Consultation: Handbook for healthcare professionals on biosimilar biologic drugs

Table of contents

• Disclaimer
• Summary
  1. Introduction
  2. Biologic drugs
     • 2.1 General
     • 2.2 Types of biologics
  3. Biosimilar drugs
  • 3.1 Biosimilars versus generic drugs
  4. The regulation of biosimilars in Canada
     • 4.1 Labelling: product monographs for biosimilars
     • 4.2 How Health Canada authorizes specific indications
     • 4.3 Addressing a key safety issue: immunogenicity
     • 4.4 Regulatory authorization
     • 4.5 International regulatory approaches to biosimilars: How Canada compares
  5. Monitoring safety and effectiveness
     • 5.1 Updating a biosimilar's labelling information
     • 5.2 Identification of biosimilars in prescribing, dispensing and ADR reporting
     • 5.3 The role of healthcare professionals in improving pharmacovigilance for biosimilars
  6. Biosimilars in Canada: access and uptake
     • 6.1 Interchangeability and switching
  7. Communicating with patients
  • 7.1 Discussions about switching
  8. Biosimilars and drug benefits programs
• Abbreviations
• Glossary
• Case Studies
  • The Authorization of Kanjinti, a biosimilar to Herceptin
  • Inflectra (infliximab) for Crohn's Disease and Ulcerative Colitis
• Acknowledgements and contributors
• References

Disclaimer

This Health Canada publication was developed for the purpose of informing and educating healthcare professionals in Canada regarding biosimilars. The handbook was developed in consultation with a working group composed of subject matter experts from Health Canada, and external healthcare professionals representing a range of professional associations. Nevertheless, the views expressed in this document are those of Health Canada and do not necessarily reflect the views of the external healthcare professionals that participated on the consultative working group.

Summary

A biosimilar is a biologic drug that is highly similar to a biologic drug already authorized for sale (known as the reference biologic drug). Unlike generic drugs, biosimilars can never be identical to their reference biologic drug, simply because they are isolated or manufactured in living organisms. However, they have been demonstrated to have no clinically meaningful differences in efficacy and safety compared to the reference biologic drug.

Health Canada authorizes biosimilars according to the same standards of quality, safety and efficacy that apply to all biologic drugs authorized in Canada.

Biosimilars are authorized based on a demonstration of similarity, using studies that compare them to their reference biologic drug. These studies include physiochemical, structural, and functional properties, and may also include clinical studies as needed. This may include a head-to-head clinical study. Once the demonstration of similarity is established, the evidence used to support the authorization of the reference biologic drug is applied to the biosimilar's authorization.

Health Canada can grant indications to the biosimilar based on the efficacy and safety of the reference biologic drug. The biosimilar may be granted all or only some of the indications based on a number of criteria. This is called an extension of indications.

Health Canada's authorization of a biosimilar is not a declaration of equivalence to the reference biologic drug. This is because the biosimilar is highly similar, but not identical to its reference biologic drug. Only provinces and territories can deem that two products are interchangeable, according to their own rules and regulations.

Once marketed, Health Canada monitors the safety of each biosimilar using the same pharmacovigilance activities used for all drugs.

In 2010, Health Canada released the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs. It communicates the requirements for the authorization of safe and effective biosimilar drugs. Health Canada released a revised guidance in 2016 to reflect experience gained over the previous 6 years. Evidence acquired over 10 years of international experience has shown no differences in safety and effectiveness between biosimilars and their reference biologic drugs.^{Footnote 1}

Perceptions and fears about biosimilars not performing to the same level as originator biologics lead to concerns about the impact of the nocebo effect. This means that the patient's beliefs and attitudes about biosimilars can cause negative expectations for treatment. These expectations may adversely affect the outcomes of their treatment.

Healthcare professionals play a vital role in:

• informing patients of the scientific and clinical evidence for biosimilar use for their particular indication
• helping patients feel confident that their biosimilar medication will be as safe and effective as the reference biologic drug they were previously prescribed

1. Introduction

Biologic drugs are used to manage various complex diseases and medical conditions. Expiry of patents and data protection for some biologic drugs is creating opportunities for subsequent entry versions. This has led to Health Canada creating a regulatory framework for biosimilars.

Health Canada and international drug regulatory authorities use the term biosimilar. It describes a biologic drug that receives market authorization based on a demonstrated high degree of similarity to the reference biologic drug previously authorized in Canada. This demonstration of similarity allows the manufacturer to support authorization of that particular drug by:

• partially relying on relevant, known information about the reference biologic drug
• seeking authorization based on a reduced non-clinical and clinical data package

Healthcare professionals need sufficient information on biosimilars so that they can confidently prescribe and manage the use of these products in patient care. This handbook will provide objective, evidence-based information on biosimilar:

• development
• authorization
• potential use

This will enable patient care decisions, shared decision-making and counselling.

2. Biologic drugs

2.1 General

Biologic drugs are isolated or manufactured using living organisms including, but not limited to:

• cell lines
• bacteria
• animal or human tissues

Many biologics are produced by recombinant DNA technology that enables the manufacturing of therapeutic proteins using living cells. When compared to chemically synthesized drugs, biologics consist of larger and more complex molecules (Figure 1).

Due to the complexity of biologic drugs and their intricate manufacturing processes, they are subject to inherent batch-to-batch variability, unlike chemically synthesized drugs.

Biologic drugs typically undergo extensive analyses of their physicochemical, structural and functional properties using state-of-the-art methods. This confirms that their quality profile will ensure the safety and efficacy of the drug.

