DRAFT Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs

This guidance is a draft version for consultation purposes only. It is not to be implemented at this time. Please refer to the Consultation on Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs

(PDF Version - 867 KB)

Foreword

Guidance documents provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. They also provide guidance to Health Canada staff on how mandates and objectives should be met fairly, consistently and effectively.

Guidance documents are administrative, not legal, instruments. This means that flexibility can be applied. However, to be acceptable, alternate approaches to the principles and practices described in this document must be justified. They should be discussed in advance with Health Canada to maximize the possibility of meeting statutory or regulatory requirements.

Health Canada reserves the right to request information or material, or define conditions not specifically described in this document, that are considered necessary to assess the safety, efficacy or quality of a therapeutic product. We are committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read along with the regulations and other applicable guidance documents.

In this guidance document, "must" is used to express a requirement that the user is obliged to satisfy to comply with the regulatory requirements; "should" is used to express a recommendation that is advised but not required; and "may" is used to express an option that is permissible within the limits of the guidance document.

1. Introduction
2. Guidance for implementation
3. Consultation with the Biologic and Radiopharmaceutical Drugs Directorate (BRDD)
4. Additional Information
Appendix A - Glossary

1. Introduction

1.1 Purpose/Overview

Health Canada, the federal regulatory authority that evaluates the safety, efficacy, and quality of drugs for approval in Canada, recognizes that manufacturers may be interested in pursuing subsequent versions of biologic drugs. The term biosimilar biologic drug, hereafter referred to as biosimilar, is used by Health Canada to describe subsequent versions of a Canadian authorized originator biologic demonstrated to be highly similar to the latter, referred to as the Canadian reference biologic drug (CRBD).

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 and provides regulatory oversight for biologics with its comprehensive reviews of biologic drug submissions covering quality, safety and efficacy.

Sponsors are encouraged to consult with BRDD for further guidance, if necessary. Refer to section 4 for contact information.

1.2 Scope and application

This guidance document applies to all biologic drug submissions where the sponsor seeks authorization for sale based on a demonstrated high degree of similarity to a previously authorized biologic drug and relies on prior information regarding that biologic drug to support, in part, a reduced clinical package as part of the submission.

The following criteria determine the scope of drugs that are eligible to be authorized as biosimilars:

a suitable CRBD exists that:
1. was originally authorized for sale based on a comprehensive quality, non-clinical and clinical data package
2. has a substantial body of evidence regarding quality, safety, efficacy and effectiveness of the CRBD, which has accumulated since market authorization
the biosimilar and CRBD can be extensively characterized by a set of modern analytical methods
the biosimilar, through extensive characterization and analysis, can be judged highly similar to the CRBD by meeting an appropriate set of pre-determined criteria

The demonstration of a high degree of similarity depends upon detailed and comprehensive drug characterization. This guidance applies to biologic drugs that contain, as their medicinal ingredient(s), well characterized proteins derived through modern biotechnological methods such as use of recombinant DNA and/or cell culture.

Short polypeptide drugs are classified as either a biologic or a pharmaceutical depending on the method of manufacture. When manufactured by recombinant DNA procedures, short polypeptides are considered biologic drugs and are eligible for authorization as a biosimilar. When chemically synthesized, they are considered pharmaceutical drugs and are eligible for authorization as a generic drug via the Abbreviated New Drug Submission (ANDS) pathway.

In Canada, Low Molecular Weight Heparins (LMWH) are regulated as biologic drugs because of their biologic origin, despite not being listed on Schedule D of the Food and Drugs Act. Sponsors of subsequent versions of LMWH products should use this guidance document in conjunction with Policy Statement: Clarifying the appropriate regulatory pathway for subsequent entry low molecular weight heparins for further guidance.

Biosimilars manufactured using methods different than those used to produce the CRBD are eligible for approval. Careful consideration should be given to expression system differences that may present challenges to demonstrating a high degree of similarity of the biosimilar candidate to the CRBD.

1.3 Policy objective

The policy objective of this document is to provide guidance to sponsors to enable them to satisfy the information and regulatory requirements under the Food and Drugs Act (FDA) and Part C of the Food and Drug Regulations (FDR) for the authorization of biosimilars in Canada.

1.4 Principles of the regulatory approach for biosimilars

Biosimilars are regulated under the FDA and Part C of the FDR. The concepts and the scientific and regulatory principles within the existing regulatory frameworks for biologic, pharmaceutical, and generic pharmaceutical drugs are used as the basis for the regulatory approach for biosimilars.

Biologic drugs are inherently heterogeneous and cannot be copied such that subsequent versions are considered pharmaceutically equivalent to the CRBD. While biosimilars are conceptually similar to generic drugs, they are not eligible for authorization through the ANDS pathway under C.08.002.1. Rather, biosimilar drug submissions are filed using the New Drug Submission (NDS) pathway in accordance with C.08.002. Health Canada's issuance of a Notice of Compliance (NOC) for a biosimilar is a confirmation of a high degree of similarity to the CRBD but is not a declaration of equivalence. A biosimilar sponsor is eligible to apply for the indication(s) and condition(s) of use that are held by the CRBD authorized in Canada.

