Health Canada announced that it had granted marketing authorization for Omnitrope (a human growth hormone), the first subsequent entry biologic (SEB) to be approved for sale in Canada. Much to the surprise of stakeholders, this April 22, 2009 announcement, occurred in the midst of a consultation period, during which Health Canada was actively seeking comments on a draft guidance document intended to establish an SEB regulatory pathway. Adding to the consternation of innovator biologic manufacturers, pending SEB submissions currently under review by Health Canada will likely be approved before the guidance document is finalized and certainly without any amendment to the current legislative scheme under the Food and Drug Regulations (Regulations).1
The original draft guidance document "Information and Submission Requirements for Subsequent Entry Biologics (SEBs)" (Original Guidance) was published by Health Canada on January 30, 2008, and was the subject of an earlier article published in Update.2 Th e Original Guidance has since been revised, and was released on March 27, 2009 (Revised Guidance). It is subject to a 60-day comment period that ended on May 26, 2009. Despite repeated submissions by innovators during the consultation following publication of the Original Guidance, the Revised Guidance states that SEB submissions will take place under the existing Regulations and without a legislative amendment to create a specific SEB approval pathway. Th e Revised Document, together with modifications to two other Health Canada guidance documents on patent and data protection, will establish the basis for an SEB approval pathway.3
What Are SEBs?
Biologics are a subset of drugs that are generated from biological sources and include gene therapies, vaccines, antibodies and other therapeutic products derived through biotechnology. Biologics are structurally complex and diffi cult to manufacture in comparison with traditional pharmaceuticals, which have a chemical entity as the active medicinal ingredient.
An SEB is defined by Health Canada as a biologic product that would enter the market subsequent to, and is similar to, an innovator product authorized for sale in Canada. Because the two products are "similar," non-clinical and clinical data generated using the innovator biologic, or "reference product," are relevant to the safety and efficacy of an SEB and may be relied upon to reduce the amount of data in an SEB submission.
In contrast to generic pharmaceuticals, where the active ingredient in a generic pharmaceutical is identical to that of a reference product or where the generic pharmaceutical is therapeutically equivalent to the reference product, "similar" in the biologic context does not imply that an SEB is identical to its reference product or that the two products are therapeutic equivalents.
Instead, by demonstrating similarity, an SEB manufacturer attempts to predict that any difference in quality attributes in relation to the reference product should have no adverse impact on the safety and efficacy of the SEB. Th us, the two key features in an SEB submission are 1) a comparison to a reference product, and 2) a reduced data requirement due to reliance on data previously generated for the reference product.
The Revised Guidance indicates that SEBs will be approved through the existing New Drug Submission (NDS) pathway under the Regulations. It is noteworthy that the NDS provisions do not contemplate a manufacturer's reliance on a reference product. Further, it is questionable whether these provisions aford Health Canada the discretion to reduce the data requirements of an NDS in the manner contemplated by the Revised Guidance.
In fact, when an abbreviated data set is contemplated, as in the case for generic pharmaceutical drugs, the Regulations carve out a specific exception—the Abbreviated New Drug Submission (ANDS) pathway. Under the ANDS pathway, a generic pharmaceutical manufacturer may rely on the safety tests of a defined "Canadian reference product" by demonstrating that the generic drug is its pharmaceutical equivalent and bioequivalent. Th e ANDS pathway cannot support the approval of SEBs because an SEB is invariably not identical to a reference biologic product. Th e structure and manufacturing processes used for biologics call for a standard of "similarity" rather than "identicality."
Regardless of these inadequacies in the current regime with respect to biologics, Health Canada intends to use this framework as the basis for the approval of SEBs.
The Revised Guidance provides some general information on the type of data that an SEB manufacturer must provide to Health Canada. As with a standard NDS, a full chemistry and manufacturing package is required to demonstrate similarity in the manufacturing processes. Comparative studies are also needed to show comparable physicochemical and immunochemical properties, biological activity and purity.