Biologics are sensitive to different:

• chemical conditions, like pH and salt
• physical conditions, like temperature and light

They're also susceptible to microbial contamination and potential harmful agents such as viruses, during manufacturing. As such, manufacturers rely on very complex and tightly controlled processes to ensure the high quality of the therapeutic drug.

Due to these risks, careful attention is paid to:

• the quality and control of raw materials
• the capabilities of the manufacturing processes to remove potentially harmful agents
• testing of the biologic product

Changes to the following factors can cause significant unexpected and/or unintended changes to the final product:

• facilities
• equipment
• raw materials
• manufacturing processes

For these reasons, all biologic drugs used in Canada are subject to strict regulatory oversight to ensure their quality, efficacy and safety.

Source:
Mellstedt, H. (2013). Clinical considerations for biosimilar antibodies. European Journal of Cancer Supplements. 11 (3), 1-11. This figure, "Monoclonal antibodies are structurally more complex than small-molecule agents and lower molecular weight biologics" by Hakan Mellstedt, Leigh Revers and Eva Furczon is licensed under CC BY-NC-ND 3.0

Figure 1 - Text description

Biosimilars shown as larger and structurally more complex than a common pharmaceutical. For example, Aspirin, which is not a biologic, is 180 daltons, while the biologic insulin is 5,808 daltons and the biologic Erythropoetin is 30,400.  A monocolonal antibody (IgG1), a more complex biologic, is in the range of 150,000 daltons.

2.2 Types of biologics

The biologics classification encompasses a large number of drugs and groups of drugs, including^{Footnote *}:

• enzymes
• cytokines
• hormones
• allergenic extracts
• monoclonal antibodies
• low molecular weight heparins
• vaccines and other immunizing agents

The Biologic and Radiopharmaceutical Drugs Directorate (BRDD) within the Health Products and Food Branch of Health Canada is the regulator of biologic drugs for human use. It provides regulatory oversight for biologics with its comprehensive reviews of biologic drug submissions covering quality, safety and efficacy.

Under the Food and Drug Regulations, manufacturers must file a New Drug Submission (NDS) to Health Canada for review to gain authorization to sell that drug in Canada. An NDS must contain sufficient information and data to demonstrate the quality, safety and efficacy of the new drug.

Health Canada has no authority to grant market authorization to any drug independent of an application from the manufacturer. The market authorization process is completely dependent on the receipt of an NDS filed by the manufacturer.

3. Biosimilar drugs

A biosimilar biologic drug, or biosimilar, is a biologic drug that is highly similar to a qualifying biologic drug that was already authorized for sale (known as the reference biologic drug). Biosimilars cannot themselves serve as a reference biologic drug for a subsequent biosimilar. A biosimilar may enter the market only after the expiry of the reference biologic drug's patents and data protection.

Biosimilars are developed with the goal of manufacturing therapeutic molecules with highly similar structural and functional profiles as their reference biologic drug. A biosimilar may contain different non-medicinal ingredients than its reference biologic drug. Due to the inherent variability of biologic drugs, biosimilars may not be identical to the reference biologic drug. However, because of the high degree of similarity, there are no expected clinically meaningful differences in efficacy and safety between a biosimilar and its reference biologic drug.

The development of new analytical methods contribute to reducing the gap between a molecule being deemed biosimilar or identical. This has been achieved with simpler biologics such as insulin and hormones, while good advances have been made for the more challenging and complex drugs such as monoclonal antibodies.

Biosimilars and their reference biologic drugs contain well-characterized proteins as their active substances. These are derived through modern biotechnological methods, such as use of recombinant DNA and/or cell culture.

The following criteria are used to determine if products are eligible to be authorized as biosimilars:

• There is a suitable reference biologic drug for the biosimilar, which:
• has been used in the post market setting
• has a substantial body of data on safety and effectiveness
• The biosimilar and reference biologic drug can be well characterized by a set of highly comprehensive and state-of-the-art analytical methods
• The biosimilar can be judged as similar to the reference biologic drug by meeting an appropriately justified set of pre-determined criteria through extensive characterization and analysis

These criteria are based on a comprehensive analysis of the reference biologic drug that establishes a target profile for the biosimilar. The impact of any residual differences between the biosimilar and the reference biologic drug must be addressed to demonstrate that these differences are not clinically meaningful.

3.1 Biosimilars versus generic drugs

Biosimilars aren't the same as generic pharmaceutical drugs (Refer to Table 1 for summary).

Generic drugs are small molecules that are chemically synthesized. They contain identical medicinal ingredients to their reference biologic drugs. Biosimilars may have different nonmedicinal ingredients than the reference biologic drug, which causes differences to their:

• size
• shape
• colour

In contrast to generics, the medicinal ingredient / active substance in a biosimilar and its reference biologic drug can be shown to be highly similar, but not identical.

Health Canada authorizes generics based on demonstrated bioequivalence with the pharmaceutical or drug. This means that there are no significant differences in the rate and extent to which the same active substance is released into the body.

Authorizing a biosimilar requires more studies than authorizing a generic. These studies have to demonstrate that the biosimilar is highly similar to its reference biologic drug by:

• including analyses comparing the physicochemical, structural and functional properties of the biosimilar and reference biologic drug
• evaluating the biosimilar and the reference biologic drug under stress conditions (like heat-stress and pH stress) to confirm the similarity of their degradation profiles

4. The regulation of biosimilars in Canada

In Canada, biosimilars are regulated as new drugs under the Food and Drugs Act and the Food and Drug Regulations. Within the context of these legislative and regulatory requirements, Health Canada has developed a robust, evidence-based regulatory framework for authorizing biosimilars for sale.