A biosimilar drug submission leverages safety and efficacy information of the CRBD. Paragraphs C.08.002(2)(g) and (h) can be satisfied by establishing a high degree of similarity to the CRBD through quality, clinical and non-clinical analyses described in this document. As such, the non-clinical package included in the biosimilar drug submission does not require certain information that is typically expected in a conventional submission for a biologic drug. The clinical package is similarly expected to be reduced relative to the content of a conventional submission for a biologic drug. A biosimilar candidate relies on establishing a high degree of similarity to its CRBD through comprehensive physicochemical and functional characterization data, which permits the submission for a biosimilar candidate to leverage clinical data that supported the authorization of the CRBD.

1.5 Background

Biologic drugs have contributed to the health of Canadians as diagnostic, treatment and preventative tools for various diseases and medical conditions. Unlike pharmaceutical drugs, biologic drugs are derived through the metabolic activity of living organisms and are heterogeneous and structurally complex. Biologics can be labile and sensitive to changes in manufacturing processes. Biological source materials, production cells, or their fermentation media can present risks to patients, such as the presence of pathogens or the growth of adventitious agents (for example, viruses). Due to these risks, stringent processes are applied to raw materials, and virus inactivation and/or clearance during product purification and product testing. Changes to source materials, manufacturing processes, equipment, or facilities can result in important and unexpected changes to the intermediate and/or final product.

The term biosimilar is used by Health Canada to describe a biologic drug that receives market authorization subsequent to an originator biologic that has been authorized in Canada (referred to as the CRBD) and demonstrated to be highly similar to the CRBD. Demonstration of a high degree of similarity enables the biosimilar sponsor to rely on relevant information about the CRBD.

1.6 Scientific considerations and principles of demonstrating similarity in the authorization of biosimilars

A biosimilar is highly similar to its CRBD in terms of physicochemical properties, functional properties, and clinical pharmacology. The purpose of a biosimilar development program is to establish a high degree of similarity between the biosimilar candidate and its CRBD based on a comprehensive comparability exercise.

A biosimilar candidate requires extensive comparative quality studies to demonstrate a high degree of similarity. These studies compare the attributes of the biosimilar candidate and its CRBD, including:

physicochemical characteristics (structure, post-translational modifications, heterogeneity, purity, impurities)
functional properties (biological activity, immunochemical binding properties, etc.)
stability profile (stress, accelerated, forced degradation profiles)

The demonstration of a high degree of similarity does not signify that the quality attributes of the two drugs being compared are identical, but that they are highly similar with two consequences: 1) that the existing knowledge of both drugs is sufficient to predict that any differences in quality attributes should have no adverse impact on safety or efficacy of the biosimilar candidate; and 2) that non-clinical and clinical data previously generated with the CRBD are applicable to the biosimilar candidate.

Given the heterogeneous nature of biologic drugs, a biosimilar can exhibit some differences compared to its CRBD. These differences between the biosimilar candidate and its CRBD may be acceptable if the sponsor can provide sufficient evidence and/or scientific justification that the differences have no impact on safety and/or efficacy.

The information required to address such differences is considered on a case-by-case basis and will depend on the specific difference(s) observed. Differences identified via physicochemical or functional studies should be investigated further in relevant in vitro models. Where a high degree of similarity can be established by a combination of structural and functional studies, and where extensive in vitro mechanistic studies are indicative of a high degree of similarity, in vivo non-clinical studies are generally not needed.

The clinical studies required to support the authorization of a biosimilar are generally limited to a comparative pharmacokinetic trial conducted to demonstrate pharmacokinetic equivalence between the biosimilar and the CRBD. The study is also expected to collect data on safety and immunogenicity. Pharmacodynamic endpoints should be included, if feasible. Clinical efficacy and safety studies are typically not required for a biosimilar candidate to a CRBD with well characterized safety, efficacy, and immunogenicity profiles when the biosimilar can be compared and extensively characterized by commonly used analytical techniques and biological assays.

Differences between a biosimilar candidate and its CRBD should be evaluated in terms of a potential effect on function and stability. If major differences are identified between a biosimilar candidate and its CRBD, it is unlikely that the drug would be considered a biosimilar. Clinical efficacy and safety studies cannot address major differences in quality attributes between a biosimilar candidate and its CRBD.

2. Guidance for implementation

2.1 General

2.1.1 Applicable regulations

Biosimilars are subject to Part C of the FDR for authorization and oversight. Conforming to the guidance provided in this document, along with other guidance for biologics, should enable a sponsor to satisfy the following notable requirements in Part C, Division 8 of the FDR:

C.08.002(1)(a): No person shall sell or advertise a new drug unless the manufacturer of the new drug has filed with the Minister a new drug submission relating to the new drug that is satisfactory to the Minister.

C.08.002(2): A new drug submission shall contain sufficient information and material to enable the Minister to assess the safety and effectiveness of the new drug.

2.1.2 Patents, intellectual property, and data protection

Biosimilars can enter the market subsequent to the CRBD previously authorized in Canada to which it has been demonstrated to be highly similar.

In a New Drug Submission (NDS), the biosimilar sponsor should clearly identify the biologic drug authorized in Canada (at the level of the Drug Identification Number (DIN)) to which it is subsequent and to which it is considered to be making a direct or indirect comparison or reference according to the Patented Medicines (Notice of Compliance) Regulations (PM(NOC) Regulations) and section C.08.004.1 of the FDR. In addition, where the sponsor makes a direct or indirect comparison to a non-Canadian sourced reference biologic drug (RBD) (refer to section 2.1.3), the sponsor must address the relationship between the non-Canadian sourced RBD, and the drug authorized in Canada (i.e. the CRBD).

