Canada

Number of Biosimilars Available

Country Spotlight: Canada

Health Canada is the department of the government of Canada with responsibility for national public health. The regulatory body for the approval of biologics is the Biologics and Genetic Therapies Directorate (BGTD) of the Health Products and Food Branch (HPFB) of Health Canada, responsible for the scientific evaluation of biologics and biosimilars for use in Canada.

In Canada, biosimilars are known as Subsequent Entry Biologics (SEBs).

Biosimilars Available

As of April 2016, there are 3 SEBs approved for use in Canada

A growth hormone used to treat patients with growth deficiencies (somatropin)
Medicines used to treat Rheumatoid Arthritis, Psoriatic Arthritis, Psoriasis, and Ankylosing Spondylitis (infliximab). Although in Europe, these medicines are approved for inflammation of the bowel, in Canada, use in these diseases was not recommended due to differences between the infliximab biosimilar and the original biologic.

Score Overview

Canada is Partially Compliant.

The overall score for Canada is 3.28/5. This means the Canadian guidance is partially or fully compliant with the WHO in many areas, and in some areas does not meet the WHO standards. An updated version of the SEB guidance is expected by mid-2016, and this analysis will be updated upon its release.

The graph below shows individual scores by each of the 28 components of biosimilar policy

There are six areas where Health Canada is not as specific as WHO, being either non-compliant, minimally compliant, or partially compliant with the WHO biosimilar policy.

Gaps

Gap 1

Reference Product:

When comparing the biosimilar to the original medicine, the Health Canada guidances do not specify that the same host cell should be used to produce the medicine.

Gap 2

Formulation:

Does not address formulation and how the formulation of the biosimilar should compare to that of the original biologic.

Gap 3

Dosage Form and Strength:

Does not address the type of container closure system that should be used, and how that container closure system should compare to that of the original biologic

Gap 4

Quality/Analytical, Immunological Analysis:

Health Canada do not provide as much detail as the WHO regarding how to compare immunogenicity between the biologic and the biosimilar

Gap 5

Quality/Analytical, Specifications:

In considering specifications for the biosimilar that are appropriate to ensure product quality, Health Canada do not specify that these specifications should be compared with those established for the original biologic

Gap 6

Nonclinical, General:

Health Canada is not as specific as the WHO in describing the types of nonclinical studies that are required to demonstrate biosimilarity

Gap 7

Nonclinical, Pharmacokinetics:

This topic is not addressed by the Health Canada guidelines.

Gap 8

Indication Extrapolation:

Health Canada does not provide the same degree of detail as the WHO in describing when it is appropriate for the biosimilar to be approved for all the indications as the original biologic, regardless of whether those indications have been studied

Gap 9

Interchangeability:

When switching between the biosimilar and original biologic, the WHO specify that the biosimilar should be clearly identifiable by a unique brand name, whereas Health Canada do not.

Gap 10

Naming:

This topic is not addressed by the Health Canada guidelines.

Overall country score as compared to peers

History of Policy

Health Canada finalized their guidelines for subsequent entry biologics (SEBs) in March 2010. In December 2015, Health Canada released an update to their SEB guidance for consultation. Comments were submitted through February 2016. A finalized document is expected by mid-2016.

Policy Guidelines

Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs).

The objective of this document is to provide guidance to those making biosimilar medicines to enable them to satisfy the requirements for the authorization of subsequent entry biologics (SEBs) in Canada.
First issued March 2010; Most recent update 2015 (revision currently in consultation period)

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

Provides answers to frequently asked questions related to the Guideline, and its implications for those developing biologics and SEBs.
First issued March 2010; Most recent update March 2010

Side by side comparison of each of the score components

For each of the 28 components of biosimilar policy evaluated, the specific wording in the FDA's biosimilar policy is listed, alongside the accompanying wording in the WHO policy (shown in the blue box).

Scope

[§ 3.0] Well-established and well-characterized biotherapeutic products such as DNA-derived therapeutic proteins. A well-established biotherapeutic is one that has been marketed for a suitable period of time with proven quality, safety, and efficacy.