Biosimilars must meet the same regulatory standards as other biologic drugs and are only authorized after a scientific evaluation by Health Canada. These rigorous standards mean that patients and healthcare professionals can have as much confidence in the quality, efficacy and safety of a biosimilar as with any other biologic.

In addition to the regulatory information required for all biologic drugs, biosimilar manufacturers must provide information to Health Canada that demonstrates the similarity of their biosimilar to the reference biologic drug. Manufacturers should use extensive comparative studies in a step-wise approach:

• beginning with physicochemical, structural and functional studies
• continuing with non-clinical and human clinical studies

Because the purpose of these studies is to demonstrate similarity, biosimilars are supported by different data than their reference biologic drugs for authorization.

For a reference biologic drug to become authorized for sale, manufacturers must demonstrate the quality, efficacy and safety of the drug. Generally, authorization of an innovator drug requires stand-alone "pivotal" phase III clinical trials. These establish efficacy and safety in each disease or medical condition that the drug is intended to treat (Table 2).

In contrast, to obtain authorization for sale, biosimilar manufacturers must (Table 2):

• demonstrate the quality of the drug
• perform extensive comparative studies to the reference biologic drug that demonstrate high similarity in:
  • function
  • structure
  • safety
  • efficacy

Biosimilars can be authorized only with extensive side-by-side comparative quality studies. They compare the characteristics of the proposed biosimilar and its reference biologic drug, including:

• functional activities
• structural properties
• purity and impurity profiles
• physicochemical properties
• immunochemical properties
• product stability and degradation profiles

Structural and functional studies are generally considered more sensitive than clinical studies for detecting differences between a biosimilar and its reference biologic drug. Biosimilars can exhibit minor differences to the reference biologic drug given the variable nature of all biologic drugs. Health Canada further evaluates the potential impact of these differences on efficacy, safety and immunogenicity by assessing:

• clinical and non-clinical studies
• analyses of physicochemical, structural and functional properties

Non-clinical and clinical studies address potential areas of remaining uncertainty after comparative quality studies have established high similarity. Non-clinical studies in cells and animals compare the effects of the proposed biosimilar and its reference biologic drug. We need clinical studies in humans to show that there are no clinically meaningful differences in efficacy, safety and immunogenicity expected between the proposed biosimilar and its reference biologic drug.

These studies will include those examining the levels of drug in the blood over a relevant period. We also usually require a clinical trial comparing the biosimilar directly to its reference biologic drug to confirm that no clinically meaningful differences exist. These comparative clinical studies must be sensitive enough to detect potential differences between the biosimilar and its reference biologic drug.

In certain circumstances, a clinical efficacy trial may not be necessary, such as where there is a validated and clinically relevant pharmacodynamic endpoint. For example, euglycaemic clamp studies (Pharmacokinetic - PK/ Pharmacodynamic - PD) would be sufficient for demonstrating similar efficacy between two insulin products. In such cases, a scientific justification is needed, and safety as well as comparative immunogenicity data are still required.

Authorization of all biosimilars is based on all of the evidence given to Health Canada, including a complete quality data package and all of the data from the following comparative studies:

• clinical and non-clinical
• structural
• functional
• physicochemical

In summary, in order to authorize a biosimilar, Health Canada must evaluate the information provided by the manufacturer and conclude that it shows that:

• the biosimilar and the reference biologic drug are highly similar; and
• there are no clinically meaningful differences in efficacy, safety and immunogenicity between the biosimilar and the reference biologic drug.

Case study: The authorization of Kanjinti, a biosimilar to Herceptin

4.1 Labelling: product monographs for biosimilars

A product monograph (PM) is a factual, scientific document containing pivotal information regarding a drug, issued upon its authorization. Along with other information that may be required for optimal, safe and effective use of the drug, the PM informs patients, consumers and healthcare professional's details regarding the drug:

• name
• therapeutic or pharmacologic classification
• claims
• properties
• indications
• dosage regimen
• conditions of safe use
• actions and/or clinical pharmacology
• conditions and considerations for safe use
• plain language summary of elements listed above

A PM also includes the drug's:

• date of last revision
• date of initial approval
• summary of revisions

The PM for a biosimilar will also include:

• a statement that the product is a biosimilar to its reference biologic drug
• a statement that indications have been granted on the basis of similarity between the biosimilar and the reference biologic drug
• comparative clinical data generated by the biosimilar sponsor summarized in tabular format
• safety information from the PM of the reference biologic drug for all indications authorized for the biosimilar

A PM cannot contain any promotional material. A PM for biosimilar should not declare therapeutic equivalence of a biosimilar to its reference biologic drug. No information on interchangeability or switching between drugs should be included in PM for biosimilars (See Section 6).

The PM for a biosimilar must be updated on an ongoing basis, as new information about the biosimilar or the reference biologic drug becomes available. The manufacturer can initiate these updates or Health Canada can mandate them. Details on the requirements for the preparation of PMs are contained in the Product Monograph: Guidance Document.

PMs for all biosimilars authorized in Canada are available in the Drug Product Database.

For more information on updating PMs, see Section 5.

4.2 How Health Canada authorizes specific indications

Once studies demonstrate similarity between the biosimilar and its reference biologic drug, Health Canada can authorize the biosimilar for some or all of the same indications as the reference biologic drug. An indication refers to the use of a drug to treat a specific disease or medical condition. We authorize many drugs, including biosimilars, for more than one indication.