For information on the data protection provisions of the FDR or on the PM(NOC) Regulations, manufacturers are encouraged to consult Health Canada's guidance documents entitled "Data Protection under C.08.004.1 of the Food and Drug Regulations" and "Patented Medicines (Notice of Compliance) Regulations", respectively, or to contact the Office of Patented Medicines and Liaison at opml-bmbl@hc-sc.gc.ca.

2.1.3 Canadian reference biologic drug (CRBD)

A thorough assessment of the physicochemical characteristics and functional properties of the reference biologic product should provide the foundation of knowledge that informs the development of the biosimilar candidate. For the demonstration of a high degree of similarity, side-by-side analyses of the biosimilar candidate with an appropriate CRBD must be conducted. The following should be considered when selecting a CRBD:

The dose, frequency of dosage, strength(s), and route(s) of administration of the biosimilar candidate should be the same as that of the CRBD.
The same CRBD should be used throughout the studies supporting the quality, non-clinical, clinical pharmacology, and immunogenicity of the drug (that is, in the development program for the biosimilar candidate).
In certain circumstances, it may be possible to use more than one RBD (for example, RBD sourced from more than one jurisdiction) in clinical studies. As a scientific matter, the type of bridging data needed will always include structural and functional data from analytical studies that directly compare all the drugs (for example, the biosimilar candidate, the U.S.-authorized drug, and the E.U.-authorized drug) and may also include clinical pharmacokinetic (PK) and, if appropriate, clinical pharmacodynamic (PD) study data for all the drugs.
The medicinal ingredient(s) of the biosimilar candidate and the CRBD must be shown to be highly similar.
The CRBD should have accumulated adequate safety and efficacy data in the pre- and post- market setting such that the demonstration of a high degree of similarity between the biosimilar candidate and the CRBD will bring into relevance for the biosimilar a substantial body of reliable data derived from the CRBD.

An authorized biosimilar should not be used as a CRBD for another biosimilar submission.

Publicly available reference standards are not to be used as the CRBD to support the demonstration of similarity.

2.1.3.1 Considerations for the use of a non-Canadian sourced RBD

Sponsors may use a non-Canadian sourced RBD as a proxy for the CRBD in the comparative studies. The onus is on the sponsor to demonstrate that the chosen RBD is suitable to support the submission. The sponsor is encouraged to consult with BRDD early in the drug development process to ensure the suitability of the non-Canadian sourced RBD.

In addition to section 2.1.3, the following should be considered when sourcing a non-Canadian RBD used for the purposes of demonstrating a high degree of similarity:

The non-Canadian sourced RBD should have the same medicinal ingredient(s), dose, frequency of dosage, and route(s) of administration as the RBD authorized in Canada. Information on the CRBD can be found in Health Canada's Drug Product Database.
The non-Canadian sourced RBD should be marketed in a jurisdiction that has regulatory standards and principles for evaluation of medicines, post-market surveillance activities, and approaches to comparability that are similar to Canada (examples include the United States of America, European Union, United Kingdom, Australia, Switzerland, Singapore and Japan).

2.1.4 Performance standard for a submission of a biosimilar candidate

A biosimilar candidate submission is filed and reviewed as an NDS. The performance standard for an NDS is outlined in Health Canada's Guidance Document: Management of Drug Submissions and Applications.

2.2 Information requirements for new drug submissions (NDS)

Part C, Division 8 of the FDR sets out the requirements for the sale of new drugs in Canada, which include biosimilars, and prohibits the sale of new drugs unless the manufacturer has filed a submission that is satisfactory to the Minister. Section C.08.002 of the FDR outlines the requirements for an NDS.

2.2.1 Organization of data

Electronic documents should be provided in electronic common technical document (eCTD) format.

The Filing submissions electronically webpage includes links to documents that provide detailed information on these formats and other information relating to filing submissions electronically.

The assessment of similarity should be organized as a distinct collection of data in section 3.2.R.5 Assessment of Similarity. Please refer to Health Canada's Guidance for industry on the preparation of the quality information for drug submissions in the CTD format: Biotherapeutic and blood products.

2.2.2 Quality information

In addition to a chemistry and manufacturing data package that is expected for a standard new biologic drug, the biosimilar submission should include extensive and robust data demonstrating a high degree of similarity with the CRBD. A comprehensive characterization of the CRBD should be undertaken to establish the quality target product profile of the biosimilar candidate. For consideration as a biosimilar, similarity should be deduced primarily from comprehensive and appropriately designed quality studies. Comparative physicochemical, functional, and stability studies to evaluate whether the proposed biosimilar candidate and the CRBD are highly similar should be included.

Analytical procedures used to demonstrate a high degree of similarity are a critical part of the quality data package and should be appropriately qualified for the intended purpose. For some analytical procedures direct or side-by-side analysis of the CRBD and the proposed biosimilar candidate may not be feasible due to matrix interference. In such cases, if samples are prepared from the finished drug product (for example, de-formulation or extraction) the impact of the technique(s) used should be appropriately documented, discussed and justified.

2.2.2.1 Considerations for demonstrating similarity

Although the comparison of two independent drug products is outside of the scope of International Council of Harmonisation (ICH) Q5E: Comparability of Biotechnology/Biological Products Subject to Changes in their Manufacturing Process, many of the principles and approaches are applicable.

