Health Canada has released a draft guidance document entitled “Information and Submission Requirements for Subsequent Entry Biologics (SEBs).” This document outlines the regulatory review process that Health Canada will use for a biologic that is similar to an approved innovator biologic.1

Biologics are drug products derived from biological sources that are listed on Schedule D of Canada’s Food and Drugs Act. The list includes blood products, cells and tissues, gene therapies, vaccines, radiopharmaceuticals and therapeutic products derived through biotechnology. Schedule D products may be listed as individual products (insulin), as product classes (immunizing agents), by reference to a particular source of the product (drugs, other than antibiotics, prepared from microorganisms) or by the methodology used to produce the biologic (drugs obtained by recombinant DNA procedures). Research and development costs for biologics are generally considerably greater than for conventional pharmaceutical drugs because biologics are structurally complex and difficult to manufacture. Small changes in manufacturing protocols for biologics can lead to considerable differences in terms of the quality, safety and efficacy of an end product.

An SEB is defined by Health Canada as “a biologic product that would enter the market subsequent to, and similar to, an approved innovator biologic, which would rely in part, on prior information regarding safety and efficacy that is deemed relevant due to the demonstration of similarity to a reference biologic product.” SEBs are sometimes called “generic” or “follow-on” biologics or “biosimilar” products. Health Canada does not endorse the use of the term “generic” biologic because this description incorrectly implies that the same approval process and marketed use for conventional generic drugs will apply to SEBs. Furthermore, because of their complex molecular structure and the unique manufacturing processes used to develop biologics, it is practically impossible for an SEB to be identical to a previously approved biologic, as a generic would be to its brand name drug. The term “follow-on” biologic is used by the U.S. Food and Drug Administration to describe biologics with similar medicinal ingredients, and the regulatory framework for these products is currently under debate.

A reference biologic is one that has received marketing approval from Health Canada on the basis of a complete quality, safety and efficacy assessment, including clinical trial data. The pharmaceutical form, strength and route of administration of the SEB is the same as that for the reference product. A manufacturer can demonstrate that a new biologic is “similar” to an approved reference product through comparative studies, relying upon data that have previously been generated for an innovator manufacturer. If the manufacturer so demonstrates, the approval process for an SEB may be considerably streamlined compared with that of an innovative biologic. Once a Notice of Compliance is granted for an SEB, it is regulated like any other biologic as regards post-marketing surveillance. Because biologics have the potential to cause immunogenic reactions in the body, pharmacovigilence and adverse event reporting are particularly important to ensure patient safety.

Regulatory Framework for Biologics and SEBs

Like conventional pharmaceutical drugs, biologics are approved for sale in Canada through the new drug submission (NDS) process outlined in Division 8 of the Food and Drug Regulations. Health Canada’s draft guidance document on SEBs indicates that the existing frameworks for biologic, pharmaceutical and generic drugs will provide the regulatory framework for SEBs and, if appropriate, the practices for regulating generic drugs will be applied to SEBs.

To be approved through the SEB pathway, a product must demonstrate “similarity” to an appropriate reference product, which will normally be a product approved in Canada, through an extensive comparison between the products. An appropriate reference product is one that has been on the market for a sufficient period of time to generate a substantial amount of safety and efficacy data. An SEB should not be used as a reference product. The determination of similarity is based upon analytical testing, biological assays, clinical data and non-clinical data as outlined in detail in the draft guidance document. The extent of clinical data required to support an NDS will depend on the level of similarity demonstrated between the SEB and its reference product. Even if they contain similar active ingredients, a product utilizing a different manufacturing process from that of its reference biologic will not be eligible for the SEB regulatory pathway. A full set of chemistry and manufacturing data will also be required as part of the SEB submission package.

One significant difference between the regulation of generic pharmaceuticals and that of SEBs pertains to the use of an innovator’s product monograph. Unlike the case for generic drugs, the manufacturer of an SEB cannot use the product monograph of the reference biologic, so instead is required to develop its own monograph in accordance with Health Canada policies.