Excludes vaccines, plasma-derived products, and their recombinant analogues.

[§ 1.2] Biologics that contain well-characterized proteins derived through modern biotechnological methods (e.g., rDNA and/or cell culture). The biosimilar must be able to be well-characterized by a set of modern analytical methods.

Products employing clearly different approaches to manufacture than the Reference Product may not be suitable for authorization as biosimilars.

Concept of Biosimilarity

[§ 4] A biosimilar is a biotherapeutic product that is similar in terms of quality, safety, and efficacy to an already licensed RP.

[§ 2.3.1.4] The demonstration of similarity signifies that the quality attributes of the two products being compared are highly similar with two consequences: (1) the existing knowledge of both products is sufficient to predict that any differences in quality attributes should have no adverse impact upon the safety or efficacy of the biosimilar; and (2) nonclinical and clinical data previously generated with the Reference Product are relevant to the biosimilar.

A final determination of similarity can be based on a combination of analytical testing, biological assays, and nonclinical and clinical data. For the product to be considered a biosimilar, however, the weight of evidence should be provided by the analytical and biological characterization.

Reference Product

[§ 7.0] The same RP should be used throughout the entire comparability exercise and it must be approved in the country/region in question (or, where the licensing country lacks an approved RP, approved and widely marketed in another jurisdiction with a well-established regulatory framework for, and experience in evaluation and post-market surveillance of, biotherapeutics).

[§ 8.1] As a general rule, the biosimilar product should be expressed and produced in the same host cell type as the RP. The applicant should determine the potential impact of changing the host cell on product quality, safety, and efficacy based on available evidence from public information and experience with previous use of the RP. The rationale for accepting a difference in host cell must be justified based upon sound science and clinical experience with the biosimilar or the RP.

"[§§ 1.2, 2.1.3] The same reference product should be used in studies supporting the safety, quality, and efficacy of the biosimilar. The reference product should: (1) be authorized for sale and marketed in Canada; (2) be originally authorized for sale based on a complete data package; and (3) have significant safety and efficacy data accumulated such that the demonstration of similarity will bring into relevance a substantial body of reliable data.

[§2.1.3.1] The applicant must identify the product authorized in Canada to which the biosimilar is similar. If a different product — that is not approved in Canada — is used in comparative studies, the applicant must show that the non-Canadian product is a suitable proxy for the version of the product approved in Canada. The Canadian and non-Canadian products must be marketed by the same company and in same dosage form. The non-Canadian product must be approved in a jurisdiction that has an established relationship with Health Canada. It also must be widely marketed in a jurisdiction that formally adopts the International Conference on Harmonization (ICH) guidelines and has regulatory standards, post-market surveillance activities, and approaches to comparability that are similar to those in Canada.

Formulation

[§ 8.1] The biosimilar manufacturer should assemble all available knowledge of the RP concerning the formulation used. The applicant should determine the potential impact of changing the formulation on product quality, safety, and efficacy based on available evidence from public information and experience with previous use of the RP. The rationale for accepting differences must be justified based upon sound science and clinical experience with the biosimilar or the RP.

Not addressed.

Dosage Form And Strength

[§ 5.0] Dosage form should be the same as that of the RP. Strength is not addressed.

[§ 8.1] The biosimilar manufacturer should assemble all available knowledge of the RP concerning the type of container closure system used. The applicant should determine the potential impact of changing the container closure on product quality, safety, and efficacy based on available evidence from public information and experience with previous use of the RP. The rationale for accepting a difference in container closure must be justified based upon sound science and clinical experience with the biosimilar or the RP.

[§ 2.1.3] Same as that of the Reference Product.

General Considerations

[§ 8] The application must contain a full quality dossier for both the drug substance and the drug product.

To evaluate comparability, the manufacturer should carry out a comprehensive physicochemical and biological characterization of the biosimilar in head-to-head comparisons with the RP. All aspects of product quality and heterogeneity should be assessed.

[§ 5] Development of the biosimilar involves a stepwise approach starting with characterization and evaluation of quality attributes. Differences should always be explained and justified and may require additional data.