The sponsor should demonstrate that the biosimilar candidate and the CRBD can be judged highly similar in terms of physicochemical characteristics, functional properties, and stability profiles; thus, support a possible conclusion of a high degree of similarity for safety and efficacy. The extent of the studies necessary to demonstrate a high degree of similarity will depend on the following:

the nature of the drug product
the availability of suitable analytical techniques to detect potential differences
the relationship between quality attributes and safety and efficacy based on overall non-clinical and clinical experience
any differences between the expression systems used to manufacture the biosimilar and the CRBD

When evaluating the high degree of similarity between the biosimilar candidate and its CRBD, the biosimilar sponsor should consider:

relevant physicochemical characteristics and functional properties
results from analysis of relevant samples from the appropriate stages of the manufacturing process (that is, drug substance and drug product)
stability data, including those generated from accelerated or stress conditions, to provide insight into potential differences in the degradation pathways of the biologic drug and potential differences in product-related substances and product-related impurities
data obtained from multiple batches of the biosimilar candidate and the CRBD to understand the heterogeneity. This evaluation might not require performing all tests on all batches; a matrix approach may be possible but should be rationalized

In addition to evaluating the data, the manufacturer should consider whether the results provide insights regarding the adequacy of the control strategy including critical control points and in-process testing. The control strategy for the biosimilar candidate should be confirmed, modified, or created, as appropriate, to ensure the quality of the drug.

The comparative physicochemical, functional, and stability studies should be supported by clinical pharmacology studies.

Lots of Reference Biologic Drugs and Biosimilars for Comparative Analytical Assessment

The data package should describe the approach to setting the robust similarity criteria and specify the number of CRBD and biosimilar candidate lots used to assess a high degree of similarity for each quality attribute taking into account the complexity and knowledge of the biologic drug. This is typically acquired through characterization of multiple lots of the biosimilar candidate and the CRBD to understand the lot-to-lot variability of both drug products and processes. The number of lots of each drug product (CRBD and biosimilar candidate) to be included in the similarity assessment should be informed by the drug product and process variability and should consider the analytical method variability and assumptions of the statistical methodologies employed.

Note that for the analytical similarity assessment, meaningful conclusions require that lot data points are independent. It is expected that all drug product lots of the biosimilars candidate included in the similarity assessment are manufactured from independent drug substance lots and are representative of the proposed shelf-life of the drug product.

Reference Standards

A reference standard is distinct from a CRBD as they serve different functions. In accordance with ICH Q6B, an appropriately characterized in-house primary reference standard, prepared from lot(s) representative of the clinical lots and commercial process, should be established and used for control of the manufacturing process and product (biosimilar candidate). Neither an international reference standard, nor the CRBD, should be used as a primary reference standard. For the development of the biosimilar candidate, a CRBD or non-Canadian RBD lot(s) may be qualified as an initial reference standard.

Once clinical lots of the biosimilar candidate are manufactured, it is expected that one of these lots will be appropriately qualified, including bridging to previous reference standards, for use as the in-house reference standard for product control and the comparative analytical studies. A two-tiered program consisting of in-house primary and secondary (or working) reference standards should be established at the time of the market application.

2.2.2.2 Quality considerations

Analytical Techniques

Analytical tests should be carefully selected and optimised to maximise the potential for detecting differences in the quality attributes of the biosimilar candidate and its CRBD. To address the full range of physicochemical characteristics or functional properties, it may be appropriate to apply more than one analytical procedure to evaluate the same quality attribute. In such cases, each method should employ different principles to collect data for the same attribute to maximise the possibility that differences between the biosimilar candidate and its CRBD may be detected. The sponsor should also consider the limitations of each analytical procedure (for example, limit of detection or resolution) when evaluating a high degree of similarity of a biosimilar candidate to its CRBD. Where appropriate, methods that provide quantifiable results should be considered.

Measurement of quality attributes in characterization studies does not necessarily require use of validated assays, but assays used should be scientifically sound and appropriately qualified for the intended use. Methods used to measure quality attributes for batch release should be validated in accordance with ICH guidelines, ICH Q2(R2): Validation of Analytical Procedures: Text and Methodology, ICH Q5C: Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products, and ICH Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products as appropriate.

Characterization

Comprehensive and robust comparative characterization studies should be performed to evaluate the proposed biosimilar candidate and its CRBD. Characterization of a biotechnological/biological drug by appropriate techniques, as described in ICH Q6B, includes the determination of physicochemical characteristics, biological activity, immunochemical properties (if any), purity, impurities, and quantity.

The type, nature, and extent of any differences between the proposed biosimilar candidate and the CRBD should be described and discussed. The discussion should explore identification and comparison of relevant quality attributes. The potential clinical effects of observed differences between the two drugs should also be assessed and supported by additional studies, if necessary.

The following criteria should be considered as key points when demonstrating a high degree of similarity:

Physicochemical Characteristics

The manufacturer should consider the concept of the desired biosimilar candidate (and its variants) as defined in ICH Q6B when designing and conducting studies to demonstrate a high degree of similarity. The complexity of the molecular entity with respect to the degree of molecular heterogeneity should also be considered. Heterogeneity in therapeutic proteins may arise in a number of ways and may affect the expected clinical performance of a protein product. When differences in the heterogeneity profile are observed between the biosimilar candidate and the CRBD at the physicochemical level, orthogonal approaches, such as functional methods, should be used to assess the potential impact of these differences on the clinical effects of the drug.

