Canada: Biosimilars In Canada: New Draft Guidelines From Health Canada

This article first appeared in Update, Issue 4, July/August 2009. Reprinted with permission of the Food and Drug Law Institute (FDLI) ©2009.

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occurred in the midst of a consultation period, during which Health Canada was actively seeking comments on a draft guidance document intended to establish an SEB regulatory pathway.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The original draft guidance document "Information and Submission Requirements for Subsequent Entry Biologics (SEBs)" (Original Guidance) was published by Health Canada on January 30,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.

Regulatory Approval

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.

Data Set

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

Patent Protection

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.

Data Protection

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 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 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.

6 Available at prodpharma/applic-demande/guide-ld/data_ donees_protection-eng.php.

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.

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.

To print this article, all you need is to be registered on

Click to Login as an existing user or Register so you can print this article.

In association with
Related Topics
Related Articles
Related Video
Up-coming Events Search
Font Size:
Mondaq on Twitter
Register for Access and our Free Biweekly Alert for
This service is completely free. Access 250,000 archived articles from 100+ countries and get a personalised email twice a week covering developments (and yes, our lawyers like to think you’ve read our Disclaimer).
Email Address
Company Name
Confirm Password
Mondaq Topics -- Select your Interests
 Law Performance
 Law Practice
 Media & IT
 Real Estate
 Wealth Mgt
Asia Pacific
European Union
Latin America
Middle East
United States
Worldwide Updates
Registration (you must scroll down to set your data preferences)

Mondaq Ltd requires you to register and provide information that personally identifies you, including your content preferences, for three primary purposes (full details of Mondaq’s use of your personal data can be found in our Privacy and Cookies Notice):

  • To allow you to personalize the Mondaq websites you are visiting to show content ("Content") relevant to your interests.
  • To enable features such as password reminder, news alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our content providers ("Contributors") who contribute Content for free for your use.

Mondaq hopes that our registered users will support us in maintaining our free to view business model by consenting to our use of your personal data as described below.

Mondaq has a "free to view" business model. Our services are paid for by Contributors in exchange for Mondaq providing them with access to information about who accesses their content. Once personal data is transferred to our Contributors they become a data controller of this personal data. They use it to measure the response that their articles are receiving, as a form of market research. They may also use it to provide Mondaq users with information about their products and services.

Details of each Contributor to which your personal data will be transferred is clearly stated within the Content that you access. For full details of how this Contributor will use your personal data, you should review the Contributor’s own Privacy Notice.

Please indicate your preference below:

Yes, I am happy to support Mondaq in maintaining its free to view business model by agreeing to allow Mondaq to share my personal data with Contributors whose Content I access
No, I do not want Mondaq to share my personal data with Contributors

Also please let us know whether you are happy to receive communications promoting products and services offered by Mondaq:

Yes, I am happy to received promotional communications from Mondaq
No, please do not send me promotional communications from Mondaq
Terms & Conditions (the Website) is owned and managed by Mondaq Ltd (Mondaq). Mondaq grants you a non-exclusive, revocable licence to access the Website and associated services, such as the Mondaq News Alerts (Services), subject to and in consideration of your compliance with the following terms and conditions of use (Terms). Your use of the Website and/or Services constitutes your agreement to the Terms. Mondaq may terminate your use of the Website and Services if you are in breach of these Terms or if Mondaq decides to terminate the licence granted hereunder for any reason whatsoever.

Use of

To Use you must be: eighteen (18) years old or over; legally capable of entering into binding contracts; and not in any way prohibited by the applicable law to enter into these Terms in the jurisdiction which you are currently located.

You may use the Website as an unregistered user, however, you are required to register as a user if you wish to read the full text of the Content or to receive the Services.

You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these Terms or with the prior written consent of Mondaq. You may not use electronic or other means to extract details or information from the Content. Nor shall you extract information about users or Contributors in order to offer them any services or products.

