety and efficacy concerns, and called for strict post-marketing surveillance monitoring of SEBs.

To date, only one SEB has been approved for marketing in Canada. Given recent trends in the U.S. and Europe, combined with the impending expiry of a number of patents covering biologics, it is expected SEB entry in Canada will soon increase dramatically. Biologic drug manufacturers may avail themselves of traditional intellectual property protection such as patent litigation and data protection. SEBs, which make direct or indirect comparison to an innovator reference product, are also subject to the requirements of the Patented Medicines (Notice of Compliance) Regulations ("NOC Regulations"). In fact, 2012 marked the initiation of the first prohibition proceeding under the NOC Regulations involving a biologic drug.

The expected increase of SEBs in the Canadian market over the next several years raises a number of new challenges for biologic drug manufacturers. For example, the validity and infringement of biologic patents, and the treatment of SEBs by provincial formularies and private insurers will all need to be addressed.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

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