Although an identical primary sequence between the biosimilar candidate and its CRBD is expected, low-level sequence variants may occur due to transcription and translation errors, especially through amino acid misincorporation during high-level expression and should be identified, if present. The presence of such variants could be acceptable if properly described and controlled. An assessment of the potential clinical impact of such variants should also be considered.

Purity and Impurities

The combination of analytical procedures selected should provide data to allow evaluation of relevant differences in the purity and product-related impurity profiles.

Differences observed in the purity and product-related impurity profiles of the biosimilar candidate relative to its CRBD should be evaluated to assess their potential impact on safety and efficacy. Where the biosimilar candidate exhibits different impurities, those impurities should be identified, characterized and quantified, when possible. The potential impact of differences in the impurity profile upon safety should be addressed and supported by the appropriate data.

The process-related impurities in the biosimilar candidate are not expected to match those observed in its CRBD and are not expected to be included in the similarity assessment. Clearance of process-related impurities should be assessed as per ICH guidelines and demonstrated to be safe.

Functional Properties

Biological assay results can serve multiple purposes in the confirmation of drug quality attributes. The manufacturer should consider the limitations of biological assays, such as high variability, that may prevent detection of differences between a biosimilar candidate and its CRBD.

When the biosimilar candidate and its CRBD have multiple biological or functional properties, a comprehensive set of functional assays designed to evaluate the range of properties should be utilized.

The physicochemical analyses should confirm the similarity of the higher order structures. The integrity of such structures should be confirmed using comparative functional assays. Multiple functional assays should be performed as part of the similarity assessment. The functional assays should reflect the mechanism(s) of action to the extent possible. These may include binding assays to determine specificity, affinity, and avidity to the target and/or Fc-effector function, viral neutralization, anti-proliferation, or cytotoxicity.

Stability

Comparative stability studies (for example, accelerated, stressed, and forced degradation studies) should be conducted to compare degradation profiles of the biosimilar candidate to those of the CRBD. In some cases, it may be possible and beneficial to conduct side-by-side stability studies on samples that have been matched, as far as possible, with respect to date of manufacture. Such stability studies may be able to detect subtle differences between the biosimilar candidate and the CRBD that are not readily detectable by the characterization studies, which may warrant additional evaluation.

ICH Q5C and ICH Q1A (R2): Stability Testing of New Drug Substances and Products should be consulted to determine the conditions for stability studies that provide relevant data for a product-to-product comparison.

2.2.2.3 Manufacturing process considerations

Therapeutic proteins can be produced in a variety of biological systems. It is expected that the expression construct for the proposed biosimilar candidate codes for the same primary amino acid sequence as the CRBD. However, minor modifications that are not expected to change the functional properties of the product may be justified. Any known differences in the manufacturing approach between the biosimilar candidate and the CRBD should be carefully considered with regards to process- and product-related substances, impurities, and contaminants.

Control Strategy

The manufacturer should define a control strategy for the biosimilar candidate that is specific and appropriate to assure product quality. Although justification of the control strategy, including the specification, may incorporate data derived from the similarity assessment, it is considered stand-alone, and not dependent of the CRBD.

2.2.2.4 Determination of similarity

A final determination of a high degree of similarity is based on all relevant data from physicochemical, functional, stability, and non-clinical and clinical studies. To be considered a biosimilar, the weight of evidence should be provided by the physicochemical, functional, and stability studies. Health Canada recommends that sponsors develop a risk assessment tool to evaluate and rank the CRBD quality attributes in terms of potential impact on activity, PK/PD, efficacy, safety, and immunogenicity. These attributes should be evaluated using quantitative analysis, considering the risk ranking of the quality attributes, as well as other factors. It should be noted, however, that some attributes may be highly critical (for example, primary sequence) but not amenable to quantitative analysis.

Consideration as a biosimilar is not appropriate if a high degree of similarity cannot be established by comparative quality studies. If major differences are detected in the quality studies, they should be addressed in the development phase. Non-clinical and clinical studies cannot address major differences detected in the comparative quality studies.

2.2.2.5 Manufacturing changes following issuance of market authorization

Any changes to the manufacturing process of the biosimilar that warrant a demonstration of comparability between the pre-change and post-change versions of the biosimilar should be conducted in accordance with ICH Q5E. Additional comparisons with the original CRBD are not required.

2.2.3 Non-clinical and clinical information

2.2.3.1 General

Non-clinical and clinical requirements outlined in this guidance document are applicable to biosimilar candidates that have been demonstrated to be highly similar to the CRBD based on the results of the comparative structural and functional studies included in the chemistry and manufacturing data package. If a high degree of similarity has not been established, then the drug cannot be deemed to be biosimilar.

This section provides general guidance on expectations related to the non-clinical and clinical information for a biosimilar candidate. Specific requirements may differ depending on the characteristics of the drug.

If clinical studies are performed, participants should receive the drug for which market authorization is sought. Chemistry and manufacturing changes introduced during the clinical development phase or at the end of the clinical development program may result in the need for additional bridging data. Refer to ICH Q5E and, if necessary, consult BRDD for additional guidance.