A final decision on similarity to a reference product will be largely based on analytical and biological characterization. Clinical and non-clinical tests are required to varying degrees depending upon the quantity and extent of demonstrated similarity between an SEB and a reference product. Th e Revised Guidance discusses the need for pharmacokinetic and pharmacodynamic studies, as well as comparative clinical trials to show similarity in efficacy and safety profiles, including immunogenicity.
Stipulations have been made with respect to the clinical indications for an SEB. An SEB will not automatically receive authorization for each of the indications for which the reference product is approved; rather, indications will depend upon the data provided by the sponsor. If, however, the mechanismof- action of an SEB strongly supports an indication, approval for that indication may be granted even in the absence of data.
Foreign Reference Product
Citing the small number of innovator biologics in Canada and the desire to provide flexibility to manufacturers, Health Canada will allow a manufacturer to use a non-Canadian reference product to demonstrate similarity between an SEB and a product authorized for sale in Canada. Th e Revised Guidance requires an SEB submission to contain sufficient evidence of the link between the foreign reference product and a Canadian approved innovative product. Preferred foreign reference products are those marketed in a country that formally adopts International Conference on Harmonization (ICH) guidelines and has an approval scheme that is similar to Canada's. Of note, the European Union (EU), which was the fi rst jurisdiction to approve an SEB in 2006, does not permit the use of a foreign reference product.4
With the Revised Guidance, Health Canada has attempted to allay fears that an SEB manufacturer could circumvent the protections afforded to innovators under the Patented Medicines (Notice of Compliance) Regulations. Th e PM(NOC) Regulations create a framework for pharmaceutical patents to be listed on Health Canada's Patent Register (which is the equivalent of the U.S. "Orange Book") if the patents claim the "medicinal ingredient," or a dosage, formulation or use thereof in respect of a particular drug.
Specifically, the PM(NOC) Regulations are triggered when a "second person" files a drug submission that, directly or indirectly, compares its drug with, or makes reference to, another drug marketed in Canada. Once triggered, the second person must either wait until the expiry of all patents on the Patent Register in respect of the reference product before receiving marketing authorization or send a notice to the "first person" innovator and initiate court proceedings to contest the listed patents.
Clearly, the language of the PM(NOC) Regulations is of concern when a non-Canadian reference product is being considered, because the non-Canadian reference product is not marketed in Canada. Health Canada has proposed revising its PM(NOC) guidance document (PM(NOC) Guidance) to attempt to clarify when an SEB sponsor will be considered a "second person." If a link has been established in a submission between a non-Canadian reference product and a drug authorized for sale in Canada, such submission will be considered to be making a comparison for the purposes of the PM(NOC) Regulations. If the Canadian version of the reference product has patents listed on the Patent Register, the SEB sponsor would be considered a second person, according to Health Canada.
Pure process patents and patents claiming processing intermediates are not listable on the Patent Register. As the authors pointed out in their previous article,5 manufacturing protocol is critical to biologic production, so it is possible that the current listing rules may not sufficiently protect an innovator's intellectual property rights in its biologic product. Th is issue is not discussed in the Revised Guidance or proposed amendment to the PM(NOC) Guidance, and it is unlikely that Health Canada will change its stance on listability requirements.
As discussed, an SEB submission relies in part on data from a previously approved innovative biologic in order to justify a reduced submission package. Concerns relating to data protection were incorporated into the "Data Protection under C.08.004.1 of the Food and Drug Regulations"6 (Guidance on Data Protection). Th is document was first published in draft form on June 25, 2007, and followed by a comment period during which stakeholders were encouraged to provide feedback. Th e final Guidance on Data Protection is effective as of March 30, 2009.