The biosimilar manufacturer does not need to conduct comparative clinical trials in all of the indications that have been granted to the reference biologic drug. We can grant some or all indications to the biosimilar based on the previously established efficacy and safety of its reference biologic drug, the pathophysiology of disease, and the mechanism of action of the drug. This concept is called extension of indications.

Extension of indications is dependent on the demonstration of similarity between the biosimilar and reference biologic drug, based on data from comparative:

• clinical and non-clinical studies
• structural studies
• functional studies

Where similarity has been established, we may grant indications even though specific clinical studies with the biosimilar weren't conducted in each of these indications.

Certain situations may warrant additional clinical data. This may include a specific clinical trial for a particular indication, before it can be authorized. For example, if an application is submitted for both intravenous and subcutaneous authorizations, comparative PK or efficacy studies would be required for both.

The indications authorized for a particular biosimilar depend on the fact that indications on the reference biologic drug can be patented at different times and indications under intellectual property protection cannot be authorized until the protection expires.

The biosimilar manufacturer chooses which indications they wish to seek for the product. Health Canada cannot force a manufacturer to apply for indications that the manufacturer does not wish to have in Canada and cannot authorize an indication that the manufacturer has not requested.

Learn more about the basis for decisions on biosimilar authorization:

• Health Canada's Summary Basis of Decision (SBD)

Case study: Inflectra (infliximab) for Crohn's Disease and Ulcerative Colitis

4.3 Addressing a key safety issue: immunogenicity

Biologic products are large molecules, usually given by injection. They can stimulate/activate the body's immune system, potentially producing anti-drug antibodies (ADA). This is called immunogenicity.

Often, immunogenicity can only be detected using sophisticated laboratory tests and has no impact on the patient. In other cases, immunogenicity can affect patient safety by causing an adverse reaction or reducing the efficacy of the drug. A number of different factors can influence the immunogenicity of a biologic drug (Figure 2).

For these reasons, biosimilar authorization needs an assessment of immunogenicity. This usually requires studies showing that there are no expected clinically meaningful differences in immunogenicity between the reference biologic drug and the biosimilar. The investigation of immunogenicity is usually part of the pivotal comparative safety and efficacy clinical trials.

Source:
Schellekens H. Bioequivalence and the immunogenicity of biopharmaceuticals. Nat Rev Drug Discov. 2002;1:457-62.

Figure 2 - Text description

The following may affect the immunogenicity of a biologic drug:

• small variations in the amino acid sequence
• post-translational modifications such as glycosylation
• impurities and contaminants introduced through the production process
• formulation of the drug (i.e. non-active ingredients)
• length of treatment
• route of administration
• patient characteristics
• dosage
• other factors

Further, it is important to remember that the type of assay used to detect immunogenicity may itself, have an impact on the detection of immunogenicity.

The comparative study or studies should characterize:

• the time-course of ADA development
• how long the ADA persist in the body
• the impact of ADA on the biosimilar's:
  • safety
  • efficacy
  • pharmacokinetics
• the incidence and magnitude of any ADA response

The manufacturer must also file a Risk Management Plan (RMP) explaining how they'll monitor immunogenicity after the biosimilar has been authorized. The RMP monitors and detects known inherent safety concerns and potentially unknown safety signals that may result from the biosimilar's impurity profile and other characteristics. The biosimilar sponsor should continue to assess unwanted immunogenicity and its clinical significance following market authorization.

For more information on RMPs, see Section 5.

The Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs includes details about the requirements for immunogenicity testing.

4.4 Regulatory authorization

As for all biologics, once a biosimilar is authorized for sale it receives:

• a Notice of Compliance (NOC)
• a unique Drug Identification Number (DIN)
• an authorized PM

4.5 International regulatory approaches to biosimilars: How Canada compares

The key principles Canada uses to evaluate biosimilars align with those of other regulators and international organizations, such as:

• the World Health Organization (WHO)
• the European Medicines Agency (EMA)
• the United States Food and Drug Administration (FDA)

Health Canada works closely on an ongoing basis with its international counterparts and participates in several initiatives aimed at:

• harmonizing approaches to the regulation of biosimilars internationally
• sharing information on regulatory issues and the authorization of specific product types

Health Canada's position on the use of biosimilars is also consistent with the International Coalition of Medicines Regulatory Authorities (ICMRA), which includes key international regulatory partners from:

• the European Union (EU)
• the United States (US)
• the United Kingdom (UK)
• Japan
• Australia

5. Monitoring safety and effectiveness

Health Canada monitors the safety of all drugs on the market, including biosimilars, by:

• conducting market surveillance
• monitoring adverse reaction reports
• investigating complaints and problem reports
• monitoring actions taken by other regulators (such as the FDA or EMA)

Each manufacturer must comply with requirements to enhance drug safety, including:

• setting up a system to monitor reported side effects
• periodically re-assessing whether the drug's benefits outweigh its risks
• notifying Health Canada about new safety information
• reporting any new information received about serious side effects to Health Canada
• submitting a Risk Management Plan (RMP) as part of the application for authorization
• requesting authorization and providing clinical data to support any major changes to the:
  • dosage regimen
  • manufacturing process
  • recommended uses of the drug
  • labelling regarding use in special populations (e.g. pregnancy), safety, or efficacy profile

As part of the authorization process, Health Canada requests that manufacturers submit and maintain an RMP for all biologics, including biosimilars. RMPs outline activities that drug manufacturers must carry out to monitor and detect potential safety signals following market authorization.