2.2.3.2 Non-clinical studies

Where a high degree of similarity is established by structural and functional studies, and where extensive in vitro mechanistic studies are indicative of a high degree of similarity, in vivo non-clinical studies are generally not needed. In exceptional circumstances where an in vivo evaluation is deemed necessary, the focus of the studies (PK and/or PD and/or safety) will depend upon the type of additional information needed.

If filed in more than one module, sponsors should provide a 'General Note to Reviewer' that communicates where in the e-CTD the non-clinical studies are located.

Specialized toxicological studies, including safety pharmacology, reproductive toxicology, mutagenicity and carcinogenicity studies, are not generally required for a biosimilar submission.

2.2.3.3 Clinical studies

The purpose of the clinical program of a biosimilar candidate is to support a demonstration of a high degree of similarity derived from the comparative analytical assessments of the physicochemical characteristics, functional properties, and stability profiles between the biosimilar candidate and the CRBD.

The clinical program should primarily include a comparative pharmacokinetic study, and if feasible, a comparative evaluation of pharmacodynamics. These studies may be followed by an additional clinical trial(s) in exceptional circumstances. Differences observed between the biosimilar candidate and the CRBD should be addressed. If differences cannot be sufficiently addressed, the candidate may not be suitable for authorization as a biosimilar.

Comparative clinical pharmacology studies

Comparative pharmacokinetic (PK) studies should be conducted to rule out PK differences between the biosimilar candidate and the CRBD. Refer to Health Canada's Guidance Document: Conduct and Analysis of Comparative Bioavailability Studies for more information on the principles of comparative PK studies.

PK studies should be conducted in healthy subjects when appropriate as they are generally considered a homogeneous and sensitive population. A sub-therapeutic dose residing on the linear part of the dose response curve should be considered if studies are performed in healthy subjects. When the biosimilar candidate cannot be safely administered to healthy subjects, PK studies should be conducted in the relevant patient population. In these studies, the dose(s) should be within the therapeutic dosing range as recommended in the product monograph of the CRBD.

The following factors should be taken into consideration when designing a comparative PK study (for example, when choosing between cross-over versus parallel-group study):

half-life of the biologic drugs
linearity of PK parameters
the endogenous levels and diurnal variations of the protein under study, where applicable
conditions and diseases to be treated
route(s) of administration

The PK comparison should not be limited to parameters reflecting absorption only. Parameters representing distribution and elimination (for example, volume of distribution, clearance and terminal half-life) should also be compared. Data should not be excluded from the analysis unless the exclusion can be justified and is considered acceptable by BRDD.

Acceptable criteria for the determination of similarity in comparative PK should be defined and justified prior to the initiation of the PK studies. Typically, these criteria are as follows:

The 90% confidence interval of the relative mean area under the concentration versus time curve to the time of the last quantifiable concentration (AUC_T) of the biosimilar candidate to CRBD should be within 80.0% ‐ 125.0% inclusive.
The relative mean maximum concentration (C_max) of the biosimilar candidate to CRBD should be within 80.0% ‐ 125.0% inclusive.

In exceptional circumstances, when such criteria cannot be employed or are not met in the comparative PK studies, a discussion should be provided regarding the implication of the findings.

If a clinically relevant pharmacodynamic (PD) marker exists and is measurable, it should be evaluated. In most cases, the measurement of the PD marker can be incorporated into a combined comparative PK/PD study. The chosen PD marker should:

reflect the primary mechanism of action(s) of the drug
have dynamic range and sensitivity to detect differences between the biosimilar candidate and the CRBD
have a temporal profile amendable to capturing a sufficient proportion of the PD profile for comparison
have a demonstrated dose-response relationship with the drug

The primary endpoint for comparative PD studies should be the area under the effect-time curve to the last quantifiable measurement (AUEC_T). Maximum effect (Emax) should also be evaluated. In general:

The 95% confidence interval of the relative geometric mean ratio (biosimilar candidate to CRBD) for AUEC_T should be entirely contained within an interval of 80.0% - 125.0%.
The relative geometric mean ratio (biosimilar candidate to CRBD) for Emax should be contained within an interval of 80.0% - 125.0%.

Justification should be provided if different criteria are applied, and discussion with Health Canada prior to a submission is recommended.

Comparison of immunogenicity should be incorporated into the comparative clinical pharmacology studies. Most important are those antibodies that have the potential to impact safety and/or efficacy. Comparative studies should characterize the incidence and magnitude of anti-drug antibody (ADA) response, the time-course of ADA development, ADA persistence, PK, and the potential impact on efficacy and/or safety.

Comparative immunogenicity testing should be conducted using a tiered approach that involves screening assays, confirmatory assays, and assays to determine whether binding ADA are neutralizing. Assays should be validated and have demonstrated the ability to sensitively detect ADA in the presence of drug. ADA positive samples should be tested for cross-reactivity against the biosimilar candidate and the CRBD. Alternative approaches may be acceptable and should be scientifically justified.

Samples that test positive for binding ADA in the confirmatory binding assays should be evaluated to determine if neutralizing ADA are present. The mechanism of action(s) of the drug should be considered when selecting an appropriate neutralizing ADA assay format.