Under the Regulations, an "innovative drug" that contains a medicinal ingredient not previously approved in a drug by Health Canada is entitled to an eight-year term of data protection. This term can be extended for an additional six months for pediatric population submissions. If a subsequent manufacturer seeks approval of its product on the basis of a direct or indirect comparison with an innovative drug marketed in Canada, the manufacturer 1) may not file its drug submission for six years;7 and 2) will not receive marketing authorization for eight years (or eight years and six months) from the date that the innovative drug was approved for sale.
The Guidance on Data Protection indicates that this prohibition will apply to a new drug submission for an SEB where approval is sought on the basis of a comparison to an innovative drug. Furthermore, Health Canada intends to amend the Guidance on Data Protection to confirm that data protection extends to an innovative drug when it is indirectly compared to an SEB by virtue of a foreign reference product. As for patent protection, when a non-Canadian reference biologic is substituted for the Canadian product and a link is established to a drug marketed in Canada, this would be considered a comparison that would trigger the data protection regime.
In their previous article, the authors noted specific concerns regarding the definition of an "innovative drug" in the context of biologics. An innovative drug is characterized by the Regulations as one that "contains a medicinal ingredient not previously approved in a drug by the Minister and that is not a variation of a previously approved medicinal ingredient such as a salt, ester, enantiomer, solvate or polymorph" (emphasis added). This definition is obviously tailored to traditional small molecule drugs, and Health Canada has provided no guidance on the meaning of "variation" as it pertains to a biologic. It is not therefore clear how this definition would be applied 1) to an SEB, or 2) to an "innovative" biologic developed using a unique production processand containing a medicinal ingredient that is related to, but not identical to, a previously approved biologic.
Several Canadian patents covering biologics have either recently expired or will expire shortly; numerous SEB approvals are thus expected in the coming years. Health Canada has indicated that a number of SEB submissions are pending and so the industry is bracing for the arrival of additional SEBs into the Canadian marketplace.
Although Health Canada made revisions to respond to certain concerns expressed by innovators over the past year, the Revised Guidance falls short in several areas. For example, there is general agreement that the demonstration of similarity will differ depending on the level of complexity and variability that is intrinsic to a particular class of biologic. The need for guidance that is specific to particular categories of SEBs has been repeatedly emphasized, but Health Canada does not intend to formulate such guidance in the near future.8 Th e unique naming of SEBs, a critical component of postmarket surveillance, is also not covered in the Revised Guidance. It is also notable that the degree of similarity that would be required to approve an SEB, and the link required to trigger intellectual property protections where a foreign reference product is used, remains ambiguous.
Health Canada has not proposed a timeline for fi nalizing the Revised Guidance but further consultation with drug manufacturers and nonindustry stakeholders is expected in the coming months.
Ms. Reguly practices intellectual property law in the law firm of Torys LLP, Toronto, Canada.
Ms. McMahon is a Partner in the law firm of Torys LLP, Toronto, Canada. She is the co-chair of the Intellectual Property and Food and Drug Regulatory practices in the firm.
1 C.R.C. c. 870, available at http://laws.justice.gc.ca/en/ showdoc/cr/C.R.C.-c.870///en?page=1.
2 McMahon, E. & Reguly, T., Follow-on Biologics in Canada: A Look at the New Draft Guidelines, Update, Issue 3, (May/June 2008), 43–45.
3 The Revised Document has been published concurrently with two notices proposing amendments to the guidance documents, titled "Patented Medicines (Notice of Compliance) Regulations" and "Data Protection under C.08.004.1 of the Food and Drug Regulations." These three documents are available at http://www.hc-sc.gc.ca/dhp-mps/consultation/ biolog/2009-03-seb-pbu-eng.php.
4 Pending biosimilar bills before the U.S. Senate do not permit the use of a foreign reference product.
5 See note 2, above.
7 Note that there is an exception for drug submissions filed under Canada's Access to Medicines Regime, which provides a mechanism for developing countries to receive generic versions of drugs and medical devices at reduced costs.
8 This is in contrast to the practice in the EU, where the European Agency for the Evaluation of Medicinal Products (EMEA) has released guidance documents for several classes of biologics.
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