[§ 8.2] Investigation of differences between the biosimilar and the RP should be based on knowledge of the relationship between quality attributes and clinical activity of the RP and related products, the clinical history of the RP, and lot-to-lot differences of commercial lots of the RP.

[§1.3] The basis for accepting a reduced nonclinical and clinical data package for a biosimilar hinges on demonstrated similarity between the biosimilar and the suitable Reference Product.

[§2.3.2.1] If the similarity of a biosimilar to the Reference Product cannot be established based on the chemistry, manufacturing, and controls package, reduced clinical data cannot be justified and the new product cannot be considered a biosimilar. Specific requirements for drug classes may differ depending on the class and on clinical parameters related to each drug product or class.

Isolation of Drug Substance

[§ 8] Methods used to isolate RP drug substance for characterization must be justified and demonstrated to be appropriate. Studies must be carried out to demonstrate that product heterogeneity and relevant attributes of the active moiety are not affected by the isolation process.

[§ 2.3.1] If excipients do not limit the sensitivity of characterization assays, it may be feasible to undertake comparability studies using the formulated drug products. Frequently, however, studies comparing drug substance may be beneficial or essential. If the reference drug substance used for characterization is isolated from a formulated Reference Product, additional studies should demonstrate that the drug substance is not changed by the isolation process.

Physicochemical Analysis

[§ 8.2.1] The comparative physicochemical characterization should include the determination of primary and higher order structure and other biophysical properties using appropriate analytical methods (e.g. mass spectrometry, NMR).

The RP and the biosimilar are likely to contain a mixture of post-translationally modified forms, and appropriate efforts should be made to investigate, identify, and quantify these forms.

[§ 2.3.1.2] The applicant should attempt to determine if the higher order structure is comparable. If this is not technologically possible, a relevant comparative biological assay could indicate a correct conformational structure.

Biological and Immunological Analysis

Biological

[§ 8.2.2] Comparative evaluation with a biological assay complements the physicochemical analyses by confirming the correct higher order structure of the molecule.

Ideally, the biological assay will reflect the understood MoA of the protein and will thus serve as a link to clinical activity.

The use of a relevant biological assay(s) with appropriate precision and accuracy provides an important means of confirming that a significant functional difference does not exist between the biosimilar and the RP.

Immunological

[§ 8.2.3] When immunochemical properties are part of the characterization (e.g., for antibody-based products), the manufacturer should confirm that the biosimilar is comparable to the RP in terms of specificity, affinity, binding kinetics, and Fc functional activity, where relevant.

Biological

[§ 2.3.1.2] If the biological assay serves to complement the physicochemical analysis, the biological assay should have suitable precision and accuracy to confirm that a change in higher order structure has not occurred.

Comparative biological characterization should cover all functional biological activities of the product.

Immunological

[§ 2.3.1.2] When immunochemical properties are part of the characterization, the manufacturer should confirm comparability of the specific properties.

Impurities

[§ 8.2.4] It is recognized that the comparison of the impurity profiles between the biosimilar and the RP will be generally difficult. Nevertheless, process- and product-related impurities should be identified, quantified by state-of-the-art technology, and compared between the biosimilar and the RP. If significant differences are observed in the impurity profiles, their potential impact on efficacy and safety, including immunogenicity, should be evaluated.

[§ 2.3.1.2] Differences between the purity and impurity profiles of the biosimilar and Reference Product should be evaluated to assess their potential impact on safety and efficacy. If the biosimilar has different impurities, the impurities should be identified and characterized if possible. Depending on the impurity type and amount, nonclinical and clinical studies will help confirm that there is no adverse impact on safety or efficacy.

Stability Studies

[§ 8.5] Head-to-head accelerated stability studies will be of value in determining the similarity of the products because they can reveal otherwise-hidden properties of a product that warrant additional evaluation. They are also important for identifying the degradation pathways of a protein product.

[§ 2.3.1.1] The applicant should provide stability data, including those generated from accelerated and stressed conditions, to provide insight into potential differences in the degradation pathways and hence differences in product-related substances and impurities.

