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Questions & Answers To Accompany the Final Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs)

  1. What is a Subsequent Entry Biologic (SEB)?
  2. What products can be approved as Subsequent Entry Biologics in Canada?
  3. What are the differences between Subsequent Entry Biologics and Generic Drugs?
  4. Will Subsequent Entry Biologics be as safe as regular biological products for Canadians?
  5. What measures are being taken to address the patient safety issues that might be associated with a Subsequent Entry Biologic?
  6. What is immunogenicity and why is it a special concern for biologics?
  7. How is immunogenicity to be addressed for SEBs?
  8. Why is Health Canada issuing a guidance document for Subsequent Entry Biologics?
  9. Does Health Canada have the authority to approve Subsequent Entry Biologics?
  10. Why is Health Canada using the New Drug Submission pathway?
  11. What is a suitable reference biologic drug? How does it contribute to the approval of a Subsequent Entry Biologic?
  12. Is it mandatory that a reference biologic drug be approved and marketed in Canada?
  13. Why is Health Canada allowing the use of a non-Canadian reference biologic drug?
  14. After an approved Subsequent Entry Biologic has been authorized, is its sponsor required to maintain its similarity to its reference biologic drug?
  15. Can a Subsequent Entry Biologic be used interchangeably with its reference biologic drug and are they automatically substitutable for indications that they share?
  16. Can a Subsequent Entry Biologic be used to effectively treat the same diseases/conditions that its reference biologic drug treats?
  17. Who are the main stakeholders involved? How have they been included in the policy development process?
  18. What were the stakeholder's key concerns and how are they addressed in this Guidance document?
  19. Is Health Canada's approach to Subsequent Entry Biologics consistent with international developments?
  20. What are the next steps following the release of this guidance document?

1. What is a Subsequent Entry Biologic (SEB)?

A Subsequent Entry Biologic is a biologic drug that enters the market subsequent to a version previously authorized in Canada, and with demonstrated similarity to a reference biologic drug. A subsequent entry biologic relies in part on prior information regarding safety and efficacy that is deemed relevant due to the demonstration of similarity to the reference biologic drug and which influences the amount and type of original data required.
A product of this type is referred to as similar biological medicinal product (biosimilar) in the European Union and follow-on protein product in the United States of America.

2. What products can be approved as Subsequent Entry Biologics in Canada?

Biologic products that contain well characterized proteins as their active substances and can be shown by a sponsor to be similar to a suitable reference product can be approved as Subsequent Entry Biologics.

3. What are the differences between Subsequent Entry Biologics and Generic Drugs?

Generic drugs are chemically derived products that are pharmaceutically equivalent to innovative drugs, whereas Subsequent Entry Biologics are products of a biologic nature that are similar to innovative biologics. It is not currently possible to demonstrate that two biologic drugs are pharmaceutically equivalent, and the regulatory approval process for generics and Subsequent Entry Biologics is different: Subsequent Entry Biologics are approved using the new drug submission pathway, while generic drugs are approved using the abbreviated new drug submission pathway. The differences between Subsequent Entry Biologics and Generic Drugs have important implications on how the drug may be used once approved for the Canadian market (see questions and answers to 15-17).

4. Will Subsequent Entry Biologics be as safe as regular biological products for Canadians?

Health Canada will use the same safety, quality, and efficacy standards used for approval of all new biologics for the approval of Subsequent Entry Biologics. Patient safety will continue to be paramount to all of Health Canada's activities and decisions related to Subsequent Entry Biologics.

5. What measures are being taken to address the patient safety issues that might be associated with a Subsequent Entry Biologic?

In addition to the rigorous pre-market approval process that addresses patient safety issues raised in the review prior to approval, Subsequent Entry Biologic sponsors will provide a detailed post-market risk management plan on how safety issues associated with their product will be managed.

6. What is immunogenicity and why is it a special concern for biologics?

Immunogenicity is the ability to stimulate an immune response. This ability generally protects people against pathogens by recognising and reacting to foreign proteins. It is a specific concern for biological drugs because they are primarily protein products that may be seen as being foreign. An immune response to a biologic drug can range from development of detectable but not clinically significant antibodies to an immune response with significant impact on patient safety. A patient's immune response may also affect a treatment's effectiveness.