In your use of the Website and/or Services you shall: comply with all applicable laws, regulations, directives and legislations which apply to your Use of the Website and/or Services in whatever country you are physically located including without limitation any and all consumer law, export control laws and regulations; provide to us true, correct and accurate information and promptly inform us in the event that any information that you have provided to us changes or becomes inaccurate; notify Mondaq immediately of any circumstances where you have reason to believe that any Intellectual Property Rights or any other rights of any third party may have been infringed; co-operate with reasonable security or other checks or requests for information made by Mondaq from time to time; and at all times be fully liable for the breach of any of these Terms by a third party using your login details to access the Website and/or Services

however, you shall not: do anything likely to impair, interfere with or damage or cause harm or distress to any persons, or the network; do anything that will infringe any Intellectual Property Rights or other rights of Mondaq or any third party; or use the Website, Services and/or Content otherwise than in accordance with these Terms; use any trade marks or service marks of Mondaq or the Contributors, or do anything which may be seen to take unfair advantage of the reputation and goodwill of Mondaq or the Contributors, or the Website, Services and/or Content.

Mondaq reserves the right, in its sole discretion, to take any action that it deems necessary and appropriate in the event it considers that there is a breach or threatened breach of the Terms.

Mondaq’s Rights and Obligations

Unless otherwise expressly set out to the contrary, nothing in these Terms shall serve to transfer from Mondaq to you, any Intellectual Property Rights owned by and/or licensed to Mondaq and all rights, title and interest in and to such Intellectual Property Rights will remain exclusively with Mondaq and/or its licensors.

Mondaq shall use its reasonable endeavours to make the Website and Services available to you at all times, but we cannot guarantee an uninterrupted and fault free service.

Mondaq reserves the right to make changes to the services and/or the Website or part thereof, from time to time, and we may add, remove, modify and/or vary any elements of features and functionalities of the Website or the services.

Mondaq also reserves the right from time to time to monitor your Use of the Website and/or services.


The Content is general information only. It is not intended to constitute legal advice or seek to be the complete and comprehensive statement of the law, nor is it intended to address your specific requirements or provide advice on which reliance should be placed. Mondaq and/or its Contributors and other suppliers make no representations about the suitability of the information contained in the Content for any purpose. All Content provided "as is" without warranty of any kind. Mondaq and/or its Contributors and other suppliers hereby exclude and disclaim all representations, warranties or guarantees with regard to the Content, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. To the maximum extent permitted by law, Mondaq expressly excludes all representations, warranties, obligations, and liabilities arising out of or in connection with all Content. In no event shall Mondaq and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use of the Content or performance of Mondaq’s Services.


Mondaq may alter or amend these Terms by amending them on the Website. By continuing to Use the Services and/or the Website after such amendment, you will be deemed to have accepted any amendment to these Terms.

These Terms shall be governed by and construed in accordance with the laws of England and Wales and you irrevocably submit to the exclusive jurisdiction of the courts of England and Wales to settle any dispute which may arise out of or in connection with these Terms. If you live outside the United Kingdom, English law shall apply only to the extent that English law shall not deprive you of any legal protection accorded in accordance with the law of the place where you are habitually resident ("Local Law"). In the event English law deprives you of any legal protection which is accorded to you under Local Law, then these terms shall be governed by Local Law and any dispute or claim arising out of or in connection with these Terms shall be subject to the non-exclusive jurisdiction of the courts where you are habitually resident.

You may print and keep a copy of these Terms, which form the entire agreement between you and Mondaq and supersede any other communications or advertising in respect of the Service and/or the Website.

No delay in exercising or non-exercise by you and/or Mondaq of any of its rights under or in connection with these Terms shall operate as a waiver or release of each of your or Mondaq’s right. Rather, any such waiver or release must be specifically granted in writing signed by the party granting it.

If any part of these Terms is held unenforceable, that part shall be enforced to the maximum extent permissible so as to give effect to the intent of the parties, and the Terms shall continue in full force and effect.

Mondaq shall not incur any liability to you on account of any loss or damage resulting from any delay or failure to perform all or any part of these Terms if such delay or failure is caused, in whole or in part, by events, occurrences, or causes beyond the control of Mondaq. Such events, occurrences or causes will include, without limitation, acts of God, strikes, lockouts, server and network failure, riots, acts of war, earthquakes, fire and explosions.

By clicking Register you state you have read and agree to our Terms and Conditions