[§ 2.3.1.2] Real-time/real-temperature stability studies should be conducted to compare the stability behavior of both products using the same storage conditions and analytical methods.

Specifications

[§ 8.3] Specifications should capture and control important quality attributes known for the RP. Their setting should be based on the experience with the biosimilar and the results of the comparability evaluation, but should not be wider than the range of variability of the RP unless justified.

Specifications should be set as described in established guidelines and monographs, where these exist. Pharmacopoeial monographs may only provide a minimum set of requirements for a particular product, and additional test parameters may be necessary

[§ 2.3.1.2] The manufacturer should confirm that the specifications for the biosimilar are appropriate to ensure product quality.

General

[§§ 9.1, 9.2] Nonclinical studies should use the final formulation intended for clinical use unless otherwise justified; the nonclinical evaluation encompasses a broad spectrum of PD, PK, and toxicity studies (per ICH S6); the amount of additional nonclinical data for safety and efficacy is dependent on product-specific factors (for example, quality, unknown or poorly understand MoA, significant toxicity, and/or narrow therapeutic index).

[§ 2.3.2.2] Appropriate nonclinical studies should be conducted before the initiation of any clinical studies. These studies should be comparative and designed to detect significant differences between the biosimilar and Reference Product.

Pharmacology

[§ 9.2] In vitro studies: Assays like receptor-binding studies or cell-based assays should normally be conducted to establish comparability of PD activity.

In vivo studies: Animal studies should be designed to maximize information obtained; be conducted in relevant species (shown to possess PD and/or toxicological activity); and employ state-of-the-art technology. In vivo studies may not be needed if highly reliable in vitro assays that reflect clinically relevant PD activity of the RP are available.

[§ 2.3.2.2] In vitro studies: Receptor-binding studies or cell-based assays should be conducted when appropriate.

In vivo studies: These should include animal PD studies relevant to the clinical application(s), at least one repeat-dose toxicity study conducted in a relevant species, and other relevant safety observations.

Toxicology

[§ 9.2] Comparative repeat-dose toxicity in relevant species (including TK measurements and antibody responses); local tolerance may need to be evaluated depending on the route of administration.

Safety pharmacology, reproductive toxicology, genotoxicity, and carcinogenicity studies are generally not needed unless cause for concern (based on repeat dose toxicity study or local tolerance study, for example).

[§ 2.3.2.2] In vivo studies should include at least one repeat-dose toxicity study (including characterization of TK parameters) conducted in relevant species and of sufficient duration so that differences in toxicity or immune responses can be detected. Other safety observations (e.g., local tolerance) can be made during the same toxicity study.

Other toxicological studies including safety pharmacology, reproductive toxicology, mutagenicity, and carcinogenicity studies are generally not required unless warranted by the results from the repeat-dose toxicological studies.

PK and PD

[§ 10] Clinical studies should be designed to demonstrate comparable safety and efficacy of the biosimilar to the RP and therefore need to employ strategies that are sensitive enough to detect relevant differences. The comparability exercise is a stepwise procedure that should begin with PK and PD studies followed by the pivotal clinical trials.

If any relevant differences between the biosimilar and the RP are detected, the reasons need to be explored and justified. If this is not possible, the new product may not qualify as a biosimilar and a full licensing application should be considered.

[§ 2.3.2.3] Comparative PK studies should be conducted. The design of the study (e.g., cross-over vs. parallel) should take into account, among other things, half-life, route(s) of administration, and indications. The comparison parameters should include both absorption and elimination. In general, the 80-125% criteria used for generic pharmaceuticals should be used unless other criteria are justified.

[§ 2.3.2.3] Parameters evaluated in comparative PD studies should be clinically relevant and surrogate markers should be validated.

Efficacy Assessment

[§ 10.1] The PK profile should always be investigated. This is best achieved with single-dose, cross-over studies in a homogenous study population using a dose where the sensitivity to detect differences is largest. Where there are dose and time-dependent pharmacokinetics, it may be necessary to perform a comparative multi-dose study.

The traditional equivalence range is often used. If this range is not met, the biosimilar may still be considered similar with sufficient evidence from other comparisons.