7. How is immunogenicity to be addressed for Subsequent Entry Biologics?

Immunogenicity will be addressed as part of the comparative clinical trials required for approval of Subsequent Entry Biologics. In addition, sponsors will be expected to provide a risk management plan as part of the application for authorization that explains how the sponsor plans to conduct a systematic evaluation of the immunogenicity potential of the Subsequent Entry Biologic during post-approval use.

8. Why is Health Canada issuing a guidance document for Subsequent Entry Biologics?

Health Canada is responding to the emergence of Subsequent Entry Biologics with the development of the guidance document to help Subsequent Entry Biologic manufacturers submit the necessary information to Health Canada for review, and it will also help ensure that different submissions are held to the same review standards.

The approval of Subsequent Entry Biologics will contribute to the health of Canadians and likely provide access to affordable alternatives to innovator biological products.

9. Does Health Canada have the authority to approve Subsequent Entry Biologics?

Yes. A Subsequent Entry Biologic is no different from any other new drug, except that its approval relies in part on comparative and historical information from a product already authorized based on a complete data package.

10. Why is Health Canada using the New Drug Submission pathway?

The New Drug Submission pathway requires all new drug sponsors to submit evidence that their drug meets safety, quality, and efficacy standards. Subsequent Entry Biologics are complex and cannot demonstrate pharmaceutical equivalence and therefore cannot be approved through the abbreviated pathway.

Subsequent Entry Biologics are not a new class of biologics. They are second versions of biologics that already exist in the Canadian market whose patents have expired. Health Canada will review the information submitted by sponsors of Subsequent Entry Biologics to assess whether it contains sufficient evidence to demonstrate that the benefits of the product will outweigh the risks. This is not different from how Health Canada will approve any other new biologic products; therefore the existing regulations are suitable.

11. What is a suitable reference biologic drug? How does it contribute to the approval of a Subsequent Entry Biologic?

A biologic drug that was authorized on the basis of a complete quality, non-clinical and clinical data package, and is the product to which a Subsequent Entry Biologic is compared in studies to demonstrate similarity. The onus is on the Subsequent Entry Biologic sponsor to demonstrate that the reference biologic drug is suitable. Criteria that are described in the guidance document under the heading 2.1.3 Reference biologic drug provide general guidance on factors affecting the choice of a suitable reference biologic drug.

The reference drug is utilized in the comparability studies to support the licensing application and it provides the basis for the sponsor to select the dose, route of administration, and design of clinical trials with the Subsequent Entry Biologic. The role of a reference biologic drug in the authorization of a Subsequent Entry Biologic is different from that of a Canadian Reference Product in the authorization of a generic drug. The use of a reference biologic drug is supportive in nature (clinical trial data using the Subsequent Entry Biologic will also be submitted by the sponsor).

12. Is it mandatory that a reference biologic drug be approved and marketed in Canada?

No, in appropriate circumstances a biologic drug that is not the version authorized for sale in Canada may be used as a reference biologic drug. However, a sponsor must name and demonstrate a link to the biologic drug authorized in Canada to which the Subsequent Entry Biologic will be subsequent. While it is preferable that the Canadian version be used in the comparative studies, criteria have been established to enable information from a non-Canadian reference biologic drug to be used as a proxy for the Canadian version to which the Subsequent Entry Biologic will be subsequent to in Canada.

13. Why is Health Canada allowing the use of a non-Canadian reference biologic drug?

New drugs can be approved using data generated outside Canada and there are insufficient reasons to create a Canadian-only restriction. Health Canada is also allowing the use of a non-Canadian reference biologic drug to address the fact that Subsequent Entry Biologics are currently being developed outside of Canada using non-Canadian reference biologic drugs. It is critically important that the non-Canadian reference biologic drug be reliable. It is the responsibility of the subsequent entry biologic sponsor to demonstrate the appropriateness of their choice of reference biologic drug, and to provide the necessary evidence to support their choice.

14. After an approved Subsequent Entry Biologic has been authorized, is its sponsor required to maintain its similarity to its reference biologic drug?