Comparative clinical efficacy and safety trial(s)

In most cases, a comparative clinical efficacy and safety trial(s) is not required. Safety and comparative immunogenicity data are still required and should be collected within the comparative clinical pharmacology studies but could be supplemented with data collected using other trial designs (e.g., studies designed to specifically focus on safety and/or immunogenicity). If a comparative clinical efficacy and safety trial(s) is deemed necessary, sponsors should provide a rationale to explain the purpose of the trial(s) in the context of a biosimilar submission.

2.2.4 Authorization of indications

A biosimilar sponsor may request authorization for all indications held by the CRBD authorized in Canada.

The decision to authorize the requested indications is dependent on the demonstration of a high degree of similarity between the biosimilar candidate and CRBD based on data derived from comparative quality, non-clinical and clinical studies. Where a high degree of similarity to the CRBD has been established, indications may be granted for the biosimilar candidate based on evidence of the safety and efficacy of the CRBD gathered in both the pre- and post-market settings. The indications that could be authorized for the biosimilar candidate are dependent on drug specific considerations (e.g., proposed presentation does not allow administration to pediatric populations).

Biosimilar candidates can only be authorized for indications held by the CRBD in Canada. Should a sponsor request an indication not held by the CRBD, the drug in question is not considered a biosimilar. In these situations, such drugs require a separate brand name from the biosimilar and are not eligible for the comparative similarity assessment reserved for biosimilar candidates. The sponsor must file a separate NDS package under the appropriate drug dossier ID, with adequate clinical data demonstrating the safety and efficacy of the drug for the new indication in question, as well as labelling documentation.

2.2.5 Labelling requirements – Product Monograph

The product monograph for a biosimilar candidate should be developed in a manner consistent with the principles, practices, and processes outlined in the most recent Health Canada Guidance Document: Product Monograph. Sponsors should use the Product Monograph Master Template when preparing a product monograph for a biosimilar candidate. The contents of the product monograph for biosimilars should include the following information:

a statement indicating that the drug is a biosimilar to the CRBD
relevant safety and efficacy information from the product monograph of the biologic drug authorized in Canada to which a reference is made, including Contraindications, Warnings and Precautions, Adverse Drug Reactions/Adverse Drug Effects, Clinical Trials and Non-Clinical Information and key post-market safety information for all indications that are authorized for the biosimilar

The product monograph of the biosimilar must be updated on an ongoing basis, as new information about the biosimilar or the CRBD becomes available, or when labelling requirements change.

The naming of all biosimilars should comply with the requirements set out in the Policy Statement on the Naming of Biologic Drugs.

2.2.6 Risk management plan

A risk management plan (RMP) should be submitted as part of the drug submission. Biosimilar sponsors are encouraged to consult the Marketed Health Products Directorate (MHPD) when preparing their RMP. The RMP should be designed to monitor and detect both known inherent safety concerns and potentially unknown safety signals that may result from the impurity profile and other characteristics of the biosimilar candidate. The biosimilar sponsor should continue the assessment of unwanted immunogenicity and its clinical significance following market authorization.

The RMP should consider all important identified and potential risks and missing information associated with the use of the CRBD, including additional risk minimization measures relevant to the CRBD. It should also provide details on how these risks will be addressed in a post-market setting. That is, the RMP of the biosimilar candidate should be based on the RMP of the CRBD. The RMP should also identify any safety concerns that are unique to the biosimilar candidate (for example, contraindication in children <2 years due to potential risk of hereditary fructose intolerance associated with a sorbitol formulated biosimilar). Biosimilar sponsors should provide justification for these discrepancies that exist between the approved RMP of the CRBD and the RMP of the biosimilar candidate. More generally, the biosimilar sponsor may add, reclassify, or remove safety concerns from the RMP compared with the safety specification of the CRBD, if appropriately justified.

The minimum surveillance criteria for the biosimilar candidate should be described in accordance with requirements for a new biologic drug. The RMP should include detailed information on systematic evaluation of the immunogenicity potential of the biosimilar candidate.

The RMP should include specific (routine or additional) pharmacovigilance and risk minimisation activities similar to those in place for the CRBD or justify that these activities are not relevant for the biosimilar candidate.

A discussion about methods to distinguish adverse event reports for the biosimilar from those for other licensed drugs, including the CRBD should be included. The RMP should be maintained and implemented throughout the life cycle of the product.

The sponsor is reminded to include an RMP / Pharmacovigilance Plan (PVP) for the biosimilar candidate. Details regarding the submission and content of RMPs in the Canadian context are available in the following Guidance Documents:

2.3 Post-market requirements

2.3.1 Adverse drug reaction (ADR) reporting and periodic reports

Biosimilar sponsors are required to comply with sections C.01.016 to C.01.019 of the FDR, which includes ADR reporting.

The biosimilar's unique brand name and non-proprietary name as well as other product-specific identifiers, such as the Drug Identification Number (DIN) and the lot number should be included in ADR reports to facilitate the traceability of an adverse reaction to a specific suspect drug product.

As requested, the manufacturer will conduct a concise, critical analysis of the ADRs and serious ADRs after such an occurrence. Health Canada may request written summary reports where risks and/or uncertainties have arisen regarding safety.

Periodic safety update reports (PSURs) or periodic benefit-risk evaluation reports (PBRERs) should be prepared and/or submitted as discussed in the risk management plan. The periodicity for the submission of PSURs or PBRERs should be consistent with appropriate ICH guidelines for marketed drugs, or as determined by the Minister, when the drug is authorized for market. Refer to the Health Canada's Guidance Document - Periodic Benefit-Risk Evaluation Report (PBRER) International Conference on Harmonisation (ICH) Topic E2C(R2) for more information on PBRERs.