A Notice of Compliance on an SEB will not automatically be granted for all the indications of its reference product. The indications for a particular SEB will be based on the data submitted during the NDS process and will be subject to considerations such as the level of reliance on the reference product, the demonstrated level of similarity, and the availability of postmarket information.

Patent Register and Data Exclusivity

The guidance document indicates that biologics, like traditional pharmaceutical drugs, are subject to the same provisions of the Patented Medicines (Notice of Compliance) Regulations (PM (NOC) Regulations) and the Food and Drug Regulations (Data Protection). Specifically, biologics that meet the definition of an “innovative drug” under C.08.004.1 of the Food and Drug Regulations may be eligible for an eight-year term of data protection (with an extra six-month period for pediatric indications). During this time, any data submitted to Health Canada relating to the innovative drug may not be used by competitors seeking marketing approval of an SEB. Patents that claim the medicinal ingredient, formulation or dosage form of a biologic, or an indication for the biologic, for which drug regulatory approval is sought may be listed on the Patent Register and therefore subject to the protections of the PM (NOC) Regulations.

Stakeholders have expressed concern over the applicability of the PM (NOC) Regulations and the data protection provisions of the Food and Drug Regulations within the current framework for biologic approval. In particular, the exclusions from the Patent Register of purely process patents and/or patents on processing intermediates may result in inadequate protection for innovator biologics because, unlike conventional pharmaceuticals, manufacturing protocol is absolutely critical to biologic production. The listing of a patent claiming the “medicinal ingredient” of a biologic, or a dosage, formulation or use thereof, may not sufficiently protect an innovator’s intellectual property rights. An SEB manufacturer could circumvent the PM (NOC) Regulations in claiming that its SEB is not identical to that of listed biologic, while still referencing the biologic for the purposes of demonstrating similarity for regulatory approval. Parallel concerns have been raised with respect to the definition of an “innovative drug” for the purposes of data protection under the Food and Drug Regulations. The term “variation” in this context must be properly interpreted so that truly innovative biologics utilizing a unique manufacturing process are afforded data protection, whereas biologics that seek approval on the basis of a direct or indirect comparison to a previously approved product do not. Amendments to both the PM (NOC) Regulations and the data protection provisions in the Food and Drug Regulations may be necessary to foster innovation in this field.

Proposed Amendments To the Regulations

The guidance document indicates that the Food and Drug Regulations will be amended to provide a comprehensive legal basis for the regulatory framework of SEBs. The amendments will include changes to the NDS pathway that are specific to SEBs with demonstrated similarity to a reference biologic. Additional guidance documents on biologics will be released that will detail information and data requirements for specific classes of SEB products. Health Canada intends to harmonize the approval process for SEBs, to the extent possible, with other regulators and international organizations such as the World Health Organization and the International Conference of Harmonization.

Several Canadian patents covering biologics have either recently expired or will expire shortly. An increase is therefore expected in the number of NDS filings and issued Notices of Compliance on SEBs over the coming years. Health Canada states that the regulatory framework for SEBs is “not intended to be a disincentive for innovation nor become unduly burdensome for SEB sponsors.” Further guidance from Health Canada will be necessary to ensure that the approval process for all biologics is fair and efficient. As discussed above, amendments to the PM (NOC) Regulations and the data protection provisions may also be required.

In light of the current and future interest in SEB products, innovator biologic manufactures should carefully consider their regulatory strategy to ensure that inventive products are protected to the full extent permitted under the PM (NOC) Regulations and the Food and Drug Regulations (Data Protection) as these currently read. Such a regulatory strategy would include an assessment whether a biologic is an “innovative product” and particular attention to the claim language in all patents relating to the product.

This article first appeared in Update, May/June 2008, issue 3. Reprinted with permission of the Food and Drug Law Institute (FDLI) (c) 2008.