The RMP should:

• consider all identified and potential risks associated with the use of the reference biologic drug
• provide details on how these risks will be addressed in a post-market setting

The RMP of a biosimilar generally includes monitoring and risk minimization activities that are similar to those in place for its reference biologic drug. Health Canada works with manufacturers to ensure the development of a suitable RMP, before authorizing the biosimilar. The surveillance criteria for the biosimilar should:

• be described in accordance with requirements for any new biologic drug
• include detailed information on how the immunogenicity potential of the biosimilar will be monitored once it is in clinical use

A biosimilar's RMP should include:

• specific (routine or additional) pharmacovigilance and risk minimization activities similar to those in place for its reference biologic drug
  • if these activities aren't relevant for the biosimilar, it should include a justification
• a discussion about methods to distinguish adverse event reports for the biosimilar from those for other licensed products, including the reference biologic drug

The RMP should be maintained and implemented throughout the life cycle of the product.

Adverse Drug Reaction (ADR) reporting is required post-market under section C.01.016 of the Food and Drug Regulations. The manufacturer must conduct a concise, critical analysis of ADRs and serious ADRs on an annual basis, or as requested by Health Canada.

Manufacturers must also prepare and submit periodic safety update reports or periodic benefit-risk evaluation reports. These reports must be consistent with the appropriate guidelines for marketed products issued by the International Council on Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Health Canada can compel drug manufacturers to do additional tests and studies at any time if there are significant uncertainties relating to the benefits or harms associated with a drug.

5.1 Updating the biosimilar's labelling information

All manufacturers must:

• monitor the post-market safety profile of their own product
• make safety updates to the biosimilar PM as appropriate

This ensures that the PM stays up to date and supports effective and safe conditions of use. At the time of authorization, the safety information in the PM for a biosimilar is based on information in the reference biologic drug PM. However once authorized, a biosimilar is considered a standalone product.

A biosimilar and its reference biologic drug aren't identical and are manufactured by independent processes. As such, newly identified safety issues that affect the reference biologic drug may or may not affect the biosimilar, and vice-versa. Therefore, manufacturers should also:

1. monitor the Canadian reference biologic drug's PM
2. assess any updates
3. reflect any updates in the PM for the biosimilar

Health Canada may ask manufacturers of both the reference biologic drug and biosimilar versions to update their PMs if a new safety issue related to that drug type or class arises.

Health Canada requests that all biosimilar manufacturers, as appropriate, assess the need to update their PMs when:

• a safety update is made to the Canadian PM of:
  • a reference biologic drug
  • another biosimilar to the same reference biologic drug, or
  • any other drug with shared active ingredients
• the plausibility of a drug class effect is established

5.2 Identification of biosimilars in prescribing, dispensing and Adverse Drug Reaction (ADR) reporting

All biologics authorized by Health Canada will have a unique brand name, a non-proprietary (common/proper) name of the active ingredient, and a unique Drug Identification Number (DIN). To help ensure effective post-market monitoring and surveillance, the specific biosimilar product should be clearly identified when:

• prescribing
• dispensing
• ADR reporting

This is particularly important as numerous biosimilars enter the market and there are more biologics with the same non-proprietary name.

The naming convention for biologic drugs, including biosimilars, consists of a unique brand name (ex. Grastofil), as well as the non-proprietary (common or proper; ex. filgrastim) name. The non-proprietary name is generally the International Nonproprietary Name (INN) assigned to the active ingredient by the World Health Organization (WHO).

Biosimilars share the same non-proprietary name as their reference biologic drug. However, they're distinguished by their unique brand names and other product-specific identifiers, such as the Drug Identification Number (DIN).

To facilitate product-level identification of biologic drugs, including biosimilars, Health Canada recommends that throughout the medication use process, health professionals use:

• unique brand names
• non-proprietary name
• other product-specific identifiers, such as the DIN and the lot number

The specific brand should be specified by the prescriber on the prescription before dispensing in a pharmacy.

Product-specific identifiers should be included in ADR reports to facilitate the traceability of an adverse reaction to a specific suspect drug product.

Learn more about:

• Health Canada's Notice to Stakeholders - Policy Statement on the Naming of Biologic Drugs

5.3 The role of healthcare professionals in improving pharmacovigilance for biosimilars

Healthcare professionals play a key role in pharmacovigilance of drugs, including biosimilars. Their reported observations of patient responses are essential to understanding a drug safety profile once it moves past the clinical trial stage and into clinical use. Healthcare professionals should report serious adverse reactions in accordance with:

• the Adverse Reaction Reporting and Health Product Safety Information - Guide for Health Professionals
• the Guidance Document Mandatory reporting of serious adverse drug reactions and medical device incidents by hospitals

By reporting an adverse reaction to Health Canada, healthcare professionals will help the department to:

• identify rare or serious adverse reactions that were previously unknown
• contribute to international data on the benefits and risks of health products
• make changes in product safety information or remove an unsafe product from the Canadian market
• develop and disseminate new and better information to enhance Canadians' knowledge about the safety of health products.