[§ 10.2] PD studies may be advisable prior to efficacy and safety trials if differences of unknown relevance have been detected in PK studies. In many cases, PD parameters are investigated in the context of combined PK/PD studies.

[§ 2.3.2.3] Comparative trials for efficacy and safety are critical, and equivalence trials are generally preferred unless non-inferiority trials are justified.

Sponsors should be aware of the possibility that the results from such trials could suggest superiority of the biosimilar relative to the Reference Product. In such instances, the superiority observed must be assessed for clinical relevance, including its impact on safety. In the event that the superiority observed is considered clinically meaningful and/or is associated with increased adverse drug reactions over those seen with the Reference Product, the product would no longer be considered as a biosimilar.

Safety

[§ 10.3] Usually, clinical trials are required to demonstrate similar efficacy. Confirmatory PK/PD may be used in lieu of efficacy trials provided there is sufficient knowledge of the PK/PD profile of the RP, at least one PD marker has a well-established relationship to efficacy, and the relationship between dose/exposure, the relevant PD marker, and response/efficacy of the RP is established.

[§ 10.4] Similar efficacy means similar treatment effects are achieved at the same dosages.

Similar efficacy will usually have to be shown in a controlled, adequately powered, study that is, preferably, double blind. Potential differences between the products should be investigated in a sensitive and well-established clinical model.

[§ 2.3.2.3] The nature, severity, and frequency of adverse events should be compared and based on data from a sufficient number of patients treated for an acceptable period of time.

Immunogenicity

[§ 10.5] Safety data should be obtained in a sufficient number of patients to provide a comparison of type, frequency, and severity of adverse events. Safety data from the efficacy trials may be sufficient for this purpose (or may need to be extended), but in any case additional monitoring is usually necessary after approval.

[§ 2.3.2.3] Immunogenicity should be evaluated using appropriate studies and methods, taking into account the potential impact on efficacy and safety. Methods should be validated and able to characterize content (concentration or titer) and type of antibodies. When neutralizing antibodies are detected, the impact on PK/PD parameters and overall efficacy and safety should be analyzed.

Extrapolation of Indications

[§ 10.6] Immunogenicity should always be investigated in humans prior to authorization, because animal data are usually not predictive and because it could affect PK, PD, or safety. Generally, the data from a comparative efficacy trial will be sufficient prior to market authorization, subject to appropriate post-market pharmacovigilance for rare adverse events or where clinically meaningful or serious antibody development has been encountered in the RP or substance class.

In the case of chronic administration, one year of data prior to market authorization is usually appropriate.

[§ 10.6] Antibody assays need to be validated for their purpose. Detected antibodies need to be characterized for their clinical implications with special attention to the possibility of interaction with endogenous protein.

[§ 2.3.2.1] Extrapolation should be justified based on MoA, pathophysiological mechanisms of disease(s), safety profile in the respective conditions and/or populations, and clinical experience with the Reference Product. A detailed scientific rationale addressing the risks/benefits of the proposal for extrapolation should be provided.

Risk Management Plans

[§ 10.7] Extrapolation to other approved indications of the RP may be possible if all of the following conditions are met: (1) a sensitive clinical test model has been used that is able to detect potential differences between the products; (2) the clinically relevant MoA and/or receptors are the same (or, if the MoA is different or not known, a strong scientific rationale and additional data will be needed); (3) safety and immunogenicity of the biosimilar have been characterized and there are no special safety issues expected with the extrapolated indication; and (4) if the efficacy trial used a non-inferiority study design and demonstrated acceptable safety and efficacy of the biosimilar compared to the RP, the applicant should provide convincing arguments that this finding can be applied to the extrapolated indications.

If these prerequisites for extrapolation of efficacy and safety data of the biosimilar to other indication(s) of the RP are not fulfilled, the manufacturer will need to submit its own clinical data to support the desired indication(s).

[§2.3.3] An RMP should be provided before marketing authorization. A PV plan also should be provided. The RMP should monitor and detect known and potentially unknown safety signals that may result from the impurity profile and other characteristics of the biosimilar. The PV plan should include periodic safety update reports.