No. Once a Notice of Compliance (NOC) is issue for a Subsequent Entry Biologic it is considered to be a new biologic drug (i.e. a "stand-alone" product) and regulated accordingly. After a manufacturing change to the Subsequent Entry Biologic or reference biologic drug, a Subsequent Entry Biologic sponsor is not required to re-establish its similarity to its reference biologic drug. There is currently no submission process for the sponsor of a Subsequent Entry Biologic to provide Health Canada with ongoing evidence of its similarity. This is relevant to considerations regarding automatic substitution and therapeutic interchange (see Q&A # 16).

15. Can a Subsequent Entry Biologic be used interchangeably with its reference biologic drug and are they automatically substitutable for indications that they share?

The guidance document states that Subsequent Entry Biologics are new drugs that are not declared to be pharmaceutically or therapeutically equivalent with their reference products, and this should inform decisions regarding interchangeability and substitutability. The authority to declare two products automatically substitutable by a pharmacist does not rest with the federal government.

It has been recommended that, as the federal regulator of drug products, Health Canada should review data that supports therapeutic interchangeability and make a recommendation as to whether this can be done safely and effectively by physicians. Specialized clinical studies can be used to support therapeutic interchangeability, however, these studies are not usually done and their relevance may not be long-lasting. Over time, as sponsors of the Subsequent Entry Biologic and the reference biologic drug make their own independent manufacturing changes, differences could be introduced that affect the drug products. For this reason, Health Canada does not support automatic substitution of a Subsequent Entry Biologic for its reference biologic drug and recommends that physicians make only well-informed decisions regarding therapeutic interchange.

16. Can a Subsequent Entry Biologic be used to effectively treat the same diseases/conditions that its reference biologic drug treats?

A Subsequent Entry Biologic will not always have the same indications for use as its reference biologic drug. A Subsequent Entry Biologic may be granted any indications held in Canada by its reference biologic drug, but only if sufficient data is provided in support of the claim. It can also be granted indications different from those of the reference biologic drug if a full clinical data package is submitted for those indications.

17. Who are the main stakeholders involved? How have they been included in the policy development process?

The main stakeholders include innovator biologic manufacturers and Subsequent Entry Biologic manufacturers, organizations representing the innovator and generic drug manufacturing industry, pharmacists, physicians, provincial and territorial governments, other regulators, and patient groups. Two draft versions of the guidance document have been the topic of separate consultations, and Health Canada has engaged a broad spectrum of stakeholders throughout the policy development process to obtain their perspectives and to inform and educate them about this initiative.

18. What were the stakeholder's key concerns and how are they addressed in this Guidance document?

Key stakeholder concerns related to intellectual property protections, criteria for reference biologic drugs, and whether or not Subsequent Entry Biologics should be considered interchangeable/substitutable for their reference biologic drugs. Many stakeholders expressed the desire for regulatory amendments specifically for Subsequent Entry Biologics.

Health Canada has addressed many concerns about intellectual property protections and the criteria for reference biologic drugs by providing further clarity in the guidance document. The guidance document now states that a Subsequent Entry Biologic sponsor is responsible for showing that any non-Canadian reference biologic drug used for the purposes of demonstrating similarity is a suitable proxy for the version of the product approved in Canada. The submission will explicitly explain the link between the two products and confirm that both are marketed by the same innovator company or corporate entity that is approved to market the medicinal ingredient in the same dosage form in Canada.

19. Is Health Canada's approach to Subsequent Entry Biologics consistent with international developments?

Health Canada has harmonized its approach as much as possible with other competent regulators, such as the European Medicines Agency and international organizations such as the World Health Organization. Health Canada has recommended that sponsors refer to the product class specific guidance documents in use by the European Medicines Agency because the scientific principles are consistent with those of Health Canada.

20. What are the next steps following the release of this guidance document?

Health Canada will be presenting its regulatory approach for Subsequent Entry Biologics in various fora to inform and educate stakeholders. An evaluation of the implementation of the guidance document will be made at an appropriate time after Subsequent Entry Biologics have been authorized and used in Canada.