Healthcare professionals can help improve pharmacovigilance for biosimilars by ensuring that key pieces of information are:

• tracked in the prescribing and dispensing of biosimilar drugs
• provided in any ADR reports

In particular, healthcare professionals should:

• record the medicine's brand name at all levels, from prescription to dispensing and patient administration
  • record the lot number whenever possible
• report the brand name and lot number in case of suspected adverse drug reactions

It is important to record the brand name and lot number for both medicines if a patient switches from:

• one biosimilar to another
• one biological medicine to a biosimilar

6. Biosimilars in Canada: access and uptake

Although the first biosimilar in Canada was authorized by Health Canada in 2009, Canada, like many jurisdictions, has struggled to increase the uptake and use of these important medications in medical practice. The potential cost savings from the increased use of biosimilars are significant, and although cost issues are outside of the scope of Health Canada's authority as a regulator, access to affordable medications is a key part of the department's overall mandate. While Health Canada authorization can make a medication available, access and uptake requires the collaboration of many different players, including:

• The Canadian Agency for Drugs and Technologies in Health (CADTH) and the Institut national d'excellence en santé et services sociaux (INESSS), which are responsible for making recommendations on funding and optimal use of health technologies to decision-makers
• The Patent Medicines Prices Review Board (PMPRB), which is responsible for ensuring that the prices of patented medicines sold in Canada aren't excessive and for reporting on pharmaceutical trends
• The pan-Canadian Pharmaceutical Alliance (pCPA), an alliance of the provincial, territorial and federal governments that collaborates on a range of public drug plan initiatives to increase and manage access to effective and affordable drug treatments

The availability of biosimilar versions of important biologic medications provides:

• the benefit of less reliance on single, global supply chains
• additional options for patient treatment plans (Figure 3)

Source: Health Canada

Figure 3 - Text description

With increased use of biosimilars, there is a potential for savings. This potential for savings can provide more affordable options for physicians, patients and payers. This affordability improves accessibility and patient outcomes. In time, this would allow for the re-allocation of resources to other areas of care. More affordable medications can result in additional patients being treated, and improvement in patient outcomes.

6.1 Interchangeability and switching

In Canada, "interchangeability" often refers to the ability for a patient to be changed from one drug to another equivalent drug, by a pharmacist, without the intervention of the original prescriber. Interchangeability includes the concept of substitution, in which one drug product is dispensed for another interchangeable drug product, at the pharmacy level without consulting the authorized prescriber.

Health Canada's authorization of a biosimilar is not a declaration of equivalence to the reference biologic drug, since the biosimilar is highly similar, but not identical to its reference biologic drug. The authority to declare two products interchangeable rests with each province and territory according to its own rules and regulations. This presents challenges related to communications, as there are varying definitions of interchangeability in different provinces and territories.

In the context of biosimilar use, Health Canada uses the term switching (distinct from interchangeability) to refer to a change from routine use of a reference biologic drug to routine use of a biosimilar, or vice versa.

Provincial and territorial governments determine the circumstances in which switching is acceptable, and policies on switching in some jurisdictions may result in a decision to switch a patient from a reference biologic drug to a biosimilar.  Provincial and territorial governments have published guidelines on switching and interchangeability policies within their jurisdictions. These policies vary by jurisdiction.

7. Communicating with patients

Health Canada has published information on biosimilars in a fact sheet. Specific information for patients is contained in the Patient Medication Information section of each biosimilar PM. Outreach to patients has also been a key element of our stakeholder engagement strategy. Despite this, some patients may have concerns that biosimilars have less rigid pre- and post- market data requirements, and are second class products.

There is an ongoing need to educate patients about the safety and efficacy of biosimilars. Healthcare professionals play a key role in helping patients understand that regulators only authorize biosimilars when they have reviewed evidence that indicates that there are no clinically meaningful differences between the biosimilar and the reference biologic drug.

7.1 Discussions about switching

Health Canada acknowledges that some healthcare professional groups and patient organizations have concerns about, and have stated different positions on, switching patients from reference biologic drugs to biosimilars. One of the main concerns from both patients and physicians is the possibility of immunogenicity rendering the biosimilar treatment less effective.

For these reasons, Health Canada requires an assessment of immunogenicity, via comparative studies prior to biosimilar authorization. The purpose of these studies is to rule out clinically meaningful differences between the biosimilar and the reference biologic drug with respect to the risk and impact of immunogenicity. Health Canada also requires that the sponsor continue assessing adverse events, including immunogenicity, and their clinical significance following market authorization. In this context, the Risk Management Plan should include detailed information on systematic evaluation of the immunogenicity potential of the biosimilar.

Analyses of switching and interchangeability over the past 10 years in the EU have shown that immunogenicity is not affected by switches between products.^{Footnote 2}

Perceptions and fears about biosimilars not performing to the same level as reference biologic drugs can lead to a nocebo effect. This is when the patient's beliefs and attitudes about biosimilars can:

• result in a negative expectation for the effectiveness of the drug
• adversely affect the outcomes of their treatment

Communication between the patient and the healthcare professional can reassure the patient that:

• the biosimilar has the same active ingredient as its reference biologic drug
• no clinically meaningful difference in response is expected with a switch to the biosimilar
• the same rigorous standards of safety, efficacy and quality are used to authorize both products

8. Biosimilars and drug benefit programs

There's no guarantee of funding through drug benefit programs when Health Canada authorizes a biosimilar or other biologic drug for sale.

In Canada, federal, provincial and territorial public plans and private plans reimburse patients for drugs. Each jurisdiction decides:

• which drugs they will or will not cover
• whether there are specific coverage criteria
• the amount or percentage of costs they will cover

Patients should refer to specific provincial and territorial guidelines and publications for information about funding.

Abbreviations

ADA

Anti-drug Antibodies

ADR

Adverse Drug Reaction

BRDD

Biologic and Radiopharmaceutical Drugs Directorate

CADTH

Canadian Agency for Drugs and Technologies in Health

DIN

Drug Identification Number

EMA

European Medicines Agency

EU

European Union

FDA

Food and Drug Administration

ICMRA

International Coalition of Medicines Regulatory Authorities

INESSS

Institut national d'excellence en santé et services sociaux

INN

International Nonproprietary Name

NDS

New Drug Submission

NOC

Notice of Compliance

PBRER

Periodic Benefit Risk Evaluation Report

pCPA

pan-Canadian Pharmaceutical Alliance

PM

Product Monograph

PMPRB

Patent Medicines Prices Review Board

PSUR

Periodic Safety Update Report

RMP

Risk Management Plan

SBD

Summary Basis of Decision

UK

United Kingdom

US

United States

WHO

World Health Organization

Glossary

Adverse Drug Reaction: a noxious and unintended response to a drug which occurs at doses normally used or tested for the diagnosis, treatment or prevention of a disease or the modification of an organic function.