The minimum criteria for surveillance for each biosimilar product should be described in accordance with the requirements for a new biologic. The RMP should include detailed information of a systematic evaluation of the immunogenicity potential of the biosimilar. A discussion about methods to distinguish adverse event reports from those for other licensed products, including the Reference Product, should be included in the RMP.

Interchangeability

[§ 11] Data from pre-authorization clinical studies are usually too limited to identify all potential unwanted effects of a biosimilar, and in particular, rare adverse events.

Therefore, further close monitoring of the clinical safety of these products in all approved indications and continued benefit-risk assessment is necessary in the post-market phase.

A safety specification and PV plan are required at the time of submission, describing safety issues for the RP, the class, and/or the biosimilar.

Any special safety monitoring imposed on the RP or product class should be incorporated into the PV plan for the biosimilar, unless there is a compelling justification not to do so.

The regional authority should provide a framework establishing the ability to ensure specific identification of the biosimilar (i.e., traceability). There should be a legal framework adequate to identify any biotherapeutic marketed in its territory that is the subject of adverse event reports.

[§ 1.3] Biosimilars are not “generic biologics.” Authorization of a biosimilar is not a declaration of pharmaceutical or therapeutic equivalence to the Reference Product.

[§ 2.5] The biosimilar cannot use the product monograph (labeling) of the Reference Product in its entirety. The biosimilar’s labeling should be developed in a manner consistent with existing product monograph guidance. It should make no claims of bioequivalence or clinical equivalence to the Reference Product.

Naming

Not addressed specifically. To be determined by national authorities.

[§ 6, bullet e] Biosimilars “are not generic medicines; and many characteristics associated with [that] authorization process generally do not apply.”

[§ 12] The biosimilar should be clearly identifiable by a unique brand name, and the prescribing information should be as similar as possible to that of the RP except for product-specific aspects such as different excipients.

Note: Naming and interchangeability should be treated as separate issues. WHO has recommended a generic name plus numbering system. Naming, per se, is not about the basic science of interchangeability.

Not addressed.

Labeling

[§ 12.0] A biosimilar should be clearly identifiable by a unique brand name. Where an international non-proprietary name (INN) is defined, it should be stated. The WHO’s policy on INNs should be followed. The provision of a lot number is essential and critical for traceability.

[Note: In July 2014, the WHO issued a proposal for unique biologic identifiers (BQs) that could be added to the INNs of biologics, whether innovative or biosimilar. See INN Working Doc. 14.342 (July 2014).]

[§ 2.5] A biosimilar cannot use the product monograph (labeling) of the Reference Product in its entirety. A biosimilar’s product monograph must include, among other things, a statement that it is a biosimilar, key data on which the decision for market authorization was made, and tables showing the results of comparisons between the biosimilar and Reference Product.

There should be no claims for bioequivalence or clinical equivalence between the biosimilar and Reference Product.

Considerations for Quality by Design

[§ 12] The prescribing information for the biosimilar should be as similar as possible to that of the RP, except for product-specific aspects, such as different excipient(s). This is particularly important for posology and safety-related information, including contraindications, warnings, and adverse events.

If the biosimilar has fewer indications than the RP, the related text in various sections may be omitted unless it is considered important to inform doctors and patients about certain risks (e.g. because of potential off-label use). In such cases it should be clearly stated in the prescribing information that the biosimilar is not indicated for use in the specific indication(s) and the reasons why.

The national regulatory authority may choose to mention the biosimilar nature of the product and the studies that have been performed with the biosimilar, including the specific RP, in the product information.

The national regulatory authority may choose to include instructions for the prescribing physician on how to use biosimilar products.

[§ 2.3.1.2] It may be appropriate to apply more than one analytical procedure to analyze the same quality attribute. In such cases, each method should employ different physicochemical or biological principals to maximize the possibility that differences may be detected.

[§ 2.3.1.2] The immunogenicity of the biosimilar should be evaluated using appropriate clinical studies with state-of-the-art methods.

CBPE