2.3.2 Post-notice of compliance (NOC) changes

A biosimilar is classified as a new drug and is subject to all of the associated regulatory requirements, including specific requirements related to changes made to a new drug that has received an NOC pursuant to section C.08.004 of the FDR (post-NOC changes). This guidance should be read in conjunction with the following Health Canada documents for specific guidance and submission documentation requirements for applicable post-NOC changes.

Information regarding general submission requirements, current processes and performance standards for post NOC changes is outlined in Health Canada's Guidance Document: Management of Drug Submissions and Applications.

Biosimilar sponsors should follow labelling requirements set out in the post-NOC guidance documents referenced above. This includes monitoring any drug class type-specific safety information that may indicate the need for a change in labelling.

There may be situations post-NOC where sponsors seek authorization of indications held by the CRBD authorized in Canada. A Supplement to a New Drug Submission (SNDS) for a biosimilar that relies on the previously demonstrated similarity provided in the original biosimilar NDS may be considered by Health Canada on a case-by-case basis. If accepted for review, these submissions would generally be considered a labelling-only SNDS. Biosimilar sponsors should submit a Sponsor Attestation: SNDS for Biosimilar Products - Addition of Indication to Product Monograph to be in line with the Canadian Reference Biologic Drug in Module 1.2.3 Certification and Attestation Forms at the time of filing. Sponsors can access this form at Forms: Applications and submissions for drug products.

3. Consultation with the Biologic and Radiopharmaceutical Drugs Directorate (BRDD)

Sponsors of biosimilar candidates are encouraged to consult with BRDD for regulatory guidance as early as possible in the development of their biosimilar submission package. Consultation can occur at any stage of the development of a biosimilar candidate.

A biosimilar sponsor may request a pre-submission meeting in order to receive advice from BRDD on their quality package early in the development process. Refer to the Guidance Document: The Management of Drug Submissions and Applications for instructions on filing a pre-meeting request and package with BRDD.

Sponsors should ensure their drug meets the eligibility criteria for a biosimilar candidate as outlined in this guidance. Sponsors may submit a request for a pre-submission meeting to the Office of Regulatory Affairs. Refer to section 4 - Additional Information - for contact details.

4. Additional Information

Health Canada will review this guidance document on an ongoing basis in response to new scientific knowledge, best practices and/or experience gained by the Department.

Contact Information:

Questions concerning biosimilar submissions should be directed to:

Office of Regulatory Affairs

Biologic and Radiopharmaceutical Drugs Directorate
Health Products and Food Branch
Health Canada
E-mail: brdd.ora@hc-sc.gc.ca

Questions or comments on this guidance document should be directed to:

Centre for Policy, Pediatrics and International Collaboration

Biologic and Radiopharmaceutical Drugs Directorate
Health Products and Food Branch
Health Canada
Email: brdd-cppic_brdd-cppci@hc-sc.gc.ca

Appendix A - Glossary

a. Acronyms

ADA: Anti-Drug Antibody
ADR: Adverse Drug Reaction
AUC: Area Under the Curve
BRDD: Biologic and Radiopharmaceutical Drugs Directorate
CRBD: Canadian Reference Biologic Drug
C_max: Maximum Concentration
CTA: Clinical Trial Application
CTD: Common Technical Document
ICH: International Council for Harmonisation
Emax: Maximum Effect
MHPD: Marketed Health Products Directorate
NDS: New Drug Submission
NOC: Notice of Compliance
PK/PD: Pharmacokinetic/Pharmacodynamic
PBRER: Periodic Benefit-Risk Evaluation Reports
PSUR: Periodic Safety Update Reports
RBD: Reference Biologic Drug
RMP: Risk Management Plan
SNDS: Supplement to a New Drug Submission

b. Terms

Biologic drug (Médicament biologique): A drug listed in Schedule D to the FDA. Schedule D lists individual products (such as insulin), product classes (such as immunizing agents), references to particular sources (such as "drugs, other than antibiotics, prepared from microorganisms"), and methodology (such as "drugs obtained by recombinant DNA procedures"). 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 biologic drug (Médicament biologique biosimilaire): A biologic drug that obtains market authorization subsequent to an originator biologic previously authorized in Canada, referred to as the Canadian Reference Biologic Drug (CRBD). In its biosimilar submission, a sponsor relies on prior information regarding safety, efficacy and effectiveness that is deemed relevant due to the demonstration of a high degree of similarity to the CRBD and which influences the amount and type of original data required. Biosimilar biologic drugs were previously referred to as Subsequent Entry Biologics.
Drug product: The dosage form in the final immediate packaging intended for marketing.
Drug substance: The defined process intermediate containing the medicinal ingredient, which is subsequently formulated with excipients to produce the drug product.
Control Strategy: A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control.
Quality Target Product Profile: A prospective summary of the quality characteristics of a drug product that will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.
Reference biologic drug (Médicament biologique de référence): 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 a high degree of similarity.
Specification (Spécification): A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a drug substance, drug product or materials at other stages of its manufacture should conform to be considered acceptable for its intended use.; Conformance to specification means that the drug substance and drug product, when tested according to the listed analytical procedures, will meet the acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of authorization.

Page details

Date modified:: 2025-06-13