Bioequivalence: the property wherein two drugs with identical active ingredients or two different dosage forms of the same drug possess similar bioavailability and produce the same effect at the site of physiological activity.

Biologic drug: a drug listed in Schedule D to the Food and Drugs Act. Biologic drugs are derived through the metabolic activity of living organisms and tend to be significantly more variable and structurally complex than chemically synthesized drugs.

Biosimilar: a biologic drug that obtains market authorization subsequent to a version previously authorized in Canada, and with demonstrated similarity to a reference biologic drug. A biosimilar relies in part on prior information regarding safety, efficacy and effectiveness that is deemed relevant due to the demonstration of similarity to the reference biologic drug.

Drug Identification Number: a computer-generated eight digit number assigned by Health Canada to a drug product prior to being marketed in Canada. A DIN uniquely identifies the following product characteristics: manufacturer; product name; active ingredient(s); strength(s) of active ingredient(s); pharmaceutical form; route of administration.

Extension of Indication: an indication granted to a biosimilar based on evidence of biosimilarity and the previously established efficacy and safety of the reference biologic drug.

Generic drug: a copy of a brand name drug. The generic drug is pharmaceutically equivalent to the brand name drug: it contains the identical medicinal ingredients, in the same amounts and in a similar dosage form.

Interchangeability: the ability for a patient to be changed from one drug to another equivalent drug, by a pharmacist, without the intervention of the prescriber who wrote the prescription.

New Drug Submission: an application for market authorization of a new drug in Canada.

Nocebo effect: a negative effect of a pharmacological or non-pharmacological medical treatment that is induced by patients' expectations, and that is unrelated to the physiological action of the treatment.

Notice of Compliance: a notification, issued pursuant to paragraph C.08.004(1)(a), indicating that a manufacturer has complied with sections C.08.002 or C.08.003 and C.08.005.1 of the Food and Drug Regulations. Notices of Compliance are issued to a manufacturer following the satisfactory review of a submission.

Periodic Benefit Risk Evaluation Report: a pharmacovigilance document intended to provide a comprehensive, concise, and critical analysis of new or emerging information on the risks of the health product, and on its benefit in approved indications, to enable an appraisal of the product's overall benefit-risk profile.

Pharmacovigilance: the science and activities relating to the detection, assessment, understanding and prevention of adverse events or any other drug-related problems.

Product Monograph: a factual, scientific document on a drug, issued with its authorization, describing the properties, claims, indications, and conditions of use for the drug, and any other information that may be required for optimal, safe, and effective use of the drug. It cannot contain any promotional material.

Reference biologic drug: a biologic drug authorized on the basis of a complete quality, non-clinical, and clinical data package, to which a biosimilar is compared to demonstrate similarity.

Risk Management Plan: a document that describes a set of pharmacovigilance activities and interventions designed to identify, characterize, prevent or minimize risks related to drug products, and the assessment of the effectiveness of those interventions.

Substitution: the practice of dispensing one product for another interchangeable product at the pharmacy level, without consulting the authorized prescriber.

Switching: a change from routine use of one specific product to routine use of another specific product.

Case Studies

The Authorization of Kanjinti, a biosimilar to Herceptin

Introduction

An NDS for the biosimilar Kanjinti was filed by Amgen Canada Inc. on August 21, 2017. The reference biologic drug was Herceptin (active ingredient trastuzumab), marketed by Hoffmann-La Roche Ltd. Herceptin is authorized in Canada for several indications relating to early breast cancer, metastatic breast cancer, and metastatic gastric cancer. The NDS for Kanjinti requested authorization for all but one of the indications authorized for Herceptin. The indication in combination with Perjeta (pertuzumab) and docetaxel for untreated HER2-positive metastatic breast cancer was not requested for Kanjinti with this NDS.

Data Submitted

The sponsor submitted data from comparative quality studies, from one comparative pharmacokinetic study in healthy male subjects, and one comparative clinical efficacy and safety study in patients with HER2-positive early breast cancer. The efficacy and safety study included a run-in chemotherapy phase, a neoadjuvant phase, and an adjuvant phase. In the neoadjuvant phase, patients were randomized to receive either Kanjinti or Herceptin along with paclitaxel every 3 weeks, for 4 cycles of treatment (or with paclitaxel, administered once weekly for 12 cycles of treatment, in regions where it is the local standard of care). Surgery, with sentinel or axillary lymph node dissection was completed 3 to 7 weeks after administration of the last dose of the investigational product in the neoadjuvant phase. In the adjuvant phase, patients received a dose of assigned drug every 3 weeks, for up to 1 year from study drug administration in the neoadjuvant phase. Pathologic complete response (pCR) was defined as the absence of invasive tumour cells in the breast tissue and axillary lymph nodes. Supportive pharmacokinetic data were also obtained through the efficacy and safety study.

Review

The structure and functions of Kanjinti and Herceptin were compared side-by-side via numerous laboratory tests using state of the art methods. No significant differences were observed. Comparable pharmacokinetics were demonstrated in the pharmacokinetic study. Although no differences in efficacy, safety and immunogenicity between Kanjinti and Herceptin were observed in the comparative safety and efficacy study, several major concerns were identified during the review of the study relating to efficacy and safety parameters, data management, analyses, and reported outcomes. This resulted in a conclusion by the review team that equivalence between Kanjinti and Herceptin was not demonstrated.

Decision made

Due to the concerns identified the request for market authorization was not granted and a Notice of Non-Compliance (NON) was issued on August 9, 2018.

Follow-up

Kanjinti was subsequently authorized on February 27, 2020 following the filing by the manufacturer of a response to the NON, which addressed the concerns identified and confirming equivalency of response in the treatment arms. Kanjinti was authorized for use in patients with early breast cancer, metastatic breast cancer and metastatic gastric cancer.

Although patients with early breast cancer in the neoadjuvant setting is recognized as a sensitive model for demonstrating comparative efficacy and safety, it did not correspond to an indication authorized in Canada for Herceptin. To avoid implying that Kanjinti is indicated in the neoadjuvant setting, the following statement was added to the PM: "The treatment of early breast cancer patients with trastuzumab in the neoadjuvant setting is a model for assessing comparative clinical safety and efficacy; however, it is not an authorized indication in Canada."

For full details of the review, decision-making and authorized indications, please refer to the Summary Basis of Decision.

Inflectra (infliximab) for Crohn's Disease and Ulcerative Colitis

Introduction

An NDS for the biosimilar Inflectra, was filed by Celltrion Healthcare Co. Ltd on November 14, 2011. The reference biologic drug was Remicade (active ingredient infliximab), marketed by Janssen Inc. and authorized for the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn's disease, ulcerative colitis and for pediatric use in Crohn's disease and ulcerative colitis. The manufacturer requested authorization, for Inflectra, for all of the indications authorized for Remicade.

Data Submitted

The sponsor submitted data from comparative quality studies, from one clinical safety and efficacy study in patients with active rheumatoid arthritis, and one pivotal PK study in patients with active ankylosing spondylitis. No clinical studies were conducted in patients with the other indications. Therefore, authorization of the remaining indications would require a robust demonstration of biosimilarity such that authorization could rely on the known safety and effectiveness of the reference biologic drug.

Review

The structure, physiochemical properties and functions of Inflectra and Remicade were compared side-by-side via numerous laboratory tests using state of the art methods. No differences were observed likely to impact safety and efficacy for the indications (rheumatic diseases) evaluated in the supporting clinical trials. In the clinical studies, treatment with Inflectra or Remicade resulted in comparable rates of response in patients. The review of secondary endpoints did not identify any concerning differences, nor did analysis of joint damage progression. The comparative PK study also compared the efficacy and safety of Inflectra with Remicade in patients with active ankylosing spondylitis (secondary to the assessment of pharmacokinetics). No clinically meaningful differences were identified and the level of responses to both products aligned with what had been reported previously for patients receiving Remicade. Assessment of other secondary endpoints supported the comparability of both products in eliciting improvements in clinical response.

Extensive rationales were provided by the manufacturer to support the authorization of the remaining indications. However, observed differences in some in vitro Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) assays, as well as other differences, led the review team to conclude that differences in the ability of the two products to induce ADCC could not be ruled out. The sponsor provided rationale to support their position that ADCC is not an important mediator of the efficacy of their product (or of Remicade). However, after reviewing literature regarding this mechanism of action, it was concluded that ADCC could not be ruled out as a mechanism of action in the inflammatory bowel diseases (IBD). It was also noted that pathophysiological differences exist between the rheumatic diseases and the IBDs making an extrapolation between the two products challenging without clinical or PK/PD bridging data.

Decision made

As differences in ADCC were observed between Inflectra and Remicade, and because ADCC may be an active mechanism of action for infliximab in IBD, but not rheumatic disease, authorization of the IBD indications was not acceptable without further evidence to demonstrate biosimilarity in ADCC. Inflectra was authorized on January 15, 2014, for use in patients with moderately to severely active rheumatoid arthritis, active ankylosing spondylitis, psoriatic arthritis and chronic moderate to severe plaque psoriasis.

Follow-up

Inflectra was authorized on June 10, 2016, for use in patients with Crohn's disease, fistulising Crohn's disease and ulcerative colitis following the filing by the manufacturer of a Supplemental NDS with supportive physicochemical and biological data.

For full details of the review and authorization, please refer to the Summary Basis of Decision.

Acknowledgements and contributors

This handbook has been prepared by the Biologic and Radiopharmaceutical Drugs Directorate at Health Canada, with valued input from a working group composed of in-house scientific evaluators and representatives from Health Canada’s Marketed Health Products Directorate and Strategic Policy Branch. In addition, the working group also included the following healthcare professionals representing a diverse array of professional associations:

• Dr. Carter Thorne, Canadian Rheumatology Association
• Dr. Lamya Arman, Canadian Pharmacists Association
• Kiet-Nghi Cao, Canadian Society of Hospital Pharmacists
• Dr. Robert Goldberg, Canadian Society of Endocrinology and Metabolism
• Dr. Glen J. Pearson, Canadian Cardiovascular Society
• Dr. Raed Alhusayen, Canadian Dermatology Association
• Dr. Sam Hanna, Canadian Dermatology Association
• Dr. Eric Benchimol, Canadian Association of Gastroenterology
• Dr. Jean Deschênes, Canadian Ophthalmological Society
• Dr. Christian El-Hadad, Canadian Ophthalmological Society
• Dr. Kathy Vu, Ontario Health (Cancer Care Ontario)
• Dr. Dan Martinusen, Canadian Society of Nephrology